............................ The Endocrine Response to Acute Illness
..
............................
Frontiers of Hormone Research Vol. 24
Series Editor
Ashley B. Grossman, London
............................
The Endocrine Response to Acute Illness
Volume Editors
Richard C. Jenkins, Sheffield Richard J.M. Ross, Sheffield
33 figures and 10 tables, 1999
............................ Richard J.M. Ross, MD, FRCP Senior Lecturer in Endocrinology, Department of Medicine, University of Sheffield, Northern General Hospital, Sheffield, UK
Richard C. Jenkins, BMedSci, MRCP Department of Medicine, University of Sheffield, Northern General Hospital, Sheffield, UK
Library of Congress Cataloging-in-Publication Data The endocrine response to acute illness / volume editors, Richard C. Jenkins, Richard J.M. Ross (Frontiers of hormone research; vol. 24) Includes bibliographical references and index. (hardcover: alk. paper). 1. Endocrine manifestations of general diseases. 2. Endocrine glands – Pathophysiology. 3. Homeostasis. 4. Hormones – Metabolism. I. Jenkins, Richard C. II. Ross, Richard J.M. III. Series. [DNLM: 1. Endocrine Glands – metabolism. 2. Hormones – metabolism. 3. Acute Disease. W1 FR946F v. 24 1999 / WK 102 E555 1999] RC649.E5225 1999 616.4 – dc21 DNLM/DLC ISSN 0301–3073 ISBN 3–8055–6822–3
Bibliographic Indices. This publication is listed in bibliographic services, including Current ContentsÔ and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Ó Copyright 1999 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–6822–3
............................
Contents
VII Preface Grossman, A.B. (London)
The Endocrine Response to Acute Illness 1 Introduction Jenkins, R.C.; Ross, R.J.M. (Sheffield) 4 Glucose Metabolism Heller, S.R.; Robinson, R.T.C. (Sheffield) 27 Salt and Water Homeostasis Arieff, A.I. (San Francisco, Calif.) 67 Calcium Metabolism Lind, L.; Ljunghall, S. (Uppsala) 87 Thyroid Hormones Hennemann, G.; Krenning, E.P. (Rotterdam) 110 The Pituitary Adrenal Axis Newell-Price, J.; Trainer, P.J. (London) 131 The Pituitary Gonadal Axis Fletcher, A.K. (Sheffield) 152 The Regulation of Growth Hormone Secretion Ghigo, E.; Arvat, E.; Gianotti, L.; Maccario, M.; Camanni, F. (Turin) 176 Growth Hormone and IGF-I as Anabolic Therapy Botfield, C.; Hinds, C.J. (London) 201 Subject Index
This page intentionally left blank
............................
Preface
I am delighted to introduce this new volume on the endocrine responses to acute illness. There is now increasing interest in the pathogenesis and phenomenology of serious critical illness, not least because of the extremely high morbidity and mortality associated with septic shock in critically ill patients, and its impact on the utilisation of clinical resources. This is particularly true in patients with multiorgan failure, in whom our apparent understanding of its pathophysiology has been associated with the increasing use of supportive techniques for the heart, lungs, liver and kidney. In spite of this, however, the mortality in such patients still remains extremely high, the reasons for which remain baffling. Research has suggested that agents such as exogenous endotoxin and the endogenous cytokines produced in response may be involved in the pathogenesis of disease in such patients, but large-scale trials based on specific therapies have recently proven to be disappointingly ineffective. In addition, large-scale trials of the use of high-dose steroids and growth hormone in large cohorts of such patients have also proven to be discouraging. The reasons for this lack of success are unclear, but almost certainly relate to our lack of understating of the molecular pathophysiology of the changes seen in critically ill patients. Specifically, unless we can understand in some detail the endocrine and metabolic changes, then any attempt at intervention is unlikely to be successful. With this in mind, I am extremely pleased to welcome this volume by Drs. Jenkins and Ross, in which a distinguished panel of international contributors describe and overview the current studies on the endocrine changes in critically ill patients. I am certain that it is only by understanding such changes in detail, and comprehending the precise molecular pathogenesis, can we begin to make any therapeutic inroads into this difficult situation. As they point out in their Introduction, once a critically ill patient has moved into a chronic phase, one
cannot necessarily argue that any of the metabolic and endocrine changes are adaptive, as there may have been no substrate on which evolution can act in terms of natural selection. Under such circumstances, it is only by increasing our understanding that eventual therapeutic improvements can be maintained. This volume is a worthy contribution to this important field.
Ashley B. Grossman London, UK
Preface
VIII
............................
Introduction
Critical illness is a modern phenomenon resulting from medical advances which allow the survival of patients who would have previously died. The effects of critical illness are manifold and not least among them are the profound changes seen in metabolic and hormonal systems. Some of these processes are disease specific and others are common to many aetiologies of critical illness. There are a number of reasons why it is important to understand these metabolic processes. Firstly, and potentially most importantly, this knowledge may allow the rational use of pharmaceutical interventions aimed at improving outcome. Secondly, the changes may have prognostic significance whether or not they have a causal role in outcome or are just markers for disease severity. Prognostic relationships suggest that a number of the metabolic changes seen in acute illness may be important in determining outcome. It has been proposed that critical illness falls into two metabolically distinct phases – acute and chronic [1]. It seems likely that the acute phase has evolved to optimise survival in the face of a temporary non-catastrophic injury or illness. Before modern medicine the organism would have survived or died and it seems unlikely therefore that there would have been pressure for the evolution of a chronic response. The chronic response we see today may thus represent human physiology reacting to circumstances which it has not evolved to deal with and its responses may thus be inappropriate and even deleterious to survival. The obvious implication of this reasoning is that interventions that modify the endocrine/metabolic response may be beneficial. A number of important studies have attempted to do this and these are discussed in the relevant chapters. In general, early small studies have been promising but larger better designed studies, often using a sledgehammer approach, have either shown no benefit or actual harm. In the light of these findings recent work has begun to suggest that subtle interventions may be of benefit.
It is important to differentiate pharmacological approaches, i.e. the use of hormones at doses far in excess of the normal physiological levels, from physiological doses, i.e. the use of hormones at doses designed to mimic the normal responses to stress. An example of this difference would be the comparison of the large negative trials of glucocorticoids [2], and the more recent encouraging lower dose trials [3]. There was a 90-fold difference in glucocorticoid dosage between the studies. A number of common themes emerge from the chapters not least of which is the idea that cytokines may provide a mechanism to link the specific insult, e.g. sepsis, trauma or burns, to the endocrine disturbance. This point is made in a number of chapters with remarkable consistency of findings – time and again the finger of suspicion points to IL-6, IL-1 and TNF-. In addition to the common mechanisms many of the chapters detail the specific effects of particular underlying pathologies such as sepsis, trauma and burns. Heller and Robinson open with a careful consideration of carbohydrate metabolism and discuss the changes seen in peripheral glucose uptake and hepatic glucose output in illness. The roles of lactate, alanine, glutamine and glycerol as gluconeogenic substrates and the possible effects of cytokines as a common pathway between diverse disease processes and perturbations of glucose homeostasis are discussed. Moving from sugar to salt, Arieff provides a comprehensive review of hyponatraemia and hypernatraemia. Body fluids, solutes, osmolality, the role of the kidneys, thirst and its regulation are considered. The clinical effects of abnormal sodium concentrations are described and the mechanisms, predominantly changes in the size of brain cells are discussed. The major effects of gender and age on the ability to tolerate deranged salt homeostasis is detailed and the changes seen in specific conditions, such as heart failure, AIDS, liver failure, cancer and surgery, are discussed. Calcium metabolism has received less attention than some of the other metabolic changes in illness and Lind and Ljunghall go some way towards redressing the balance. They briefly describe the important physiological roles of calcium, phosphate and magnesium and their homeostatic mechanisms in health before detailing work which suggests that there is hypersecretion of parathyroid hormone from an early stage of illness. They also describe the effects of calcium supplementation on haemodynamic indices. Hennemann and Krenning describe the characteristic changes seen in thyroid hormone concentrations during illness and also the underlying pathophysiological processes. The tissue effects of reduced thyroid hormone concentrations and studies in which subjects have been given exogenous thyroid hormones in an attempt to correct the low thyroid hormone state are reviewed.
Introduction
2
The hypothalamo-pituitary-adrenal axis has been extensively studied in acute illness. Newell-Price and Trainer review the normal physiology, methods of assessing the axis and the effects of specific disease processes on the axis. They describe the adrenal adaptation to stress and the biphasic changes seen in the axis as acute illness becomes chronic. The incidence of adrenal failure in acute illness and the results of important studies of the effects of exogenous glucocorticoids in acute illness are described. Fletcher reviews the hypogonadism of acute illness and analyses the relative contributions of central and peripheral processes. The effects of specific disease processes are detailed before the results of trials of the use of androgens as anabolic agents are discussed. Two chapters examine the GH/IGF-I axis. Ghigo et al. review in detail the physiology and pathophysiology of the axis. They describe the major molecules and receptors which form the axis and also review the control of GH secretion. They consider the effects of sleep, age, exercise, fasting and obesity on GH secretion and then consider the neuroendocrine control of GH secretion and interactions with other metabolic factors such as fatty acids, glucose, thyroid hormones and glucocorticoids. Botfield and Hinds briefly review the physiology of the GH/IGF-I before moving on to examine the anabolic properties of GH and IGF-I. They review GH dosages, side-effects and compare the effects of separate and combined GH and IGF-I treatment in terms of metabolic changes and more importantly functional outcomes. We hope that this volume will both provide an overview of the current state of knowledge of endocrine and metabolic function in acute illness and stimulate further research in this important area. R.C. Jenkins, Sheffield, UK R.J.M. Ross, Sheffield, UK
References 1 2
3
Van den Berghe G, De Zegher F, Bouillon R: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827–1834. The Veterans Administration Systemic Sepsis Cooperative Study Group: Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. New England Journal of Medicine 1987;317:659–665. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A: Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–650.
Introduction
3
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 4–26
............................
Glucose Metabolism Simon R. Heller, Robert T.C. Robinson Section of Medicine, Division of Clinical Sciences, University of Sheffield, UK
Contents Introduction ................................................................................................ Changes in Metabolism in Trauma and Hypovolaemic Shock ............................... Carbohydrate Metabolism in Health ............................................................. Carbohydrate Metabolism during Feeding ..................................................... Carbohydrate Metabolism during Fasting ......................................................... Decreased Peripheral Glucose Uptake ....................................................... Hepatic Glucose Output ......................................................................... Lactate ................................................................................................ Alanine and Glutamine .......................................................................... Glycerol ............................................................................................... Ketone Body Production ............................................................................ Control of Carbohydrate Metabolism in Health .............................................. Metabolism in Critical Illness ......................................................................... Increased Hepatic Glucose Output ............................................................... Lactate ................................................................................................ Glycerol ............................................................................................... Peripheral Glucose Uptake ......................................................................... Glucose Oxidation ................................................................................. Mediators of Alterations in Carbohydrate Metabolism in Critical Illness ............. Role of Cytokines ......................................................................................... Other Effects ............................................................................................... Abnormalities in Other Situations: Burns and Infection ....................................... Relevance of These Changes to Treatment ......................................................... Limitations of Experimental Methods and Future Research ................................. Areas of Uncertainty ..................................................................................... Conclusions ................................................................................................. References ...................................................................................................
5 5 5 6 6 6 7 7 8 9 9 10 10 11 11 12 12 13 13 15 16 16 19 21 22 23 23
Introduction The main metabolic changes following surgical and physical trauma were first described over 60 years ago, but in the last 20 years the application of modern scientific techniques has given us a better understanding of the pathophysiological response to critical illness. Much remains unknown but it has become clear that the metabolic responses in humans to extreme physical stress are fairly consistent despite a variety of precipitating causes. The changes appear designed to ensure fuel delivery to those tissues which are obligatory users of glucose leaving other tissues to metabolize alternative fuels. During sepsis, the initial changes in carbohydrate metabolism are similar but if infection progresses, then important differences develop, presumably due to different circulating mediators of the inflammatory response. It is clearly important to recognize and anticipate these differences since in the clinical situation they may require a different therapeutic approach. The purpose of this chapter is to review the changes in carbohydrate metabolism which occur during critical illness, in response to both trauma and infective stress, to discuss the mechanisms responsible and to consider their relevance to treatment. Much of the information, which has been gathered over the last 20 years, has been obtained from animal and in vitro models. Although it may shed light on changes in humans, the resemblance to the clinical situation may be limited. In our review we have tried to identify these limitations, noted those areas where information is lacking and made suggestions for further research.
Changes in Metabolism in Trauma and Hypovolaemic Shock Carbohydrate Metabolism in Health To understand the metabolic changes that occur during critical illness it is important to review briefly the control of glucose metabolism during health. Mammals have to overcome a number of challenges, particularly that energy intake may be intermittent and also that a number of specialized tissues, such as the central nervous system, are obligatory users of glucose, at least in the short term. The metabolic responses, which have evolved to deal with these demands, have to make the most use of feeding to ensure that fuel supply to tissues is continuously maintained and to store energy in sites where it can readily be called upon when demand increases or when food is unavailable [1]. This fast/feed cycle is largely controlled by the balance between the ‘regulatory’ hormone insulin and the counterregulatory hormones, glucagon, adrenaline, growth hormone and cortisol [2]. During feeding, energy intake is largely directed to storing excess as lipid, which is then made available during fasting.
Glucose Metabolism
5
Fuel stores in protein and carbohydrate are relatively preserved to keep them available for other functions; proteins in skeletal muscle and enzymes, and carbohydrate as an immediate energy supply in acute stress and anoxia to maintain glucose delivery to the brain. Carbohydrate Metabolism during Feeding Insulin is an anabolic hormone. As insulin levels rise, lipolysis is suppressed and triglyceride synthesis stimulated in adipose tissue [3]. Suppression of lipolysis and a fall in circulating nonesterified fatty acid (NEFA) levels leads to increased lipid and skeletal muscle glucose uptake (as described below). Hepatic glucose output is suppressed by up to 60% around 2 h after food [4]. At relatively high insulin concentrations (?30 mU/l), there is also direct stimulation of skeletal muscle glucose uptake through activation of the insulinresponsive GLUT-4 glucose transporters [5]. Insulin promotes phosphorylation of glucose, which locks it into the cell since only the liver and kidney possess glucose-6-phosphatase [6]. A proportion of glucose-6-phosphate proceeds down the glycolytic pathway with the eventual formation of pyruvate but during feeding around 30% of glucose entering skeletal muscle is converted to glycogen due to insulin-activated glycogen synthase. Approximately 50% is oxidized in the TCA cycle but the remainder is converted to lactate and alanine and contributes to the formation of hepatic glycogen [7]. Recent work suggests that during a carbohydrate-rich meal, up to 40–60% of hepatic glycogen is derived from lactate and other gluconeogenic precursors [8–10]. These are formed in peripheral tissue and transported to the liver, passing up the gluconeogenic pathway to form first, glucose-6-phosphate and then glycogen. The balance between this indirect pathway of glycogen synthesis and direct synthesis from glucose, which enters hepatocytes and is then phosphorylated, may vary with time and also depends upon the carbohydrate content of the meal [10]. It may help to regulate glycogen synthesis and is clinically relevant to the use of glucose infusions when treating the critically ill. In addition, high insulin concentrations inhibit the breakdown of protein and reduce the availability of amino acid gluconeogenic precursors such as alanine [2, 11]. Carbohydrate Metabolism during Fasting Decreased Peripheral Glucose Uptake During fasting, as glucose concentrations fall, insulin production is inhibited and the altered balance between the levels of insulin, counterregulatory hormones and sympathoadrenal activation rapidly mobilizes energy from its stores. Of all the metabolic effects of insulin, its effect on lipolysis is probably the most sensitive, with suppression at insulin concentrations of 10 mU/l or above [12]. However, as glucose and insulin levels fall, circulating levels of
Heller/Robinson
6
Fig. 1. Lactate recycling (the Cori cycle).
NEFA begin to rise. Uptake of NEFA leads to reduced peripheral glucose uptake in skeletal muscle, an effect known as the glucose/fatty acid or Randle cycle [13]. The inhibitory effect of NEFA on peripheral glucose uptake is caused by its conversion to acetyl CoA and citrate. This inhibits key enzymes in the glycolytic pathway, particularly phosphofructokinase which catalyses conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and in turn, the formation of pyruvate. Increased cytoplasmic concentrations of acetyl CoA and citrate also inhibit glucose transport across the cell membrane [14, 15]. Hepatic Glucose Output In the postabsorptive state, during the first 24 h of fasting, around 40% of the glucose output from liver is derived from glycogenolysis. Within 24 h, liver glycogen is largely depleted and glucose output is generated from gluconeogenic precursors [16, 17]. The kidney also makes an increasing contribution to gluconeogenesis if a fast is prolonged [18]. Lactate In skeletal muscle and some other tissues including white and red blood cells, glucose is metabolized to pyruvate and lactate and then released into the circulation [1]. The Cori cycle (fig. 1) describes the process of peripheral production of lactate from glucose originally released by the liver, the transfer of lactate back to the liver and its gluconeogenic conversion to glucose [19].
Glucose Metabolism
7
Fig. 2. Alanine and glutamine as gluconeogenic substrates.
Two molecules of 3 carbon lactate are needed to produce one molecule of 6 carbon glucose with energy provided from the hepatic oxidation of NEFA. It is clearly an energy-inefficient process but has the important effect of limiting the breakdown of skeletal muscle to produce glucose during fasting. Alanine and Glutamine Alanine and glutamine are the main protein-derived gluconeogenic substrates, released by skeletal muscle and then converted to glucose by the liver and to a lesser extent, the kidney (fig. 2). They are partly derived from branched chain amino acids such as valine, isoleucine and leucine [20]. Some glucose taken up by skeletal muscle is metabolized to pyruvate and then transaminated to form alanine, which is then converted back to glucose in the liver [21]. The glucose-alanine cycle originally described by Felig [21] and others is thus analogous to the Cori cycle, requiring energy, yet not contributing to the formation of new glucose. It too may play a part in reducing the breakdown of muscle during fasting. Others have suggested an additional role in allowing the transfer in a nonharmful form of potentially toxic ammonia produced during metabolism in the periphery, which is then converted to urea in the liver and excreted [22].
Heller/Robinson
8
Fig. 3. Glycerol as a gluconeogenic substrate.
Glycerol Glycerol, derived from the breakdown of triglyceride in adipose tissue, normally accounts for only a small proportion (around 2%) of hepatic glucose output (fig. 3) in the postabsorptive state but during a prolonged fast this proportion may increase to around 20% [6]. Ketone Body Production The energy that drives gluconeogenesis is derived from the oxidation of circulating NEFA which enter the liver down a concentration gradient. NEFA are converted into acetyl CoA after transfer into hepatic mitochondria as acyl carnitine. Acetoacetate and other ketone bodies are formed from acetyl CoA and then released into the circulation [1]. The critical step in the formation of ketone bodies is the formation of acyl carnitine catalysed by carnitine palmitoyl-transferase [15]. This enzyme is in turn inhibited by malonyl CoA whose intracellular concentration is increased by insulin and decreased by glucagon. Thus the portal insulin/ glucagon ratio has a critical effect on the rate of ketone production. Ketone bodies can be metabolized by many tissues which utilize NEFA and contribute to reducing peripheral glucose uptake. Indeed during a prolonged fast, tissues such as the central nervous system, which can normally metabolize only glucose, are able to utilize increasing amounts of ketone bodies [23]. This has a major effect in reducing the amount of glucose that needs to be provided by gluconeogenesis and significantly lengthens the period that a fast can be sustained.
Glucose Metabolism
9
Control of Carbohydrate Metabolism in Health The regulatory and glucose-lowering effects of insulin are opposed by the counterregulatory hormones, glucagon, adrenaline, cortisol and growth hormone as well as activation of the sympathoadrenal system. The prevailing glucose concentration has a direct effect on and islet cell function with the portal insulin/glucagon ratio controlling hepatic gluconeogenesis and glycogenolysis and determining the hepatic glucose output. Normally, insulin concentrations of 30 mU/l are sufficient to totally suppress hepatic glucose release. Insulin increases peripheral glucose uptake indirectly by suppressing lipolysis at relatively low concentrations but direct stimulation of peripheral glucose uptake in skeletal and cardiac muscle and adipose tissue only occurs at substantially higher concentrations, above 30–40 mU/l [12]. However, since under basal conditions most glucose uptake is into insulin-independent tissues such as brain and red blood cells, insulin normally has little effect on peripheral glucose uptake [6]. Catecholamines, such as circulating adrenaline and noradrenaline released from post-ganglionic sympathetic neurones, have a direct effect on hepatic glycogenolysis and gluconeogenesis. Other effects are indirect. Increased lipolysis and rising NEFA levels reduce peripheral glucose uptake and increase glycerol delivery to the liver. Glucagon release is stimulated through a -adrenergic effect and importantly, insulin release is inhibited through an effect. Cortisol stimulates hepatic gluconeogenesis directly, as well as increasing hepatic delivery of the gluconeogenic substrates, alanine and lactate through effects on skeletal muscle and adipose tissue. Growth hormone also increases lipolysis and directly stimulates hepatic gluconeogenesis and other hormones, such as vasopressin and angiotensin II, may also play a role. Finally, glucose itself can regulate carbohydrate metabolism by directly stimulating peripheral glucose uptake and inhibiting hepatic glucose output.
Metabolism in Critical Illness Critical illness is characterized by a state of hypermetabolism with fever, leucocytosis, increased oxygen consumption, protein catabolism, and raised glucose turnover [2, 24]. In the liver, glucose output rises due to a combination of glycogenolysis and raised rates of gluconeogenesis. In peripheral tissue, this results in increased uptake and utilization, a rise in lactate concentrations and glucose intolerance. A state of insulin resistance results in higher circulating insulin concentrations but these are insufficient to prevent a slight increase in fasting blood glucose. The relatively modest rise in fasting blood glucose is probably because most peripheral glucose uptake in the fasting state (around
Heller/Robinson
10
70%) occurs in tissues not responsive to insulin (the brain and red blood cells). These metabolic changes are in part a response to fasting but also result from additional circulating mediators released as a result of injury to tissue. Thus, some of the responses reflect increased activity of existing metabolic processes while others are unique to the pathophysiology of critical illness. In addition, the imposition of a septic state may fundamentally alter some of these responses, as a result of circulating endotoxin and a resultant modulation of cytokine production. Increased Hepatic Glucose Output Hepatic glucose output increases during critical illness despite insulin concentrations, which are either raised or in the normal range [25, 26]. Furthermore, this increase is accompanied by an increase in blood glucose that normally suppresses hepatic glucose production by negative feedback. This failure of glucose to suppress hepatic glucose output is not only observed in the basal situation. Normally, exogenous glucose infusions will totally suppress hepatic glucose output [27] but in surgical trauma or infection, suppression is only partial [28]. Indeed, during glucose infusion following surgical trauma or in critical illness, the degree of hepatic insulin resistance may be sufficient to produce a rise in glucose concentrations despite maximal endogenous insulin release. Increases in hepatic glucose production could occur due to the direct effect of counterregulatory hormones or might be driven by an increased supply of gluconeogenic precursors. There is considerable evidence that traditional counterregulatory hormones are responsible for the increase in hepatic glucose production (see below); however, we also need to consider the contribution of gluconeogenic precursors. Since skeletal muscle is broken down during stress, with the release of amino acids, particularly alanine, it initially appeared that the increased delivery of alanine to the liver was driving gluconeogenesis and increasing hepatic glucose output. However, Wolfe et al. [29] showed that in normal subjects, an alanine infusion did not increase hepatic glucose output whereas an infusion of glucose significantly increased alanine release from the periphery. This suggested that skeletal muscle glucose metabolism controls the formation of alanine, presumably via the generation of pyruvate. This finding together with the observation that amino-acid concentrations are generally lowered in critical illness argues against a major role for protein-derived substrate in driving hepatic glucose production. Lactate Lactate levels rise during critical illness and kinetic studies have demonstrated that both production and uptake are increased. Increased production
Glucose Metabolism
11
might be a result of tissue hypoperfusion and anaerobic glycolysis. However, as Mizock [22] has pointed out, if this was the case then during critical illness, patients would demonstrate an increased lactate to pyruvate ratio. Since pyruvate concentrations often appear to increase in the critically ill leaving the lactate/pyruvate ratio unchanged [30], then increased lactate production in the periphery may actually reflect rising glycolytic activity as the rates of peripheral glucose uptake and skeletal muscle glycogenolysis increase. Clearly, raised lactate concentrations may indicate tissue hypoxaemia although under these circumstances, patients would presumably exhibit other indicators such as a low pO2 or metabolic acidosis. The increase in hepatic glucose output during stress is accounted for in part by an increase in lactate recycling [31, 32]. However, the increase in plasma lactate concentrations suggests that hepatic lactate uptake does not match the increase in peripheral production. Conversely, a normal lactate level in critically ill patients does not exclude the possibility of peripheral hypoxaemia as increased hepatic clearance may overcome increased peripheral delivery. Glycerol Glycerol usually contributes only a small proportion to overall hepatic glucose output. However, as lipolysis increases, then this proportion will rise, since glycerol clearance depends upon its conversion into glucose in the liver. Rates as high as 20% have been reported in patients with sepsis [6]. Peripheral Glucose Uptake In addition to increased hepatic glucose output, increased turnover is reflected in higher peripheral glucose utilization, much of which occurs independently of insulin [33]. Glucose uptake in the brain, white and red blood cells and other tissues which contain high numbers of macrophages is insulin independent (non-insulin-mediated glucose uptake, NIMGU) [34]. Even in skeletal muscle and adipose tissue, a proportion of glucose uptake is not dependent on insulin. The increased uptake occurs down a concentration gradient due to increased activity of glucose transporters, probably GLUT-1 [35]. NIMGU is not mediated through counterregulatory hormones. A number of studies have shown that tumour necrosis factor (TNF), interleukin-1 (IL-1) and other cytokines can increase glucose uptake in a variety of tissues [36–38], perhaps by increasing the activity of the non-insulin-regulated glucose transporter, GLUT-1 [39]. Increases in NIMGU may be particularly important in conditions of large tissue injury, such as burns, since there is evidence that the wound itself may significantly increase peripheral glucose uptake [40]. At relatively high concentrations (above those needed to suppress hepatic glucose output), insulin will increase peripheral glucose uptake, particularly
Heller/Robinson
12
Table 1. Summary of the changes in carbohydrate metabolism during critical illness Gluconeogenesis1 Lactate production Glycogen synthesis Peripheral glucose uptake Peripheral glucose utilization Glucose intolerance Insulin resistance
! ! ! ! ! !
1
In severe sepsis, initial hyperglycaemia during which gluconeogenesis is increased is often followed by suppressed gluconeogenesis and hypoglycaemia.
in skeletal muscle [41]. However, studies have suggested that in surgical trauma or burns, there is resistance to this action of insulin. Insulin levels may have to be doubled in burns patients to produce the same effect on glucose uptake as in normal subjects [26]. This is important therapeutically since, in the presence of exogenous glucose delivery, endogenous insulin production may be insufficient to control the rise in blood glucose [22]. Thus, although the rise in glucose concentrations is partly attenuated by the accompanying increase in NIMGU, a therapeutic insulin infusion may be needed to keep blood glucose from rising, particularly if glucose is being infused to provide nutrition. Glucose Oxidation There has been a trend to reduce the amount of glucose delivered during parenteral nutrition in critical illness and replace it by lipid. This recommendation arose as a result of a number of studies apparently demonstrating suppression of pyruvate oxidation produced by glycolysis which then resulted in an accumulation of lactate [26, 28, 42]. A number of investigators had concluded that glucose oxidation was almost totally suppressed in the critically ill and confined to cerebral tissue only [43]. However these studies used labelled glucose infusions to obtain indirect measurements of pyruvate oxidation. As Mizock [22] has commented, this may have led to an underestimate of glucose oxidation rates due to a failure to take into account the contribution of muscle glycogenolysis. More recent work using stable isotopes has actually demonstrated an increase in glucose oxidation in patients with burns [44]. Mediators of Alterations in Carbohydrate Metabolism in Critical Illness A number of possible mechanisms could mediate the changes described above (table 1). These include the effects of counterregulatory hormones,
Glucose Metabolism
13
]] ]]
Glucose concentration (m g/dl)
20
]]
]]
10 0
(m g/kg × m in)
Glucose production
-10
-20 0 ] ]
]
]]
-0.5
]
]
(m l/kg × m in)
Glucose clearance
-1.0 0
]]
-1 0
30
60 90 M inutes
]
120
]
]
150
180
Fig. 4. Change from basal in plasma glucose concentration, glucose production rate, and glucose clearance due to a somatostatin (W) or somatostatin plus insulin (X) infusion. Results are expressed as mean×SEM. *p=0.05, **p 0.01. Values were significantly different from basal (p=0.05). Reproduced from Jahoor et al. [45] with permission.
activation of the sympathoadrenal system, changes in peripheral perfusion and cytokine release as a result of acute stress or injury. In addition, bacterial infection results in the release of endotoxin which may have profound metabolic effects, either directly or indirectly, by altering blood flow and the release of counterregulatory hormones or cytokines. The experiments which have explored these changes include observational studies in humans with infection or burns, animal in vivo models and intervention studies in humans. Jahoor et al. [45] have pharmacologically blocked the action of counterregulatory hormones (fig. 4) in patients with burn injury and compared rates of glucose production to controls. They infused somatostatin, which blocks release of insulin, glucagon and growth hormone and replaced basal levels of insulin by an exogenous insulin infusion. They found that hepatic glucose production rates fell in the injured patients, suggesting that glucagon plays an important role in this situation. Blockade of the other counterregulatory
Heller/Robinson
14
hormones has not been tested in human models of injury; however, adrenergic blockade in a dog model of injury had relatively little effect suggesting that glucagon and possibly growth hormone secretion have a more important role in increasing hepatic glucose production [46]. Other animal models have confirmed the importance of the actions of individual hormones. Liddell et al. [47] infused cortisol and glucagon into a rat model and produced raised lactate and glucose levels but no change in protein breakdown. However, when adrenaline was added to the infusion, there was an additional increase in lipid oxidation and protein catabolism. Adrenaline stimulates the release of glucagon through a effect, directly increases hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and by stimulating lipolysis, indirectly diminishes peripheral glucose uptake [2]. There is other evidence that counterregulatory hormones may act synergistically. Bessey et al. [48] showed that the effects of combined infusions of glucagon, cortisol and adrenaline on raising blood glucose were greater than when any were infused in isolation. Thus, the combination of sympathoadrenal activation, counterregulatory hormone release and the specific effects of different hormones make a major contribution to the alteration in carbohydrate metabolism. However, circulating counterregulatory hormones cannot entirely account for the metabolic responses to critical illness. Frayn [46] has pointed out that levels of counterregulatory hormones often begin to fall before metabolic changes have peaked. Wolfe and Shaw [28] have also shown that activation of the sympathetic nervous system contributes to the changes in carbohydrate metabolism in a septic dog model. Nevertheless, it is difficult to distinguish between the effects of circulating adrenaline and sympathetic activity [43]. Circulating noradrenaline, if derived from spillover from adrenergic neurones, may reflect sympathoadrenal activation but at best is only a crude measurement [49]. It provides no information on differential sympathetic responses and cannot distinguish between noradrenaline released with adrenaline from the adrenal gland and that derived from spillover. To our knowledge more modern techniques such as noradrenaline forearm turnover or microneurography have not yet been used to elucidate the role of the sympathetic nervous system in critical illness.
Role of Cytokines The metabolic changes in critical illness were originally thought to be mediated by an alteration in the balance between insulin and the counterregulatory hormones arising as a result of physical stress. However, recent work has highlighted the contribution of local and systemic effects of the release of cytokines. These contribute both to the changes in carbohydrate metabolism
Glucose Metabolism
15
seen following trauma and also to the specific changes observed during severe infection. As described above, cytokines may be responsible for the basal increase in peripheral glucose uptake which is largely non-insulin-mediated. TNF can increase muscle glucose transport in vitro [50] and in a dog hindlimb in vivo model [51]. IL-1 can also promote glucose uptake through an increase in glucose transporters [37] while other cytokines have been shown to increase GLUT-1 mRNA in a rat model of endotoxin shock [52]. Some studies have suggested that cytokines have indirect effects on carbohydrate metabolism, perhaps by stimulating secretion of counterregulatory hormones [2]. An intraperitoneal injection of IL-1 can increase glucose production but has no effect on isolated hepatocytes. IL-1 increases concentrations of circulating insulin and glucagon as well as activating production of cortisol via ACTH [53]. In the rat these effects may in part be mediated by central activation of the sympathetic nervous system [54]. What remains unclear is which effects predominate in the clinical situation and the extent to which different cytokines are specific in their actions. This is clearly an important area for further research, particularly in the area of potential pharmacological blockade.
Other Effects Alterations in the microcirculation could have a profound effect on metabolism. The delivery of substrate from the periphery to the liver and the effects of counterregulatory hormones clearly depend upon the integrity of the circulatory system. When effective circulating blood volume falls then gluconeogenic substrate may accumulate and contribute to profound metabolic derangement such as lactic acidosis. A fuller description is beyond the scope of this chapter and the reader is directed elsewhere for a comprehensive review [55]. Metabolic changes may also be modulated by interplay between the microcirculation and circulating hormones. Insulin is a potentially important regulatory factor since as a local vasodilator it could modify the microcirculation [56]. It is not clear whether the insulin resistance experienced by patients during critical illness affects any local vasodilatory effects and the relevance of these potential effects needs further investigation.
Abnormalities in Other Situations: Burns and Infection The important differences between severe infection and other causes of critical illness have been apparent for over 20 years although it is only recently
Heller/Robinson
16
Serum glucose (m g/10 m l)
Burn (n = 7) Burn infected (n = 6)
116
114
110
% change serum glucose
+8 +6 +4 +2 0 -2 -4 -6 0
10
20
30
40 50 Tim e (m in)
60
90
120
Fig. 5. Seven burned patients – average burn size 48% of total body surface, mean weight 70.5 kg, and 6 burned patients with blood cultures positive for gram-negative organisms, mean burn size of 71.5%, weight 64.6 kg, received a rapid injection of alanine. a No differences were present on comparison of glucose concentrations between the groups. b SE of ×16–20 occurred because of a wide variation in data from septic patients, but the response to alanine between the two groups was significantly different when comparing the response or percent change over the first hour. Reproduced from Wilmore et al. [57], with permission.
that the precise mechanisms have begun to be delineated. In 1976, Wilmore et al. [57] made the important observation that an alanine infusion (fig. 5) increased hepatic glucose output in patients with burn injury but had no effect in patients with burns and superadded sepsis. The implication that the infected state blocked hepatic glucose output has been borne out by further study. Initially, the metabolic state in infected patients is similar to other injury states but infected patients appear to go through a two-stage process of a raised hepatic glucose output which progressively falls. Thus, although absolute levels of hepatic glucose production may be increased, hypoglycaemia can develop since peripheral tissue uptake of glucose is also raised [58] as described above. Groves et al. [59] demonstrated impaired gluconeogenesis in a dog model of Escherichia coli bacteraemia in 1974. They noted hypoglycaemia with accompanying high levels of amino acids, alanine and glycine, and raised lactate
Glucose Metabolism
17
levels. They speculated that these changes could be caused by a block in hepatic gluconeogenesis at a level between pyruvate and glucose. Other animal studies demonstrated differences between hypovolaemic and endotoxic shock [60]. Animals rendered hypovolaemic became hyperglycaemic while those in whom infection was induced developed a fall in glucose level. Clemens et al. [61] attempted to elucidate possible mechanisms using isolated rat livers. They demonstrated that infusion of lactate raised glucose output half as much in livers removed from rats previously rendered septic compared to livers from control animals. Lysine (a nonglycogenic amino acid) restored hepatic glucose output, had no effect on O2 consumption and did not restore any response to phenylephrine. The data suggested that sepsis caused a primary cellular defect and diminished sensitivity to -adrenergic stimulation. They speculated that the effect of lysine might have been to improve mitochondrial function. They also suggested that the initially high rates of hepatic glucose production could be sustained by increased substrate delivery and intense -adrenergic stimulation. This might mask a gluconeogenic defect developing at the start of the septic state. Their data also suggested that gluconeogenic activity may have contributed to the progression of cellular damage. Wolfe and co-workers [32, 62, 63] have performed an extensive series of studies using a guinea-pig model of burn alone and burns with sepsis. They demonstrated increased metabolic rates and counterregulatory hormone levels in both. However, while the burned animals had increased rates of glucose production and clearance, the septic animals had reduced glucose production rates. -Blockade increased glucose production in burned animals and reduced it in the septic group (fig. 6). They and others have speculated that the inhibitory effect on the liver may be mediated by circulating bacterial endotoxin. Others have suggested that inflammatory mediators produced endogenously may reduce hepatic gluconeogenesis. Certainly some cytokines can inhibit phosphoenolpyruvate carboxykinase (PEPCK), the key enzyme in gluconeogenesis [64]. Since inducing infection in experimental animals can reduce both PEPCK activity and its gene expression, this is good evidence that the block is occurring in the liver [65]. Others have suggested that inhibition of GLUT-2 glucose transporters may also contribute to hypoglycaemia in endotoxic shock by inhibiting the hepatic release of glucose [39]. In summary, an important difference between sepsis and other critical illness states is the potential fall in hepatic glucose output if infection is severe or prolonged. This appears to be due to inhibition of gluconeogenesis although whether this is a direct effect of endotoxin or caused by circulating cytokines is not clear. In animal models of sepsis, since peripheral glucose uptake is already increased this may reduce blood glucose and hypoglycaemia is com-
Heller/Robinson
18
+25
Control
% plasm a glucose
Septic s
Burn
100 s
s
s
s s
s
s
s
s
s
-25
% glucose production
+25
s
s s s
100
-25
% glucose clearance
s
+25
s
s
s
100
-25 0
20 M inutes
40
60
Fig. 6. Effect of propranolol (2.5 mg/kg) on glucose metabolism control, septic, and burned guinea pigs. Values are expressed as deviation from basal values (×SEM). Reproduced from Durkott et al. [77] with permission.
mon. The relevance of these observations to the clinical situation in humans is less clear. Hypoglycaemia has been described in case reports of overwhelming sepsis and unsurprisingly is thought to indicate a poor prognosis [66].
Relevance of These Changes to Treatment The changes described above will influence a number of therapeutic goals in the critically ill, particularly the choice of nutritional supplement, whether this is delivered through the gastrointestinal tract or intravenously. They will also direct the target blood glucose and the appropriate use of insulin and
Glucose Metabolism
19
glucose infusions to keep within the desired range. In the short term, maintenance of blood glucose is critical, but within a few days, nutritional support becomes progressively more important. As described above, marked insulin resistance in the liver leads to considerable increases in hepatic glucose output. However, blood glucose levels are frequently raised only slightly since there are accompanying increases in NIMGU due to the effects of circulating cytokines and glucose uptake into large wounds such as burns. Patients with severe and prolonged infection may actually be at risk of hypoglycaemia due to impaired hepatic gluconeogenesis. However, NIMGU frequently becomes saturated and glucose concentration rises, particularly during the infusion of glucose containing fluids or with parenteral nutrition. In these circumstances, peripheral and hepatic insulin resistance can only be overcome by high rates of insulin infusion, sufficient to raise circulating insulin concentrations above 50–60 mU/l. A full discussion of the nutritional issues surrounding the critically ill is well beyond the scope of this chapter. However, a fundamental problem is how to provide sufficient exogenous nutritional support to maintain the optimum level of blood glucose and limit the breakdown of endogenous stores, particularly protein and to a lesser extent, fat. Since additional substrate appears to have little effect in preventing protein catabolism, it is only important to ensure that blood glucose does not fall below normal and provoke the release of additional counterregulatory hormones. The provision of excess glucose may increase CO2 production and O2 consumption sufficiently to compromise the ventilated patient [67]. A number of superficially attractive interventions have been tried without success. Nakao et al. [68] investigated the effects of phentolamine, an -blocker during surgery in an attempt to prevent the -mediated adrenergic suppression of insulin release. They found no significant effect although surgery is arguably a rather poor model for the critically ill. Since many of the physiological responses to critical illness appear designed to increase fuel delivery to peripheral tissues, it seems reasonable to maintain an elevated blood glucose level. Barton [43, 72] has highlighted additional potential benefits of maintaining a moderate level of hyperglycaemia. Stremple et al. [69] were able to demonstrate improved survival following an infusion of hypertonic glucose into pigs following severe haemorrhage. They attributed this to improved myocardial function although others have demonstrated a general ability of hyperglycaemic animals to withstand fluid loss, perhaps due to the osmotic effect of glucose [70]. A glucose concentration between 9 and 11 mmol/l should ensure a reasonable glucose supply while preventing fluid and electrolyte losses due to an osmotic diuresis.
Heller/Robinson
20
In the past, a substantial proportion of energy during parenteral nutrition was provided by fat as it was believed that large amounts of glucose would lead to excessive lactate production due to a failure to completely oxidize glucose. However the recent work described above suggests that glucose oxidation continues to occur even during severe illness. Thus, even if suppression of hepatic glucose production by exogenous glucose is reduced during critical illness, it may be preferable to deliver the bulk of energy needs as glucose, although other circumstances may demand the use of alternative energy sources. Wolfe [6] and others have demonstrated that glucose infusion cannot totally suppress hepatic glucose output. Nevertheless, since hepatic glucose output is increased in the critically ill even partial suppression may reduce hepatic glucose production by a significant and clinically useful amount. Black et al. [71] have shown that exogenous insulin cannot prevent glucose concentrations from rising during glucose infusion at rates of ?6 mg/kg/min. The combination of insulin and glucose infusion below these rates will provide a useful source of calories although insulin will not increase glucose oxidation. However, despite the additional theoretical potential benefit that insulin might increase rates of protein synthesis, the few clinical trials have not revealed any major benefits of therapeutic insulin as measured by important clinical endpoints.
Limitations of Experimental Methods and Future Research Much of the evidence concerning the alteration in carbohydrate metabolism in the critically ill has been obtained from animal models of injury and infection. While many of these data have added to our understanding and could not have been obtained in any other way, it is important to appreciate their limitations when considering their relevance to the clinical situation. In vitro models often provide precise information on single metabolic pathways in a particular tissue. However, they cannot easily reflect the effects of the combination of circulating factors such as insulin and counterregulatory hormones, which may be modulating the response. It is often difficult to ensure that the concentrations of factors under test such as endotoxin accurately represent the clinical situation. This is also true of in vivo studies where large amounts of bacteria or endotoxin are administered to experimental animals to demonstrate an effect. It is also important to consider the relevance of the particular animal model when assessing the significance of the data. One commonly used experimental model is the burned guinea pig. Extensive burns will produce profound alterations in fluid shifts and circulating blood volume, particularly in small
Glucose Metabolism
21
mammals and these additional changes may exaggerate the effects of the various influences under test. There are species differences in the control of carbohydrate metabolism. For example, in the rat, growth hormone concentrations show significant falls in different experimental models [72] in contrast to human patients whose levels generally increase albeit temporarily after injury [73, 74]. In vitro experimental models involving rat livers are more resistant to the effects of catecholamines compared to the human situation. Hypoglycaemia is considerably less common during critical illness in humans compared to experimental animals and may reflect greater resistance to the suppressive effects of endotoxin on human hepatic gluconeogenic mechanisms [75]. In vivo studies in animals generally involve the use of anaesthetics which may introduce artefactual changes [76]. Halothane anaesthesia can modify hepatic function, increasing rates of hepatic glycogenylosis in experimental rats [77]. The models of greatest potential relevance are clearly those that involve human subjects. Due to the condition under test it is inevitable that the majority of the experimental work consists of observational studies. Any invasive technique or investigation involving pharmaceutical blockade raises important ethical issues. These studies tend to involve relatively small numbers for obvious reasons, and there is always a danger that they are underpowered and that potentially important differences between groups will be missed. The testing of new therapeutic interventions using randomized clinical trials will have to be multicentre.
Areas of Uncertainty There are a number of areas which require further study. We need to establish whether the defects in gluconeogenesis during sepsis which have been clearly demonstrated in experimental animals operate in the clinical situation. We need to know which particular cytokines modulate the metabolic response to critical illness and whether they exert their effects directly or by modifying the release and actions of counterregulatory hormones and the sympathetic nervous system. The time course of cytokine action, particularly their role in mediating the effects on carbohydrate metabolism, needs clarifying. The work until now has largely involved the administration of high concentrations into animal models. The data suggest their involvement in trauma and infection but the relevance of these early studies, largely performed in animals, needs to be examined in humans. There is still considerable uncertainty about the mechanisms which drive the catabolic process, particularly those which regulate muscle breakdown.
Heller/Robinson
22
The precise sites of insulin resistance, both within the liver and in the periphery, is also not known, although much of the evidence suggests the defect lies within post-receptor signalling pathways. Many of the data described above are based on burn injury or following large doses of endotoxin in animal models. We need to establish to what extent these mechanisms are operating in patients.
Conclusions In this review we have described the changes in carbohydrate metabolism in the critically ill. Many of the experimental data have been obtained from animal models and may not always reliably reflect the clinical situation. However, the basic mechanisms which have been described in experimental studies do appear to operate in sick patients. There is increased glucose turnover, greater peripheral glucose uptake due to stimulation of NIMGU and raised hepatic glucose output. Glucose concentrations rise slightly in the basal state despite a rise in insulin level, reflecting insulin resistance. During glucose infusion, endogenous insulin secretion may be insufficient to prevent glucose levels rising and therapeutic insulin is often required. Superadded infection may inhibit gluconeogenesis and reduce hepatic glucose output although the importance of this in humans is unclear. These changes are brought about by a combination of increases in counterregulatory hormones, activation of the sympathoadrenal system and circulating cytokines. There are a number of potential targets for therapeutic intervention but a better understanding of the interaction between these various factors is probably necessary before we can test specific treatments in clinical trials.
References 1 2 3 4
5 6 7
Cahill GF: Starvation in man. N Engl J Med 1970;282:668–675. Kinney JM. Metabolic responses of the critically ill patient. Crit Care Clin 1995;11:569–585. Dineen S, Gerich J, Rizza R: Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 1992;327:707–713. Jackson RA, Roshania RD, Hawa MI, Sim BM, DiSilvio L: Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: An analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab 1986;63:541–549. Guma A, Zierath JR, Wallberg-Henrikkson N, Klip A: Insulin induces translocation of GLUT 4 glucose transporters in human skeletal muscle. Am J Physiol 1995;268:E613–E622 Wolfe RR: Carbohydrate metabolism in the critically ill patient. Crit Care Clin 1987;3:11–24. Kelley D, Mitrakou A, Marsh H, Schwenk F, Benn J, Sonnenberg G, Arcangeli M, Aoki T, Sorensen J, Berger M: Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J Clin Invest 1988;81:1563–1571.
Glucose Metabolism
23
8 9 10
11 12
13 14 15 16
17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Newgard CB, Hirsch LJ, Foster DW, McGarry JD: Studies on the mechanism by which exogenous glucose is converted into liver glycogen in the rat. J Biol Chem 1983;258:8046–8052. Lang CH, Bagby GJ, Blakesley HL, Johnson JL, Spitzer JJ: Plasma glucose concentration determines direct versus indirect liver glycogen synthesis. Am J Physiol 1986;251:E584–E590. Moore MC, Cherrington AD, Cline G, Pagliassotti MJ, Jones EM, Neal DW, Badet C, Shulman GI: Sources of carbon for hepatic glycogen synthesis in the conscious dog. J Clin Invest 1991;88: 578–587. Pozefsky T, Felig P, Tobin JD, Soeldner JS, Cahill GF: Amino acid balance across tissues of the forearm in postabsorptive man: Effects of insulin at two dose levels. J Clin Invest 1969;48:2273–2282. Zierler KL, Rabinowitz D: Effect of very small concentrations of insulin on forearm metabolism: Persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest 1964;43:950–956. Randle PJ, Garland PB, Hales CN: The glucose and fatty acids cycle: Its role in insulin sensitivity and the metabolic disturbance of diabetes mellitus. Lancet 1963;i:785–789. Boden G, Jadali F: Effects of lipid on basal carbohydrate metabolism in normal men. Diabetes 1991;40:686–692. Sharp P, Johnston DG: Mechanisms of hyperglycaemia and disorders of intermediary metabolism; in Williams G, Pickup J (eds): Textbook of Diabetes. Oxford, Blackwell Scientific, 1991, pp 303–312. Consoli A, Kennedy F, Miles J, Gerich J: Determination of Krebs cycle metabolic carbon exchange in vivo and its use to estimate the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output in man. J Clin Invest 1987;80:1303–1310. Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI: Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 1991;254:573–576. Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF: Liver and kidney during prolonged starvation. J Clin Invest 1969;48:574–583. Cori CF: Mammalian carbohydrate metabolism. Physiol Rev 1931;11:143–285. Haymond MW, Miles JM: Branched chain amino acids as a major source of alanine nitrogen in man. Diabetes 1982;31:86–89. Felig P: The glucose-alanine cycle. Metabolism 1973;22:179–207. Mizock BA: Alterations in carbohydrate metabolism during stress: A review of the literature. Am J Med 1995;98:75–84. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF: Brain metabolism during fasting. J Clin Invest 1967;46:1589–1595. Cerra FB: Hypermetabolism, organ failure, and metabolic support. Surgery 1987;101:1–13. Gump FE, Long CL, Geiger JW, Kinney JM: The significance of altered gluconeogenesis in surgical catabolism. J Trauma 1975;15:704–712. Wolfe RR, Durkot MJ, Allsop JR, Burke JF: Glucose metabolism in severely burned patients. Metabolism 1979;28:1031–1039. Wolfe RR, Allsop JR, Burke JF: Glucose metabolism in man: Response to intravenous glucose infusion. Metabolism 1979;28:210–220. Wolfe RR, Shaw JHF: Glucose and FFA kinetics in sepsis: Role of glucagon and sympathetic nervous system activity. Am J Physiol 1985;248:E236–E243. Wolfe RR, Jahoor F, Herndon DN, Wolfe MH: The glucose-alanine cycle: Origin of control. J Parenter Enter Nutr 1985;9:107. Siegel JH, Cerra FB, Coleman B: Physiological and metabolic correlations in human sepsis. Surgery 1979;86:163–193. Long CL, Spencer JL, Kinney JM, Geiger JW: Carbohydrate metabolism in man: Effect of elective operations and major injury. J Appl Physiol 1971;31:110–116. Wolfe RR, Burke JF: Effect of glucose infusion on glucose and lactate metabolism in normal and burned guinea pigs. J Trauma 1978;18:800–805. Lang CH, Dobrescu C: Gram-negative infection increases noninsulin-mediated glucose disposal. Endocrinology 1991;128:645–653. Meszaros K, Lang CH, Bagby GJ, Spitzer JJ: Contribution of different organs to increased glucose consumption after endotoxin administration. J Biol Chem 1987;262:10965–10970.
Heller/Robinson
24
35
36 37 38 39 40 41 42 43 44
45 46 47 48 49 50 51 52
53 54
55 56 57 58 59 60 61
Stephens JM, Bagby GJ, Pekala PH, Shepherd RE, Spitzer JJ, Lang CH: Differential regulation of glucose transporter gene expression in adipose tissue of septic rats. Biochem Biophys Res Commun 1992;183:417–422. Meszaros K, Lang CH, Bagby GJ, Spitzer JJ: Tumour necrosis factor increases in vivo glucose utilization of macrophage-rich tissues. Biochem Biophys Res Commun 1987;149:1–6. Bird TA, Davies A, Baldwin SA, Saklatvala J: Interleukin-1 stimulates hexose transport in fibroblasts by increasing the expression of glucose transporters. J Biol Chem 1990;265:13578–13583. Cornelius P, Lee MD, Marlow M, Pekala PH: Monokine regulation of glucose transporter mRNA in L6 myotubes. Biochem Biophys Res Commun 1989;165:429–436. Zeller WE, Goto M, Parker J: Glucose transporters (GLUT1, 2, and 4) in fat, muscle, and liver in a rat model of endotoxic shock. Biochem Biophys Res Commun 1994;198:923–927. Wilmore DW, Aulick LH, Mason AD, Pruitt BA: Influence of the burn wound on local and systemic responses to injury. Ann Surg 1998;186:444–458. Rizza RA, Mandarino LJ, Gerich JE: Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 1981;240:E630–E639. Stoner HB, Little RA, Frayn KN, Elebute AE, Tresadern J: The effect of sepsis on the oxidation of carbohydrate and fat. Br J Surg 1983;70:32–35. Barton RN: Neuroendocrine mobilization of body fuels after injury. Br Med Bull 1985;41:218– 225. Wolfe RR, Jahoor F, Herndon DN, Miyoshi H: Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: Effect of dichloroacetate and glucose infusion. Surgery 1991;110:54–67. Jahoor F, Herndon DN, Wolfe RR: Role of insulin and glucagon in the response of glucose and alanine kinetics in burn-injured patients. J Clin Invest 1986;78:807–814. Wolfe RR: Substrate kinetics in sepsis; in Frayn KN, Little RA (eds): The Scientific Basis of the Critically Ill. Manchester, Manchester University Press, 1985. Liddell MJ, Maclean LD, Shizgal HM: The role of stress hormones in the catabolic metabolism of shock. Surg Gynecol Obstet 1979;149:822–830. Bessey PQ, Watters JM, Aoki TT, Wilmore DW: Combined hormonal infusion simulates the metabolic response to injury. Ann Surg 1984;200:264–281. Esler M: Assessment of sympathetic nervous function in humans. Clin Sci 1982;62:247–254. Lee MD, Zentella A, Pekala PH, Cerami A: Effect of endotoxin-induced monokines on glucose metabolism in the muscle cell line L6. Proc Natl Acad Sci USA 1987;84:2590–2594. Evans DA, Jacobs DO, Wilmore DW: Tumour necrosis factor enhances glucose uptake by peripheral tissues. Am J Physiol 1989;257:R1182–R1189. Zeller WP, The SM, Sweet M, Goto M, Gottschalk ME, Hurley RM, Filkins JP, Hofmann C: Altered glucose transporter mRNAabundance in a rat model of endotoxic shock. Biochem Biophys Res Commun 1991;176:535–540. Besedovsky H, del Rey A, Sorkin E, Dinarello CA: Immunoregulatory feedback between interleukin1 and glucocorticoid hormones. Science 1998;233:652–654. Petit F, Jarrous A, Dickinson RD, Molina PE, Abumrad NN, Lang CH: Contribution of central and peripheral adrenergic stimulation to IL-1-alpha-mediated glucoregulation. Am J Physiol 1994; 267:E49–E56. Mizock BA: Lactic acidosis. Dis Mon 1989;35:233–300. Baron AD: Hemodynamic actions of insulin. Am J Physiol 1994;267:E187–E202. Wilmore DW, Mason JAD, Pruitt JBA: Impaired glucose flow in burned patients with gram-negative sepsis. Surg Gynecol Obstet 1976;143:720–724. Wolfe RR, Elahi D, Spitzer JJ: Glucose and lactate kinetics after endotoxin administration in dogs. Am J Physiol 1977;232:E180–E185. Groves AC, Woolf LI, O’Regan PJ, Beach C, Hasinoff C, Sutherland WH: Impaired gluconeogenesis in dogs with E. coli bacteraemia. Surgery 1974;76:533–541. Garcia-Barreno P, Balibrea JL: Metabolic response in shock. Surg Gynecol Obstet 1978;146:182–190. Clemens MG, Chaudry IH, McDermott PH, Baue AE: Regulation of glucose production from lactate in experimental sepsis. Am J Physiol 1983;244:R794–R800.
Glucose Metabolism
25
62 63 64 65
66 67 68 69 70 71 72 73 74 75 76 77 78
Wolfe RR, Miller HI: Cardiovascular and metabolic responses during burn shock in the guinea pig. Am J Physiol 1976;231:892–897. Wolfe RR, Burke JF: Glucose and lactate metabolism in experimental septic shock. Am J Physiol 1978;235:R219–R227. Hill M, McCallum R: Altered transcriptional regulation of phosphoenolpyruvate carboxykinase in rats following endotoxin treatment. J Clin Invest 1991;88:811–816. Deutschman CS, DeMaio A, Buchman TG, Clemens MG: Sepsis-induced alterations in phosphoenolpyruvate carboxykinase expression: The role of insulin and glucagon. Circ Shock 1993;40: 295–302. Miller SI, Wallace RJ, Musher DM, Septimus EJ, Kohl S, Baughn RE: Hypoglycemia as a manifestation of sepsis. Am J Med 1980;68:649–654. Fellows IW, Woolfson AMJ: Effects of therapeutic intervention on the metabolic responses to injury. Brit Med Bull 1985;41:287–294. Nakao K, Miyata M: The influence of phentolamine, an adrenergic blocking agent on insulin secretion during surgery. Eur J Clin Invest 1977;7:41–45. Stremple JF, Thomas H, Sakach V, Trelka D: Myocardial utilisation of hypertonic glucose during hemorrhagic shock. Surgery 1976;80:4–12. Ja¨rhult J: Osmotic fluid transfer from tissue to blood during hemorrhage. Acta Physiol Scand 1973; 89:213–226. Black PR, Brooks DC, Bessey PQ, Wolfe RR, Wilmore DW: Mechanisms of insulin resistance following injury. Ann Surg 1982;196:420–433. Barton RN: Effect of limb ischaemia and scalding on the concentrations of growth hormone and corticosterone in rat plasma. J Endocrinol 1977;73:347–353. Carey LC, Cloutier CT, Lowery BD: Growth hormone and adrenal cortical response to shock and trauma in the human. Ann Surg 1971;174:451–458. Frayn KN, Price DA, Maycock PF, Carroll SM: Plasma somatomedin activity after injury in man and its relationship to other hormonal and metabolic changes. Clin Endocrinol 1984;20:179–187. Frayn KN: Substrate turnover after injury. Br Med Bull 1985;41:232–239. Wolfe RR, Bagby GJ: Lipid metabolism in shock; in Altura BM, Lefer AM, Schumer W (eds): Handbook of Shock and Trauma, vol 1: Basic Science. New York, Raven Press, 1983, pp 199–216. Heath DF, Frayn KN, Rose JG: Effects of halothane on glucose metabolism after injury in the rat. Br J Anaesth 1978;50:899–904. Durkott MJ, Wolfe RR: Effects of adrenergic blockade on glucose kinetics in septic and burned guinea pigs. Am J Physiol 1981;241:R222–R227.
Simon R. Heller, MD, University of Sheffield, Division of Clinical Sciences, Northern General Hospital, Sheffield, S5 7AU (UK) Tel. +44 114 271 4008, Fax +44 114 256 0458, E-Mail
[email protected] Heller/Robinson
26
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 27–66
............................
Salt and Water Homeostasis Allen I. Arieff Department of Medicine, University of California at San Francisco, San Francisco, Calif., USA
Contents Introduction ................................................................................................ Total Body Water ......................................................................................... Body Fluid Composition and Solute Distribution ............................................... Regulation of Extracellular Sodium and Water .................................................. Free Water Clearance ................................................................................. Osmolality ............................................................................................... Tonicity (Effective Osmolality) ..................................................................... Thirst and Its Regulation ............................................................................... Hormones and Thirst Regulation ................................................................. Impaired Thirst Regulation ......................................................................... Hormonal Effects on Brain Sodium, Water and Volume Homeostasis .................... Vasopressin (ADH, Arginine Vasopressin), Vasopressin Secretion and Receptors Cerebral Effects of Vasopressin .................................................................... Stimuli for Release of ADH – Appropriate and Inappropriate ........................... Estrogen, Progesterone and Androgens ......................................................... Atrial Natriuretic Peptide ........................................................................... Physical Factors ........................................................................................ Sodium, Water and Brain Cell Volume Regulation .............................................. Hyperosmolar States ..................................................................................... Age-Related Changes in Sodium and Water Homeostasis .................................... Diabetes insipidus ......................................................................................... Hyponatremia .............................................................................................. Clinical Manifestations of Hyponatremia ...................................................... Postoperative Hyponatremia ....................................................................... Polydipsia-Hyponatremia Syndrome ............................................................. Congestive Heart Failure ............................................................................ Pharmacologic Agents ............................................................................... Acquired Immune Deficiency Syndrome (AIDS) ............................................. Hepatic Insufficiency ..................................................................................
28 29 29 30 30 31 31 32 33 34 34 35 35 36 37 37 38 38 39 40 40 43 43 44 46 48 48 49 49
Malignancy-Associated Hyponatremia .......................................................... Management of Hyponatremia .................................................................... Hypernatremic States .................................................................................... Brain Adaptation to Hypernatremia ............................................................. Causes of Hypernatremia ........................................................................... Clinical Manifestations of Hypernatremia ...................................................... Morbidity and Mortality of Hypernatremia ................................................... Essential Hypernatremia ............................................................................. Hypernatremia and Liver Disease ................................................................ Treatment of Hypernatremia ....................................................................... Sodium and Water Complications in the Postoperative Patient .............................. References ...................................................................................................
50 50 52 53 54 54 55 55 56 56 58 59
Introduction The major constituent of all body fluids is water and the major solutes are sodium, potassium and their anions. The body water is divided into two major fluid compartments which are the intracellular and extracellular spaces, and the extracellular space is further separated into plasma and interstitial components. Intracellular solutes are very different from those found in extracellular fluid. However, osmotic equilibrium dictates that the chemical potential of water must be the same in intra- and extracellular fluid. Since all cell membranes are readily permeable to water, osmolality throughout the body fluids is essentially the same, with only a few exceptions (renal medulla, cerebrospinal fluid (CSF)). The volume and composition of both the intracellular and extracellular fluid may be altered by a variety of circumstances. In order for normal metabolic activity to be carried out, there must be maintenance of an optimal body fluid osmolality in intracellular fluid. Homeostatic mechanisms are therefore constantly at work to maintain such an environment. Most major metabolic activities do not occur in the extracellular fluid, so there can be substantial alteration in its osmolality without causing any adverse effects. Extracellular fluid serves to transmit substances (electrolytes, metabolites, nutrients) between cells and the various organ systems. It regulates both the intracellular volume and ionic composition. Because of the requirement for osmotic equilibrium between the cells and the extracellular fluid, any alteration in extracellular fluid osmolality is accompanied by identical changes in intracellular osmolality, often with a concomitant change in cell volume. The brain, on the other hand, appears to regulate its osmolality primarily by alteration of intracellular solute content rather than by changes in cell volume [1, 2]. The ability of the extracellular fluid to transmit substances from plasma to organs and cells requires maintenance of a near-normal extracellular fluid
Arieff
28
volume. Maintenance of an intact plasma volume is also necessary to maintain cardiovascular stability and adequate tissue oxygen delivery. This chapter will describe the normal and abnormal regulation of body water, intracellular and extracellular volume, antidiuretic hormone, sodium, potassium and osmolality. Abnormalities of sodium, osmolality, water, and antidiuretic hormone and the effects of aging, as well as their management, will be described. Traditionally, most chapters about sodium and water describe their renal handling and physiology. This chapter will be concerned with the endocrine aspects of sodium and water metabolism and their effects upon the brain. More traditional aspects of sodium and water physiology can be found elsewhere [3, 4].
Total Body Water Total body water (TBW) varies as a function of age, sex, body mass index (BMI) and weight. The relative water content of the body is highest in infants and children and decreases progressively with aging [5]. The water content also depends on the percent of body fat, which is best expressed by the BMI [weight, kg/(height, meters)2] and is greater for women and obese individuals [6]. The frequently quoted figure for TBW as 60% of body weight applies primarily to healthy young males [7]. The percent of TBW varies widely as a function of age, sex and body habitus, with a range of 42% (obese elderly women) to 75% (young children), while the mean figure for hospitalized adults is about 50% of body weight [7]. The intracellular volume is estimated from TBW and extracellular volume, but the extracellular volume can be measured directly by use of various chemical markers (insulin, sucrose, sulfate, ClÖ, CNSÖ, BrÖ). Measurement of TBW by various dilution techniques is relatively reproducible, but measurement of the extracellular volume is technically difficult, because there is no material which is known to distribute exclusively in extracellular fluid. Thus, depending on the type of marker used, the extracellular volume will vary from 27 to 45% of TBW [8].
Body Fluid Composition and Solute Distribution The values for electrolyte concentrations in plasma are well known but, because about 7% of plasma consists of solids (primarily proteins), the concentrations of all ions increase by about 7% when expressed in terms of plasma water. The normal serum sodium concentration is commonly expressed as 140 mmol/l plasma, but in fact, it is 152 mmol/l plasma water. The concentrations
Salt and Water Homeostasis
29
of electrolytes in interstitial fluid are different from those in the plasma because the concentration of proteins is lower in the interstitial fluid. The Donnan equilibrium, which is based on differences in protein concentration between the two compartments, will determine the concentrations of electrolytes in the interstitial fluid. The plasma concentrations for calcium and magnesium are lower than values predicted by the Donnan equilibrium, because a substantial fraction of these ions are bound to plasma proteins [8]. When two solutions are separated by a membrane permeable to water and small ions, and when one of the solutions contains more nonpermeant ions than the other, the distribution of permeant ions occurs in a predictable manner. The distribution is predicted by the requirements of the Donnan equilibrium. Across the capillary membrane, there is a substantial difference in protein concentration, which causes other diffusible ions to distribute themselves according to the Donnan equilibrium. The total solute concentration of the plasma is higher than that of interstitial fluid, not only because of the higher protein concentration (about 0.8 mmol/l in the plasma vs. 0.4 mmol/l in the interstitial fluid), but also because of the higher concentration of diffusible solutes [8]. The differences in osmotic pressure between plasma and interstitial fluid compartments can be calculated by the van’t Hoff equation [9]. The plasma oncotic pressure is the difference in osmotic pressure created by the presence and absence of proteins (assuming that the plasma is equilibrated against a solution having the same ionic composition as plasma but lacking protein). Using the Donnan equation, it can be shown that the concentration of diffusible ions is higher in the plasma than in the interstitial fluid compartment by 0.43 mmol/l.
Regulation of Extracellular Sodium and Water There are several basic concepts relating to extracellular sodium and water homeostasis which must be understood. These include concepts of free water clearance, osmolality, tonicity and thirst regulation, and their relationships to the release of antidiuretic hormone (ADH). It is also important to understand the role played by osmolality, tonicity and thirst in the regulation of cell volume and the distribution of body water. Free Water Clearance Hyponatremia occurs: (a) when the intake of free water is in excess of the ability of the kidney to excrete it; or (b) when there is urinary loss of monovalent cation (sodium+potassium) at a concentration which exceeds the intake. Free water clearance can be conceptualized by dividing the urine volume
Arieff
30
(V) into two fractions. The first fraction, osmolar clearance (Cosm), represents the volume of urine (l/day) which is necessary to excrete all of the daily solute load at an osmolality equivalent to plasma. The second fraction, free water clearance (CH2O), represents the difference between the total urine volume (l/day) and the osmolar clearance (CH2O>VÖCosm). This represents the volume of urine from which solute has been completely removed during formation of a dilute urine. To maintain a normal plasma osmolality it is necessary that the CH2O equals the intake of free water minus insensible losses (normally about 600 ml/day). If the free water intake exceeds CH2O, then plasma osmolality (and sodium) must fall. The ability to generate free water clearance and thereby dilute the urine (below isotonicity) depends on three factors: (a) adequate delivery of solute to the distal diluting segments in the loop of Henle and distal convoluted tubule; (b) the distal diluting segments must be functional so that sodium and chloride can be removed, thereby generating free water; (c) ADH must be suppressed so that the free water generated at the distal diluting sites is not reabsorbed in the collecting system. Although urinary loss of sodium at a concentration greater than that of plasma can lead to hyponatremia, such clinical circumstances are quite rare, occurring primarily in patients with adrenal insufficiency or those who have an idiosyncratic reaction to thiazide diuretics. Osmolality Osmolality is defined as the total number of solute particles in a given volume of solvent and is unaffected by the molecular weight of the particles. It is generally expressed as the number of milliosmoles of solute per 1 kg (liter) of water, and is usually determined by freezing-point depression. An increase in extracellular osmolality by solutes that diffuse freely into cells (urea, ethanol), leads to rapid osmotic equilibrium between extracellular and intracellular compartments because of solute diffusion across the plasma membrane. However, when extracellular fluid osmolality is increased by solutes which are impermeable to cell membranes (sodium, glucose, mannitol, glycerol and radiocontrast agents), intracellular osmolality will increase only because of the shift of water from the intracellular to the extracellular compartment. Solutes which freely penetrate cell membranes are called ineffective osmoles and those which do not are called effective osmoles. The total osmolality of any solution is the sum of both the effective and ineffective osmoles. Tonicity (Effective Osmolality) Solutes that contribute to effective osmolality determine tonicity, and the body strives to regulate tonicity and not osmolality. Thus, thirst and ADH release respond only to tonicity and not to total plasma osmolality. Extracellu-
Salt and Water Homeostasis
31
lar fluid is said to be hypertonic if the effective osmolality is greater than that which is physiologically normal (i.e., ?287 mosm/kg water). It is said to be hypotonic when effective osmolality is less than normal. Thus, hypertonic fluid is one that causes cellular dehydration by pulling water from cells, while hypotonic fluid causes cell swelling as a result of intracellular water movement to produce osmotic equilibrium. An increase of extracellular osmolality by solutes which diffuse freely into cells (urea, ethanol), leads to rapid osmotic equilibrium between intracellular and extracellular fluids (diffusion of the solutes into the intracellular fluid space). However, when the extracellular fluid osmolality is increased by solutes which do not penetrate into cells, intracellular osmolality increases due to a shift of water from cells into the extracellular space. Examples of such solutes include sodium, glucose, mannitol, radioactive contrast media and glycerol [10]. Such solutes are all considered to be ‘effective’ osmoles because they are largely restricted to the extracellular fluid space [11]. Glucose is not an effective osmole for all cells. It does not enter most cells in the brain without first being metabolized. In addition, it stimulates the generation of ‘idiogenic osmoles’ so that the brain is not dehydrated by glucose infusion [12, 13]. However, when we consider a substance to be an effective osmole, it is usually in reference to the carcass (primarily skeletal muscle), which represents the greatest quantity of body mass of any tissue [14].
Thirst and Its Regulation Afferent stimuli for thirst sensation include both increase in plasma osmolality and decrease in extracellular volume. Also, increases in either plasma or CSF sodium concentrations will stimulate thirst and cause ADH to be released. At a normal plasma osmolality of approximately 285 mosm/kg water, circulating plasma ADH level is approximately 2 pg/ml, which is the level needed to produce a half-maximal urine concentration of approximately 600 mosm/kg. Normal individuals do not usually experience thirst at this level of plasma osmolality. With dehydration, thirst is first expressed only when plasma osmolality reaches approximately 294 mosm/kg water. This level of plasma osmolality represents a 2% increase above normal and is generally referred to as the ‘osmolar threshold’ for thirst. At this level of plasma osmolality, ADH is maximally stimulated (usually ?5 pg/ml) and is sufficient to achieve a maximally concentrated urine (?1000 mosm/kg in young adults). A number of pharmacologic agents increase thirst, including tricyclic antidepressants and antihistamines. Certain hormones increase thirst, including ADH and angiotensin II [15].
Arieff
32
A patient with defective thirst mechanism and intact osmolar regulatory center will appropriately release ADH in response to volume contraction and hypertonicity, but will become increasingly dehydrated because of the lack of thirst sensation. Such patients will not have the desire to drink, and have to be taught to drink water on a routine basis. They also have to learn to increase water intake with increased ambient temperature and increased physical activity. Such patients are classically described as having ‘essential hypernatremia’ as their ability to normalize their serum sodium depends entirely on the ability to take in sufficient amounts of oral fluids. On the contrary, patients with intact thirst mechanism and decreased circulating ADH (diabetes insipidus) can often exist quite normally because of voluntary water intake stimulated by thirst. These patients may get into trouble only if access to water is prevented, as in the case of physical or mental incapacitation. The afferent stimuli for the sensation of thirst include both osmolar and volume signals. However, it is not clear how these signals are transmitted to the thirst center. For example, increases in either plasma or CSF sodium concentrations can stimulate thirst (and ADH release); but it is not clear which is more important, or if changes in tonicity or sodium concentration are the primary stimuli. As is true for ADH release, it is clear that ‘effective’ osmoles (those which are relatively restricted to the extracellular fluid, such as sodium salts or mannitol) are effective thirst stimuli. The cellular mechanisms by which changes in osmolality are translated into thirst are also unknown, although changes in brain cell volume have been proposed [16]. Changes in intracellular volume seem more important in regulating thirst than changes in intracellular osmolality (without a change in intracellular volume), or changes in extracellular volume (without a change in intracellular volume) [16]. Hormones and Thirst Regulation Complex roles for enkephalins and other opiate mediators in thirst regulation have recently been proposed, and the roles for prostaglandins and other neuroactive substances are also being explored. ADH may also have central dipsogenic effects [16]. Thirst may also alter ADH distribution and metabolism and substances such as isoproterenol may affect it by altering angiotensin II levels. Angiotensin II has substantial dipsogenic properties within the brain, but it does not cross the blood-brain barrier as does angiotensin I. Angiotensin I readily crosses the blood-brain barrier, and the brain has its own angiotensinconverting enzyme system, which converts angiotensin I to angiotensin II. The exact biochemical mechanisms by which angiotensin II activates the cerebral thirst center is unknown. Such mechanisms are similar to those proposed for osmolar stimuli, suggesting that there may be a final common pathway for the two normal (physiologic) thirst stimuli [16].
Salt and Water Homeostasis
33
Impaired Thirst Regulation Primary hypodipsia is a ‘pure’ deficit in the thirst mechanism, requiring that all other aspects of osmoregulation be normal. The results of such a ‘pure’ deficit in thirst may then be predicted as follows. The loss of thirst would result initially in decreased water intake and a tendency both to hyperosmolality and to effective arterial blood volume depletion. Both changes would stimulate ADH release and thereby increase renal water conservation. If water conservation is sufficient to offset the decrease in water intake (if plasma osmolality and blood volume are returned to near normal), the thirst deficit may go unrecognized by the patient. On the other hand, if renal water conservation is insufficient to compensate for the decreased water intake, symptoms of hyperosmolality and hypovolemia would supervene. A meaningful evaluation of thirst deficits is difficult because drinking behavior is influenced by many stimuli which are unrelated to osmoregulation or volume regulation [17]. Definitive testing for thirst deficits should include both osmolar and volumetric stimuli, but only the former is usually evaluated. The test subject must be alert, oriented, and able to indicate whether or not thirst sensation is present. When studies of osmolar thirst stimuli are performed, the subject should be euvolemic (normal blood volume), and other dipsogenic stimuli (hyperthermia, exercise) should be minimized. A commonly used testing method is the administration of intravenous hypertonic NaCl (514 mM NaCl) solution at a rate sufficient to elevate the plasma osmolality from baseline to some arbitrary level which is at least 10% above baseline. The plasma osmolality should be determined at the baseline and at 30-min intervals until the sensation of thirst is reported, or until the plasma osmolality has increased by at least 10% [17]. This technique will increase both blood volume and plasma osmolality, and the increased blood volume will tend to decrease hypovolemia-induced thirst. Moreover, the conclusion of the test is arbitrary if thirst is not elicited; thus, total absence of thirst (adipsia) can never be defined with certainty.
Hormonal Effects on Brain Sodium, Water and Volume Homeostasis The ability of the brain to adapt to either hyperosmolar or hypo-osmolar states is markedly influenced by the effects of both hormones and physical factors (water content, ratio of brain size to skull size). The most important of these hormones are vasopressin, estrogens, androgens, progesterone and atriopeptin. The most important effects of physical factors on brain adaptation are the progressive alterations between the ratio of brain size to skull capacity which occurs with the aging process [18], and the gender differences between men and women [1].
Arieff
34
Vasopressin (ADH, Arginine Vasopressin), Vasopressin Secretion and Receptors ADH (vasopressin) is the principal hormone responsible for the regulation of body water. It is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and most is stored for release at sites in the posterior pituitary [17, 19]. There are two major types of vasopressin receptors which have been well described at this time – the V1 and V2 receptors [20]. The V2 receptors are located primarily in the kidney. After binding to V2 receptors, vasopressin acts largely through activation of adenylate cyclase, elevating cyclic adenosine monophosphate (cyclic AMP) in the distal nephron. The vasopressin analogue desmopressin (dDAVP) also binds to vasopressin V2 receptors, and thus has an action on the kidney which is similar to that of vasopressin. Vasopressin V1 receptors are located in brain, blood vessels and choroid plexus. ADH is synthesized in brain in the hypothalamus, and after being secreted into the CSF of the third ventricle, binds to V1 receptor sites on neurons and blood vessels. While in the CSF, vasopressin binds directly to brain cells [21], where its cerebral effects are mediated by intracellular second messengers [22, 23] which include nitric oxide, cyclic GMP and inositol triphosphate (IP3). After its release from the hypothalamus, vasopressin migrates in the CSF of the third ventricle to portal blood flowing to the pituitary gland [24, 25]. In general, neither ADH nor most other hormones which have effects on the brain have access to the brain parenchyma (insulin may be an exception), as such access is not needed. All these substances bind to brain cells and exert their effects inside the brain by means of second messengers. For ADH in brain, an important second messenger is IP3 [26, 27]. A linkage has been demonstrated between IP3 and vasopressin V1 receptors in the brain [27, 28]. ADH is eventually secreted by the posterior pituitary into the bloodstream. Cerebral Effects of Vasopressin There are multiple cerebral effects of vasopressin. Vasopressin administration in the rat, acting through cerebral V1 receptors, results in water movement into the brain in the absence of hyponatremia or hypo-osmolality [23, 29, 30]. There is also a significant decline in brain synthesis of ATP [31], decreased brain blood flow and CSF production [22], decreased cerebral perfusion [32], a lowering of brain intracellular pH [31, 33] and decrease of Ca2+ influx [28]. There is impairment of several possible pathways for sodium efflux during hyponatremia [28, 34] and inhibition of Na+,K+-ATPase in blood vessels [35]. All of these processes impair outward transport of Na+ and K+ [36, 37], impairing brain cell volume regulation [38]. The decline of cerebral ATP synthesis in female rats after vasopressin administration [31] may be related in part to brain ischemia from cerebral vasoconstriction [39]. Many of the
Salt and Water Homeostasis
35
aforementioned cerebral actions of ADH also require the presence of estrogen. The vascular reactivity of vasopressin, a potent vasoconstrictive agent, is significantly greater in female rats than in males, both in vitro [40] and in vivo [39], and following blood loss, plasma vasopressin levels are significantly higher in female rats than in males [41]. Stimuli for Release of ADH-Appropriate and Inappropriate There are two primary stimuli for the release of ADH: (a) increased plasma osmolality, and (b) decreased intravascular volume [17, 19]. With ADH release, ingested water is retained abnormally, which lowers plasma osmolality, alleviates thirst and repletes plasma volume. As these parameters are satisfied, ADH release is inhibited and any excess water taken is eliminated as urine. If a patient with normal kidneys takes in a normal daily solute load (1,000 mosm), and is able to produce a maximally dilute urine (50 mosm/kg), he will theoretically be able to ingest up to 20 liters of water/day without becoming hyponatremic. However, in patients with poor nutrition (solute load of 250 mosm/ day) as in the case of beer potomania [42], water intake in excess of 5 liters could lead to the development of hyponatremia. A number of factors other than elevated plasma osmolality and hypovolemia can cause ADH release, and override the effects of osmolality and volume. These include many medications, tumors, pulmonary lesions, intracranial processes, emesis, nausea, stress, hypoxia and even anxiety and fear [43]. Elevation in ADH levels secondary to these entities is often referred to as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Patients with elevated ADH levels may develop a clinical syndrome consisting of a normal to increased intravascular volume, with hypo-osmolality, urine osmolality ?100 mosm/kg, and decreased plasma levels of sodium, urea, uric acid and creatinine. Traditionally, the patient must have no other reason for increased ADH, such as volume depletion or hyperosmolality. The so-called SIADH was described in 1957–1960 [44, 45], and in modern times, the term no longer has a useful meaning. The term SIADH has been indiscriminately applied to essentially all conditions characterized by hyponatremia with urine osmolality greater than that of plasma. In many such conditions, including congestive heart failure and hepatic cirrhosis, there is in fact a decreased effective arterial volume [46–48]. In postoperative patients, the effective arterial volume is also decreased [49–51]. There are a number of drugs which either stimulate ADH production or enhance its action [43]. In addition, a number of tumors either produce ADH or a similar acting peptide [43, 44]. Asymptomatic hyponatremia is often present in the elderly [52], frequently resulting in the unsubstantiated overdiagnosis of SIADH [53]. The causes of the hyponatremia are most often not demonstrable [52], although a minority are due to SIADH associated with
Arieff
36
pharmacologic agents, pneumonia or intracranial lesions [53]. As the patients are usually asymptomatic, there is no need for active therapy (hypertonic NaCl) in such patients – fluid restriction is usually adequate [53]. Estrogen, Progesterone and Androgens The early adaptation of the brain to hyponatremia is by loss of blood and CSF, followed by extrusion of sodium from brain cells [54]. Loss of potassium and to some extent, organic molecules, follow later, in an attempt to decrease brain cell osmolality without a gain of water [54–56]. After an initial loss of CSF via bulk flow, extrusion of sodium is the most important early defense of the brain against hyponatremia [54]. The major reasons for the increased morbidity and mortality in females compared to males include a diminished ability of the female brain to adapt to hyponatremia by limiting the amount of brain swelling. There is increasing evidence that these effects of gender may be mediated in part through the actions of certain steroid and peptide hormones, including estrogen, progesterone and testosterone [38]. Estrogens stimulate vasopressin release, while androgens appear to suppress it [57–59]. In addition to effects on vasopressin release, estrogens may antagonize brain adaptation via the Na+,K+-ATPase system [36, 60] while androgens may enhance such adaptation [61]. The extrusion of sodium from brain cells is by several pathways, including sodium channels, the Na+,K+-ATPase system and the Na+/Ca2+ exchanger [38, 62]. Hyponatremic male laboratory animals are better able to extrude sodium to decrease brain cell osmolality than are females, resulting in significantly less brain swelling in males than in females both in vivo and in vitro [38]. Atrial Natriuretic Peptide Atrial natriuretic peptide (ANP) may improve brain adaptation to hyponatremia. In the central nervous system, ANP appears to play an important role in the regulation of brain water content in several pathologic states characterized by cerebral edema [63]. During the regulatory volume decrease observed with hyponatremia, an important initial response in the brain is a loss of sodium [54]. ANP may act to decrease cell volume by effecting a net decrease of the intracellular sodium concentration in nerve cells [34]. Sodium is constantly being removed from brain cells, much of it by the Na+,K+-ATPase system [31]. By decreasing sodium uptake in pathological states, the net effect of ANP would be a decrease in intracellular sodium, as it continues to be pumped out by Na+,K+-ATPase. The effect of ANP appears to be opposite to that of vasopressin, both in vivo [30, 64] and in astrocytes in vitro [29]. ANP also affects the regulation of CSF production [65, 66] and hence, the CSF pressure [64].
Salt and Water Homeostasis
37
Physical Factors There are two important factors which impact the physical elements of brain adaptation. The first is the aging process, which is marked by progressive alterations between the ratio of brain size to skull capacity. This ratio is highest at birth and progressively decreases with age. The second factor is gender. For reasons yet unknown, the ratio between skull size and brain size is different between adult men and women [18]. Other physical factors include CSF volume and brain water and electrolyte content. Physical factors may play an important role in adaptation to hyponatremia, particularly in small children and the elderly. In humans and laboratory animals, brain water content is more than 2.5 times higher in the young, decreasing progressively with advancing age [18]. In children, the ratio of brain to skull size is such that there is less room for expansion of the pediatric brain in the skull than there is in the adult [18]. Adult brain size is reached at about age 6, while full skull size is not reached until about age 16. Additionally, the intracerebral volume of CSF is more than 10% greater in the adult than in the young [18]. When brain swelling occurs, the intracerebral loss of CSF increases the available volume in which the brain can expand. Since the percentage of CSF in the brain increases with age, adults have more room in the rigid skull for the brain to expand than do children [18]. In neonatal rats and dogs with hyponatremia, the ability of the brain to adapt to hyponatremia is impaired [1]. The net result of the aforementioned physical factors is manifest in prepubescent children and menstruant women with hyponatremia [67]. When symptomatic hyponatremia occurs in either group, the morbidity and mortality are very high, largely because of the effects of physical factors and decreased ability of the brain to adapt [67].
Sodium, Water and Brain Cell Volume Regulation Disorders of water and sodium exert their most severe manifestations upon the brain. In general, hypo-osmolar states tend to result in brain swelling, while hyperosmolar states lead to brain shrinkage. To understand how these conditions can affect the central nervous system, it is first necessary to understand how the brain can defend itself against alterations in body water and electrolytes. The principal osmotically active constituents of brain consist of inorganic solutes (sodium and potassium) with a lesser role played by organic molecules [2, 55, 68–70]. Substantial evidence exists, both in humans and experimental animals, that there are several clinical situations where changes in plasma osmolality occur, but the apparent net loss or gain of cellular water and solute in brain does not account for the apparent change in tissue osmolality [71]. In these instances there may be: (a) inactivation of intracellular
Arieff
38
solute; (b) a gain in solute which is not the same as the usual commonly measured substances (urea, glucose, sodium, potassium, lactate). This undetermined solute has been called idiogenic osmoles. The brain undergoes osmotic adaptation to hyperosmolar states in a manner which is distinctly different from that of most other mammalian tissues. In clinical situations characterized by hypo-osmolality, the brain minimizes swelling by lowering its intracellular osmolality with extrusion of sodium, potassium, chloride and organic molecules [1, 55]. The lowering of brain osmolality in this manner prevents the influx of water which would lower brain osmolality at the expense of a gain in brain cell volume. In several different mammalian species, when hyponatremia is produced over periods of days to weeks, brain water content is normal to only slightly increased, and there is a markedly reduced cell content of both sodium and potassium [1].
Hyperosmolar States The response of the brain to hyperosmolality has been extensively studied, with hyperosmolality produced using either NaCl, glucose, mannitol, glycerol, ethyl alcohol, or urea [10]. It has been shown that the brain response depends on the type of solute accumulated. When hyperosmolality is caused by endogenous solutes, such as in hypernatremia or hyperglycemia, the increase in intracellular solute content necessary for osmotic equilibrium is largely accounted for by osmoles of undetermined nature (idiogenic osmoles) and to a lesser extent by increases in Na, K, and Cl and organic molecules [2, 72, 73]. Other potential idiogenic osmoles present in the brain of animals with hypernatremia include myoinositol, betaine, phosphocreatine and glycerophosphorylcholine, creatine, other methylamines, choline and taurine [68, 72]. However, the osmotic contributions of any of these organic compounds has not been determined. It is possible that idiogenic osmoles arise from the osmotic activation of some solutes normally bound to polyvalent anions and released in response to the increase in ionic strength. The speed of brain volume regulation in hyperosmolality seems to vary with the type of solutes which cause the hyperosmolality. It appears that the speed of volume regulation is similar during hyperglycemia and hypernatremia. In glucose-induced hyperosmolality (in rabbits), the brain volume is restored to normal within 4 h [10], similar to the findings after 4 h of NaCl-induced hyperosmolarity [2]. Rapid infusion of urea can cause brain dehydration because the equilibration of urea in the brain is relatively slow [74]. Although it takes less than 1 h for urea to equilibrate in skeletal muscle, it takes 4–10 h to reach equilibrium in the brain. In chronic uremia, despite the absence of a urea concentration gradient, there is substantial accumulation
Salt and Water Homeostasis
39
of idiogenic osmoles, suggesting that shrinkage of brain cells is not required for the formation of idiogenic osmoles. In contrast to chronic uremia [75], there is no accumulation of idiogenic osmoles in experimental acute uremia [76, 77].
Age-Related Changes in Sodium and Water Homeostasis Hypernatremia is a frequent problem in older patients [78]. Thus, changes which may occur in the physiological responses of the elderly to hypernatremia may be of particular interest in understanding the pathogenesis of hypernatremia in the elderly. If healthy elderly men are compared to younger controls there are differences in the response to 24 h of water deprivation [79]. In the older men, there are deficits in both the intensity and threshold of the thirst response to specific stimuli, and in the subsequent water intake which follows the thirst. The ability to produce a concentrated urine during water deprivation also declines with advancing age. This may be related to a relative increase in renal medullary blood flow which washes out medullary tonicity; increases in solute load per nephron (because of nephron dropout) resulting in an obligate osmotic diuresis; or impairment of renal tubular responsiveness to osmolalitymediated vasopressin release. Although there is an enhanced responsiveness to osmolality-mediated vasopressin release, there may be impaired responsiveness of vasopressin release to volume and pressure stimuli [79]. There is both a decline in glomerular filtration rate and an increased incidence of renal disease with advancing age, both of which may contribute to impaired ability to conserve water [80–82].
Diabetes insipidus The absence of ADH effect upon the kidney results in diabetes insipidus. Diabetes insipidus is a clinical condition characterized by decreased or absent renal effects of the hormone vasopressin, and it can be either nephrogenic or central in origin. Vasopressin is synthesized by the hypothalamus and is both stored and secreted by the posterior pituitary gland. In central diabetes insipidus, there is an impairment of either synthesis or release of vasopressin into the circulation. In nephrogenic diabetes insipidus, vasopressin is usually present in the circulation but the kidney response to the hormone is impaired or absent. Criteria for the diagnosis of diabetes insipidus include the presence of polyuria (urine output ?250 ml/h) with hypotonic urine (urine osmolality =100 mosm/kg) and thirst in the absence of osmotic diuresis (plasma osmola-
Arieff
40
lity is about =300 mosm/kg without elevations in plasma levels of impermiant solutes, such as glucose, mannitol, urea). The diagnosis of central diabetes insipidus can be established by the above findings plus the following: (a) before the onset of polyuria, patients were able to excrete a hypertonic urine (urine osmolality ?300 mosm/kg); (b) after several days of polyuria, when plasma is concentrated, the urine osmolality should remain =100 mosm/kg. At this time, vasopressin stimulation should be maximal and urine intensely concentrated; (c) no drugs have been administred, nor was there any medical condition present, which would predispose the patients to the development of nephrogenic diabetes insipidus; (d) findings by radiologic evaluation or autopsy should demonstrate hypothalamic/pituitary damage but normal kidneys and renal tubular function. Both central and nephrogenic diabetes insipidus can lead to hypernatremia and permanent brain damage [83]. In the syndrome of central diabetes insipidus, ADH is either not synthesized at all, or is not released into the circulation in quantities sufficient to maintain normal water balance. Complete diabetes insipidus is the inability to produce a urine of greater osmotic concentration that that of plasma under an appropriate osmotic stimulus. Patients with partial diabetes insipidus include those who can produce a urine hypertonic to plasma but whose ADH production is below normal. Conscious patients with diabetes insipidus do not become dehydrated unless they also have a thirst defect, a combination which may occur with stroke, hypothalamic disease or after hypothalamic surgery. Renal function is normal in pituitary diabetes insipidus. Mild serum hyperosmolality and increased sodium concentration may be the only laboratory abnormalities detectable. Unconscious patients manifest polyuria and hypernatremia with worsening dehydration. If ADH is absent but thirst is normal, the patient will drink sufficient water to prevent the serum sodium from rising but will manifest polyuria and polydipsia as well. If ADH secretion is normal and thirst is absent, the patient will become progressively dehydrated with hypernatremia and small volumes of concentrated urine unless he drinks deliberately (primarily hypodipsia). If ADH and thirst are both absent, the patient will become very dehydrated and will manifest hypernatremia. The extreme dehydration will eventually lead to a reduction of glomerular filtration rate (GFR) and the production of small volumes of concentrated urine. If ADH is partially deficient and thirst is normal, the patient will have a water diuresis with a normal plasma osmolality, leading to an eventual increase of plasma osmolality. This will provoke thirst and polydipsia (incomplete pituitary diabetes insipidus). If thirst is absent, the patient with partial diabetes insipidus will lose water and will not drink. The loss of water will raise serum sodium and osmolality to such a level that the quantity of ADH released is sufficient to permit the excretion of
Salt and Water Homeostasis
41
concentrated urine. This condition, sometimes described as ‘essential hypernatremia’ is usually caused by a hypothalamic lesion [17]. With nephrogenic diabetes insipidus, there is not an impairment of the ability to secrete vasopressin, but there is rather an impairment of the ability of the hormone to affect the kidney. Arginine vasopressin binds to the vasopressin V-2 receptor in the renal distal tubule (thick ascending limb of the loop of Henle) and collecting tubules. The V-2 receptor is coupled to an adenylate cyclase which generates cyclic AMP when stimulated. A number of pharmacological agents can lead to nephrogenic diabetes insipidus, and these include lithium, demethylchlortetracycline, methoxyflurane and certain hypoglycemia agents, such as glyburide [84]. Hypercalcemia can lead to nephrogenic diabetes insipidus [85], as can a number of renal interstitial disorders [83] and chronic lithium administration [86]. Diabetes insipidus is most commonly of undetermined cause and is occasionally familial. The familial form, which is probably due to atrophy of the nerve cells in the area of the hypothalamus where ADH is synthesized, may present at any age. When the etiology is known, it most often results from metastatic tumors (breast or lung), granulomas (including sarcoidosis) in the areas of the sella or hypothalamus, surgical interruption of the hypothalamicneurohypophyseal system, skull fractures, head trauma or cerebral vascular accidents. Cerebral hypoxemia is another cause of diabetes insipidus, where patients have cerebral encephalomalacia associated with severe brain damage secondary to clinical circumstances such as asphyxia, drug-induced respiratory failure, cardiac arrest or shock [87]. Diabetes insipidus has been infrequently reported after cerebral herniation complicating symptomatic hyponatremia [67, 88], or cerebral edema associated with diabetic ketoacidosis or nonketotic hyperosmolar coma [89]. In rare situations, clinical diabetes insipidus may not be apparent if both anterior and posterior pituitary cease to function, because glucocorticoid secretion may be impaired secondary to ACTH deficiency. The diabetes insipidus will become apparent only when glucocorticoid replacement therapy is given [84]. Diabetes insipidus is a well-recognized complication of blunt head trauma [83, 90, 91]. Delay in diagnosis can occur when head trauma does not appear to be severe or when the patient is admitted to a service other than neurosurgery. Detailed assessment of anterior pituitary function in patients with traumatic diabetes insipidus usually requires a delay until the patient is medically stable [92]. Generally these patients are initially treated with adrenal steroid therapy for cerebral edema, and detailed evaluation of endocrine function is often difficult to obtain. The diabetes insipidus caused by head trauma may persist for several years, and may become permanent if the patient does not recover within 4–6 months [91, 93].
Arieff
42
Diabetes insipidus with polyuria also may complicate pregnancy due to a physiologic decrease in osmostat sensitivity [94, 95]. There may also be increased vasopressin turnover due to placental vasopressinase [96]. In many cases, there is a relative deficiency of ADH which is unmasked by pregnancy, perhaps by placental vasopressinase [91].
Hyponatremia While diabetes insipidus generally occurs because of the absence of ADH effect upon the kidney, hyponatremia is usually associated with elevated plasma levels of ADH. Hyponatremia can be succinctly defined as an abnormally low plasma sodium concentration (lower than the mean value Ö2 SD). Although the kidney is important in the pathogenesis of hyponatremia, the target organ for changes which produce morbidity and mortality is the brain. Hyponatremia has few important sequelae or clinical manifestations other than those associated with the central nervous system. Hyponatremia is the most common electrolyte abnormality seen in a general hospital population, with an incidence and prevalence of about 1.0 and 2.5%, respectively [97]. The incidence of hyponatremia is similar among men and women, but brain damage occurs predominantly in young (menstruant) females and prepubertal individuals [67, 97]. Brain damage from hyponatremia is generally uncommon in men and older (postmenopausal) women [97]. It is now clear that brain damage from hyponatremia can be associated with either hyponatremic encephalopathy or improper therapy of symptomatic hyponatremia. Clinical evidence suggests that the vast majority of brain damage from hyponatremia (?95%) is associated with untreated hyponatremic encephalopathy [98], and occurs primarily in a limited number of clinical settings [99]. These include: (a) the postoperative state; (b) polydipsiahyponatremia syndrome; (c) pharmacologic agents; (d) congestive heart failure; (e) acquired immunodeficiency syndrome (AIDS); (f) hepatic insufficiency, and (g) malignancy (fig. 1). Clinical Manifestations of Hyponatremia The clinical signs and symptoms of hyponatremia are directly related to the development of cerebral edema, increased intracellular pressure and cerebral hypoxia. Neurological manifestations of hyponatremia may be observed when the plasma sodium is =130 mM. Early symptoms of hyponatremia from any cause may include apathy, weakness, muscular cramps, nausea, vomiting and headache. The type of symptoms vary enormously among individuals, and no individual is likely to have all ascribed symptoms. More advanced clinical manifestations are shown in table 1. In general, symptoms are more severe
Salt and Water Homeostasis
43
250,000
25,000
Hepatic cirrhosis (n = 2,500)
Cancer (n = 2,500
Schizophrenia (n = 25,000)
Postoperative (n = 250,000)
3,000
Heart failure (n = 400,000)
Num ber of patients/year
400,000
Fig. 1. The clinical causes of hyponatremia which are likely to be associated with death or permanent brain damage. Of the five causes, only in the case of postoperative hyponatremia is there solid epidemiologic data. The other causes are estimated from the current literature. There is not enough data in the current literature to estimate the incidence of hyponatremia associated with AIDS, diuretic therapy or hyponatremia-polydipsia syndrome.
and occur at a higher level of serum sodium in younger women (age 16–49) than in either men or older women (fig. 2) [99]. Patients with chronic hyponatremia are said to have less severe symptoms and a lower morbidity and mortality [100]. However, in most clinical situations, it is very difficult to determine the duration of the hyponatremia, and the separation may in fact be largely artificial [101]. In several clinical situations, the underlying diseases associated with chronic hyponatremia – congestive heart failure, hepatic cirrhosis – are of such severity that the associated morbidity is substantially higher. Since chronic hyponatremia is more common in both men and elderly women, the less severe symptoms may be due not so much to the duration of the hyponatremia as to the age, sex and hormonal status of the patients. Young women are not prone to many of the disorders which may be associated with chronic hyponatremia, such as congestive heart failure and hepatic insufficiency. Postoperative Hyponatremia Postoperative hyponatremia is a common clinical problem in the USA and Western Europe, with an occurrence of about 1% [97, 98], or about 250,000
Arieff
44
Table 1. Clinical manifestations of hyponatremic encephalopathy Early1
Anorexia Headache Nausea Emesis Muscular cramps Weakness
Advanced1
Impaired response to verbal stimuli Impaired response to painful stimuli Bizarre (inappropriate) behavior Hallucinations (auditory or visual) Asterixis Obtundation Incontinence (urinary or fecal) Respiratory insufficiency
Far advanced1
Decorticate and/or decerebrate posturing Bradycardia Hyper- or hypotension Altered temperature regulation (hypo- or hyperthermia) Dilated pupils Seizure activity (usually grand mal) Respiratory arrest Coma Polyuria (secondary to central diabetes insipidus)
1 Any manifestation may be observed at any stage, and some patients will have only minimal symptoms.
cases/year in the USA, with an overall morbidity of approximately 5% [98] (fig. 3). In the vast majority of cases, the patients tolerated the surgery without complications, being able to walk, talk and eat after surgery before symptoms of encephalopathy developed. Initial symptoms are usually quite mild (table 1). Because these symptoms are somewhat nonspecific, they are often mistakenly attributed to routine postoperative sequelae. However, if the symptoms are due to hyponatremia and left untreated, the patient may progress to more advanced manifestations (table 1) [88, 102]. Thus, symptomatic hyponatremia in postoperative patients is particularly dangerous and should be promptly treated. In this setting, premenopausal women are particularly at risk of developing hyponatremic encephalopathy and respiratory insufficiency when compared to men and postmenopausal women [97] (fig. 2). Additionally, respiratory arrest occurs at a significantly higher plasma sodium level in menstruant
Salt and Water Homeostasis
45
140
] p < 0.001
Serum sodium (m m ol/l)
130
] p < 0.001
120
110
100 111
110
117
109
117
107
M en (n = 43)
PW (n = 14)
M W (n = 48)
PW (n = 30)
M W (n = 45)
PW (n = 24)
90
80 Headache, nausea em esis only
Seizures, respiratory failure
Death or incapacitation
Fig. 2. The plasma sodium in 136 patients with hyponatremic encephalopathy. The men and postmenopausal women (PW ) with headache, nausea and emesis only, did not progress to respiratory failure. We have observed less than 10 menstruant women (MW) with headache, nausea and emesis who did not progress to respiratory failure and these are not included because of the small sample. The plasma sodium in menstruant women who progressed to respiratory failure or permanent brain damage was significantly higher (p=0.001) than that of postmenopausal women who progressed to respiratory failure or permanent brain damage. The plasma sodium in menstruant women who progressed to respiratory failure or permanent brain damage was also significantly higher (p=0.001) than that of either men or postmenopausal women who had headache, nausea and emesis only (p=0.01). We have observed less than 10 men (all age groups) with headache, nausea and emesis who progressed to either respiratory failure, death or permanent brain damage and these are not included because of the small sample size. The data is presented as the mean×2 SD. Figure modified from Fraser and Arieff [99].
women than in postmenopausal women (fig. 2). Although the frequency of permanent brain damage from hyponatremia following elective surgery is not known, recent studies suggest a morbidity of about 20% in patients with encephalopathy [98] (fig. 3). Polydipsia-Hyponatremia Syndrome Another common setting in which symptomatic hyponatremia can occur is with polydipsia. The polydipsia-hyponatremia syndrome (frequently known
Arieff
46
Num ber of patients/year
25 m illion
250,000
50,000
25,000
10,000 Total surgeries in the USA
Postoperative hyponatrem ia
Hyponatrem ic encephalopathy
Hyponatrem ic brain dam age or death
Fig. 3. The mortality associated with postoperative hyponatremia in the USA. Among 25 million inpatient surgical procedures per year in the USA (including cesarian section but excluding uncomplicated in-hospital childbirth), the incidence of hyponatremia is about 1%. Among patients with postoperative hyponatremia, about 20% develop hyponatremic encephalopathy, of whom about 20%, or about 11,000, do not survive. Data extracted from Ayus et al. [97].
as psychogenic polydipsia) occurs primarily in individuals who have either schizophrenia, bipolar disorder [103] or certain eating disorders [104]. The average daily solute intake is about 1,000 mmol/day and if the kidney can elaborate a maximally dilute urine (=100 mosm/kg), the normal individual should theoretically be able to excrete in excess of 20 l/day. To lower plasma sodium to =120 mmol/l requires retention of ?80 ml/kg of water, so that to develop hyponatremia in the absence of elevated plasma levels of ADH requires ingestion of ?20 l/day in a 60-kg adult. Most patients with polydipsia-hyponatremia syndrome have actually ingested less water than theoretically required. Instead, they have less fluid intake but both abnormal urinary diluting capacity and elevated plasma ADH levels [103, 105, 106]. Beer potomania is a variation of polydipsia-hyponatremia syndrome, where the hyponatremia is associated with poor nutrition and massive ingestion of beer instead of water [42]. Primary polydipsia has been reported in almost all age groups, from the very young to the elderly. Symptoms of drug-induced primary polydipsia can often be mistaken for symptoms stemming from nonrelated psychiatric disorders (confusion, hallucinations, bizarre behavior). Accurate diagnosis of
Salt and Water Homeostasis
47
symptoms stemming from drug-induced polydipsia and symptomatic hyponatremia may therefore be challenging. The clinical picture may be further complicated when the patient is taking phenothiazines or tricyclic antidepressants, which may increase ADH release, or diuretics, which can interfere with renal water excretion [107–117]. Such patients may ingest excessive quantities of water, which can lead to symptomatic hyponatremia. The mainstay of therapy of polydipsia is water restriction and treatment of underlying reversible causes of the disease. Such causes include drugs, certain psychiatric or neurologic disorders, hypercalcemia and potassium depletion (resulting in nephrogenic diabetes insipidus). However, these patients are very adept at obtaining water, even under well-controlled circumstances, and their psychiatric disturbances may not easily be amenable to therapy. Congestive Heart Failure The most common cause of hyponatremia in the USA is congestive heart failure with an incidence of about 400,000 per year (fig. 1) [118]. The pathogenesis of the hyponatremia is complex and may include activation of vasoconstrictor hormones, thirst stimulation, diuretic therapy, impaired renal water excretion, high plasma ADH levels, and elevated plasma renin activity. The 1-year mortality among patients with congestive heart failure exceeds 50%, although an undetermined number of these actually die from hyponatremia. Although the mortality from hyponatremia among patients with heart failure is thus difficult to estimate, there are many reported deaths and a low plasma sodium is of major prognostic importance [47]. Recent studies suggest that the renin-angiotensin system is of major importance in the pathogenesis of hyponatremia in patients with heart failure, and that both the hyponatremia and long-term outcome can be improved by converting-enzyme inhibition [118]. However, converting-enzyme inhibition also improves survival in patients with heart failure without hyponatremia [119], and addition of frusemide is often required. Pharmacologic Agents A number of pharmacologic agents may interfere with the ability of the kidney to excrete free water. Included are large numbers of sedatives, hypnotics, analgesics, oral hypoglycemic agents, tranquilizers, narcotics, antineoplastic drugs, antidepressant agents and diuretics [43]. In most such instances, there is excessive net retention of ingested or infused free water. Those diuretics most commonly associated with hyponatremia are thiazides and ‘loop’ diuretics [107, 108, 120–122]. In patients with thiazide-associated hyponatremia, there may be an idiosyncratic reaction to the drug, resulting in massive acute losses of sodium and potassium in the urine, often with associated polydipsia [123].
Arieff
48
Acquired Immunodeficiency Syndrome (AIDS) AIDS is a major cause of hyponatremia in the USA [124]. The hyponatremia in patients with AIDS may be secondary to SIADH, volume deficiency with hypotonic replacement fluids, or adrenal insufficiency [125, 126]. Even in the presence of mineralocorticoid deficiency, glucocorticoid function may be intact, resulting in a normal ACTH stimulation test. Adrenal insufficiency is particularly suspect in hyponatremic AIDS patients who have disseminated cytomegalovirus or tuberculosis [127]. Therapy with fludrocortisone acetate is indicated only if adrenal insufficiency is documented in hyponatremic patients with renal salt-wasting [126]. Current data strongly suggests that patients who have AIDS and hyponatremia have both a higher mortality and longer duration of hospitalization than those who are normonatremic [128]. However, with such a virulent disease as AIDS, it is difficult to determine the exact role of hyponatremia in the associated morbidity. Hepatic Insufficiency Hyponatremia is a common disorder in patients with liver disease and it is almost always associated with excessive retention of free water. Regardless of the volume status in such patients, the total body exchangeable cation (potassium+sodium) is ‘diluted’ by relatively greater amounts of total body water [48]. Even in the setting of hypo-osmolality, ADH levels, which are normally suppressed, are not [129]. Hyponatremia is a major risk factor among patients with hepatic insufficiency, although it is unclear if the hyponatremia actually increases the mortality, or is merely a marker for more severe degrees of hepatic insufficiency. The best therapy for hyponatremia in patients with liver disease is prevention by judicious monitoring of serum electrolytes, fluid balance and response to diuretic therapy. Discontinuation of diuretics and restriction of water intake will improve hyponatremia, but the response is generally slow, usually =2 mmol/l/day. A major new advance may be the use of aquaretic agents in the therapy of patients with cirrhosis, ascites and hyponatremia [130]. Such agents include vasopressin V-1 and V2 receptor blockers and -opioid antagonists, although none of these agents are currently available for clinical use [130–134]. Patients with hyponatremia and cirrhosis often have concomitant cerebral edema [135–138], and could thus potentially benefit from blockade of both V-1 and V-2 vasopressin receptors. Among patients with hepatic insufficiency who have undergone liver transplantation, postoperative hyponatremia carries a prohibitive mortality [139]. Cerebral demyelinative lesions are frequent in such patients, and appear to be related to upward changes in the plasma sodium concentration. Thus, patients with hepatic insufficiency, particularly those who have undergone liver transplantation, are at greatly increased risk for development of cerebral demyelinative lesions [140, 141].
Salt and Water Homeostasis
49
There is not a consensus of opinion regarding the optimal method or rate of correction of symptomatic hyponatremia in patients with liver disease. There is substantial clinical evidence that correction of severe symptomatic hyponatremia to mildly hyponatremic levels in nonalcoholic patients does not usually result in cerebral demyelinating lesions, such as central pontine myelinolysis. However, there is only limited data available in patients with liver disease, and data in patients who have undergone liver transplantation suggests that any increment of plasma sodium, whether such patients are hyponatremic or not, is potentially dangerous [139–141]. Recent studies suggest that the major determinants of the occurrence of permanent brain damage in patients with liver disease and hyponatremia include at least four factors [48, 142]: (a) the occurrence of a hypoxic episode (arterial pO2 =75 mm Hg); (b) correction of serum sodium ?128–132 mmol/l within the initial 48 h of therapy; (c) elevation of serum sodium by ?25 mmol within the initial 24–48 h of therapy; (d) the presence of hypernatremia (serum sodium ?145 mmol/l) in patients with liver disease receiving lactulose. The mortality in patients who have both liver disease and serum sodium =120 mmol/l accompanied by central nervous symptoms is probably ?40% [48]. Malignancy-Associated Hyponatremia A major group of patients with asymptomatic hyponatremia and normal to slightly expanded extracellular volume are those who have a malignancy which secretes a peptide having actions similar to ADH, although some tumors actually secrete ADH [45, 143]. The most common such malignancy associated with SIADH is lung cancer, particularly oat cell bronchogenic carcinoma, although a large number of malignancies may be associated with elaboration of ADH [43]. It is difficult to even estimate the mortality of hyponatremia associated with malignancy, because most patients eventually die of the primary disease. Management of Hyponatremia The management of hyponatremia may be broadly divided into four groups: (a) active (usually hypertonic NaCl intravenously); (b) passive (usually water restriction); (c) supportive modalities (respiratory support, diuretics, intubation), and (d) antagonism of effects of ADH on the kidney, using demeclocycline, lithium or vasopressin V-2 receptor antagonists. The most important decision is whether to treat a patient in a passive manner (water restriction being the cornerstone of such therapy) or if there is a need for active therapeutic intervention (infusion of hypertonic NaCl (500–850 mM NaCl), either with or without a loop diuretic). The decision should be primarily based upon the presence or absence of neurologic symptomatology.
Arieff
50
In patients whose hyponatremia is asymptomatic, active therapy is not indicated. If the patient is volume depleted, isotonic (154 mM) NaCl is usually the fluid of choice. If there is a hormone deficiency (adrenal, thyroid) appropriate replacement is indicated. If the patient has received a drug which may interfere with renal handling of sodium or water, the drug should be discontinued whenever possible. Although water restriction can theoretically be of benefit in some of these disorders, practical considerations diminish its usefulness. There are several medical regimens for the long-term management of patients with stable asymptomatic hyponatremia. Demeclocycline, a tetracycline antibiotic, in doses ?600 mg/day, can be effectively used to produce a state of nephrogenic diabetes insipidus and has been successful in treating patients with SIADH [43]. The most important measures for the management of at-risk patients are prophylactic. Every hospitalized patient in the four groups discussed above should be considered at risk for the development of hyponatremia, and appropriate measures undertaken. The most important measure is the avoidance of intravenous hypotonic fluid to hospitalized patients. Other important procedures include monitoring of daily electrolytes, weight and strict fluid input and output. Symptomatic hyponatremia is a medical emergency, with a morbidity in excess of 15% [98]. In patients with hyponatremic encephalopathy, the preponderance of clinical evidence demonstrates that correction by water restriction results in an unacceptable morbidity and mortality. Among surviving patients with hyponatremic encephalopathy and brain damage, the morbidity is substantial (fig. 4). Patients with hyponatremic encephalopathy should be constantly monitored, preferably in an intensive care unit. The first step in management of such patients is a secure airway, with assisted ventilation if required. Therapy should be initiated with intravenous hypertonic sodium chloride (514 mmol/l) using an infusion pump, with the infusion designed to raise plasma sodium at a rate of about 1 mmol/l/h. If the patient is actively seizing or has other clinical evidence of increased intracranial pressure, then the rate of hypertonic fluid administration should be adjusted to elevate plasma sodium by about 4–5 mmol/l/h over the first hour. Therapy with hypertonic NaCl should be discontinued when either: (a) the patient becomes asymptomatic; (b) the patient’s plasma sodium has increased by 20 mmol/l, or (c) the plasma sodium reaches a value in the range of 120–125 mmol/l. While active correction of symptomatic hyponatremia is in progress, monitoring of plasma electrolytes should be carried out every 2 h, until the patient has become neurologically stable. In addition to hypertonic NaCl, therapy should include supportive measures when required. The plasma sodium should never be acutely elevated to hyper- or normonatremic levels, and should not be elevated ?25 mmol/l during the initial 48 h of therapy [142]. The technique has been described in detail elsewhere [43].
Salt and Water Homeostasis
51
80
60 50 40
73
30
Independent living capacity decreased
Death
4
4
1
1 Deaf
8
0
Blind
8 Persistent vegetative state
10
M ental capacity decreased
20
Lim b paralysis
Percent of patients
70
Fig. 4. The neurologic sequelae in 143 patients who had hyponatremic encephalopathy and died or developed permanent brain damage. The patients are the same ones as shown in figure 5.
There are possible complications of the therapy of hyponatremia although therapy is usually not an important factor in the genesis of permanent brain damage because the vast majority of patients who have developed such complications have not been treated [88, 98]. It had been suggested that the development of cerebral demyelinating lesions might somehow be related to the correction of hyponatremia [43]. However, the risk factors for improper therapy have now been well defined [142]. Cerebral demyelinating lesions develop only when patients with hyponatremia (a) are inadvertently made hypernatremic during treatment; (b) have an absolute increase in plasma sodium which is ?25 mmol/l in the first 24–48 h of therapy; (c) suffer a hypoxic event, or (d) have severe liver disease [139, 142, 144]. On the other hand, there is overwhelming evidence that treatment of symptomatic hyponatremia with hypertonic NaCl is associated with recovery and survival [43].
Hypernatremic States Hypernatremia can be succinctly defined as an abnormally high concentration of plasma sodium (higher than the mean+2 SD). Because sodium with
Arieff
52
its accompanying anions comprises the great majority of osmoles in the plasma, hypertonicity always accompanies hypernatremia. However, a hyperosmolar state can exist in the absence of hypernatremia if another solute (such as glucose or urea) is present in excessive amounts. The subjects of uremia [77], hyperglycemic nonketotic hyperosmolar coma and diabetic keotacidosis, are discussed in detail elsewhere and will not be covered here [10, 145]. Brain Adaptation to Hypernatremia Adaptation of the brain to hypernatremia determines survival, and a rapid increase of plasma sodium without the brain having an opportunity to adapt usually leads to permanent brain damage. The response of excitable cells (central nervous system) to a hyperosmolar external fluid can be described as follows. Initially the cells shrink due to osmotic water abstraction, but ultimately the cells nearly regain water by virtue of a combination of net solute uptake and generation of solute de novo. Several important differences exist in the response of brain cells versus those of other tissues, such as skeletal muscle and kidney. These are mainly in the types and quantity of solutes which accumulate within the cells as well as the mechanisms by which they accumulate [70]. There is some uptake of electrolytes (sodium and potassium) during adaptation of the rat brain to hypernatremia [2]. However, while regulatory increases in brain cell volume occur largely due to increases in brain cell content of monovalent cations, these are not the only solutes which accumulate during regulatory increases in brain cell volume. Recent studies have provided good support for the notion that organic compounds account for some of the increase in total brain osmoles [2, 72]. Studies of hypernatremia have shown that over the course of 7 days, water content of the brain decreases by approximately 10% but ultimately recovers to within 98–99% of control [2]. This is largely accompanied by an increase in brain solute content. Most of this increase is accounted for by inorganic ions (Na+, K+, Cl), amino acids, other organic molecules and undetermined solute. Recent studies suggest that much of the undetermined solute may in fact be organic molecules which include glutamine, glutamate, myo-inositol, phosphocreatine, glycerophosphorylcholine, choline, betaine, and taurine [72, 73]. Hypernatremia in fact results in up-regulation of Na+/myo-inositol cotransporter transcription in the brain [146, 147]. The increase in undetermined solute begins after about 1 h of hypernatremia and changes very little during 4 h to 1 week of hypernatremia [2]. The increase in undetermined solute serves to protect brain cell volume from further dehydration. However, this initial protective effect may eventually become deleterious during correction of hypernatermia if the plasma sodium is somehow decreased at a more rapid rate than the brain is able to dissipate
Salt and Water Homeostasis
53
the idiogenic osmoles. During treatment of experimental hypernatremia, brain edema may develop despite a significant decrease in brain content of (sodium+ potassium), due to failure of amino acids and idiogenic osmoles to dissipate [2]. Causes of Hypernatremia The causes of hypernatremia in children and adults have recently been reviewed [148]. There are a number of medical conditions which are commonly associated with hypernatremia, the etiology of which are quite different in children and adults. In infants, gastroenteritis with diarrhea is the most common cause of hypernatremia [149, 150]. Small children may also become hypernatremic after accidental administration of a high solute load, particularly accidental substitution of NaCl for sugar in preparation of formula feeds or improper dilution of concentrated formulas. In adults, common causes of hypernatremia include nasogastric hyperalimentation, nonketotic hyperosmolar coma, dehydration secondary to either fever or elevated ambient temperature, sodium bicarbonate administration, diabetes insipidus and the postoperative state [81]. Generally, diabetes insipidus is associated with hypernatremia only under circumstances where the patient is unable to freely obtain water or when the lesion responsible for the diabetes insipidus results in a decrease in thirst. Excessive administration of hypertonic solutions of sodium bicarbonate to critically ill patients suffering cardiac arrest or lactic acidosis has been associated with a dangerously elevated plasma osmolality and infrequent survival [151]. Severe hypernatremia has also been observed in patients inadvertently receiving intravenous hypertonic NaCl for therapeutic abortion [152, 153]. Clinical Manifestations of Hypernatremia The signs and symptoms of hypernatremia are variable. In experimental hyperosmolality, findings include nystagmus, myoclonic jerking of the extremities, severe weight loss, decreased food intake, and ultimately respiratory failure and death [2]. In human subjects, pre-existing abnormalities of mental status may make it difficult to detect any new neurological findings. In addition, since hypernatremia frequently occurs in the setting of a coexistent pathologic process, it may be difficult to ascribe any particular symptom or group of symptoms to hypertonicity per se. In children, there may be alternating periods of lethargy and irritability. A history compatible with gastroenteritis is frequently obtained, and may be the cause of the hypernatremia; conversely, nausea and vomiting are often seen even in the absence of diarrhea. Associated abnormalities include metabolic acidosis, hyperglycemia and weight loss [2, 150, 154].
Arieff
54
In the elderly some important differences exist [81]. When considering only patients who were hypernatremic at the time of hospital admission, women were predominant. Although nearly half the hypernatremic patients had a febrile illness, other associated conditions assume more prominence than in infants. These include the postoperative state, diuretic administration, excessive intravenous solute administration (including nutritional supplements), mental illness and diabetes mellitus as the leading causes [78, 155]. Depression of the sensorium is frequently present and is highly correlated with the degree of hypernatremia. Altered mental status is also an independent predictor of subsequent mortality at any level of hypernatremia [78, 81]. Morbidity and Mortality of Hypernatremia Hypernatremia is associated with considerable long-term morbidity and mortality both in children and adults. Most studies in children report morbidity and mortality figures of 14–70%, with survivors of hypernatremia having a 10–15% likelihood of having permanent neurological deficits. In adults, the figures are similar. In the older literature, the mortality in adults with hypernatremia was consistently found to exceed 50% [149, 156, 157]. In the aforementioned studies, most of the patients had severe associated medical disorders, such as stroke, diabetic coma, pneumonia, and head injury. In addition, there was not a control population for comparison. In a more recent study, the mortality in 162 elderly patients with hypernatremia was found to be 42%, versus the mortality in 4,853 patients in a control population of only 6% [81]. Neurological morbidity, as assessed by changes in level of care, was present in 38% of the survivors [81]. Permanent brain damage in patients who recover from hypernatremia has been reported for over 40 years [156, 158], and may be related to the recent findings of permanent brain damage in experimental animals with hypernatremia [2]. The mortality of about 50% in adult patients with hypernatremia may be related to cachexia and weight loss [159], which are often associated with hypernatremia [150, 160, 161]. The mortality in excess of 40% has recently been confirmed by several additional large studies of adults with hypernatremia [78, 155, 161]. One especially noteworthy finding in several of these series was the fact that mortality was higher in patients whose hypernatremia developed in the hospital [78, 81, 155, 161]. This finding has been attributed to a more complicated clinical setting and delayed recognition of hypertonicity in hospitalized subjects. Essential Hypernatremia The initial descriptions of the syndrome of essential hypernatremia included the following elements: (a) asymptomatic chronic hypernatremia, (b) clinical euvolemia, (c) hypodipsia, (d) partial central diabetes insipidus,
Salt and Water Homeostasis
55
and (e) absence of nephrogenic diabetes insipidus. In more physiologic terms, essential hypernatremia is a disorder of osmoregulation where the regulatory systems (ADH and thirst) are at least partially responsive to osmolar and volumetric stimuli. In the steady state, patients are hypernatremic, euvolemic (by the usual clinical evaluation), and asymptomatic (absence of thirst). By definition, if the plasma osmolality is substantially elevated, this steady state represents an upward resetting of the osmolar set-point for ADH release and probably of the osmolar threshold for thirst perception (if the steady-state plasma osmolality is about ?294 mosm/kg). Volumetric stimuli for ADH release and for thirst perception must operate at normal or near-normal settings to maintain clinical euvolemia. Thus, the syndrome of essential hypernatremia is the hyperosmolar counterpart of the syndrome of ‘reset osmostat’. In the latter syndrome, asymptomatic euvolemic hyponatremia is maintained with a decreased osmolar set-point for ADH release and a decreased osmolar threshold for thirst. Hypernatremia and Liver Disease A group of adult patients in which the entity of hypernatremia with its attendant sequelae is not appreciated are chronic alcoholic subjects with endstage liver disease who present with fulminant liver failure and hepatic encephalopathy [162]. Such patients are often treated with oral lactulose as therapy for their hepatic encephalopathy. Hypernatremia may complicate such therapy [162]. Patients with lactulose-associated hypernatremia had a mortality of 87 vs. 60% in those patients who did not develop hypernatremia. Hypernatremia in patients with severe liver disease may be quite a common occurrence after therapy with intravenous osmotic diuretic agents or oral lactulose [162]. The hypernatremia is associated with a high mortality and appears to be directly related to a negative free water balance. Patients with liver disease who develop hypernatremia are particularly susceptible to the development of cerebral demyelinating lesions [142]. Treatment of Hypernatremia The goal of therapy in hypernatremia is the reduction of plasma osmolality towards normal by the administration of free water in excess of solute. Hypernatremia is uncommonly associated with administration of excessive quantities of NaCl but when such a situation is present, removal of solute must be considered. Removal of solute is usually accomplished by dialysis. When water administration is planned, the major therapeutic questions are the type and quantity of fluid to be given. In adult patients with hypernatremia, although 280 mmol/l dextrose in water has commonly been utilized, this therapeutic modality has recently come into question.
Arieff
56
Patients with hypernatremic dehydration should be treated with fluid which provides free water in excess of electrolytes. In both children and adults, fluid therapy is usually calculated so as to be administered over a period of about 48 h. Despite such recommendations, little data in humans or animals is available as to the ideal rate of fluid administration. Fatal cases of cerebral edema, as well as permanent brain damage, have occurred when hypernatremia was completely corrected within 24 h, while seizures with cerebral edema occur in ?50% of hypernatremic rabbits when plasma sodium is reduced from 185 to 142 mmol/l in 4 h. The pathophysiology of cerebral edema complicating rapid (=24 h) correction of experimental hypernatremia (in rabbits) has recently been described [2]. These studies highlight the dangers of overly rapid correction of hypernatremia. In addition, recent information suggests that therapy of hypernatremia with glucose-containing solutions (280 mM glucose/ H2O) may lead to cerebral intracellular lactic acidosis [163], with increased mortality [154]. Current recommendations for treatment of chronic hypernatremia in adults, when the hypernatremia is primarily due to water loss, are: (1) If there is evidence of circulatory collapse, the patient should receive initial resuscitation with colloid, such as plasma or a plasma substitute, rapidly enough to correct shock and stabilize the circulatory system. (2) Fluid deficit should be estimated on the basis of serum sodium, body weight and total body water. The deficit should be given over a 48-hour period, aiming for a decrement in serum osmolality of approximately 1–2 mosm/l/h. Maintenance fluids, which include replacement of urine volume with hypotonic fluid, are given in addition to the deficit. (3) Hypotonic fluid should be administered. The usual replacement fluid will be 77 mmol/l NaCl. In general, solutions containing glucose should be avoided if possible. (4) Plasma electrolytes should be monitored at frequent intervals, usually about every 2 h. It should be stressed that many adult patients with hypernatremia have serious underlying systemic illness, such as stroke, dementia, infection or head trauma. Many such patients appear to die of their underlying illness, rather than of hypernatremia per se. Close attention should be given to the treatment of associated medical conditions. (5) If the hypernatremia is secondary to excessive loss of other body fluids, the replacement fluid should be similar to the fluid actually lost. The ideal treatment of hypernatremia represents a balance between free water administration and solute (sodium) excretion. If hypernatremia is associated with an excess of total body sodium [151, 153, 164, 165], removal of sodium can be accomplished with diuretics or dialysis. Infusion of glucosecontaining fluids can be associated with intracellular lactic acidosis, and they should be avoided if possible. Overzealous correction can be accompanied by
Salt and Water Homeostasis
57
642,000
Incidence
Num ber of patients
600,000
M ortality
500,000 312,000
400,000 250,000
300,000 200,000 100,000 0
80,000 40,000
13,000
Hypernatrem ia Hyponatrem ia
25,000
Pulm onary edem a
78,000
Com bined
Fig. 5. The incidence and mortality of the three major postoperative fluid and electrolyte complications in the USA – hypernatremia, hyponatremia and pulmonary edema. More than 640,000 individuals are affected, with a mortality of 78,000 per year. The data is extracted from Rosenthal and Arieff [51].
rehydration seizures which are probably due to acute cerebral edema from brain cellular water uptake [2, 166, 167].
Sodium and Water Complications in the Postoperative Patient A number of fluid and electrolyte complications may occur in postoperative patients. These include hyponatremia, hypernatremia, pulmonary edema, hypokalemia, hypocalcemia, metabolic alkalosis, metabolic acidosis and magnesium depletion. These complications are discussed in this chapter (see above) and elsewhere [51, 148, 168]. Three of these postoperative disorders, hyponatremia, hypernatremia and pulmonary edema, account for in excess of 75,000 deaths per year in the USA (fig. 5). Pulmonary edema is a well-known postoperative complication [169], but the incidence and mortality are not known [50, 170, 171]. Although the usual clinical manifestations of pulmonary edema are well known, the presentation of postoperative pulmonary edema is poorly appreciated. There are several possible etiologic factors which may lead to postoperative pulmonary edema, including pre-existing heart disease [171]. The most common sequence would be fluid overload resulting in high hydrostatic pressures and left ventricular dysfunction [169, 172], particularly in patients who have suffered an intraoper-
Arieff
58
ative myocardial infarction [173]. The differential would include neurogenic (noncardiogenic) pulmonary edema secondary to postoperative hyponatremic encephalopathy [102]. Postoperative pulmonary edema has been a reported complication in generally healthy postoperative subjects receiving known amounts of intravenous fluids [51]. The incidence of pulmonary edema is uncertain, but in a generally elderly, mostly male population (83, 958 patients), the incidence of postoperative pulmonary edema was 2.3% [171], while in 14,707 generally young female patients, following hysteroscopic hysterectomy, the incidence was about 0.2% [174]. Extrapolation to the 25 million noncardiac surgeries performed annually in the USA [173, 175] suggests an incidence in excess of 300,000 per year, with a projected annual mortality [176] in excess of 25,000.
References 1
2 3 4
5 6 7
8 9 10
11 12
13
14
Arieff AI, Kozniewska E, Roberts T, Vexler ZS, Ayus JC, Kucharczyk J: Age, gender and vasopressin affect survival and brain adaptation in rats with metabolic encephalopathy. Am J Physiol 1995;268: R1143–R1152. Ayus JC, Armstrong DL, Arieff AI: Effects of hypernatraemia in the central nervous system and its therapy in rats and rabbits. J Physiol (Lond) 1996;492:243–255. Levinsky NG: Sodium and water; in Isselbacher KJ, Braunwald E, Wilson JD (eds): Harrison’s Principles of Internal Medicine. New York, McGraw-Hill, 1994, pp 242–248. Bakris GL, Stein JH: Sodium metabolism and maintenance of extracellular fluid volume; in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1995, pp 29–50. Prothro JW, Rosenbloom CA: Body measurements of black and white elderly persons with emphasis on body composition. Gerontology 1995;41:22–38. Aloia JF, Vaswani A, Ma R, Flaster E: Aging in women – The four-compartment model of body composition. Metabolism 1996;45:43–48. Park R, Guisado R, Arieff AI: Nutrient deficiencies in man and animals: Water; in Rechcigl M Jr (ed): CRC Handbook of Nutrition and Food. Section E, Nutritional Disorders. West Palm Beach, CRC Press, 1978, pp 363–400. Oh MS, Carroll HJ: Regulation of intracellular and extracellular volume; in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1995, pp 1–28. Landis EM, Pappenheimer JR: Exchange of substances through the capillary walls; in Hamilton WF (ed): Handbook of Physiology. Washington, American Physiological Society, 1963, p 961. Arieff AI, Guisado R, Lazarowitz VC: Pathophysiology of hyperosmolar states; in Andreoli TE, Grantham JJ, Rector FC Jr (eds): Disturbances in Body Fluid Osmolality. Bethesda, American Physiological Society, 1977, pp 227–250. Gennari FJ: Serum osmolality. N Engl J Med 1984;310:102–105. Arieff AI, Kleeman CR, Kerian A, Bagdoyan H: Cerebral edema in diabetic comas. II. Effects of hyperosmolality, hyperglycemia and insulin in diabetic rabbits. J Clin Endocrinol Metab 1974;38: 1057–1067. Arieff AI, Kleeman CR, Keushkerian A, Bagdoyan H: Studies on mechanisms of cerebral edema in diabetic comas. Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. J Clin Invest 1973;52:571–583. Forbes GB, Lewis AM: Total sodium, potassium and chloride in adult man. J Clin Invest 1956; 35:596–605.
Salt and Water Homeostasis
59
15
16
17
18 19 20
21 22 23 24 25
26
27 28 29 30
31 32
33 34 35 36 37
Moses AM, Blumenthal SA, Streeten DHP: Drugs and water metabolism; in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1985, pp 1145–1158. McKinley MJ, Allen A, Congiu M, et al: Central integration of osmoregulatory vasopressin secretion, thirst and sodium excretion; in Crowley AW, Laird JF, Ausiello DA (eds): Vasopressin: Cellular and Integrative Functions. New York, Raven Press, 1988, pp 185–192. Zerbe R, Robertson G: Osmotic and nonosmotic regulation of thirst and vasopressin secretion; in Narins RG (ed): Clinical Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1994, pp 81–100. Gur RC, Mozley PD, Resnick SM, et al: Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci USA 1991;88:2845–2849. Share L: Control of vasopressin release: An old but continuing story. News Physiol Sci 1996;11: 7–13. Moal ML, Mormede P, Stinus L: The behavioral neuroendocrinology of arginine vasopressin, adrenocorticotropic hormone, and opioids; in Nemeroff CB (ed): Neuroendocrinology. Boca Raton, CRC Press, 1992, pp 365–396. Phillips PA, Abrams JM, Kelly J, et al: Localization of vasopressin binding sites in rat brain by in vitro autoradiography using a radioiodinated V1 receptor antagonist. Neuroscience 1988;27:749–761. Faraci FM, Mayhan WG, Heistad DD: Effect of vasopressin on production of cerebrospinal fluid: Possible role of vasopressin (V1)-receptors. Am J Physiol 1990;258:R94–R98. Rosenberg GA, Estrada E, Kyner WT: Vasopressin-induced brain edema is mediated by the V1 receptor. Adv Neurol 1990;52:149–154. Rapoport SI: Nonbarrier regions in the nervous system; in Rapoport SI (ed): Blood-Brain Barrier in Physiology and Medicine. New York, Raven Press, 1976, pp 77–79. Knigge KM, Morris M, Scott DE, et al: Distribution of hormones by cerebrospinal fluid; in Cserr HF, Fenstermacher JD, Fencl V (eds): Fluid Environment of the Brain. New York, Academic Press, 1975, pp 237–253. Williamson JR, Hansen CA, Verhoeven A: Mechanism of action of vasopressin as a calcium mobilizing hormone; in Crowley AW, Laird JF, Ausiello DA (eds): Vasopressin: Cellular and Integrative Functions. New York, Raven Press, 1988, pp 33–45. Fraser CL, Sarnacki P: Inositol 1,4,5-tris-phosphate may regulate cystolic Ca++ in rat brain synaptosomes. J Clin Invest 1990;86:2169–2173. Kanda F, Arieff AI: Vasopressin inhibits calcium-coupled sodium efflux system in rat brain synaptosomes. Am J Physiol 1994;266:R1169–R1173. Del Bigio MR, Fedoroff S: Swelling of astroglia in vitro and the effect of arginine vasopressin and atrial natriuretic peptide. Acta Neurochir 1990;(suppl 51):14–16. Doczi T, Joo´ F, Szerdahelyi P, Bodosi M: Regulation of brain water and electrolyte contents: The opposite actions of central vasopressin and atrial natriuretic factor. Acta Neurochir Suppl (Wien) 1988;43:186–188. Fraser CL, Kucharczyk J, Arieff AI, Rollin C, Sarnacki P, Norman D: Sex differences result in increased morbidity from hyponatremia in female rats. Am J Physiol 1989;256:R880–R885. Arieff AI, Kozniewska E, Roberts TPL, Vexler ZS, Kanda F, Kucharczyk J: Role of vasopressin in brain damage from hyponatremic encephalopathy; in Gross P, Richter D, Robertson GL (eds): Vasopressin. Montrouge, Libbey Eurotext, 1993, pp 243–257. Adler S, Simplaceanu V: Effect of acute hyponatremia on rat brain pH and rat brain buffering. Am J Physiol 1989;256:F113–F119. Kanda F, Sarnacki P, Arieff AI: Atrial natriuretic peptide inhibits the amiloride-sensitive sodiumhydrogen exchanger in rat brain. Am J Physiol 1992;263:R279–R283. Okada K, Caramelo C, Tsai P, Schrier RW: Effect of inhibition of Na+/K+-adenosine triphosphatase on vascular action of vasopressin. J Clin Invest 1990;86:1241–1248. Fraser CL, Sarnacki P: Na+,K+-ATPase pump function in male rat brain synaptosomes is different from that of females. Am J Physiol 1989;257:E284–E289. Okada Y, Hazama A: Volume-regulatory ion channels in epithelial cells. News Physiol Sci 1989;4: 238–242.
Arieff
60
38 39
40 41 42 43 44
45
46
47
48 49 50 51
52 53 54 55 56 57 58 59 60 61
Fraser CL, Swanson RA: Female sex hormones inhibit volume regulation in rat brain astrocyte culture. Am J Physiol 1994;267:C909–C914. Kozniewska E, Roberts TPL, Vexler ZS, Oseka M, Kucharczyk J, Arieff AI: Hormonal dependence of the effects of metabolic encephalopathy on cerebral perfusion and oxygen utilization in the rat. Circ Res 1995;76:551–558. Stallone JN, Crofton JT, Share L: Sexual dimorphism in vasopressin-induced contraction of rat aorta. Am J Physiol 1991;260:H453–H458. Stone JD, Crofton JT, Share L: Sex differences in central adrenoreceptor-mediated vasopressin response to hemorrhage. Am J Physiol 1991;260:E780–E786. Fenves AZ, Thomas S, Knochel JP: Beer potomania: Two cases and review of the literature. Clin Nephrol 1996;45:61–64. DeFronzo RA, Arieff AI: Hyponatremia: Pathophysiology and treatment; in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1995, pp 255–303. Schwartz WB, Tassel D, Bartter FC: Further observations on hyponatremia and renal sodium loss probably resulting from inappropriate secretion of antidiuretic hormone. N Engl J Med 1960;262: 743–748. Schwartz WB, Bennett W, Curelop S, Bartter FC: Syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529– 542. Schrier RW: Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy. Parts 1 and 2. N Engl J Med 1988;319: 1065–1072, 1127–1134. Packer M, Lee WH, Kessler PD, Medina N, Yushak M, Gottlieb SS: Identification of hyponatremia as a risk ractor for the development of functional renal insufficiency during converting enzyme inhibition in severe heart failure. J Am Coll Cardiol 1987;10:837–844. Papadakis MA, Fraser CL, Arieff AI: Hyponatraemia in patients with cirrhosis. Q J Med 1990; 76:675–688. Judd BA, Haycock GB, Dalton N, Chantler C: Antidiuretic hormone following surgery in children. Acta Paediatr Scand 1990;79:461–466. Roth E, Lax LC, Maloney JV: Ringer’s lactate solution and extracellular fluid volume in the surgical patient: A critical analysis. Ann Surg 1969;169:149–164. Rosenthal MH, Arieff AI: Fluid and electrolyte therapy in critically ill patients and those who are pre-, post- or intraoperative; in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1995, pp 597–632. Refoyo A, Macias-Nunez JF: The maintenance of plasma sodium in the healthy aged. Geriatr Nephrol Urol 1991;1:65–68. Hirshberg B, Ben-Yehuda A: The syndrome of inappropriate antidiuretic hormone secretion in the elderly. Am J Med 1997;103:270–273. Melton JE, Patlak CS, Pettigrew KD, Cserr HF: Volume regulatory loss of Na, Cl, and K from rat brain during acute hyponatremia. Am J Physiol 1987;252:F661–F669. Videen JS, Michaelis T, Pinto P, Ross BD: Human cerebral osmolytes during chronic hyponatremia: A proton magnetic resonance spectroscopy study. J Clin Invest 1995;95:788–793. Arieff AI, Llach F, Massry SG, Kerian A: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine (Baltimore) 1976;55:121–129. Skowsky VR, Swan L, Smith P: Effects of sex hormones on arginine vasopressin in intact and castrated male and female rats. Endocrinology 1979;104:105–108. Stone JD, Crofton JST, Share L: Sex differences in central adrenergic control of vasopressin release. Am J Physiol 1989;257:R1040–R1045. Akaishi T, Sakuma Y: Estrogen-induced modulation of hypothalamic osmoregulation in female rats. Am J Physiol 1990;258:R924–R929. del Castillo AR, Battaner E, Guerra M, Alonso T, Mas M: Regional changes of brain Na+, K+transporting adenosine triphosphate related to ovarian function. Brain Res 1987;416:113–118. Guerra M, del Castillo AR, Battaner E, Mas M: Androgens stimulate preoptic area Na+,K+ATPase activity in male rats. Neurosci Lett 1987;78:97–100.
Salt and Water Homeostasis
61
62
63 64
65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88
Vexler ZS, Ayus JC, Roberts TPL, Kucharczyk J, Fraser CL, Arieff AI: Ischemic or hypoxic hypoxia exacerbates brain injury associated with metabolic encephalopathy in laboratory animals. J Clin Invest 1994;93:256–264. Ayus JC, Arieff AI: Pathogenesis and prevention of hyponatremic encephalopathy. Endocrinol Metab Clin North Am 1993;22:425–446. Doczi T, Joo F, Vacsernyes M, Bodosi M: Increased concentration of atrial natriuretic factor in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage and raised intracranial pressure. Neurosurgery 1988;23:16–19. Steardo H, Nathanson JA: Brain barrier tissues: End organs for atriopeptins. Science 1987;235: 470–473. Tsutsumi K, Niwa M, Himeno A, et al: Atrial natriuretic peptide binding sites in the rat choroid plexus are increased in the presence of hydrocephalus. Neurosci Lett 1988;87:93–98. Arieff AI, Ayus JC, Fraser CL: Hyponatraemia and death or permanent brain damage in healthy children. BMJ 1992;304:1218–1222. Lee JH, Arcinue E, Ross BD: Organic osmolytes in the brain of an infant with hypernatremia. N Engl J Med 1994;331:439–442. Strange K, Morrison R: Volume regulation during recovery from chronic hypertonicity in brain glial cells. Am J Physiol 1992;263:C412–C419. Strange K: Regulation of solute and water balance and cell volume in the central nervous system. J Am Soc Nephrol 1992;3:12–27. McManus ML, Churchwell KB, Strange K: Regulation of cell volume in health and disease. N Engl J Med 1995;333:1260–1266. Lien YH, Shapiro JI, Chan L: Effects of hypernatremia on organic brain osmoles. J Clin Invest 1990;85:1427–1435. Heilig CW, Stromski ME, Blumenfeld JD, Lee JP, Gullans SR: Characterization of the major brain osmolytes that accumulate in salt-loaded rats. Am J Physiol 1989;257:F1108–F1116. Kleeman CR, Davson H, Levin E: Urea transport in the central nervous system. Am J Physiol 1962;203:739–747. Mahoney CA, Arieff AI, Leach WJ, Lazarowitz VC: Central and peripheral nervous system effects of chronic renal failure. Kidney Int 1983;24:170–177. Arieff AI, Massry SG, Barrientos A, Kleeman CR: Brain water and electrolyte metabolism in uremia: Effects of slow and rapid hemodialysis. Kidney Int 1973;4:177–187. Fraser CL, Arieff AI: Nervous system manifestations of renal failure; in Schrier RW, Gottschalk CW (eds): Diseases of the Kidney. Boston, Little, Brown, 1997, pp 2625–2646. Palevsky PM, Bhagrath R, Greenberg A: Hypernatremia in hospitalized patients. Ann Intern Med 1996;124:197–203. Phillips PA, Rolls BJ, Ledingham JGG, et al: Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984;311:753–759. Rowe JW, Resnick NM: Disorders of the kidney and urinary tract; in Andres R, Bierman EC, Hazzard WR (eds): Principles of Geriatric Medicine. New York, McGraw Hill, 1985, p 616. Synder NA, Arieff AI: Neurological manifestations of hypernatremia; in Griggs RA, Arieff AI (eds): Metabolic Brain Dysfunction in Systemic Disorders. Boston, Little, Brown, 1992, pp 87–106. Ayus JC, Arieff AI: Abnormalities of water metabolism in the elderly; in Martinez-Maldonado M (ed): Seminars in Nephrology. Philadelphia, Saunders, 1996, pp 277–288. Vin-Christian K, Arieff AI: Diabetes insipidus, massive polyuria and hypernatremia leading to permanent brain damage. Am J Med 1993;94:341–342. Morrison G, Singer I: Hyperosmolal states; in Narins RG (ed): Clinical Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1994, pp 617–658. Epstein FH: Calcium and the kidney. Am J Med 1968;45:700–714. Simard M, Gumbiner B, Lee A, Lewis H, Norman D: Lithium carbonate intoxication. Arch Intern Med 1989;149:36–46. Glauser FL: Diabetes insipidus in hypoxemic encephalopathy. JAMA 1976;235:932–933. Fraser CL, Arieff AI: Fatal central diabetes mellitus and insipidus resulting from untreated hyponatremia: A new syndrome. Ann Intern Med 1990;112:113–119.
Arieff
62
89 90 91 92 93 94
95 96 97 98 99 100 101 102 103 104
105 106 107
108 109 110 111 112 113 114 115 116
Taubin H, Matz R: Cerebral edema, diabetes insipidus and sudden death during treatment of diabetic ketoacidosis. Diabetes 1968;17:108–109. Park GR, Flanagan JP: Hypernatremic dehydration following a road traffic accident. J R Soc Med 1985;78:771–773. Buonocore CM, Robinson AG: The diagnosis and management of diabetes insipidus during medical emergencies. Endocrinol Metab Clin North Am 1993;22:411–424. Maffly RH: Diabetes insipidus; in Andreoli TE, Grantham JJ, Rector FC (eds): Disturbances in Body Fluid Osmolality. Bethesda, American Physiological Society, 1977, pp 285–307. Trost HA, Gaab MR: Plasma osmolality, osmoregulation and prognosis after head injury. Acta Neurochir (Wien) 1992;116:33–37. Durr JA, Stamoutsos B, Lindheimer MD: Osmoregulation during pregnancy in the rat. Evidence for resetting of the threshold for vasopressin release during gestation. J Clin Invest 1981;68:337– 346. Davidson JM, Gilmore EA, Durr J, Robertson GL, Lindheimer MD: Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol 1984;246:F105–F109. Durr JA: Diabetes insipidus in pregnancy. Am J Kidney Dis 1987;9:276–283. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992;117:891–897. Ayus JC, Arieff AI: Brain damage and postoperative hyponatremia: Role of gender. Neurology 1996;46:323–328. Fraser CL, Arieff AI: Epidemiology, pathophysiology and management of hyponatremic encephalopathy. Am J Med 1997;102:67–77. Zarinetchi F, Berl T: Evaluation and management of severe hyponatremia. Adv Intern Med 1996; 41:251–283. Lauriat S, Berl T: The hyponatremic patient: Practical focus on therapy. J Am Soc Nephrol 1997; 8:1599–1607. Ayus JC, Arieff AI: Pulmonary complications of hyponatremic encephalopathy: Noncardiogenic pulmonary edema and hypercapnic respiratory failure. Chest 1995;107:517–521. Vieweg WVR: Special topics in water balance in schizophrenia; in Schnur DB, Kirch DG (eds): Water Balance in Schizophrenia. London, American Psychiatric Press, 1996, pp 43–52. Demitrack MA, Kalogeras KT, Altemus M, Pigott TA, Listwak SJ, Gold PW: Plasma and cerebrospinal fluid measures of arginine vasopressin secretion in patients with bulimia nervosa and in healthy subjects. J Clin Endocrinol Metab 1992;74:1277–1283. Saikaley A, Bichet D, Kucharczyk D, Peterson LN: Neuroendocrine factors mediating polydipsia induced by dietary electrolyte depletion. Am J Physiol 1986;251:R1071–R1077. Goldman MB, Luchini DJ, Robertson GL: Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med 1988;318:397–403. Kennedy RM, Early LE: Profound hyponatremia resulting from a thiazide-induced decrease in urinary diluting capacity in a patient with primary polydipsia. N Engl J Med 1970;202:1185– 1186. Beresford HR: Polydipsia, hydrochlorothiazide and water intoxication. JAMA 1970;214:879. Sandifer MG: Hyponatremia due to psychotropic drugs. J Clin Psychiatry 1983;44:301–303. Illowsky BP, Kirch DG: Polydipsia and hyponatremia in psychotic patients. Am J Psychiatry 1988; 145:675–683. Raskind M: Psychosis, polydipsia, and water intoxication: Report of a fatal case. Arch Gen Psychiatry 1974;30:112–114. Cronin RE: Psychogenic polydipsia with hyponatremia: Report of eleven cases. Am J Kidney Dis 1987;9:410–416. Dubovsky SL, Grabson S, Berl T, Schrier RW: Syndrome of inappropriate secretion of antidiuretic hormone with exacerbated psychosis. Ann Intern Med 1973;79:551–554. Rosenbaum JF: Psychosis and water intoxication. J Clin Psychiatry 1979;40:287. Rendell M, McGrane D, Cuesta M: Fatal compulsive water drinking. JAMA 1978;240:2557–2559. Hariprasad MK, Eisinger RP, Nadler IM, Padmanabhan CS: Hyponatremia in psychogenic polydipsia. Arch Intern Med 1980;140:1639–1642.
Salt and Water Homeostasis
63
117
118
119 120 121 122 123 124 125 126 127
128
129
130 131
132 133 134 135 136 137 138 139 140
Cheng JC, Zikos D, Skopicki HA, Peterson DR, Fisher KA: Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: The effect of rapid correction. Am J Med 1990;88:561–566. Lee WH, Packer M: Prognostic importance of serum sodium concentration and its modification by converting enzyme inhibition in patients with severe chronic heart failure. Circulation 1986;73: 257–267. SOLVD: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. Fichman MP, Vorherr H, Kleeman CR, et al: Diuretic-induced hyponatremia. Ann Intern Med 1971;75:853. Sonnenblick M, Friedlander Y, Rosin AJ: Diuretic-induced severe hyponatremia: Review and analysis of 129 reported patients. Chest 1993;103:601–606. Abramow M, Cogan E: Clinical aspects and pathophysiology of diuretic-induced hyponatremia. Adv Nephrol (Paris) 1984;13:1–28. Ashraf N, Locksley R, Arieff AI: Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981;70:1163–1168. Vitting KE, Gardenswartz MH, Zabetakis PM, et al: Frequency of hyponatremia and nonosmolar vasopressin release in the acquired immunodeficiency syndrome. JAMA 1990;263:973–978. Hoen B, Tallot B, May T, et al: Hyponatremia in AIDS: Etiology and Diagnosis. Presse Me´d 1991; 20:1028–1031. Grinspoon SK, Bilezikian JP: HIV disease and the endocrine system. N Engl J Med 1992;327: 1360–1365. Cobbs R, Pepper GM, Torres JG, Gruenspan HL: Adrenocortical insufficiency with normal cortisol levels and hyporeninaemia in a patient with acquired immunodeficiency syndrome (AIDS). J Intern Med 1991;230:179–181. Tang WW, Kaptein EM, Feinstein EI, Massry SG: Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. Am J Med 1993;94: 169–174. Schrier RW, Caramelo C, Bichet DG: Vasopressin and water metabolism in cirrhosis; in Crowley AW, Laird JF, Ausiello DA (eds): Vasopressin: Cellular and Integrative Functions. New York, Raven Press, 1988, pp 249–257. Gines PWJ: Aquaretic agents: A new potential treatment of dilutional hyponatremia in cirrhosis. J Hepatol 1996;24:506–512. Saito T, Fujita N, Fujisawa G, Tsuboi Y, Honda K, Okada K: Correction of water retention due to vasopressin excess by non-peptide vasopressin antagonists; in Saito T, Karokaw K, Yoshida S (eds): Neurohypophysis. Amsterdam, Elsevier, 1995, pp 635–642. Rosenberg GA, Scremin O, Estrada E, Kyner WT: Arginine vasopressin V1 antagonist and atrial natriuretic peptide reduce hemorrhagic brain edema in rats. Stroke 1992;23:1767–1773. Verbalis JG: Hyponatremia: Epidemiology, pathophysiology, and therapy. Curr Opin Nephrol Hypertens 1993;2:636–652. Yamamura Y, Ogawa H, Chihara T, et al: OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist. Science 1992;252:572–574. Ware AJ, D’Agostino AN, Combes B: Cerebral edema: A major complication of massive hepatic necrosis. Gastroenterology 1971;61:877–884. Kato MD, Huges RD, Keays RT, Williams R: Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 1992;15:1060–1066. Cordoba J, Blei A: Brain edema and fulminant hepatic failure. Trop Gastroenterol 1994;15: 45–54. Davies MH, Mutimer D, Lowes J, Elias E, Neuberger J: Recovery despite impaired cerebral perfusion in fulminant hepatic failure. Lancet 1994;343:1329–1330. Singh N, Yu VL, Gayowski T: Central nervous system lesions in adult liver transplant recipients. Medicine (Baltimore) 1994;73:110–118. Wszolek ZK, McComb RD, Pfeiffer RF, et al: Pontine and extrapontine myelinolysis following liver transplantation. Transplantation 1989;48:1006–1012.
Arieff
64
141 142 143 144 145
146 147 148
149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168
Estol CJ, Faris AA, Martinez AJ, Barmada MA: Central pontine myelinolysis after liver transplantation. Neurology 1989;39:493–498. Ayus JC, Krothapalli RK, Arieff AI: Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med 1987;317:1190–1195. Bartter FE, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967;42:790–806. Tien R, Arieff AI, Kucharczyk W, Wasik A, Kucharczyk J: Hyponatremic encephalopathy: Is central pontine myelinolysis a component? Am J Med 1992;92:513–522. Halperin ML, Goguen JM, Cheema-Dhadli S, Kamel KS: Diabetic emergencies; in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1995, pp 741–775. Strange K, Morrison R, Heilig CW, Dipietro S, Gullans SR: Upregulation of inositol transport mediates inositol accumulation in hyperosmolar brain cells. Am J Physiol 1991;260:C784–C790. Minami Y, Inoue K, Shimada S, et al: Rapid and transient up-regulation of Na+/myo-inositol cotransporter transcription in the brain of acute hypernatremic rats. Mol Brain Res 1996;40:64–70. Arieff AI: Acid-base, electrolyte, and metabolic abnormalities; in Parrillo JE, Bone RC (eds): Critical Care Medicine: Principles of Diagnosis and Management. Philadelphia, Mosby-Year Book, 1995, pp 1071–1105. Schoolman HM, Dubin A, Hoffman WS: Clinical syndromes associated with hypernatremia. Arch Intern Med 1955;95:15–23. Finberg L: Hypernatremic (hypertonic) dehydration in infants. N Engl J Med 1973;289:196–198. Mattar JA, Weil MH, Shubin H, Stein L: Cardiac arrest in the critically ill. II. Hyperosmolar states following cardiac arrest. Am J Med 1974;56:162–168. Cameron JM, Dayan AD: Association of brain damage with therapeutic abortion induced by amniotic-fluid replacement: Report of two cases. Br Med J 1966;i:1010–1013. De Villota ED, Cavanilles JM, Stein L, et al: Hyperosmolar crisis following infusion of hypertonic sodium chloride for purposes of therapeutic abortion. Am J Med 1973;55:116–121. Ayus JC, Arieff AI: Metabolic consequences of hypernatremia in rats. J Am Soc Nephrol 1996;7: 1346. Long CA, Marin P, Bayer AJ, Shetty HGM, Pathy MSJ: Hypernatraemia in an adult in-patient population. Postgrad Med J 1991;67:643–645. Zierler KL: Hyperosmolarity in adults: A critical review. J Chronic Dis 1958;7:1–23. Mahowald JM, Himmelstein DU: Hypernatremia in the elderly: Relation to infection and mortality. J Am Geriatr Soc 1981;29:177–180. Ross EJ, Christie SBM: Hypernatremia. Medicine (Baltimore) 1969;48:441–473. Haussinger D, Roth E, Lang F, Gerok W: Cellular hydration state: An important determinant of protein catabolism in health and disease. Lancet 1993;341:1330–1332. Arieff AI, Ayus JC: Pathogenesis and management of hypernatremia. Curr Opin Crit Care 1996; 2:418–423. Macdonald NJ, McConnell KN, Stephen MR, Dunnigan MG: Hypernatraemic dehydration in patients in a large hospital for the mentally handicapped. BMJ 1989;299:1426–1429. Fraser CL, Arieff AI: Hepatic encephalopathy. N Engl J Med 1985;313:865–873. Sheldon RA, Partridge JC, Ferriero DM: Postischemic hyperglycemia is not protective to the neonatal rat brain. Pediatr Res 1992;32:489–493. Smith RJ, Block MR, Arieff AI, Blumenkrantz MJ, Coburn JW: Hypernatremic, hyperosmolar coma complicating chronic peritoneal dialysis. Proc Clin Dial Trans Forum 1974;4:96–99. Finberg L, Kiley J, Luttrell CN: Mass accidental salt poisoning in infancy: A study of a hospital disaster. JAMA 1963;184:187–190. Banister A, Siddiqi S, Hatcher GW: Treatment of hypernatremia dehydration in infancy. Arch Dis Child 1975;50:179. Hogan GR: Hypernatremia – Problems in management. Pediatr Clin North Am 1976;23:569–574. Farber MD, Schmidt RD, Bear RA, Narins RG: Management of fluid, electrolyte and acid-base disorders in surgical patients; in Narins RG, Maxwell MH, Kleeman CR (eds): Clinical Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1994, pp 1407–1436.
Salt and Water Homeostasis
65
169 170 171
172 173
174 175
176 177
Lowell JA, Schifferdecker C, Driscoll DF, Benotti PN, Bistrian BR: Postoperative fluid overload: Not a benign problem. Crit Care Med 1990;18:728–733. Finn JC, Rosenthal MH: Pulmonary edema in trauma and critically ill patients. Semin Anesth 1989;8:265–274. Khuri SF, Daley J, Henderson W, Barbour G, Lowry P, Irvin G: The National Veterans Administration surgical risk study: Risk adjustment for the comparative assessment of the quality of surgical care. J Am Coll Surg 1995;180:519–531. Katz AM: Cardiomyopathy of overload. N Engl J Med 1990;322:100–110. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM: Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 1990;323:1781–1788. Baggish MS, Sze EH: Endometrial ablation: A series of 568 patients treated over an 11-year period. Am J Obstet Gynecol 1996;174:908–913. Kozak LJ: Hospital inpatient surgery: United States, 1983–87; in Department of Health and Human Services (DHHS) Publ No PHS 89-1250 ed. Hospital Inpatient Surgery: United States, 1983–87, Hyattsville, Md 1989. Ayus JC, Arieff AI: Epidemiology of postoperative hyponatremic mortality: Studies in 107,253 asymptomatic adult subjects. Clin Res 1993;41:176A. Snyder NA, Feigal DW, Arieff AI: Hypernatremia in elderly patients. A heterogeneous, morbid, and iatrogenic entity. Ann Intern Med 1987;107:309–319.
Allen I. Arieff, MD, FACP, Department of Medicine, University of California, San Francisco, 299 South Street, Sausalito, CA 94965 (USA) Tel. +1 415 386 4454, Fax +1 415 332 1205
Arieff
66
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 67–86
............................
Calcium Metabolism Lars Lind, Sverker Ljunghall Department of Internal Medicine, University Hospital, Uppsala, Sweden
Contents Introduction ................................................................................................ Measurements of Calcium Metabolism ............................................................. Prevalence of Hypocalcemia ........................................................................... Etiology of Hypocalcemia .............................................................................. PTH Levels in the Circulation and PTH Secretion .............................................. Calcium Metabolism as a Prognostic Index ....................................................... Calcium Supplementation in the Critically Ill .................................................... Late Hypercalcemia ...................................................................................... Phosphate Levels in Critical Illness .................................................................. Magnesium Levels in the Critically Ill .............................................................. Calcitonin and Procalcitonin .......................................................................... Summary .................................................................................................... References ....................................................................................................
67 68 70 72 74 76 77 78 79 81 82 83 83
Introduction The calcium ion is a universal regulator of a variety of physiological events and is involved in the contraction of muscle cells, secretion of hormones and neurotransmitters, cell replication, the coagulation process, membrane stability and also acts as a structural component of bone. Although it is generally the free intracellular level that determines the diverse actions of the calcium ion, tight control is found for the extracellular calcium levels. In the general population the mean level of total serum calcium is slightly ?2.40 mmol/l with a standard deviation of only 0.1 mmol/l. The intra-individual variation is considerably lower. The variability is the second lowest among the many chemical variables measured in the human circulation; only
the variability for pH is lower. This indicates the importance of a stable level of the calcium ion in the extracellular space. The intracellular level of the calcium ion is 1,000–10,000 times lower than that measured in the circulation. The cell membrane is highly impermeable for the calcium ion, and both the entry and removal of calcium from the intracellular compartment are governed by highly specific mechanisms. Calcium enters the cell mainly through highly selective calcium channels. There are two main calcium channels; voltageoperated, acting through changes in the cell membrane potential, and receptoroperated channels, acting through activation of membrane receptors sensitive to a variety of endocrine and paracrine substances. Once in the cell the calcium ion can either remain in the ionized state to take part as the regulator of intracellular events or be extruded from the cell by an energy-dependent Ca-ATPase. The calcium ion can also be stored within the cell in the endoplasmic reticulum or in the mitochondria and later reappear in the cascade of intracellular events regulated by the concentration of calcium ions. Other systems for exchange of the calcium ion through the cell membrane exist, such as the Na-Ca exchange mechanism, but the quantitative importance of these is not fully known. The principal regulator of the extracellular calcium level is parathyroid hormone (PTH). This hormone, secreted from the parathyroid glands, protects against hypocalcemia by stimulating calcium resorption from bone via activation of osteoclasts, and reducing calcium excretion in urine by a direct action in the proximal tubuli in the kidneys. PTH also facilitates the formation of the active vitamin D metabolite, 1,25-dihydroxyvitamin D, in the kidneys, which acts as a hormone and raises the circulating levels of calcium mainly by facilitating calcium uptake from the intestine. The calcium-lowering hormone calcitonin, secreted from the C cells in the thyroid gland, probably only plays a minor role in the fine tuning of the circulating calcium levels and is mainly secreted in response to food intake.
Measurements of Calcium Metabolism About half of the circulating calcium content is protein-bound, mainly to albumin. The ionized form of calcium constitutes about 40% of the calcium content and the remaining part is chelated (10%). In most clinical practice the total serum concentration of calcium is measured. This component is highly dependent on the circulating levels of albumin such that hypoalbuminemia results in low levels of total serum calcium. However, it is the ionized part of calcium in the circulation that represents the biologically active form, and studies in critically ill patients have shown
Lind/Ljunghall
68
that there is a poor correlation between the total serum calcium levels and the ionized form, even after adjusting for the serum albumin level [1–3]. This is mainly due to the fact that the critically ill patient often has disturbances in factors such as circulating free fatty acid levels and pH. Elevated levels of free fatty acids increase the binding of calcium to albumin and this is also supported by a reduction in pH. Thus, it is necessary to measure the ionized fraction of calcium in the circulation of the critical ill. Today reliable devices with ion-sensitive electrodes are available for this purpose. It is possible to measure the total content of calcium in biopsies from different tissues, but as it is the free intracellular level that acts as a regulator of the intracellular events it is warranted to measure only this fraction. This could be performed by loading cells with fluorescent calcium indicators and by measuring in different fluorometers the free intracellular calcium levels in cell suspension or in single cells. Most often blood cells have been used for these types of measurements. The free intracellular concentration has in recent years also been measurable by use of MR spectroscopy. PTH exists in the circulation in various forms. Both the C-terminal and the N-terminal part of the hormone can be measured, as well as mid-portion fragments. The problem is that most earlier studies on calcium metabolism in the critically ill have used radioimmunoassays recognizing different, variable proportions of PTH fragments. Furthermore, accelerated proteolytic degradation of PTH has been demonstrated in sera from critically ill patients [4, 5]. It is therefore likely that many previously published reports do not include reliable measurements of the PTH levels. During the last decade a two-site immunoradiometric assay for PTH measuring the intact hormone levels without interference from PTH fragments is on the market [6]. As this assay exclusively measures the intact hormone this method should be preferred in critically ill patients since the degradation and metabolism of different PTH fragments could provide a distorted picture. Although measurements of circulating PTH in combination with determination of serum-ionized calcium give information about calcium metabolism, dynamic tests are necessary to study PTH secretion in detail. For several years, calcium infusions have been performed in order to study suppression of PTH secretion. However, in most cases it is more relevant to study stimulation of PTH release from the parathyroid gland. This has been tested by the use of EDTA infusion [7]. Recently these two approaches have been combined in the so-called CiCa clamp [8], in which citrate is infused for 2 h at a decreasing rate, lowering the serum-ionized calcium level by 0.15–0.20 mmol/l to a plateau lasting 1 h. Thereafter the citrate infusion is discontinued and a calcium infusion is initiated to raise the serum-ionized calcium level by 0.15–0.20 mmol/l to a new plateau over the following hour. By this approach both the rapid and the late phase of
Calcium Metabolism
69
stimulated PTH secretion as well as the degree of suppression of PTH release can be studied in relation to the achieved calcium level. A fraction of the circulating magnesium is bound to albumin and therefore measurements of serum-ionized magnesium are to be preferred to the total magnesium level in analogy with calcium measurements. Furthermore, as magnesium principally is an intracellularly located ion, measurements of serum magnesium give only a vague picture of the intracellular magnesium stores. A normal value of serum magnesium does therefore not exclude magnesium deficiency. Low levels of serum magnesium, on the other hand, are usually taken as a sign of a poor magnesium status. One way to measure magnesium status is to measure the magnesium content in circulating blood cells by MR spectroscopy or using fluorescent indicators although this can rarely be performed in clinical practice. Another way to assess magnesium deficiency is to infuse a known amount of magnesium and measure the urinary output of the ion. A low excretion in relation to the infused amount is taken as a reliable sign of magnesium deficiency. However, this approach is complicated in critically ill patients due to the frequent occurrence of acute renal failure and the use of diuretic treatment. Serum phosphate can be accurately measured in the critically ill using routine methods. However, it should be emphasized that serum phosphate levels change rapidly with the pH level and measurements have to be repeated when acid-base disturbances have been corrected or when large amounts of insulin have been administered, since insulin-mediated glucose transfer from extracellular to intracellular compartments could result in a pronounced decline in serum phosphate levels.
Prevalence of Hypocalcemia It is well known to every physician having worked in an intensive care unit (ICU) that hypocalcemia is commonly encountered in critically ill patients. Total serum calcium levels have been found to be decreased in 70–90% of ICU patients [1] and low serum-ionized calcium is found in 15–70% [1, 9, 10]. Hypocalcemia has been described in a variety of ICU conditions, such as sepsis, acute pancreatitis, acute renal failure, hemorrhage, as well as during other states with tissue hypoperfusion. Hypocalcemia is also a common finding in critically ill children [11]. There are few studies of the natural course of hypocalcemia in critically ill patients. In a series of 25 surgical intensive care patients, Burchard et al. [12], showed that the decreased levels of serum-ionized calcium returned to normal after 5–6 days. In our own study, in which we followed patients sub-
Lind/Ljunghall
70
200 180 Serum PTH (pg/m l)
160 140 120 100 80 60 40 20
a
0 1
2
4 3 Day in ICU
5
6
1
2
3 4 Day in ICU
5
6
Serum ionized calcium (m m ol/l)
1.18
b
1.16 1.14 1.12 1.1 1.08 1.06 1.04 1.02 1 0.98
Fig. 1. PTH serum levels (a) and serum-ionized calcium (b) levels in a representative patient with sepsis during 6 days in the ICU. Serum levels of PTH ?55 pg/ml are considered as elevated.
jected to elective abdominal aortic aneurysm surgery as well as patients with sepsis, a similar trend was found. In most cases the hypocalcemia normalized within 3 days (fig. 1). In another series of consecutive ICU patients with a variety of different underlying diagnoses, the decline in serum calcium levels was more pronounced and more long-lasting in the patients with serum creatinine ?180 mol/l, indicating renal failure, than in those with normal renal function. A similar picture of the dynamics of hypocalcemia has been seen in animal models of sepsis. In a series of pigs subjected to cecal ligation and incision, Burchard et al. [13] reported that the serum levels of ionized calcium returned to baseline 8 days following surgery.
Calcium Metabolism
71
Table 1. Potential mechanisms that could induce hypocalcemia in the critically ill Impaired PTH secretion due to hypo- or hypermagnesemia Impaired formation of 1,25-dihydroxyvitamin D in the kidney End-organ resistance to PTH or vitamin D in bone, kidney or intestine Increased urinary excretion of calcium Acid-base disturbances Chelation/precipitation of calcium in the extracellular space Intracellular accumulation of calcium High calcitonin levels
Etiology of Hypocalcemia Hypocalcemia develops when the counterregulatory mechanisms are insufficient. Several impairments, listed in table 1, may theoretically lead to this condition: An inability of the parathyroid gland to secrete PTH in response to circulating hypocalcemia, resistance to PTH action in bone and kidney, failure of the kidney to hydroxylate 25-OH vitamin D to 1,25-dihydroxyvitamin D, or resistance to active vitamin D in target organs. Also, increased levels of calcitonin could theoretically impair the ability of PTH and 1,25-dihydroxyvitamin D to mobilize appropriate amounts of calcium to the circulation. Apart from these potentially ‘endogenous’ impairments, several interventions performed in critically ill patients may lower calcium levels. Calcium chelation/precipitation may occur after blood transfusions when citrate is used as a blood anticoagulant. However, in subjects without critical illness subjected to surgery, only a minority developed hypocalcemia when given citrated blood [14, 15]. Furthermore, the effects of citrated blood transfusions on ionized calcium levels in the circulation are usually transient since citrate is metabolized in the tissues and excreted by the liver and kidney. This metabolic clearance of citrate may be impaired during hypothermia and in subjects with hepatic or renal failure. Therefore, while citrate-induced hypocalcemia is not a major problem in most patients subjected to surgery, patients with multiple organ failure may respond to citrated blood transfusion in a more pronounced way resulting in hypocalcemia. However, this matter has not been systematically investigated. Both hypo- and hypermagnesemia may cause impaired PTH secretion in response to hypocalcemia. Hypomagnesemia can also result in resistance to PTH action in bone. However, while mild hypomagnesemia is found in a substantial proportion of hospitalized patients, especially in the elderly [16–19], severe hypomagnesemia is not a common finding. Neither is hypermagnesemia common in the ICU. Chernow et al. [20] demonstrated that the levels of serum-
Lind/Ljunghall
72
ionized calcium were similar in intensive care patients with severe hypomagnesemia, when compared to those with normal magnesium levels. On the other hand, when a magnesium loading test was used to define magnesium deficiency, this condition was associated with low levels of serum-ionized calcium [21], suggesting that magnesium depletion could play a role in hypocalcemia in the ICU. Low levels of circulating PTH, despite low ionized calcium levels, have been described in sepsis, as well as in patients with acute pancreatitis and in those with rhabdomyolysis [9, 22–24]. Although it has been suggested that circulating factors impairing parathyroid gland function exist, no conclusive evidence supporting their presence has been presented. However, it might be worthwhile to consider the actions of pro-inflammatory cytokines on PTH secretion since immunological and functional similarities have been reported between parathyroid cells and lymphocytes, the major pro-inflammatory cytokine-producing cells. Apart from expression of CD4, a molecule involved in the recognition of antigens associated with MHC class II structures, an antigen important for the intracellular calcium regulation has been found on both cell types [25]. Increased intracellular levels of calcium have been reported both in critically ill patients and in experimental models of sepsis [26–29]. This has been attributed to increased calcium influx, without alterations in the efflux of the ion [29]. In a septic rat model, treatment with the oxygen radical scavenger superoxide dismutase restored the increased calcium influx, as well as lowered the cytoplasmic intracellular levels in hepatocytes [29]. Thus, intracellular accumulation of calcium could be an important cause of hypocalcemia. More precise determinations of calcium content have to be made in the endoplasmic reticulum and in mitochondria in order to determine if an increase of the total intracellular content of calcium could explain the degree of hypocalcemia seen in the critically ill. Many ICU patients are elderly and might have a poor vitamin D status even before the episode of critical illness. Although it has been shown that the hydroxylation step in the liver to form 25-hydroxyvitamin D is impaired only in patients with a pronounced reduction in liver function, this is the case in a substantial proportion of patients with multiple organ failure. In the only study which has systematically measured levels of 25-hydroxyvitamin D, circulating levels of this prohormone were found to be reduced in ICU patients, especially in those presenting with hypocalcemia and sepsis [9]. Furthermore, the renal synthesis of vitamin D is frequently impaired in several patient groups treated in the ICU, such as acute pancreatitis, sepsis, burns and patients with rhabdomyolysis [9, 24]. The circulating levels of 1,25-dihydroxyvitamin D have been found to be almost undetectable in a large proportion of the critically ill subjects with sepsis and hypocalcemia [9]. As in the case of PTH, it is also possible that an end-organ resistance to vitamin D may exist. This would then grossly impair calcium absorption from the intestine and calcium mobilization
Calcium Metabolism
73
Serum PTH (pg/m l)
100
75
50
25
0
0-5
6 -10 11 -15 APACHE-II score
>15
Fig. 2. Serum PTH levels in relation to the severity of illness, as assessed by the APACHE-II score in patients admitted to the emergency department. Means×SEM are given. Serum levels of PTH ?55 pg/ml are considered as elevated.
from bone, the latter probably being more important in the critically ill patient, who is often fed solely by the parental route. Evidence of end-organ resistance to PTH or vitamin D is sparse and we have found that the urinary excretion of calcium is generally low in critical illness and related to the levels of serum-ionized calcium. Furthermore, it has recently been shown that urinary pyridinium cross-link excretion is increased in critically ill surgical patients [30], suggesting that bone resorption is in fact increased.
PTH Levels in the Circulation and PTH Secretion The first opportunity to study calcium metabolism in critically ill patients is in the emergency department. In our own study investigating unselected patients admitted to the emergency department with various disorders, such as myocardial infarction, trauma, infections, stroke, obstructive lung disease, etc., the circulating levels of intact PTH were elevated in 16% of the cases [31]. This elevation in PTH levels was not limited to any specific disease, but rather to the severity of the disease in a broader sense, as the circulating levels of serum PTH were related to the APACHE-II score (fig. 2), a scoring system used to assess severity of illness in critically ill patients [32]. Thus, the elevation of serum PTH levels seen in severely acutely ill patients is an early event in the course of the disease and not a consequence of any kind of medical therapy.
Lind/Ljunghall
74
Serum PTH (pg/m l)
150
100
50
0
0 -5
6 -10 11 -15 APACHE-II score
>15
Fig. 3. Serum PTH levels in relation to the severity of illness, as assessed by the APACHE-II score in patients admitted to the ICU. Means×SEM are given. Serum levels of PTH ?55 pg/ml are considered as elevated.
Although PTH levels have been found to be increased in certain disorders such as acute pancreatitis [33], sepsis [9] and surgery with complications in the postoperative period [12], few studies have been devoted to study PTH levels in consecutive ICU patients. We measured serum levels of intact PTH in 48 consecutive ICU admissions during the first 24 h on the ward. We found that serum levels of PTH were elevated in 35% of the patients. This series of patients consisted of a broad mixture of diagnoses. Also in these patients the levels of serum PTH were related to the APACHE-II score (fig. 3), suggesting that PTH secretion was enhanced in proportion to the severity of illness. It might seem appropriate to increase PTH secretion in response to hypocalcemia in the critically ill patient. However, a more detailed analysis suggests that the elevated PTH levels are inappropriately high in relation to the calcium level in a majority of the critically ill. In order to study the dynamic interplay between the circulating levels of ionized calcium and PTH in greater detail, we measured plasma-ionized calcium and serum intact PTH daily during the first week in a group of ICU patients with sepsis as well as in those subjected to elective abdominal aortic aneurysm surgery. It could then be seen that the levels of serum-ionized calcium usually normalized within 2–3 days while the serum levels of intact PTH changed only marginally and remained elevated throughout the study period. This change in serum-ionized calcium and PTH
Calcium Metabolism
75
during the first week in the ICU is given in a representative patient in figure 1. Thus, although the elevation in serum PTH seen during the first day in the ICU might be appropriate for the prevailing hypocalcemia at that time, it is obvious that the levels of serum PTH do not respond as expected when hypocalcemia was normalized. This could be due either to other factors stimulating PTH secretion or to disturbances of calcium sensitivity. We have also performed dynamic studies of PTH secretion in a smaller group, including septic patients and those subjected to major surgery, using the CiCa clamp. It could be seen that the parathyroids of critically ill patients responded with an increase in PTH levels to citrate infusion which had lowered the serum calcium levels. Furthermore, critically ill patients showed a reduction in PTH levels when serum calcium levels were increased by a calcium infusion. However, as can be seen in figure 4, PTH levels were elevated from the beginning and during this dynamic test the PTH levels were shifted upwards during infusion of both citrate and calcium compared to the normal subject despite similar levels of serum-ionized calcium. This finding further supports the idea that PTH secretion at a given level of extracellular calcium is elevated in the critically ill patient. This pattern was more pronounced in septic patients than in those who were subjected to major surgery although an alteration in PTH secretion was seen in both of these groups. In a minority of the ICU patients, very low levels of serum PTH were found despite hypocalcemia, suggesting that in some critically ill patients the parathyroids are unable to secrete sufficient PTH. This was however a rare condition associated with a very poor prognosis.
Calcium Metabolism as a Prognostic Index Burchard et al. [12] reported in 1990 that in surgical intensive care patients, serum-ionized calcium levels were significantly lower and PTH levels were significantly higher within the first day in the ICU in nonsurviving patients compared to those who survived. Similar results have been reported in other groups of surgical [34] and medical ICU patients [35]. We have observed similar results in randomly selected patients upon admission to the emergency department, whose serum levels of intact PTH were a significant predictor of hospital mortality. Furthermore, the serum levels of PTH were a significant predictor of mortality independent of the APACHE-II score, suggesting that calcium metabolism adds to other physiological variables in terms of predicting mortality. Also in patients with acute pancreatitis, serum levels of PTH were increased in those with a fatal outcome compared to patients with an uncomplicated course [33].
Lind/Ljunghall
76
Serum ionized calcium (m m ol/l)
1.4
a
1.35 1.3 1.25 1.2 1.15 1.1 1.05 1 0.95 0
5
50 80 10 20 40 M inutes during CiCa clam p
95
115
0
5
50 80 10 20 40 M inutes during CiCa clam p
95
115
275 250 Serum PTH (pg/m l)
225 200 175 150 125 100 75 50 25
b
0
Fig. 4. Serum-ionized calcium levels (a) and PTH serum levels (b) in 1 representative patient with sepsis (X) and 1 control subject (W) during the CiCa clamp. During this test, citrate is infused for 50 min and thereafter calcium is given intravenously for 60 min.
It is possible that hypersecretion of PTH is not a benign event in critically ill patients. However, whether deranged calcium metabolism contributes to mortality remains to be settled.
Calcium Supplementation in the Critically Ill A compromised circulation is one of the major problems in most ICU patients. A number of studies in humans have evaluated the hemodynamic effects of calcium infusion in healthy volunteers and in patients with various diseases [36–41]. In the majority of these studies, acute calcium supplemen-
Calcium Metabolism
77
tation resulted in an increase in arterial blood pressure and in most studies a transient increase in cardiac output was noted. As heart rate was not generally affected, this suggests that acute calcium supplementation has an inotropic effect. However, in these studies a wide range of serum calcium levels prior to the initiation of the calcium infusions were observed. In a recent study of critically ill patients managed with a pulmonary artery catheter because of circulatory instability, baseline hemodynamic variables were similar in the patients with hypocalcemia (mean level of serum-ionized calcium 0.91 mmol/l) and in those with normocalcemia. Rapid intravenous infusion of 1 g calcium chloride resulted in an increase in mean artery blood pressure, as well as rise in left ventricular stroke index [42]. It thus seems that calcium supplementation is justified in patients with hypocalcemia and deranged hemodynamic status, especially in those with low blood pressure and poor cardiac performance. It must however be emphasized that no randomized studies of the effect of calcium supplementation on mortality or surrogate end-points, such as circulatory variables, have been performed in critically ill patients. Two experimental studies in septic rats have shown that both high-dose and low-dose calcium administration actually increased mortality [43, 44]. In the light of these findings and reports that the intracellular calcium concentration has been found to be elevated in human lymphocytes from septic patients, as well as in hepatocytes, adipocytes and aortic smooth muscle cells in experimental animals [26–29], it seems wise not to recommend a generalized use of calcium supplementation in critically ill patients before this matter has been properly evaluated in randomized clinical trials.
Late Hypercalcemia More than 10 years ago it was reported that in surgical patients with a prolonged ICU stay, elevated levels of serum-ionized calcium were found in 15% of cases [45]. This group was characterized by a more severe hypocalcemia earlier in their hospital course as well as a more severe illness, compared to those without late hypercalcemia. Furthermore, these patients had elevated levels of serum PTH. In our own study of a sample of 83 critically ill patients whose serum calcium values were followed daily in the ICU, 32% developed hypercalcemia late in their ICU stay [46]. The hypercalcemia was generally mild (mean 2.71×0.12 mmol/l) and the mean number of days in the ICU before hypercalcemia developed was 17×13. These hypercalcemic episodes were more common and occurred earlier in patients with coexisting acute renal failure. Multiple regression analysis showed that the number of failing organs on the
Lind/Ljunghall
78
first day in the ICU was the best predictor of late hypercalcemia. When serum PTH levels were measured in 6 of the patients without acute renal failure during their hypercalcemic episodes, PTH, as well as serum calcium, was found to be elevated to a similar level as in a sample of patients subjected to elective surgery for mild primary hyperparathyroidism. Thus, it seems that critical illness is associated with an initial phase of hypocalcemia which triggers some as yet unknown events resulting in an inappropriate PTH secretion relative to the prevailing extracellular calcium level. After a few days the circulating calcium levels normalize, but PTH levels remain high suggesting a sustained shift in the set-point for the extracellular calcium/PTH secretion coupling. At this stage a resistance to the hypercalcemic action of PTH seems to exist, as serum calcium levels generally are normal. During the course of critical illness, serum calcium levels gradually increase to become hypercalcemic in the part of the ICU population with the most pronounced illness. The mechanisms behind these dynamic derangements in calcium metabolism are unknown, but seem to be initiated early as they were already present upon admission to the emergency department. Thus, although a part of this phenomenon might be due to therapeutic actions known to interfere with calcium metabolism, such as blood transfusion and catecholamine administration, our therapeutic efforts cannot explain more than a small part of the derangement in calcium metabolism seen in critically ill patients. It is well known that infusion of catecholamines to levels seen during stress results in lowering of serum calcium and an increase in PTH levels [47]. Endogenous catecholamines, which are elevated in patients with critical illness, might be a mechanism that triggers the impairment in calcium metabolism seen in the critically ill. As the derangement in calcium metabolism is most pronounced in patients with septic conditions [48–50], the role of pro-inflammatory cytokines, such as TNF-, interleukin-1 and interleukin-6, and other factors involved in sepsis in the pathogenesis of the altered calcium homeostasis should be explored. It seems unlikely that immobilization alone in the critically ill patients would cause late hypercalcemia, as has been described in orthopedic patients with a prolonged period of immobilization, since this condition causes hypercalcemia with predominantly low PTH levels.
Phosphate Levels in Critical Illness Hypophosphatemia is a common finding in critically ill patients [51, 52]. It may lead to respiratory insufficiency, general muscle weakness, and to neurological symptoms such as tremor, ataxia or seizures [53–56].
Calcium Metabolism
79
Serum phosphate (m m ol/l)
1.5
1.0
0.5
0.0
1
2
3 4 5 Day in the ICU
6
7
Fig. 5. Serum phosphate levels in a series of patients during the first week in the ICU. Means×SEM are given.
In a series of trauma patients, Daily et al. [51] showed that serum phosphate levels declined during the first day in the ICU, accompanied by increased urinary output of phosphate. It has also been documented that the intracellular levels of phosphate are reduced following trauma [57]. Daily et al. [51] also supplemented one half of their trauma patients with intravenous phosphate during the first 48 h after admission to the ICU and found that in this group serum levels of phosphate could be kept at a normal level, preventing the negative phosphate balance noted in the nonsupplemented patients. In our own series of consecutive critically ill patients whose serum phosphate was followed daily for 1 week, a drop in serum phosphate levels was generally seen between the first and the second day in the ICU (fig. 5), whereafter they tended to normalize. The serum level of phosphate was considerably higher in patients who developed acute renal failure early in the course in the ICU when compared to those with normal renal function. Several factors might be involved in the urinary loss of phosphate in ICU patients; these factors include hormones known to be elevated in stressful conditions such as glucagon, cortisol and catecholamines [58]. However, it seems likely that the major cause of phosphate wasting in the kidney is the increased levels of PTH, which have powerful phosphaturic properties. Hypophosphatemia in the critically ill could also be a consequence of a shift of phosphate from the extracellular to the intracellular compartment, e.g. induced by catecholamines or insulin. This has also been demonstrated when nutrients are given to critically ill patients, who have gone through a
Lind/Ljunghall
80
period of starvation. Such ‘refeeding hypophosphatemia’ has been shown to occur in at least one third of the ICU patients [59]. Increased insulin levels and a change in pH are factors likely to explain this decline in the serum phosphate level, which in some patients could be pronounced. In one study the time necessary to wean patients off ventilation was inversely related to the serum phosphate level and phosphate supplementation improved diaphragmatic contractility in mechanically ventilated patients [60]. Furthermore, in patients with septic shock, 20 mmol elemental phosphorus given over 60 min improved cardiac performance and raised blood pressure without altering cardiac filling pressures [61]. Although no prospective randomized trials have been performed of phosphate supplementation in unselected critically ill patients, it seems likely that it is beneficial to normalize low serum phosphate levels. Phosphate supplementation to parenteral nutrition might cover requirements in patients without hypophosphatemia, but in patients with low phosphate levels extra phosphate has to be added. Two recent studies have shown that an additional 15–30 mmol phosphate as a potassium salt could be safely given during the first hours in the ICU to patients with lowered serum phosphate levels [62].
Magnesium Levels in the Critically Ill There are several reports that hypomagnesemia is common in critically ill patients. Total serum magnesium concentrations have been reported to be below normal in 44–60% of the patients with normal renal function, both in a medical ICU and in postoperative intensive care patients [16, 20, 63, 64]. Slightly higher prevalences of hypomagnesemia have been reported for the magnesium content in blood cells [64, 65]. When magnesium loading was used to evaluate magnesium status, 70% of a sample of ICU patients showed retention of more than 65% of the loading dose, indicating a considerable magnesium deficiency [66]. None of the patients in that study displayed a normal loading test suggesting that measurements of magnesium levels in the circulation underestimate the prevalence of magnesium deficiency, as only 60% of the patients had a serum magnesium value =0.80 mmol/l. In a series of surgical ICU patients, the degree of hypomagnesemia was not related to the severity of illness, as assessed by the APACHE-II score; however, patients with severe hypomagnesemia had a high mortality rate indicating that at least severe hypomagnesemia is a poor prognostic sign in the critically ill [20]. The mechanisms of hypomagnesemia in critically ill patients are not known. A high proportion of elderly people are known to have a poor magne-
Calcium Metabolism
81
sium status [17, 67]. Furthermore, several of the hormones involved in the stress response, such as catecholamines, are known to decrease circulating levels of magnesium [68]. Also, several therapeutic agents commonly used in intensive care, such as aminoglycosides, diuretics and digitalis, have been associated with hypomagnesemia [19, 69–71]. As with the other ions, no randomized clinical trials have evaluated the usefulness of supplementation with magnesium in critically ill patients. In contrast to the experimental indications that calcium supplementation might be harmful in sepsis, rats subjected to an endotoxin challenge had an increased survival rate when given magnesium [72]. It seems reasonable to increase magnesium intake in ICU patients with severe hypomagnesemia and in those with neurological symptoms or cardiac problems, especially ventricular tachycardias. Furthermore, reduced levels of serum potassium in critically ill patients can often not be reversed without concomitant magnesium supplementation [73, 74].
Calcitonin and Procalcitonin De Bastiani et al. [75] first reported high levels of circulating calcitonin in multiple trauma patients. In our previous study of consecutive intensive care patients, a profound increase in circulating calcitonin levels was seen [76] and only 11% of the patients had normal levels. The circulating levels of calcitonin were higher in septic than nonseptic patients and were related to the severity of illness, evaluated by the APACHE-II score. Furthermore, circulating calcitonin levels correlated with the length of stay in the ICU and were higher in patients who did not survive when compared to survivors. Gel chromatography in a fast protein liquid chromatography system disclosed that most of the measured calcitonin was due to high molecular forms of this hormone. During recent years it has become evident that the elevated serum levels of calcitonin measured in the studies cited above were possibly actually procalcitonin. In a large series of patients admitted to the emergency department with suspected infections, Zeni et al. [77] showed that procalcitonin levels were more than 10-fold higher in patients with sepsis than in those without sepsis. Furthermore, a futher 10-fold rise in procalcitonin levels was seen when patients with septic shock were compared to those without shock. In a study of healthy volunteers [78], injections of bacterial endotoxin resulted in grossly elevated procalcitonin levels within 4 h of the injection, suggesting that procalcitonin levels indeed are affected by bacterial infections. In a series of patients with peritonitis [79], procalcitonin levels were elevated and generally declined within 24 h in those who survived, while no decrease
Lind/Ljunghall
82
in procalcitonin levels was seen during the same period in nonsurvivors. It should be emphasized that procalcitonin levels are not only elevated following bacterial infections. In our series of patients with ischemic heart disease subjected to coronary artery bypass grafting, surgery induced an elevation of procalcitonin levels. The physiological role of procalcitonin is uncertain. In our study of intensive care patients, no relationship between the serum levels of calcium and calcitonin was seen. Similar results have also been reported by others [80], while in burn patients a relationship between procalcitonin levels and calcium matabolism was reported [81]. It is evident that further studies are needed to clarify the role of elevated procalcitonin levels. In summary: Many patients with critical illness have hypocalcemia, hypophosphatemia and hypomagnesemia. This derangement in calcium homeostasis is accompanied by an inappropriate elevation of serum PTH levels sustained over several days despite normalization of the serum calcium level. Deviations in these parameters are associated with increased mortality. Although it seems apparent that supplementation should be performed in cases of severe deficiency or when associated with clinical symptoms, prospective, randomized clinical trials are needed to establish the role of calcium supplementation in critically ill patients.
References 1 2 3 4
5 6 7
8
9 10
Zaloga GP, Chernow B, Cook D, et al: Assessment of calcium homeostatis in the critically ill patient. Ann Surg 1985;202:587–594. Zaloga GP, Chernow B: Hypocalcemia in critical illness. JAMA 1986;256:1924–1929. Ladenson JH, Lewis JW, Boyd JC: Failure of total calcium corrected for protein, albumin, and pH to correctly assess from calcium status. J Clin Endocrinol Metabl 1978;46:986–993. Hermon-Taylor J, Magee AI, Grant DAW, Jones PA, Marshall CE, Dunham J: Cleavage of peptide hormones by 2-macroglobulin trypsin complex and its relation to the pathogenesis and chemotherapy of acute pancreatitis. Clin Chem Acta 1981;109:203–209. Brodrick JW, Largman C, Ray SB, Geokas MC: Proteolysis of parathyroid hormone in vitro by sera from acute pancreatitis patients. Proc Soc Exp Biol Med 1981;167:588–596. Logue FC, Beastall GH, Fraser WD, O’Reilly D: Intact parathyroid hormone assays. BMJ 1990; 300:210–211. ˚ kerstro¨m G, Ljunghall S: Stimulation of parathyroid hormone Benson L, Rastad J, Wide L, A secretion by EDTA infusion – A test for the differential diagnosis of hypercalcemia. Acta Endocrinol 1986;111:498–506. Schwarz P, Sørensen HA, McNair P, Transbøl I: CiCa-clamp technique: A method for quantifying parathyroid hormone secretion: A sequential citrate and calcium clamp study. Eur J Clin Invest 1993;23:546–553. Zaloga GP, Chernow B: The multifactorial basis for hypocalcemia during sepsis. Studies of the parathyroid hormone-vitamin D axis. Ann Intern Med 1987;107:36–41. Desai TK, Carlson RW, Thill-Baharozian M, et al: A direct relationship between ionized calcium and arterial pressure among patients in an intensive care unit. Crit Care Med 1988;16:578–582.
Calcium Metabolism
83
11
12 13 14 15 16 17 18 19
20 21 22 23 24 25
26 27 28 29 30 31
32 33 34 35 36
Sanchez GJ, Venkataraman PS, Pryor RW, Parker MK, Fry HD, Blick KE: Hypercalcitoninemia and hypocalcemia in acutely ill children: Studies in serum calcium, blood-ionized calcium, and calcium-regulating hormones. J Pediatr 1989;114:952–956. Burchard W, Gann DS, Colliton J, Forster J: Ionized calcium parathormone, and mortality in critically ill surgical patients. Ann Surg 1990;221:543–569. Burchard KW, Simms H, Robinson A, DiAmico R, Gann DS: Hypocalemia during sepsis. Relationship to resuscitation and hemodynamics. Arch Surg 1992;127:265–272. Howland WS, Schweizer O, Jascott D, et al: Factors influencing the ionization of calcium during major surgical procedures. Surg Gynecol Obstet 1976;143:895–900. Kahn RC, Jascott D, Carlon GC, et al: Massive blood replacement: Correlation of ionized calcium, citrate, and hydrogen ion concentration. Anesth Analg 1979;58:274–278. Ryzen E: Magnesium homeostasis in critically ill patients. Magnesium 1989;8:201–212. Touitou Y, Godard JP, Ferment O, Chastang C, Proust J, Bogden A, et al: Prevalence of magnesium and potassium deficiencies in the elderly. Clin Chem 1987;33:518–523. Whang R, Oei TO, Watanabe A: Frequency of hypomagnesemia in hospitalized patients receiving digitalis. Arch Intern Med 1985;145:655–656. Whang R, Oei TO, Aikawa JK, Watanabe A, Vannatta J, Fryer A, et al: Predictors of clinical hypomagnesemia: Hypokalemia, hypophosphatemia, hyponatremia and hypocalcemia. Arch Intern Med 1984;144:1794–1796. Chernow B, Bamberger S, Stoiko M, Vadnais M, Mills S, Hoellerich V, Warshaw AL: Hypomagnesemia in patients in postoperative intensive care. Chest 1989;95:391–397. Hebert P, Mehta N, Wang J, Hindmarsh T, Jones G, Cardinal P: Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med 1997;25:749–755. Haldimann B, Goldstein DA, Akmal M, et al: Renal function and blood levels of divalent ions in acute pancreatitis. Miner Electrolyte Metab 1980;3:190–199. Condon JR, Ives D, Knight MJ, et al: The aetiology of hypocalcemia in acute pancreatitis. Br J Surg 1975;62:115–118. Zaloga GP, Chernow B: Hypocalcemia and rhabdomyolysis. JAMA 1987;257:626. Posillico JT, Srikanta S, Eisenbarth G, Quaranta V, Kajiji S, Brown EM: Binding of monoclonal antibody (4F2) to its cell surface antigen on dispersed adenomatous parathyroid cells raises cytosolic calcium and inhibits parathyroid hormone secretion. J Clin Endocrinol Metab 1987;64:43–50. Song S-K, Karl IE, Ackerman JJH, Hotchkiss RS: Increased intracellular Ca2+: A critical link in the pathophysiology of sepsis? Med Sci 1993;90:3933–3937. Zaloga GP, Washburn D, Black KW, Prielipp R: Human sepsis increases lymphocyte intracellular calcium. Crit Care Med 1993;21:196–202. Sayeed MM, Maitra SR: Effect of diltiazem on altered cellular regulation during endotoxic shock. Am J Physiol 1987;253:R549–R554. Rose S, Sayeed MM: Superoxide radical scavenging prevents cellular calcium dysregulation during abdominal sepsis. Shock 1997;7:263–268. Shapses SA, Weissman O, Seibel MJ, Chowdhury HA: Urinary pyridinium cross-link excretion is increased in critically ill surgical patients. Crit Care Med 1997;25:85–90. Carlstedt F, Lind L, Wide L, Lindahl B, Ha¨nni A, Rastad J, Ljunghall S: Serum levels of parathyroid hormone are related to the mortality and severity of illness in patients in the emergency department. Eur J Clin Invest 1997;27:977–981. Knaus AW, Draper EA, Wagner DP, et al: APACHE-II, a severity of disease classification system. Crit Care Med 1985;113:818–829. McKay C, Beastall GH, Imrie CW, Baxter JN: Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994;81:357–360. Wilson RF, Soullier G, Antonenko D: Ionized calcium levels in critically ill surgical patients. Am Surg 1979;45:485–490. Desai TK, Carlson RW, Geheb MA: Prevalence and clinical implications of hypercalcemia in acutely ill patients in a medical intensive care setting. Am J Med 1988;84:209–214. Macrone C, Beretta-Piccoli C, Weidmann P: Acute hypercalcemic hypertension in man: Role of hemodynamics, catecholamines, and renin. Kidney Int 1980;20:92–96.
Lind/Ljunghall
84
37 38 39 40 41 42 43 44 45 46 47
48 49 50 51 52 53 54 55 56 57 58 59 60
61 62
Maynard JC, Cruz C, Kleerekoper M, et al: Blood pressure response to changes in serum-ionized calcium during hemodialysis. Ann Intern Med 1986;104:358–361. Carlon GC, Howland WS, Kahn RC, et al: Calcium chloride administration in normocalcemic critically ill patients. Crit Care Med 1980;8:209–212. Lang RM, Fellner SK, Neumann A, et al: Left ventricular contractility varies directly with bloodionized calcium. Ann Intern Med 1988;108:524–529. Mori K: The effects of infusion of calcium and magnesium ions on the cardiovascular system in man. Jpn Heart J 1978;19:226–236. Weidmann P, Massry SG, Coburn JW, et al: Blood pressure effects of acute hypercalcemia. Ann Intern Med 1972;76:741–745. Vincent JL, Bredas P, Jankowski S, Kahn RJ: Correction of hypocalcaemia in the critically ill: What is the haemodynamic benefit? Intensive Care Med 1995;21:838–841. Zaloga GP, Sager A, Black KW, Prielipp R: Low dose calcium administration increases mortality during septic peritonitis in rats. Circ Shock 1992;37:226–229. Malcolm DS, Zaloga GP, Holaday JW: Calcium administration increases the mortality of endotoxic shock in rats. Crit Care Med 1989;17:900–903. Forster J, Querusio L, Burchard KW, Gann D: Hypercalcemia in critically ill surgical patients. Ann Surg 1985;202:512–518. Lind L, Ljunghall S: Critical care hypercalcemia – A hyperparathyroid state. Exp Clin Endocrinol 1992;100:148–151. ˚ kerstro¨m G, Benson L, Hetta J, Rudberg C, Wide L: Effects of epinephrine and Ljunghall S, A norepinephrine on serum parathyroid hormone and calcium in normal subjects. Exp Clin Endocrinol 1984;84:313–318. Taylor B, Sibbald WJ, Edmonds MW, Holliday RL, Williams C: Ionized hypocalcemia in critically ill patients with sepsis. Can J Surg 1978;21:429–433. Aderka D, Schwartz D, Dan M, Levo Y: Bacteremic hypocalcemia: A comparison between the calcium levels of bacteremic and nonbacteremic patients with infection. Arch Intern Med 1987;147:232–236. Woo P, Carpenter MA, Trunkey D: Ionized calcium: The effect of septic shock in the human. J Surg Res 1979;26:605–610. Daily WH, Tonnesen AS, Allen SJ: Hypophosphatemia – Incidence, etiology and prevention in the trauma patient. Crit Care Med 1990;18:1210–1214. Finsterer U, Betz J, Braun S, et al: Metabolism of phosphate and calcium after severe accidental trauma. Scand J Clin Lab Invest 1983;43:117. Lotz M, Zisman E, Bartter FC: Evidence for a phosphorus depletion syndrome in man. N Engl J Med 1968;278:409. Newman JH, Neff TA, Ziporin P: Acute respiratory failure associated with hypophosphatemia. N Engl J Med 1977;296:1101. Silvis SE, Paragas PD: Paresthesias, weakness, seizures and hypophosphatemia in patients receiving hyperalimentation. Gastroenterology 1972;62:513. Yawata Y, Craddoc P, Hebbel R, et al: Hyperalimentation hypophosphatemia: Hematologic neurologic dysfunction due to ATP depletion. Clin Res 1973;21:729. Love´n L, Gidlo¨f A, Larsson L, Sjo¨berg HE, Lennquist S: Changes in serum phosphate and calcitonin concentrations during elective surgery of the knee. Acta Chir Scand 1992;148:27–31. Massare F, Cammani F: Propranolol block of adrenalin-induced hypophosphatemia in man. Clin Sci 1970:38:245. Marik PE, Bedigian MK: Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study. Arch Surg 1996;131:1043–1047. Aubier M, Murciano D, Lecocguic Y, Viires N, Jacquens Y, Squara P, Pariente R: Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985;313:420–424. Bollaert PE, Levy B, Nace L, Laterre PF, Larcan A: Hemodynamic and metabolic effects of rapid correction of hypophosphatemmia in patients with septic shock. Chest 1995;107:1698–1701. Rosen GH, Boullata JI, O’Rangers EA, Enow NB, Shin B: Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia. Crit Care Med 1995;23:1204–1210.
Calcium Metabolism
85
63 64 65 66
67
68 69 70 71 72 73
74
75 76 77
78 79
80 81
Perreault MM, Ostrop NJ, Tierney MG: Efficacy and safety of intravenous phosphate replacement in critically ill patients. Ann Pharmacother 1997;31:683–688. Ryzen E, Wagers PW, Singer FR, Rude RK: Magnesium deficiency in a medical ICU population. Crit Care Med 1985;13:19–21. Guerin C, Cousin C, Mignot F, Manchon M, Fournier G: Serum and erythrocyte magnesium in critically ill patients. Intensive Care Med 1996;22:724–727. Sacks GS, Brown RO, Dickerson RN, Bhattacharya S, Lee PD, Mowatt-Larssen C, Ilardi G, Kudsk KA: Mononuclear blood cell magnesium content and serum magnesium concentration in critically ill hypomagnesemic patients after replacement therapy. Nutrition 1997;13:303–308. Saur PM, Zielmann S, Roth AT, Frank L, Warneke G, Radke A, Ensink FB, Kettler D: Diagnosis of magnesium deficiency in intensive care patients. Ana¨sthesiol Intensivmed Notfallmed Schmerzther 1996;31:37–41. Sherwood RA, Aryanayagam P, Rocks BF, Mankikar GD: Hypomagnesemia in the elderly. Gerontology 1986;32:105–109. Whyte KF, Addis GJ, Whitesmith R, Reid JL: Adrenergic control of plasma magnesium in man. Clin Sci 1987;72:135–138. Zaloga GP, Chernow B, Pock A, Wood B, Zaritsky A, Zucher A: Hypomagnesemia is a common complication of aminoglycoside therapy. Surg Gynecol Obstet 1984;158:561–565. Ryan MP: Diuretics and potassium/magnesium depletion: Directions for treatment. Am J Med 1987;82:38–47. Sheehan J, White A: Diuretic-associated hypomagnesemia. Br Med J 1982;285:1157–1159. Salem M, Kasinski N, Munoz R, Chernow B: Progressive magnesium deficiency increases mortality from endotoxin challenge: Protective effects of acute magnesium replacement therapy. Crit Care Med 1995;23:108–118. Hamill-Ruth RJ, McGory R: Magnesium repletion and its effect on potassium homeostasis in critically ill adults: Results of a double-blind, randomized, controlled trial. Crit Care Med 1996; 24:38–45. De Bastiani G, Mosconi F, Spagnol G, Nicolato A, Ferrari S, Aprili G: High calcitonin levels in unconscious polytrauma patients. J Bone Joint Surg 1992;74:101–104. Lind L, Bucht E, Ljunghall S: Pronounced elevation in circulating calcitonin in critical care patients is related to the severity of illness and survival. Intensive Care Med 1995;21:63–66. Zeni F, Viallon A, Assicot M, Tardy B, Vindimian V, Page Y, Lafond P, Bertrand JC, Bohuon C: Procalcitonin serum concentrations and severity of sepsis (abstract). Clin Intensive Care Suppl 1994; 5:2. Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, Bohuon C: Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab 1994;79:1605–1608. Gramm HJ, Dollinger P, Beier W: Procalcitonin – Ein neuer Marker der inflammatorischen Wirtsantwort. Longitudinalstudien bei Patienten mit Sepsis und Peritonitis. Chir Gastroenterol 1995;11: 51–54. Davis TME, Assicot M, Bohuon C, St John A, Li GQ, Anh TK: Serum procalcitonin concentrations in acute malaria. Trans R Soc Trop Med Hyg 1994;88:670–671. O’Neill WJ, Jordan MH, Lewis MS, Snider RH, Moore ChF, Becker KL: Serum calcitonin may be a marker for inhalation injury in burns. J Burn Care Rehabil 1992;13:605–616.
Dr. Lars Lind, Department of Internal Medicine, University Hospital, S–751 85 Uppsala (Sweden) Tel. +46 18 66 13 92, Fax +46 18 51 18 90, E-Mail
[email protected] Lind/Ljunghall
86
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 87–109
............................
Thyroid Hormones G. Hennemann, E.P. Krenning Department of Nuclear Medicine, University Hospital Rotterdam, The Netherlands
Contents Introduction ............................................................................................... 87 Alterations in Serum Binding and Concentration of Thyroid Hormones in Illness and in Starvation .................................................................................. 88 Kinetics of Thyroid Hormones in Nonthyroidal Illness and in Starvation .............. 90 90 T4 and T3 Kinetics ................................................................................ 91 3,3,5-Triidothyronine (Reverse T3, rT3) Kinetics ........................................ Pathophysiology Underlying the Abnormal Iodothyronine Serum Profile in NTI and Starvation ........................................................................................... 92 93 Pathophysiology of the Low Plasma T3 Production in NTI and Starvation ............ 93 Inhibition of T4 Uptake into the Liver ...................................................... 95 Inhibition of Liver T4 to T3 Conversion .................................................... Decrease in Cofactor Availability in NTI and Starvation ............................. 95 Decrease in ID-I Protein ........................................................................ 96 Other Factors ...................................................................................... 97 98 Pathophysiology of Abnormal Reverse T3 Kinetics in NTI and in Starvation ......... Thyroid-Stimulating Hormone in NTI and in Starvation ................................... 98 99 Tissue Effects of the Low T3 Syndrome ........................................................... The Low T3 Syndrome: Adaptation or Maladaptation, to Treat or Not to Treat? .... 102 References .................................................................................................. 104
Introduction During illness, but also in caloric deprivation, serum concentrations of thyroid hormones are often found to be abnormal. These abnormalities follow a pattern that is related to the severity of disease (fig. 1). The abnormal thyroid hormone values are the result of changes in serum binding of thyroid hormones and alterations in thyroid hormone production rates and metabolic clearances. The most constant finding is a low serum 3,3,5-triiodothyronine (T3) level
Serum thyroid horm one levels
High TT4
Norm al TT4
Low TT4 Total rT3
Norm al range
Free T4D
Total T4
Total T3
M ild
M oderate Severity of illness
Severe
Fig. 1. Schematic representation of the continuum of changes in serum thyroid hormone levels in patients with nonthyroidal disorders relative to the severity of the illness [from 14, p. 299, with permission].
that progressively decreases with increasing severity of disease and that is always lowered as well during caloric deprivation. The abnormal serum thyroid hormone profile is present in so-called nonthyroidal illness, i.e. all acute and chronic illnesses that have a clinical impact and, as mentioned, in caloric deprivation. As the low serum T3 level is the most characteristic feature, the term ‘low T3 syndrome’ is used synonymously with the term ‘euthyroid sick syndrome’ because, despite the low serum T3, patients seem clinically to be euthyroid. The following aspects will be discussed: alterations in serum binding and concentration of thyroid hormones; alterations in thyroid hormone kinetics during illness and starvation; the biological significance of the low T3 syndrome, and whether thyroid hormone treatment in the low T3 syndrome is effective.
Allterations in Serum Binding and Concentration of Thyroid Hormones in Illness and in Starvation There are three major thyroid hormone-binding proteins present in human serum, namely thyroxine-binding globulin (TBG), transthyretin (TTR, preal-
Hennemann/Krenning
88
bumin) and albumin. Normally about 0.03% of 3,3,5,5-tetraiodothyronine (thyroxine, T4) and 0.3% of T3 is in the free form, while the remaining is bound to these three major thyroid hormone-binding proteins. TBG binds about 70% of circulating T4 and T3, TTR 10–20%, and albumin about 10–20% [1, 2]. A minor fraction of T4 and T3 is carried by lipoproteins [3]. As TBG is the most important binding protein, changes in its concentration markedly affect total T4 and T3 concentrations. Thus, in pregnancy, when TBG capacity is elevated, and in congenital TBG deficiency, total T4 and T3 levels are increased and decreased respectively [4]. Changes in total thyroid hormone levels in illness and in starvation are the result of alterations in thyroid hormone-binding capacity of serum proteins and thyroid hormone production and clearance rates (see below). The capacity of all three binding proteins to bind thyroid hormone is generally decreased in nonthyroidal illness [5, 6]. Also, in starvation decreased capacities of thyroid hormone-binding proteins have been reported [7]. Although low albumin and TTR capacity to bind thyroid hormone in catabolic states, as in nonthyroidal illness and starvation, really reflect low protein concentrations, there is controversy with regard to the cause of the lowered capacity of TBG to bind thyroxine. It has been postulated that in serum of patients with nonthyroid illness (NTI), low binding of T4 by TBG is caused, at least in some patients, by a circulating inhibitor [8, 9]. However, others could not find evidence of such an inhibitor [10, 11]. One of these studies [10] suggested that lowered binding of T4 to TBG was caused by an increased percentage of desialylated TBG exhibiting lowered affinity for T4 but having normal immunoreactivity. This slow (S)-TBG migrates slowly on electrophoresis and has been found to be present in NTI [12]. TBG as determined by radioimmunoassay may be elevated in patients with liver disease such as hepatitis, cirrhosis or primary carcinoma [13]. Total and free T4 are often somewhat increased in mild NTI, normal or low normal in moderate NTI and decreased in critical illness. T4 production rate is usually normal in NTI and starvation, but may be slightly decreased in severe illness, whilst plasma T4 clearance is generally decreased (see below). The initially increased T4 parameters are explained by a normal production rate in combination with decreased plasma disappearance [6, 14]. With increasing severity of the clinical condition, protein binding of T4 in plasma diminishes resulting in a decrease of total plasma T4, that is often subnormal in critical illness. There are problems with the interpretation of free T4 estimates. Although determination of free thyroid hormone concentrations using the tracer equilibrium dialysis method is considered by many as the gold standard, underestimation of the free concentration occurs at low levels of thyroid hormone-binding proteins, notably TBG [15]. There is a vast literature with regard to the accuracy of free thyroid hormone measurements. There is probably no method available that measures
Thyroid Hormones
89
the free hormone moiety in a direct way in undiluted serum in physiological conditions. There are various types of kits on the market for free T4 and T3 determination, that estimate different concentrations under different conditions and are not comparable. The most promising methods (not generally available) are probably direct equilibrium dialysis and ultrafiltration of undiluted serum. These methods yield normal free T4 values in critical disease [16]. For further reviews see Stockigt et al. [4] and Docter et al. [6]. Total and free T3 values are generally reported to be decreased in accordance with normal plasma T3 clearance but diminished production (see below) and the decrease correlates with severity of disease [6]. Recently however, normal free T3 concentrations in NTI have been reported using the technique of ultrafiltration and immunoextraction [17]. Serum levels of reverse T3 are increased in most of the patients with NTI and in starvation. However, in patients with renal disease total rT3 concentrations are generally normal [18].
Kinetics of Thyroid Hormones in Nonthyroidal Ilness and in Starvation T4 and T3 Kinetics Although in the rat the low T3 syndrome is caused not only by decreased T3 production from T4 but, more importantly, by a decreased T4 production rate [19], T4 production rate in man is usually normal in NTI and in starvation, but sometimes modestly decreased in severe illness [14]. Uptake of T4 into tissues, as reflected by the fractional plasma exit rate (Kii), is decreased in various forms of NTI and in caloric deprivation [14, 20]. In the healthy human about 20% of plasma T3 production originates from direct thyroidal secretion, whereas the remaining 80% is generated from T4 in peripheral tissues in which the liver plays an important role [21]. Thyroidal T3 production in NTI has been found to be normal [22], but peripheral T3 production rate is invariably decreased in NTI and in starvation, while Kii is usually normal [23, 24]. From this it can be concluded that low plasma T3 values are the result of the low plasma T4 production rate (fig. 2) and as thyroidal secretion of T3 in these situations is normal, the decreased production rate is confined to extrathyroidal T3 generation from T4. It follows that, as the T4 production rate is usually normal or only slightly affected in NTI and in starvation, the decreased production rate of T3 from T4 finds its origin in a decreased effective T4 to T3 conversion rate. This may be either due to (1) decreased availability of T4 for conversion to T3 and/or (2) a decreased T4 to T3 conversion rate per se. Kinetically, both mechanisms will be reflected by a reduced net tissue uptake of T4 in T3-producing tissues. Indeed, such a phenomenon has been found in patients with NTI and during starvation. In a group of patients with acute
Hennemann/Krenning
90
% 100
0 A
B T3
C
Fig. 2. T3 kinetics in the low T3 syndrome. A>Serum concentration; B>plasma clearance; C>production rate (% of normal value).
critical NTI, transfer of serum T4 to tissues was inhibited by 50% and plasma T3 production rate was decreased by 75% [24]. In these subjects, plasma T4 production rate was mostly within the normal range as was serum exit of T3. An inhibition of T4 tissue uptake of 50% would lead to a 50% decrease in plasma T3 production if the conversion reaction itself was not impaired. The fact that T3 production rate is more suppressed than tissue uptake of T4 suggests an additional effect, that is a decrease of enzyme 5-deiodinating activity (catalyzes T4 to T3 deiodination). This enzyme (type I iodothyronine deiodinase (ID-I)), is located in the human liver and plays a major role in plasma T3 production. The contribution of skeletal muscle, which contains type II iodothyronine deiodinase (ID-II) that catalizes the same reaction to plasma T3 production in healthy subjects and in the low T3 syndrome, is not known at present [25]. In a further study in NTI it was found that entry of T4 into the rapid equilibrating compartment (REP; liver and kidney), was inhibited by 70%, whereas inhibition of T4 uptake into the slowly equilibrating compartment (SEP; nonhepatic, nonrenal tissues) amounted to about 30% [27]. Several other studies also found a reduced uptake of T4 into the REP in NTI [26]. A 29% decrease of T4 transport into the REP was reported in subjects during caloric deprivation, whereas plasma T3 production rate was decreased by 42%, again suggesting that both T4 transport and 5-deiodinase activity were involved [23]. 3,3,5-Triidothyronine (Reverse T3, rT3) Kinetics Virtually all plasma rT3 is produced outside the thyroid gland. It is produced from T4 in 5-deiodinase type III (ID-III)-containing tissues such as
Thyroid Hormones
91
%
100
0 A
B rT3
C
Fig. 3. rT3 kinetics in the low T3 syndrome. A>Serum concentration; B>plasma clearance; C>production rate (% of normal value).
brain, skin and placenta [31]. Plasma rT3 production rates are normal during NTI and starvation, but the metabolic clearance rate (MCR) that occurs exclusively by the liver [32] is markedly inhibited. In a study of patients with severe acute NTI due to varied diseases, 60% inhibition of MCR was noted [24]. Others [33] found in patients with NTI due to liver cirrhosis a reduced MCR of 45%. In obese, but otherwise healthy subjects, a 13-day fast resulted in a reduction of rT3 MCR of about 30% [34]. Thus, in NTI and starvation elevated rT3 levels are explained by a decreased plasma clearance of rT3 while production rate remains unaltered (fig. 3). An exception to the general finding of increased serum rT3 concentration is end-stage renal disease where rT3 concentrations in serum, plasma production and MCRs are normal [18]. Serum rT3 values are normal or reduced in patients with acute renal failure, nephrotic syndrome, AIDS, and primary hyperparathyroidism, but here alterations are seen in rT3 plasma production and clearance rates [36].
Pathophysiology Underlying the Abnormal Iodothyronine Serum Profile in NTI and Starvation The elevated total and free T4 levels occasionally seen in mild disease are explained by a normal T4 production rate but decreased tissue uptake of T4, while the decrease in total T4 with increasing severity of disease is predominantly explained by a decreased capacity of serum proteins to bind thyroxine [36] (see also above). As serum T3 is less avidly bound to TBG than is T4, the
Hennemann/Krenning
92
Table 1. Factors that inhibit T4 uptake into liver cells 1. Decrease in hepatocyte ATP concentration 2. Serum compounds 3-Carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) Indoxyl sulfate Bilirubin Nonesterified fatty acids 3. Drugs Amiodarone X-ray contrast agents
decrease in serum T3 is mainly determined by its decreased plasma production rate, whilst the increase in serum rT3 is explained by its decreased metabolic clearance by the liver (see above). In the following paragraphs the mechanisms underlying the decreased plasma T3 production rate, in the so-called low T3 syndrome, and the elevated plasma rT3 levels, will be discussed.
Pathophysiology of the Low Plasma T3 Production in NTI and Starvation Evidence has been found both for inhibition of T4 uptake into liver cells and for inhibition of conversion of T4 into T3 in the liver as the cause of the low T3 syndrome. Both these phenomena contribute to the decrease in plasma T4 clearance in patients with NTI or starvation and will be separately discussed below. Inhibition of T4 Uptake into the Liver (table 1) As uptake and metabolic handling of thyroid hormones by rat hepatocytes is very similar to that by human hepatocytes [37, 38], rat hepatocytes can be used as a model for iodothyronine handling by human hepatocytes. ATP dependency of uptake of T4 and T3 has been shown both in rat and in human hepatocytes [37, 39], and a small decrease of ATP concentration results in a marked inhibition of T4 (and rT3) entry into hepatocytes, but only a mild inhibition of T3 entry (fig. 4). Studies in humans, injected with fructose to decrease liver ATP, showed a decreased uptake of T4 into the REP. Studies in perfused intact rat livers showed similar effects and the inhibitioin of T4 transport into the liver was paralleled by decreases in liver ATP [40]. Decreased liver ATP concentrations have been detected in humans and rats using in vivo
Thyroid Hormones
93
100 T3 s rT3
Uptake (% of control)
T4
s
50
s
s
s
s ]
× s
s
s
s
10
2
0
1
Fructose
0 0
s 4
s 6.7 m M
Glucose 50
100
Cellular ATP (% of control)
Fig. 4. Uptake of T3, rT3 and T4 versus ATP concentration in rat hepatocytes [from 39, with permission].
hepatic 31P-magnetic resonance spectroscopy during fructose infusion, NTI and starvation [41–44]. From all these studies it is apparent that a decrease in liver ATP could very well have an inhibitory effect on T4 transport into the liver and contribute to low plasma T3 production in NTI and starvation. Important factors in the induction of the low T3 syndrome in humans are several circulating substances that are present in increased amounts in patients with NTI and in starvation and inhibit T4 entry into liver cells. In uremics, these substances are the furan fatty acid 3-caboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate. Bilirubin, that is often increased not only in patients with liver disease but generally in critically ill subjects, and nonesterified acids (NEFA) that are also often increased in NTI and also in caloric deprivation, are also important [45–47]. These substances may act in various combinations and concentrations in the spectrum of NTI. Further evidence that serum factors inhibiting T4 entry into the liver may have an effect on plasma T3 production, has recently been reported [48]. In this study it was shown (fig. 5) that patients whose serum had a greater inhibitory activity on T4 transport into rat hepatocytes had lower serum T3 concentrations. Lower values of T4 have been found in livers of 12 patients dying from NTI than in
Hennemann/Krenning
94
4 r = 0.69
Serum T3 (nm ol/l)
3
2
1
0 0
25
50
75
100
125
150
% Iodide production from T4
Fig. 5. Relationship between iodide production from T4, as a measure for cellular uptake in cultured rat hepatocytes, in the presence of NTI serum (expressed as percentage of uptake in the presence of normal serum) and serum T3. r>0.69 [from 41, with permission].
10 healthy individuals dying suddenly from trauma; the mean decrease in T4 concentration was 33% [49]. Inhibition of Liver T4 to T3 Conversion (table 2) The evidence for inhibition of T4 to T3 conversion in the liver in humans is more indirect than for inhibition of T4 uptake by the liver because, for obvious reasons, direct determination of liver ID-I activity in humans is difficult. On the other hand, metabolism such as deiodination, in rat hepatocytes is qualitatively similar to that in human hepatocytes and it is not unreasonable to assume that liver deiodinase in the human reacts similarly to NTI and starvation as in the rat. There is evidence from experiments in rats, that a decreased ID-I activity in NTI and in starvation is induced by two mechanisms, i.e. a decrease in cofactor availability and a decrease in enzyme concentration. Both aspects and the role of other factors will be separately discussed in the following sections. a. Decrease in Cofactor Availability in NTI and Starvation Deiodination of iodothyronine involves a reductive reaction in which the enzyme becomes oxidized and inactivated. The cofactors that may be involved
Thyroid Hormones
95
Table 2. Factors that inhibit T4 to T3 conversion in liver cells
Cofactor (-SH groups) depletion ID-I protein reduction Cytokines? Selenium deficiency Drugs Amiodarone X-ray contrast agents Propranolol Glucocorticoids
} Negative energy balance Insulin
Oxidation
s
Starvation Illness
1. 2. 3. 4. 5.
Glucagon
NEFA
s
s
Body fat
Peroxisom al H2O2
s
Peroxidase s
H2O2 + 2-glutathione-SH (GSH)
2 H2O + GSSG
Fig. 6. A negative energy balance during starvation and NTI leads to lipolysis and subsequent H2O2 production from NEFA oxidation in liver peroxisomes. Subsequent inactivation of H2O2 leads to cofactor (GSH) depletion.
in (re)activating (i.e. reducing) ID-I are glutathione, glutaredoxin, and thioredoxin. These compounds transfer reductive equivalents from NADPH to the enzyme [50]. A 50% decrease in ID-I activity has been found in livers of fasted rats, due to decrease in cofactor [51, 52]. In rats with NTI, induced by injury and during starvation, reduced levels of glutathione have been found in brain, heart, muscle, and liver [53]. The biochemical basis of cofactor reduction is schematically represented in figure 6. In NTI, as well as in starvation, the negative energy balance induces lipolysis under the stimulus of glucagon. The released NEFA are metabolized in liver peroxisomes resulting in the production of hydrogen peroxide. Hydrogen peroxide, a toxic substance rendering oxygen radicals, is detoxified by peroxidase using the same cofactors as reducing agents. Depletion of reduced cofactors by this reaction results in less availability of these compounds for reactivation of ID-I. The decrease in reduced cofactors during starvation occurs within 24 h. Dependency of the human ID-I on the presence of reducing cofactors has been established [54].
Hennemann/Krenning
96
b. Decrease in ID-I Protein In liver homogenates and in liver slices from fasted rats, a substantial (30–50%) reduction in 5-deiodination has been found due to a decrease in enzyme protein [for review, see 55]. In these experiments the conclusion that protein synthesis was decreased was based on a decreased Vmax of the reaction. Subsequently, a decrease in ID-I-mRNA was shown to be present in rat liver in starvation and in NTI caused by streptozotocin-induced diabetes mellitus. The decrease in hepatic ID-I-mRNA was seen at day 2 of starvation while ID-I protein concentration was still normal; ID-I protein decreased between days 2 and 4. As administration of T3 during fasting restores ID-I concentrations, it is concluded that the decrease in ID-I protein is caused by tissue hypothyroidism that in turn is caused by the mechanisms related to transport of T4 into the liver (see above) and the decrease in cofactor availability for the 5-ID-I catalyzed reaction [55]. c. Other Factors The role of cytokines such as tumor necrosis factor- (TNF-), interleukin (IL)-1 and IL-6 in the induction of the low T3 syndrome by inhibition of ID-I is uncertain. In rats, administration of IL-1, IL-6 and TNF- have been reported to induce an NTI-like syndrome [56–58]. However, in none of these studies was ID-I activity actually measured and, serum TSH was suppressed [56, 58]. In another study the effect of these three cytokines was measured on ID-I enzyme activity and on ID-I-mRNA levels in rat liver cells. It appeared that all three cytokines stimulated ID-I activity but left ID-I-mRNA levels unchanged [59], thus not supporting the hypothesis that these cytokines exert their effects via ID-I inhbition, but rather by suppression of thyroid function. The role of cytokines in humans is also uncertain. Intravenous administration of IL-6, TNF-, or interferon- [60–62] induced a thyroid hormone profile like NTI or starvation, in combination with a fall in serum TSH [60, 61]. Negative correlations between IL-6 or TNF- and serum T3 levels have been reported in a variety of diseases [63, 64]. These findings, however, were not confirmed in another study [65]. It should be noted that administration of cytokines often induces general malaise with fever and it is therefore also possible that these substances cause the low T3 syndrome indirectly. Further studies are necessary with respect to the influence of cytokines on the induction of the abnormal thyroid hormone profile. Several drugs, such as amiodarone and X-ray contrast agents, can influence thyroid function and thyroid hormone metabolism, some of them mimicking the low T3 syndrome [for reviews, see 66, 67]. All three deiodinases are socalled selenoenzymes. For practical reasons this means that selenium should be present for the enzymes to exert their function. In a recent report, selenium
Thyroid Hormones
97
deficiency was documented in intensive care unit patients and selenium levels correlated with serum T3 values, suggesting that in this group selenium deficiency may be added to the causes of the low T3 syndrome [68].
Pathophysiology of Abnormal Reverse T3 Kinetics in NTI and in Starvation Plasma rT3 is virtually all produced by 5-deiodination of T4 by ID-IIIcontaining tissues, i.e. brain, skin and placenta. Although ID-I catalyzes both 5- and 5-deiodination, the rT3 produced in the liver is locally further deiodinated and does not reach the plasma compartment [32]. The reduced metabolic clearance rate that is usually present in NTI and in starvation is explained by a reduced uptake and deiodination of rT3 by the liver [6]. It is assumed that rT3 deiodination is impaired on the same basis as that found for decreased T4 to T3 generation (see above). The inhibition of rT3 liver uptake is also suggested to be caused by ATP depletion as, like T4, rT3 uptake is markedly reduced even by a small decrease in liver ATP [40]. To our knowledge no studies have been performed to study the effect of serum inhibitors on rT3 transport into the liver as have been done for T4. Although a similar dependency on ATP of liver uptake of T4 and rT3 suggests a shared uptake mechanism, recent evidence from studies in humans suggests that this is not the case [69]. Two conclusions can be drawn from the fact that plasma rT3 production rate is normal. First, that T4 transport in ID-III-containing tissues is normal (to provide a substrate for reverse T3 production), and secondly, that ID-III activity is not inhibited in NTI and in starvation.
Thyroid-Stimulating Hormone in NTI and in Starvation In situtions that induce the low T3 syndrome, serum thyroid-stimulating hormone (TSH) values are usually normal. In a study in 374 hospitalized patients with NTI, the specificity of the second-generation TSH assay (immunoradiometric assay, IRMA) was 97%. In other words, only 3% of patients with the low T3 syndrome had serum TSH values outside the normal range. In a study using a third-generation TSH assay based on chemiluminescent labelling it appeared that 68% of those patients that had undetectable TSH levels, using the IRMA technique, actually had detectable levels using this sensitive method, although all were below the lower normal level [70, 71]. Thus in patients with NTI, serum TSH measurement is the first parameter and the best one to distinguish between normal and abnormal thyroid function.
Hennemann/Krenning
98
The question of why serum TSH is inappropriately low for the prevailing low T3 and sometimes also low T4 serum values is difficult to answer. In the first place, recent but unconfirmed studies suggest that free T4 and free T3 may be normal despite low total T4 and T3 concentrations (see above), but there is a small proportion of patients who have TSH levels suppressed below normal. Furthermore, serum TSH bioactivity has been found to be increased in the majority of critically ill patients [72], possibly due to decreased TSH sialylation [73]. It has been suggested that 3,3,5-triodothyroacetic acid (T3-AC), a T3 metabolite, is produced in large amounts in NTI [74]. Studies were performed using rat pituitaries to evaluate the TSH-suppressive effects of iodothyronines and these showed that, on a molar basis, T3-AC was more active than T3 to suppress TSH, while 3,3,5,5-tetraiodothyroacetic acid (T4-AC), a metabolite of T4, was less potent than T3, but more than T4 [75, 76]. T4-AC has also been suggested to act as a TSH suppressor in NTI [77]. These findings underline the possibility of a role for these thyroid hormone analogues in keeping TSH low during the low T3 syndrome. In another study, elevated levels of 3,5diiodothyronine (3,5-T2) were found in sera of patients with NTI [78] and as this iodothyronine metabolite possesses metabolic activity at the mitochondrial level [79] it may also contribute to the TSH-suppressive effect in the low T3 syndrome. Cytokines are produced in increased amounts in NTI in humans and experiments in rats have shown that both IL-1 and IL-6 suppress TSH release from the pituitary [80–82]. Serum cortisol levels are increased in stress situations like NTI and starvation, and are also known to suppress serum TSH. It has recently been published that neuromedin, with known TSHsuppressive activity, is elevated in rat pituitaries during NTI caused by diabetes mellitus and starvation [83]. Although mean TSH levels are mostly normal in NTI, nocturnal TSH secretion is frequently decreased while abnormalities in pulse frequency and amplitude are present [84, 85]. Recently, decreased hypothalamic TRH-gene expression has been found in patients who died from nonthyroidal illness. Furthermore, a positive correlation of TRH-mRNA was found with serum T3 and with log TSH but not with serum T4 [86]. When patients recover from NTI a mild temporary increase in serum TSH is often seen [87]. A schematic representation of factors involved in the generation of the low T3 syndrome is shown in figure 7.
Tissue Effects of the Low T3 Syndrome As the induction of the low T3 syndrome in the rat is primarily due to a decrease in thyroid function and therefore a true situation of hypothyrodism, any comparison at the tissue level with the situation in the human is inappro-
Thyroid Hormones
99
-?
-
TRH + T3-AC -
-? -?
-
T4-AC
Neurom edin ? Cortisol Cytokines ?
TSH +
T4-AC 3,5-T2
T4
T4
T3-AC CM PF Bilirubin
-
+ ATP
NEFA Indoxyl sulfate T3 T4 + SH groups Selenium
T3 To other organs
Fig. 7. Factors operative in the low T3 syndrome in nonthyroidal illness and in starvation (for explanation, see text). T3-AC>3,3,5-Triiodothyroacetic acid (TRIAC); T4-AC>3,3,5,5tetraiodothyroacetic acid (TETRAC); CMPF>3-carboxyl-4-methyl-5-propyl-2-furan propanoic acid; NEFA>nonesterified fatty acids.
Hennemann/Krenning
100
priate. Indeed, in the human, thyroid secretion of T4 and T3 is usually normal during NTI and in starvation. As T4 is mainly a prohormone with little, if any, biological activity that becomes activated upon conversion to T3, the question of whether humans suffering from the low T3 syndrome are hypothyroid or, by some adaptation euthyroid, is very important. For obvious reasons no data in humans are available which measure thyroid hormone effects at the tissue level during illness and caloric deprivation. All of the (limited) data are thus indirect. During caloric deprivation energy expenditure, as reflected by oxygen consumption, is decreased in parallel with a reduction in the thyroid hormone-responsive enzyme -glycerol phosphate dehydrogenase in adipose tissue [88]. In a later study it was shown that the redution in oxygen consumption reverted to normal when physiological doses of T3 were administered without changing calory intake [89]. The QKd interval, being the time interval between the Q wave on the electrocardiogram and the onset of the Korotkoff sounds at diastolic pressure at the brachial artery, represents the pre-ejection period and pulse transmission time. The QKd interval has been shown to be a sensitive and effective measure of thyroid hormone effect. In a 2-week period of calory restriction in obese volunteers, this interval was significantly prolonged but normalized upon addition of T3. Also the fall in pulse rate during diet reverts to normal with T3 administration [90]. A classical clinical sign of tissue hypothyroidism is the prolongation of the Achilles reflex half-relaxation time (ART). In patients with anorexia nervosa the ART is prolonged and it appears that a low dose of T3 daily can normalize the ART in these patients (fig. 8) [91]. From these reports it is suggested that tissue hypothyroidism is created by restricted caloric intake, because the situation can be normalized by administration of physiological doses of T3. Serum angiotensin-converting enzyme is depressed in hypothyroid patients and in a study in patients with NTI even lower levels were found [92]. Also, a negative correlation between T3 and delivery-dependent oxygen consumption was found in severely ill patients [93]. In contrast, no correlation was found between thyroid hormonedependent sex hormone-binding globulin or osteocalcin, and serum T3 levels in patients with systemic NTI [94]. When T3 receptor mRNAs were measured in peripheral mononuclear cells, increased expression was found in patients with NTI that may be a compensatory mechanism for the low serum T3 levels and explain clinical euthyroidism [95]. The ratio of rubidium uptake to the number of pump units in the same cell, which is a useful index of peripheral thyroid hormone status, was found to be normal in the low T3 syndrome due to chronic renal failue or neoplastic disorders [96]. Thus from these studies that are to a certain degree all indirect ones, no clear picture emerges with regard to the thyroid hormone status of the tissues. Further studies into this area are certainly necessary.
Thyroid Hormones
101
580 540 500
20
380 340 300 260 220
a
0
420
180
ART fall (m s)
ART (m s)
460
40 60 80 100 120 140 160 Norm al
Anorexia
b
Fig. 8. a The Achilles reflex half-relaxation time (ART) in patients with anorexia nervosa. The shaded area represents the normal range (mean×2 SD). b The fall in ART after 4 weeks of treatment with oral T3 40 g daily in 18 euthyroid subjects and 11 patients with anorexia nervosa [from 79, with permission].
The Low T3 Syndrome: Adaptation or Maladaptation, to Treat or Not to Treat? Studies to investigate the question of whether the low T3 syndrome is an advantageous adaptation during stress, illness or caloric deprivation, or whether the opposite, i.e. that decreased T3 production worsens the situation, have focused on subjects during caloric deprivation. Systemic illness is too complex a condition as many other factors such as the type of disease, fever and effects of drugs, complicate interpretation of the results. Two aspects of caloric deprivation have been studied, namely the relationship between oxygen need and the decrease in serum T3 and the effects of lowered plasma T3 on protein metabolism. Over 30 years ago it was shown that when obese subjects were put on a caloric-restricted diet, the resulting decrease in oxygen consumption was restored to the initial level when T3 was administered. The dose administered was, however, very high, i.e. 250 g/day [97]. In a similar study of obese women, administration of 60 g T3 /day prevented the decrease in basal metabolic rate that occurred in a control group without T3 treatment [102]. Even administration of a dose as low as 10 g/day prevented a decrease in oxygen consumption during a restricted diet consisting only of protein as
Hennemann/Krenning
102
compared to control obese subjects [98]. In a recent study the decrease in oxygen consumption and CO2 production during fasting did not subsequenly reverse after administration of 60 g T3 daily for 3 days. In this study, however, a control group without T3 supplementation was lacking [99]. The results described here suggest that the decrease in oxygen consumption during caloric deprivation is causally related to the decrease in T3 production as administration of T3 restores energy expenditure to pre-diet levels. Furthermore, it seems that this effect is induced by a wide range of T3 doses suggesting a permissive effect of T3 rather than a dose-dependent effect. With regard to the significance of the low T3 syndrome in starvation as a protein-sparing phenomemon, results are controversial. When normal men were fasted for 80 h without T3 supplementation and then fasting was repeated, with the administration of 5 g T3 every 3 h, protein excretion was significantly higher in the second test period [100]. In another study in obese subjects on a low calory diet for 4 weeks, protein loss was inversely related to the fall in plasma T3 during the first 2 weeks of this period, but increased significantly during the second 2 weeks when 150 g T3 daily was administered, while the control group without T3 supplementation had significantly lower protein loss [101]. In other studies, however, no increase in protein loss was seen during caloric restriction with concomitant administration of T3 as compared to controls without T3. In one study, obese women subjected to a protein-sparing diet for 18 days did not lose more protein when concomitantly given 10 g T3 daily as compared to controls [98] while in another study using a dose of 60 g T3/day, that was administered during the second week of a 2-week fasting period, there was no change in protein metabolism as compared to a control group [102]. The differences in these results are not explained by the dose administered nor by the duration of starvation. Studies to evaluate the effects of thyroid hormone treatment in the low T3 syndrome, in particular in NTI, have not shown any important positive or negative effect on outcome. Intravenous administration of T4 in a dose of 1.5 g/kg/day for 14 days to 11 patients with severe NTI and low serum T4 and T3 did not alter outcome as compared to a control group of 12 similar patients not treated with T4. It is note worthy that in the T4-treated group serum T3 did not increase despite normalization of serum T4 [103]. T3 administration to patients with burn injury did not affect mortality as compared to placebo-treated controls [104]. More extensive studies have been performed in patients undergoing coronary artery bypass surgery. In a group of 142 patients undergoing this procedure and all having depressed left ventricular function, 0.8 g/kg T3 was administered as a bolus after completion of surgery with a subsequent 6-hour infusion of 0.113 g/kg T3/h. Although no difference in outcome was seen as compared to placebo treatment, T3 administration
Thyroid Hormones
103
increased cardiac output and lowered systemic vascular resistance [105]. A subsequent publication on the same study [106] reported that T3 administration also decreased the incidence and need for treatment of postoperative atrial fibrillation. In another study, however, an identical regimen of T3 administration to a similar group of patients did not show any dramatic effect on hemodynamic variables, other than an increase in heart rate [107]. One group concludes ‘while anecdotal clinical experience suggests that T3 repletion should be of clinical benefit, rigorous clinical trials have failed to support routine repletion of T3 in cardiac surgery. Based on the results of these clinical trials, we do not recommend routine administration of T3 to patients undergoing cardiac surgery’ [108]. It can be stated that, so far, routine administration is not warranted in the low T3 syndrome in general. Further investigations are necessary to assess the significance of lowered plasma T3 production as a defense mechanism in situations of stress.
References 1 2 3 4 5
6
7
8 9
10
11
12
Prince´ HP, Ramsden DB: A new theoretical description of the binding of thyroid hormones by serum proteins. Clin Endocrinol 1977;7:325–342. Robbins J, Bartalena L: Plasma transport of thyroid hormones; in Hennemann G (ed): Thyroid Hormone Metabolism. New York, Dekker, 1986, pp 3–38. Benvenga S, Gregg RE, Robbins J: Binding of thyroid hormones to human plasma lipoproteins. J Clin Endocrinol Metab 1988;67:616. Stockigt JR, Lim CF, Barlow JW, Topliss DJ: Thyroid hormone transport; in Weetman AP, Grossman A (eds): Pharmaco-Therapeutics of the Thyroid Gland. Berlin, Springer, 1997, pp 119–150. Csako G, Zweig MH, Glieckman J, Ruddel M, Ka¨stner J: Direct and indirect techniques for free thyroxine compared in patients with non-thyroidal illness. II. Effect of prealbumin, albumin, and thyroxine-binding globulin. Clin Chem 1989;35:1655–1662. Docter R, Krenning EP, de Jong M, Hennemann G: The sick euthyroid syndrome: Changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol 1993;39:499– 518. Tamai H, Mori K, Matsubayashi S, Kiyohara K, Nakagawa T, Okimura MC, Walter RM Jr, Kumagai LF, Nagataki S: Hypothalamic-pituitary-thyroidal dysfunctions in anorexia nervosa. Psychother Psychosom 1986;46:127–131. Chopra IJ, Huang TS, Bredero A, Solomon DH, Chua-Teco GN: Serum thyroid hormone binding inhibitor in nonthyroidal illnesses. Metabolism 1986;35:125–159. Wilcox RB, Nelson JC, Tomei RT: Heterogeneity in affinities of serum proteins for thyroxine among patients with non-thyroidal illness as indicated by the serum free thyroxine response to serum dilution. Eur J Endocrinol 1994;131:9–13. Mendel CM, Laughton CW, McMahon FA, Cavalieri RR: Inability to detect an inhibitor of thyroxine-serum protein binding in sera from patients with nonthyroidal illness. Metabolism 1991; 40:491–502. Benvenga S, Constante G, Melluso R, Luzza G, Pustorino S, Turiano S, Turimarchi F: Failure to find evidence of immunoglobulin inhibitor(s) of thyroid hormone binding to serum proteins in nonthyroid illness. Acta Endocrinol (Copenh) 1983;103:46–52. Reilly CP, Wellby L: Show thyroxine binding globulin in the pathogenesis of increased dialysable fraction of thyroxine in nonthyroidal illnesses. J Clin Endocrinol Metab 1983;57:15–18.
Hennemann/Krenning
104
13
14 15
16 17 18 19 20 21 22
23
24
25 26
27 28 29
30 31
32
33
34
Huang MJ, Liaw YF: Thyroxine-binding globulin in patients with chronic hepatitis B virus infection: Different implications in hepatitis and hepatocellular carcinoma. Am J Gastroenterol 1990;85: 281–284. Kaptein EM: Thyroid hormone metabolism in illness; in Hennemann G (ed): Thyroid Hormone Metabolism. New York, Dekker, 1986, pp 297–333. Nelson JC, Wilcox RB, Pandian MR: Dependence of free thyroxine estimates obtained with equilibrium tracer dialysis on the concentration of thyroxine-binding globulin. Clin Chem 1992;38: 1294–1300. Kaptein EM: Clinical application of free thyroxine determinations. Clin Lab Med 1993;13:653–672. Faber J, Sierbaek-Nielsen K: Serum free 3,5,3-triiodothyronine (T3) in non-thyroidal somatic illness, as measured by ultrafiltration and immunoextraction. Clin Chim Acta 1996;256:115–123. Kaptein EM: Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996;17:45–63. Kinlaw WB, Schwartz HL, Oppenheimer JH: Decreased serum triiodothyronine in starving rats is primarily due to diminished thyroidal secretion of thyroxine. J Clin Invest 1985;75:1238–1241. Docter R, Krenning EP: Role of cellular transport systems in the regulation of thyroid hormone bioactivity; in Greer MA (ed): The Thyroid Gland. New York, Raven Press, 1990, pp 233–254. Hennemann G: Thyroid hormone deiodination in healthy man; in Hennemann G (ed): Thyroid Hormone Metabolism. New York, Dekker, 1986, pp 277–298. Lim VS, Fang VS, Catz AI, Refetoff S: Thyroid dysfunction in chronic renal failure: A study of the pituitary-thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine. J Clin Invest 1977;60:522–534. Van der Heyden JTM, Docter R, van Toor H, Wilson JHP, Hennemann G, Krenning EP: Effects of caloric deprivation on thyroid hormone tissue uptake and generation of low T3 syndrome. Am J Physiol 1986;251:E156–E163. Kaptein EM, Robbinson WJ, Grieb DH, Nicoloff JT: Peripheral serum thyroxine, triiodothyronine and reverse triiodothyronine kinetics in the low thyroxine state of acute nonthyroidal illness. J Clin Invest 1981;69:526–535. Larsen PR: An update on thyroxine activation in humans; in Visser TJ, Krenning EP (eds): Thyroid International. Darmstadt, Merck, 1997, pp 8–14. Kaptein EM, Kaptein JS, Change EI, Egodage PM, Nicoloff JT, Massry SG: Thyroxine transfer and distribution in critical nonthyroidal illnesses, chronic renal failure, and chronic ethanol abuse. J Clin Endocrinol Metab 1987;65:606–616. Kaptein EM, Feinstein EI, Nicoloff JT, Massry SG: Serum reverse triiodothyronine and thyroxine kinetics in patients with chronic renal failure. J Clin Endocrinol Metab 1983;57:181–189. Lennon EJ, Engbring NH, Engstrom WW: Studies of the rate of disappearance of labeled thyroxine from the intravascular compartment. J Clin Invest 1961;40:996–1005. Oppenheimer JH, Bernstein G, Hasen J: Estimation of rapidly exchangeable cellular thyroxine from the plasma disappearance curves of simultaneously administered thyroxine-131I and albumin-125I. J Clin Invest 1967;46:762–777. Zaninovich AA, Volpe´ R, Soto RJ, Ezrin C: Accumulation and release of thyroid hormones by the normal and diseased human liver. Acta Endocrinol (Copenh) 1969;60:412–422. Hennemann G, Visser TJ: Thyroid hormone synthesis, plasma membrane transport and metabolism; in Weetman AP, Grossman A (eds): Handbook of Experimental Pharmacology. Berlin, Springer, 1997, pp 75–117. Bauer AGC, Wilson JHP, Lamberts SWJ, Docter R, Hennemann G, Visser TJ: Handing of iodothyronines by liver and kidney in patients with chronic liver disease. Acta Endocrinol (Copenh) 1987; 116:339–346. Faber J, Thomson HF, Lumholtz IB, Kirkegaard C, Siersbaek-Nielsen K, Friis T: Kinetic studies of thyroxine, 3,5,3-triiodothyronine, 3,3,5-triiodothyronine, 3,5-diiodothyronine, 3,3-diiodothyronine, and 3-monoiodothyronine in patients with liver cirrhosis. J Clin Endocrinol Metab 1981; 53:978–984. LoPresti JS, Gray D, Nicoloff JF: Influence of fasting and refeeding on 3,35-triiodothyronine metabolism in man. J Clin Endocrinol Metab 1991;72:130–136.
Thyroid Hormones
105
35
36 37
38
39
40
41 42
43
44
45
46
47
48
49 50
51 52 53
Kaptein EM: The effects of systemic illness on thyroid hormone metabolism; in Wu SY (ed): Current Issues in Endocrinology and Metabolism: Thyoid Hormone Metabolism – Regulation and Clinical Implications. Boston, Blackwell Scientific, 1991, pp 211–237. Kaptein EM: Clinical relevance of thyroid hormone alterations in nonthyroidal illness; in Visser TJ, Krenning EP (eds): Thyroid International. Darmstadt, Merck, 1997, pp 22–25. de Jong M, Visser TJ, Bernard HF, Docter R, Vos RA, Hennemann G, Krenning EP: Transport and metabolism of iodothyronines in cultured human hepatocytes. J Clin Endocrinol Metab 1993; 77:139–143. van Stralen PG, van der Hoek HJ, Docter R, de Jong M, Krenning EP, Everts ME, Hennemann G: Uptake and metabolism of 3,5,3-triiodothyronine and 3,3,5-triiodothyronine by human liverderived cells: HepG2 cells as a model for thyroid hormone handling by human liver. J Clin Endocrinol Metab 1996;81:244–248. Krenning EP, Docter R, Bernard HF, Visser TJ, Hennemann G: Decreased transport of thyroxine (T4), 3,3,5-triiodothyronine (T3) and 3,3,5-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs. FEBS Lett 1982;140:229–233. de Jong M, Docter R, Bernard HF, van der Heijden JT, van Toor H, Krenning EP, Hennemann G: T4 uptake into the perfused rat liver and liver T4 uptake in humans are inhibited by fructose. Am J Physiol 1994;266:E768–E775. Menon DK, Harris M, Sargentoni J, Taylor-Robinson SD, Cox IJ, Morgan MY: In vivo hepatic 31Pmagnetic resonance spectroscopy in chronic alcohol abusers. Gastroenterology 1959;108:776–788. Brinkmann G, Melchert UH, Lalk G, Emde L, Link J, Muhle C, Steffens JC, Heller M: The total entropy for evaluating 31P-magnetic resonance spectra of the liver in healthy volunteers and patients with metastases. Invest Radiol 1997;32:100–104. Masson S, Henriksen O, Stengaard A, Thomsen C, Quistoff B: Hepatic metabolism during constant infusion of fructose: Comparative studies with 31P-magnetic resonance spectroscopy in men and rats. Biochim Biophys Acta 1994;119:166–174. Bodoky G, Yang ZJ, Meguid MM, Laviano A, Szeverenyi N: Effects of fasting, intermittent feeding, or continuous parenteral nutrition on rat liver and brain energy metabolism as assessed by 31PNMR. Physiol Behav 1995;58:521–527. Lim CF, Bernard HF, de Jong M, Docter R, Krenning EP, Hennemann G: A furan fatty acid and indoxyl sulphate are the putative inhibitors of thyroxine hepatocyte transport in uremia. J Clin Endocrinol Metab 1993;76:318–324. Lim CF, Docter R, Visser TJ, Krenning EP, Bernard HF, van Toor H, de Jong M, Hennemann G: Inhibition of thyroxine transport into cultured rat hepatocytes by serum of non-uremic criticallyill patients by bilirubin and non-esterified fatty acids. J Clin Endocrinol Metab 1993;76:1165– 1172. Lim CF, Docter R, Krenning EP, van Toor H, Bernard HF, de Jong M, Hennemann G: Transport of thyroxine into cultured rat hepatocytes: Effects of mild non-thyroidal illness and caloric restriction in obese subjects. Clin Endocrinol 1994;40:79–85. Vos RA, de Jong M, Bernard HF, Docter R, Krenning EP, Hennemann G: Impaired thyroxine and 3,5,3-triiodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthyroidal illness. J Clin Endocrinol Metab 1995;80:2364–2370. Arem R, Wiener GJ, Kaplan SG, Kim HS, Reichlin S, Kaplan MM: Reduced tissue thyroid hormone levels in fatal illness. Metabolism 1993;42:1102–1108. Visser TJ: Role of glutathione and other thiols in thyroid hormone metabolism; in Dolphin D, Poulson R, Avramovic O (eds): Glutathione: Chemical, Biochemical, and Medical Aspects. New York, Wiley, 1989, part B, pp 572–612. Kaplan MM: Subcellular alterations causing reduced hepatic thyroxine 5-monodeiodinase activity in fasted rats. Endocrinology 1979;104:58–64. Leonard JL: Identification and structure analysis of iodothyronine deiodinases; in Greer MA (ed): The Thyroid Gland. New York, Raven Press, 1990, pp 285–306. Ma˚rtensson J, Goodwin CW, Blake R: Mitochondrial glutathione in hypermetabolic rats following burn injury and thyroid hormone administration: Evidence of a selective effect on brain glutathione by burn injury. Metabolism 1992;42:273–277.
Hennemann/Krenning
106
54 55 56
57 58
59 60
61 62
63
64
65 66 67 68 69 70
71
72
73 74 75
Visser TJ, Kaptein E, Terpstra OT, Krenning EP: Deiodination of thyroid hormone by human liver. J Clin Endocrinol Metab 1988;67:17–24. Kaplan MM: Regulatory influences on iodothyronine deiodination in animal tissues; in Hennemann G (ed): Thyroid Hormone Metabolism. New York, Dekker, 1986, pp 231–253. Hermus RM, Sweep CG, van der Meer MJ, Ross HA, Smals AG, Benraad TJ, Kloppenborg PW: Continuous infusion of interleukin-1-beta induces a nonthyroidal illness syndrome in the rat. Endocrinology 1992;131:2139–2146. Bartalena L, Grasso L, Brogioni S, Martino E: Interleukin-6 effects on the pituitary-thyroid axis in the rat. Eur J Endocrinol 1994;131:302–306. Pang XP, Hershman JM, Mirell CJ, Pekary AE: Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-alpha (Cachectin). Endocrinology 1989;125:76–84. Davies PH, Sheppard MC, Franklyn JA: Inflammatory cytokines and type I 5-deiodinase expression in PHI 1 rat liver cells. Mol Cell Endocrinol 1997;129:191–198. Stouthart JM, van der Poll T, Endert E, Bakker PJ, Veenhof CH, Sauerwein HP, Romijn JA: Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 1994;79:1342–1346. van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP: Tumor necrosis factor: A putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990;71:1567–1572. Corssmit EP, Heyligenberg R, Endert E, Sauerwein HP, Romijn JA: Acute effects of interferonalpha administration on thyroid hormone metabolism in healthy man. J Clin Endocrinol Metab 1995;80:3140–3144. Davies PH, Black EG, Sheppard MC, Franklin JA: Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness. Clin Endocrinol (Oxf) 1996;44:199–205. Boelen A, Schiphorst MCPT, Wiersinga WM: Soluble cytokine receptors and the low 3,5,3-triiodothyronine syndrome in patients with nonthyroidal disease. J Clin Endocrinol Metab 1995;80:971– 976. Chopra IJ, Sakane S, Teco GN: A study of the serum concentration of tumor necrosis factor-alpha in thyroidal and non-thyroidal illnesses. J Clin Endocrinol Metab 1991;72:1113–1116. Cavalieri RR: Effects of drugs on human thyroid hormone metabolism; in Hennemann G (ed): Thyroid Hormone Metabolism. New York, Dekker, 1986, pp 359–582. Cavalieri RR: The effects of nonthyroid disease and drugs on thyroid function tests. Med Clin North Am 1991;75:27–39. Berger MM, Lemarchand-Be´raud T, Cavadini C, Chiole´ro R: Relationship between selenium status and the low T3 syndrome after major trauma. Intensive Care Med 1996;22:575–581. Kaptein EM: Hormone-specific alterations of T4, T3, and reverse T3 metabolism with recent ethanol abstinence in humans. Am J Physiol 1997;272:E191–E200. Krenning EP, Docter R, van Toor H, Poppelaars AC, Postema PTE, Visser TJ, Hennemann G: Strategy of thyroid-function testing, a comparative study using TT4, FT4I, various FT4 and IRMATSH kits. J Endocrinol Invest 1986;9(suppl 4):95–104. Spencer CA, LoPresti JS, Patel A, Go¨ttler RB, Eigen A, Shen D, Gray D, Nicoloff JT: Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990;70:453–460. Kakezomo F, Yamashita S, Yokoyama N, Morita S, Kubo I, Ohtakaza S, Okamoto S, Marimoto I, Ikari N, Izumi M, Nagataki S: Stimulation of thyroid adenylate cyclase activity by sera from patients with non-thyroidal illness. Acta Endocrinol (Copenh) 1986;113:340–345. Magner J, Roy P, Fainter L, Barnard V, Fletcher P: Transiently decreased sialylation of thyrotropin (TSH) in a patient with euthyroid sick syndrome. Thyroid 1997;7:55–61. LoPresti JS, Dlott RS: Augmented conversion of T3 to TRIAC (T3AC) is the major regulator of the low T3 state in fasting man (abstract). Thyroid 1992;2(suppl 1):39. Everts ME, Visser TJ, Moerings EPCM, Docter R, van Toor H, Tempelaars AMP, de Jong M, Krenning EP, Hennemann G: Uptake of triiodothyroacetic acid and is effect on thyrotropin secretion in cultured anterior pituitary cells. Endocrinology 1994;135:2700–2707.
Thyroid Hormones
107
76
77 78
79
80 81
82
83
84 85 86
87
88 89 90
91 92
93
94
95
Everts ME, Visser TJ, Moerings EPCM, Tempelaars AMP, van Toor H, Docter R, de Jong M, Krenning EP, Hennemann G: Uptake of 3,3,5,5-tetraiodothyroacetic acid and 3,3,5-triiodothyronine in cultured rat anterior pituitary cells and their effects on thyrotropin secretion. Endocrinology 1995;136:4454–4461. Carlin K, Carlin S: Etiology for euthyroid sick syndrome. Med Hypoth 1993;40:38–43. Pinna G, Meinhold H, Hidra L, Thoma R, Hoell T, Gra¨f K-J, Stoltenburg-Didinger G, Eravci M, Prengel H, Bro¨del O, Finke R, Baumgartner A: Elevated 3,5-diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors. J Clin Endocrinol Metab 1997;83: 1535–1542. Lanni A, Moreno M, Lombardi A, Goglia F: Rapid stimulation in vitro of rat liver cytochrome oxidase activity by 3,5-diiodo-L-thyronine and by 3,3-diiodo-L-thyronine. Mol Cell Endocrinol 1994;99:89–94. Bartalena L, Grasso L, Brochioni S, Martino E: Interleukin-6 effects on the pituitary-thyroid axis in the rat. Eur J Endocrinol 1994;131:302–306. van Haasteren GAC, van der Meer MJM, Hermus ARMM, Linkels E, Klootwijk W, Kaptein E, van Toor H, Sweep CGJ, Visser TJ, de Greef WJ: Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroid axis. Endocrinology 1994; 135:1336–1345. Wassen FWJS, Moerings EPCM, van Toor H, de Vrey EA, Hennemann G, Everts ME: Effects of interleukin-1-beta on thyrotropin secretion and thyroid hormone uptake in cultured rat anteriorpituitary cells. Endocrinology 1996;137:1591–1598. Ortiga-Carvalho TM, Curty FH, Nascimento-Saba CC, Moura EG, Polak J, Pazos-Moura CC: Pituitary neuromedin B content in experimental fasting and diabetes mellitus and correlation with thyrotropin secretion. Metabolism 1997;46:149–153. Custro N, Scafidi V, Notarbartolo A: Alterations in circadian rhythm of serum thyrotropin in critically ill ptients. Acta Endocrinol (Copenh) 1992;127:18–22. Adriaanse R, Romijn JA, Brabant G, Endert E, Wiersinga WM: Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1313–1317. Fliers E, Guldenaar SEF, Wiersinga WM, Swaab DF: Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab 1997;82: 4032–4036. Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim C-F, Tuxen DV, Topliss DJ, Stockigt JR: Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab 1986;62:717–722. Bray GA: Effect of caloric restriction on energy expenditure in obese patients. Lancet 1969;ii: 397–398. Moore R, Grant AM, Howard AN, Millts IH: Treatment of obesity with triiodothyronine and a very-low-calory liquid formula diet. Lancet 1980;i:223–226. Osburn RC, Mayers EA, Rodbard D, Burman KD, Georgus LP, O’Brian JT: Adaptation to hypocaloric feeding: Physiologic significance of the fall in serum T3 as measured by the pulse wave arrival time (QKd). Metabolism 1983;32:9–13. Croxson MS, Ibbertson HK: Low serum triiodothyronine (T3) and hypothyrodism in anorexia nervosa. J Clin Endocrinol Metab 1977;44:167–174. Brent GA, Hershman JM, Reed AW, Sastre A, Lieberman J: Serum angiotensin-converting enzyme in severe nonthyroidal illnesses associated with low thyroxine concentration. Ann Intern Med 1984; 100:680–683. Palazzo MG, Suter PM: Delivery-dependent oxygen consumption in patients with septic shock: Daily variations, relationship with outcome and the sick-euthyroid syndrome. Intensive Care Med 1991;17:325–332. Seppel T, Becker A, Lippert F, Schlaghecke R: Serum sex hormone-binding globulin and osteocalcin in systemic nonthyroidal illness associated with low thyroid hormone concentrations. J Clin Endocrinol Metab 1996;81:1663–1665. Williams GR, Franklyn JA, Neuberger JM, Sheppard MC: Thyroid hormone receptor expression in the ‘sick euthyroid’ syndrome. Lancet 1989;ii:1477–1481.
Hennemann/Krenning
108
96
97
98 99 100 101 102
103 104
105 106
107
108
Ogasawara H, Nishikawa M: Evaluation of peripheral metabolic status by determination of Na-K ATPase pump activity in circulating erythrocytes in patients with thyroid diseases and nonthyroidal illnesses. Endocr J 1993;40:27–33. Bray GA: Effect of diet and triiodothyronine on the activity of sn-glycerol-3-phosphate dehydrogenase on the metabolism of glucose and pyruvate by adipose tissue of obese patients. J Clin Invest 1969;48:1413–1422. Rozen R, Abraham G, Falcou R, Apfelbaum M: Effects of a ‘physiological’ dose of triiodothyronine on obese subjects during a protein-sparing diet. Int J Obes 1986;10:303–312. Byerley LO, Heber D: Metabolic effects of triiodothyronine replacement during fasting in obese subjects. J Clin Endocrinol Metab 1996;81:968–976. Gardner DF, Kaplan MM, Stanley CA, Utiger RD: Effect of triiodothyronine replacement on the metabolic and pituitary responses to starvation. N Engl J Med 1979;100:579–584. Koppeschaar HPF, Meinders AE, Schwarz F: Metabolic responses in grossly obese subjects treated with a very-low-calorie diet with and without triiodothyronine treatment. Int J Obes 1983;7:133–141. Nair KS, Halliday D, Ford GC, Garrow JS: Effect of triiodothyronine on leucine kinetics, metabolic rate, glucose concentration and insulin secretion rate during two weeks of fasting in obese women. Int J Obes 1989;13:487–496. Brent GA, Hershman JM: Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986;63:1–8. Becker RA, Vaughn GM, Siegler MG, Seraile LG, Goldfarb IW, Mansour E, McManus WF, Pruitt BA Jr, Mason AD Jr: Hypermetabolic low triiodothyronine syndrome of burn injury. Crit Care Med 1982;10:870–875. Klemperer JD, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW, Krieger K: Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995;333:1522–1527. Klemperer JD, Klein I, Ojamaa K, Helm RE, Gomez M, Isom OW, Krieger KH: Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996; 61:1323–1327. Bennett-Guerro E, Jimenez JL, White WD, d’Amico EB, Baldwyn BI, Schwinn DA: Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo-controlled trial. Duke T3 study group. JAMA 1996;275: 687–692. Broderick TJ, Wechsler AS: Triiodothyronine in cardiac surgery. Thyroid 1997;7:133–145.
Prof Dr. G. Hennemann, Vijverweg 32, NL–3062 JP Rotterdam (The Netherlands) Tel. +31 10 4139898, Fax +31 10 4135504
Thyroid Hormones
109
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 110–130
............................
The Pituitary Adrenal Axis John Newell-Price a, Peter J. Trainer b Departments of Endocrinology, St Bartholomew’s Hospital, London, and The Christie Hospital, Manchester, UK
Contents Introduction ............................................................................................... Physiology .................................................................................................. Integration with the Immune System ............................................................... Assessment of the HPA Axis in Man .............................................................. Acute Responses ......................................................................................... Biphasic Changes following Surgical Intervention .............................................. Burns ........................................................................................................ Sepsis ........................................................................................................ Adrenal Steroidal Adaptation ........................................................................ Adrenal Insufficiency .................................................................................... Therapy ..................................................................................................... Conclusions ................................................................................................ References ..................................................................................................
110 111 113 115 116 117 119 120 120 122 123 124 125
Introduction It has long been known that a functioning hypothalamic-pituitary-adrenal (HPA) axis is essential for life. Glucocorticoids regulate salt and water handling, maintain vascular tone, stimulate gluconeogenesis and glycogenesis, modulate the immune system and induce muscle catabolism, but the relative importance of these effects under varying physiological conditions is unknown. Cortisol deficiency is surprisingly well tolerated in unstressed patients, but when challenged the absence of an appropriate stress-induced rise will result in rapid decompensation with catastrophic consequence. Plumpton and Besser [1] demonstrated in healthy individuals undergoing elective surgery that serum cortisol rose to at least 580 nmol/l, and argued that patients with HPA disease
need to have a similar response to insulin-induced hypoglycaemia to safely withstand surgery. This is an important observation for patient care but does not address the precise function of cortisol in the acutely unwell subject or when enough cortisol becomes too much? Furthermore, the steroidogenic synthetic pathways may be altered during critical illness and this may influence the patterns of secretion observed. This is particularly true in the setting of modern intensive care practice, as our ability to significantly prolong life in previously fatal circumstances is allowing the disclosure of previously unrecognized responses of the HPA axis [2]. Measurement of plasma cortisol does not provide the entire story as an additional level of complexity comes from the glucocorticoid receptor as a modulator of cortisol action. Alterations in glucocorticoid receptor function occur in the peripheral lymphocytes of patients with advanced AIDS [3], steroid-resistant asthma [4] and sepsis [5] with co-existent elevated cortisol levels. In patients undergoing major abdominal surgery, circulating cortisol and growth hormone (GH) levels are raised and the pattern of secretion abnormal [6]. Despite the elevated GH levels, serum IGF-I is low indicative of GH resistance; this observation and others gave rise to the notion that patients in ITU are functionally GH-deficient and that this might contribute to their catabolic state. A placebo-controlled trial of GH therapy in ITU patients designed to test this hypothesis had to be prematurely terminated because of a doubling of mortality in the actively treated group, reinforcing the need to better understand the endocrinology of critical illness [see C.J. Hinds, this issue]. The HPA axis lacks an equivalent to IGF-I, but by analogy to the GH axis, the elevated circulating cortisol levels encountered in patients in ITU may be secondary to glucocorticoid resistance, either generalized or tissue-specific, for example at the hypothalamo-pituitary axis or locally at the site of injury. Hence at a cellular level glucocorticoid action may be neither excessive nor inappropriate. Improved understanding of the biology of the HPA axis in critical illness may allow rational manipulation of circulating levels and avoid the experience of GH treatment in ITU. Below we review the literature and attempt to discriminate between ‘cause and effect’ and phenomenology in the HPA axis in critical illness, although often such a delineation is not clear cut.
Physiology The major systems mediating the response to acute stress are the HPA and catecholamine axes. Under the influences of higher cortical function, spinal and peripheral baroreceptors, there is a response to an acute physical stress, be it traumatic, circulatory or septic, resulting in a rapid rise in circulat-
The Pituitary Adrenal Axis
111
Fig. 1. Schematic illustration of glucocorticoid (GR) signalling. See text for details.
ing ACTH, in turn driven by hypothalamic secretagogues including CRH and vasopressin. This is influenced by mediators of the immune response, and it is likely that other secretagogues are also involved. Although immunoreactive CRH levels are detectable in plasma [7], whether these reflect hypothalamic secretion is unclear [8], and it is doubtful that the concentration in the systemic circulation reflects those in the hypothalamic and pituitary vessels. Furthermore, in a rat model of severe stress, acute immune neutralization of CRH was not sufficient to inhibit ACTH, -endorphin and corticosterone secretion suggesting the involvement of other secretagogues of the pituitary adrenal axis [9] and a permissive role for CRH. ACTH causes the de novo synthesis and secretion of cortisol from the adrenal cortex, resulting in a rapid rise in circulating plasma cortisol. In normal individuals under nonstressed circumstances, more than 90% of circulating cortisol is bound to cortisol-binding globulin (CBG) [10]. Once the binding capacity is exceeded, unbound circulating cortisol is filtered by the kidney and secreted as urinary-free cortisol (UFC). Cortisol is highly lipophilic and passes easily through cell membranes where it binds its cytoplasmic receptor (GR) causing the disassociation from heatshock protein 90 (HSP 90) (fig. 1). The activated GR translocates into the nucleus and binds as a dimer to response elements located within gene promoters. This results in activation or inhibition of transcription. Activation
Newell-Price/Trainer
112
may occur either directly as a consequence of dimer binding or through the recruitment of recently identified co-activators such as steroid receptor coactivator 1 and CBP/p300 [11, 12]. These co-activators have either direct, or recruit, histone acetelase activity causing the remodelling of chromatin into an open configuration that permits transcriptional machinery access to DNA allowing transcription and the synthesis of mRNA. In addition, the activated GR may also stabilize some mRNA transcripts and thus potentiate peptide translation. The net result of this is to alter carbohydrate, fat and protein metabolism such that anabolism is inhibited therefore directing available energy to vital organs. In the chronic inappropriately elevated circulating glucocorticoid levels seen in patients with Cushing’s syndrome, muscle wasting and catabolism are major causes of morbidity, whilst in the critically ill patient with ‘appropriately’ raised circulating cortisol levels catabolism may be a means of providing vital nutrients. In addition, glucocorticoids appear to protect cells form heat damage, offsetting some of the deleterious effects of systemic pyrexia [13]. Adrenal cortical HSP 70 is rapidly and specifically induced in response to stress, an effect that is abolished in hypophysectomized rats and restored with administration of exogenous ACTH [14, 15]. It has thus been proposed as one of the mediators of the adrenocortical responses to ACTH.
Integration with the Immune System A tight interplay exists between the immune system and the HPA axis [16]: prevailing hypercortisolism will tend to diminish the activated immune response, whilst the immune mediators themselves have important influences on the activity of the HPA axis (see below). This reciprocal relationship may be perceived as preventing the various defence reactions from ‘overshooting’ [17]. Glucocorticoids diminish the expression of nitric oxide synthase 2, phospholipase A2 and cyclo-oxygenase genes and have potent anti-inflammatory actions by diminishing the production of NO, prostaglandins and leucotrienes [18–23]. Of the ever-expanding list of cytokines, interleukin (IL)-1, IL-6 and tumour necrosis factor- (TNF) have documented major effects on HPA activation. Increased levels of IL-1 are found in endotoxaemic stress [24] and cause the rapid release of ACTH via the release of CRH [25–27]. IL-6 has similar ACTH-releasing properties [28], and has a synergistic effect with IL1 and TNF [29]. In rat models the levels of IL-6 are elevated in response to stress, an effect that is in part mediated by the actions of catecholamines [30]. IL-1 and TNF stimulate the secretion of IL-6, which in turn feeds back to inhibit the secretion of IL-1 and TNF (fig. 2). Thus IL-6 plays a central role in mediating the stress response of catecholamines, and provides an integrating
The Pituitary Adrenal Axis
113
Fig. 2. Interactions of IL-1, TNF and IL-6 with the HPA and catecholamine axes. See text for details.
‘bridge’ between the two major stress response pathways. Furthermore, the central role of IL-6 is illustrated by experiments in which immunoneutralization of this cytokine in rats prevents the lipopolysaccharide activation of the HPA axis [31]. In man, administration of recombinant IL-6 results in significant elevation of ACTH and cortisol [32] and in turn glucocorticoids increase hepatocyte expression of IL-6 receptors: IL-6 stimulates increased uptake of amino acids by the liver, which may be important in maintaining crucial metabolic pathways during severe stress [33]. Conversely, glucocorticoids inhibit the activating actions of all these cytokines on the HPA axis [34]. A further layer of complexity has recently been identified: IL-1 and TNF specifically upregulate the reductase activity of 11-hydroxysteroid dehydrogenase. The reductase activity of this enzyme catalyses the shuttling of cortisone (the inactive metabolite of cortisol) back to cortisol, so counterbalancing the proinflammatory effects of these cytokines [19]. IL-1 and TNF have been implicated in the pathogenesis of the septic shock cascade, with levels rising before the onset of circulatory failure; in animal models IL-6 and glucocorticoids have been employed to beneficial effect in an effort to diminish their effect [35, 36]. In burns injury, the increased IL-6 levels are negatively correlated with CBG production which probably represents a mechanism to ensure high prevailing levels of free cortisol, whilst IL-6 levels are elevated in neonatal sepsis and this acts as a predictor of bacterial infection [37–39]. Glucocorticoids increase the concentration of circulating soluble type II IL-1 receptor contributing to their anti-inflammatory properties by decreasing the bioavailabilty of IL-1 [40]. Two reports have
Newell-Price/Trainer
114
investigated the role of glucocorticoid receptors in severe illness in man, and the interplay with the immune system. In a mitogen-stimulated lymphocyte proliferation assay the peripheral blood mononuclear leucocytes from 15 individuals with severe sepsis were more sensitive to the suppressive effects of dexamethasone, an effect that was antagonized by IL-1, IL-2, IL-6 and TNF; this increased sensitivity was reversed on recovery from the septic episode [41]. The authors concluded that this increased sensitivity of lymphocytes to glucocorticoids may result in their apoptosis and limit the extent of the immune cascade in the circulation but locally produced cytokines at the site of inflammation might antagonize the anti-apoptotic effects of glucocorticoids, thus allowing an adequate response at the site of injury, despite higher systemic circulating glucocorticoid levels. Interestingly, using binding assays these same authors reported the same number of GR per cell from 15 septic patients (it is not stated whether these are the same 15 as in their previous report) compared to healthy controls, but decreased affinity for dexamethasone [5]. These data suggest that the increased sensitivity of the peripheral lymphocytes to the effects of glucocorticoids is mediated downstream of glucocorticoidGR binding. Recently, the 09:00 h levels of plasma leptin have been demonstrated to be elevated in survivors of acute septic illness, and this was not attributable to differences in nutritional status [42]. In the nonstressed state there is a reciprocal circadian rhythm of leptin and glucocorticoid, with higher leptin levels at night [43]. Glucocorticoids [44] and IL-1 [45] are known to stimulate the expression of leptin, and since both are elevated in acute sepsis this may in part explain the elevated levels and loss of rhythmicity of leptin. Leptin has also been shown to have immunostimulatory properties since it enhances the production and phagocytic properties of macrophages [46], and modulates the T-cell response [47]. Therefore, induction of leptin secretion under the influence of HPA activation may have beneficial effects for host defence, and further integrate the immune system and HPA axis.
Assessment of the HPA Axis in Man Normally, the level of circulating plasma-free cortisol reflects the product of the relationship between its production, binding to CBG and clearance. Whilst the latter two parameters may be relatively easily assessed, direct assessment of cortisol production may only be made by isotopic dilution methods that are not easily performed on critically ill individuals. Isotopic dilution studies have indicated that a mean level of plasma cortisol, as assessed by sampling at five points during the day, of 150–300 nmol/l equates to a normal
The Pituitary Adrenal Axis
115
cortisol production rate in nonstressed subjects [48]. Therefore this means of assessment may serve as a surrogate to reflect the cortisol production rate. However, in acute illness the levels of CBG and clearance of cortisol may be significantly altered and the average plasma levels may not accurately reflect production. The optimal clinical and biochemical means of assessing the HPA axis in nonacutely stressed individuals remain controversial and may account for some of the discrepancies between the conclusions drawn from different studies of the HPA axis in the critical care setting. Many of the tests used to study critically ill patients such as estimation of UFC, dexamethasone suppression tests and testing with corticotrophin-releasing hormone were validated for the investigation of Cushing’s syndrome [49]. Similarly, the assessment of primary hypoadrenalism is far from uniform, and the shortfalls are increasingly recognized of some traditional approaches, such as the short ACTH (1–24) test. In the intensive care (ITU) setting the situation is made more complex with the compounding effects of varied therapeutic interventions such as catecholamine infusions and possibly the most heterogeneous group of patients submitted to endocrinological study. These caveats need to borne in mind in the discussions below.
Acute Responses Major acute stress such as major surgical procedures cause profound activation of the HPA axis inducing considerable elevations in plasma ACTH and cortisol levels [50–53]. In the ITU setting where patients present with a variety of insults, data are conflicting as to whether the severity of insult is reflected in the degree of activation of the HPA axis. Elevated plasma cortisol levels have been documented in patients with myocardial infarction with the levels correlating to the extent of infarction as evaluated by changes in cardiac enzymes [54, 55]. Assessment of HPA activity soon after admission to the ITU in a group of patients with heterogeneous aetiologies of insults, revealed that the basal plasma cortisol level correlated positively with severity of insult and mortality, whilst the best outcome was seen in those with a low basal plasma cortisol that responded well to administration of ACTH, suggesting that a fully preserved adrenal reserve is advantageous [56]. Only one of the seventy studied showed evidence of adrenal insufficiency, as assessed by the cortisol response to ACTH (1-24) 250 g i.v. More recently, a similar relationship has been observed in 159 long-stay individuals studied on the ITU with the levels of plasma cortisol assessed weekly correlating with mortality and the severity scoring system – the modified Acute Physiological and Chronic Health Evaluation II score (mAPACHE II) [57]: the plasma cortisol levels were highest in
Newell-Price/Trainer
116
those requiring vasoactive drugs, those with higher mAPACHE II score (the higher the score the worse the prognosis) and in nonsurvivors. Two of the 159 studied exhibited a subnormal response to ACTH (1-24), suggesting adrenal insufficiency. In contrast, other workers have found that the HPA axis is variably activated when studied within the first 24 h of admission to the ITU: patients demonstrated a greater basal and stimulated response to ACTH (1-24), compared to nonacutely ill patients awaiting cardiac catheterization and the levels of plasma cortisol did not correlate with disease severity as assessed by ventilator or inotrope dependency [58]. This may reflect the smaller numbers studied or the alternative scoring system used to assess severity. Nevertheless, plasma cortisol was lower in the 29 survivors compared to the 11 nonsurvivors, and none had documented evidence of adrenal insufficiency. Thus in terms of long-term outcome the level of plasma cortisol would appear to positively correlate with a worse prognosis. It is not possible from these, or other studies, to determine whether HPA activation (or overactivation) is responsible for the differences in mortality or whether the changes merely reflect severity of illness. In an attempt to further understand and assess the integrity of the HPA axis during critical illness, Reincke et al. [59] studied a heterogeneous group of 53 acutely ill patients presenting to the intensive care unit as soon as practicable after admission. Using a 3-mg overnight low-dose dexamethasonesuppression test (a dose that has been little validated in other settings, but is more than sufficient to suppress 09:00 h plasma cortisol in normal volunteers) the patient group had significantly higher circulating plasma cortisol levels before and after dexamethasone compared to controls, and interestingly the values correlated with the severity of stress but not aetiology of insult. In the patient group the basal circulating plasma cortisol values were elevated to levels that might be predicted to suppress the release of hypothalamic secretagogues and reduce the synthesis and secretion of ACTH; however, exogenously administered human-sequence CRH caused a significantly greater rise in plasma ACTH compared to controls. Possible explanations for these observations include relative resistance of corticotrophs to glucocorticoid feedback, increased tone of secretagogues such as vasopressin that act in synergy with CRH, or increased hypothalamic and pituitary drive under the influence of immune mediators (see above).
Biphasic Changes following Surgical Intervention Debate exists as to how long the HPA axis remains stimulated following major surgery or trauma. Initial reports suggested that a period of as little as 24 h following surgical stress was required before the return of corticosteroids
The Pituitary Adrenal Axis
117
to basal levels [50–53]. More recently a longer duration of HPA activation has been observed, with the period positively correlating with the severity of insult [60, 61]. The normal circadian rhythm of plasma cortisol is disturbed. Some studies report persistence of the circadian rhythm but reset higher, and with an elevated mean plasma cortisol [62]. Careful circadian rhythm studies, with sampling for plasma ACTH and cortisol at hourly intervals for 24 h before and 7 days after operative intervention, revealed a biphasic response in which initially both plasma ACTH and cortisol are elevated, but after 48 h the plasma ACTH was suppressed whilst plasma cortisol remained elevated [63]. Furthermore, and in contrast to the situation observed above [62], there was little evidence of a persisting circadian rhythm. By the seventh postoperative day the levels of plasma ACTH and cortisol had returned to normal as had the circadian rhythm (fig. 3). In parallel studies, changes in plasma CRH followed a similar time course to plasma ACTH, with levels returning to baseline 1 week after surgery. Interestingly, although the plasma cortisol on the second postoperative day was elevated compared to preoperative levels, there was a similar percentage suppression of plasma cortisol following intravenous administration of dexamethasone, suggesting that the hypothalamus and pituitary remain susceptible to the inhibitory effects of glucocorticoid. Furthermore, the responses of plasma cortisol to synthetic ACTH (1-24) were significantly greater on the second postoperative day compared to preoperatively. A possible explanation of these observations is that although the postoperative levels of cortisol may be sufficient to suppress immunoreactive levels of ACTH, the adrenal cortex may become sensitized and respond to low levels of ACTH, possibly in synergy with other factors acting directly on the adrenal. ACTH is known to upregulate its own receptor [64], and thus it is conceivable that the high immediate peri- and postoperative values might account for this effect. Alternatively the adrenal cortex may be stimulated directly by other factors (such as IL-1 and IL-6) acting either independently of, or in synergy with, ACTH. Other circulating factors might also be acting to suppress ACTH synthesis and secretion. Evidence for these proposals comes from the observations that plasma endothelin 1 (ET1) and atrial natriuretic peptide (ANP) are elevated in the postoperative period when ACTH is suppressed [65]. ANP has been shown to suppress the release of ACTH in animal models [66, 67], and to inhibit the CRH-mediated release of ACTH in humans [68], although this effect is not seen at physiological doses [69]. In the critical care setting the levels of ANP may be significantly elevated and these may account, in addition to the effects of high circulating cortisol, for the lower plasma ACTH levels observed. At the same time, ET1, which may be at pharmacological levels during the second phase of critical illness [65], has been shown to have a direct stimulatory effect on adrenal steroidal synthesis in vitro, and potentiate the
Newell-Price/Trainer
118
Fig. 3. Biphasic response of plasma cortisol (X) and ACTH (W) following major surgery. Reproduced with permission from Naito et al. [63].
response to ACTH in vivo [70]. Therefore, elevated levels of ET1 may contribute to the continued secretion of adrenal steroids at times when ACTH is low.
Burns Severe thermal injury represents an acute and then prolonged stress stimulus. Recovery may frequently take many weeks to months and this is reflected in the HPA activation. From 1 to 5 days following thermal injury the level of
The Pituitary Adrenal Axis
119
dihydroepiandrosterone sulphate (DHEAS) is reduced to one third of normal levels, whilst cortisol is increased 2-fold [71]. A further fall in DHEAS occurs 5–66 days postinjury, whilst the plasma cortisol remains relatively constant, but individuals do not become Cushingoid suggesting glucocorticoid resistance. Indeed this divergence between adrenocortical androgen levels and cortisol (see below) may last for months and only return to normal once the burn is fully healed [72].
Sepsis In contrast to the responses seen to trauma or abdominal surgery there does not appear to be a predictable response to sepsis. This may simply reflect differences in the activation of the HPA by varying infective agents. In a study of 37 patients treated on the ITU for acute sepsis (35 were receiving intravenous dopamine), investigated within 13 h of admission there were no differences between the plasma cortisol levels in survivors and nonsurvivors [73]. Although the circulating cortisol was higher in Gram-positive than in Gram-negative septicaemia, the source of infection, the use of vasopressive agents and the severity were unrelated to the level of plasma cortisol. Similarly, the biphasic response (discussed above) in circulating ACTH and cortisol levels following trauma is not apparent after sepsis [74]. ET1 levels are greatly elevated whilst septic [75], and this may provide a peripheral drive to adrenocortical stimulation. This vasoconstrictive peptide may also contribute to diminished tissue perfusion and ultimately organ failure, and possibly influence the pattern of adrenocortical steroidogenesis [76]. Thus although the absolute level of circulating cortisol in response to sepsis may reflect HPA activation, the degree to which this occurs is variable and the predictable time course to recovery, and patterns of secretion seen following uncomplicated abdominal surgery, are not apparent.
Adrenal Steroidal Adaptation Evolutionary selective pressure ensures the preservation of physiological mechanisms necessary for survival of acute life-threatening insults. The adrenal has the means to synthesize and secrete a diverse spectrum of steroid hormones, and yet cortisol is the only one necessary for life. Intuitively, it might be predicted that mechanisms should exist to ensure the continued secretion of cortisol potentially at the cost of other adrenal steroids. Indeed such adaptation to critical illness is apparent in the spectrum of steroidal secretion observed
Newell-Price/Trainer
120
in response to severe illness. A syndrome of hyperreninaemic hypoaldosteronism in a subset of critically ill individuals was initially described by Zipser et al. [77] in 1981. In this report all 28 individuals studied were septic and there was no aldosterone response to either ACTH or angiotensin II infusions whilst ill. On recovery, normal responses were seen, indicating the reversibility of this phenomenon. In certain individuals this syndrome has also been shown to be associated with hypotension [78] and others have demonstrated increased mortality associated with lower aldosterone levels [79]. Although this might suggest a deficiency in the renin-angiotensin system, no differences were seen in the levels of plasma angiotensin II or indeed of ACTH or potassium, indicating that the effect is liable to be due to intra-adrenal shuttling of adrenocortical steroidogenic hormones. Interestingly, the low levels of aldosterone do not correlate with a higher mAPACHE II score [80]. Cortisol may act as a mineralocorticoid. Cortisol and aldosterone have high affinities for the mineralocorticoid receptor (MR) in the kidney, but as cortisol circulates at greater concentrations than aldosterone, cortisol would saturate the MR were it not for the effects of 11-hydroxysteroid dehydrogenase type II (11HSD). 11HSD type II converts cortisol to the inactive metabolite cortisone. At a sufficiently high level of plasma cortisol, 11HSD type II becomes saturated and hence cortisol is available to bind the MR [81], obviating the need for mineralocorticoids. Such an effect is typically seen in severe Cushing’s syndrome and is associated with hypertension and hypokalaemic alkalosis [49]. However, cortisol acting as mineralocorticoid in severely ill patients does not explain the elevated plasma renin in hyperreninaemic hypoaldosteronism, as this would be suppressed if sufficient mineralocorticoid were acting in the circulation. Hyperreninaemic hypoaldosteronism remains an unexplained phenomenon and it seems likely that it represents a true adrenocortical adaptation. To further investigate the nature of this change, Raff and Findling [80] carefully assessed the effects on aldosterone secretion of intravenous bolus synthetic ACTH (1-24) and the dopamine receptor antagonist metaclopramide. Since zona glomerulosa function is under tonic inhibition by dopamine, acute administration metaclopramide causes a rapid increase in plasma aldosterone [82], but this effect depends on an intact spinal cord [83]. In contrast, ANP directly inhibits aldosterone secretion [84]. In their study, there was a subnormal elevation of aldosterone in response to synthetic ACTH (1-24) in all critically ill patients regardless of plasma renin activity, whilst normal stimulated responses of plasma aldosterone were seen following metaclopramide administration even in those with a low aldosterone:renin ratio [80]. Furthermore, in those with hyperreninaemic hypoaldosteronism there were no increases in the circulating level of ANP, and no association with APACHE
The Pituitary Adrenal Axis
121
scores. These data suggest that the effect is reversible and may well be mediated by dopaminergic neurones innervating the adrenal cortex. From these observations it might be predicted that the use of dopamine on the ITU may lead to this syndrome, but to date data for such an effect are lacking. Moreover those with pre-existing autonomic neuropathy, or those who develop such a neuropathy whilst on ITU, might be expected to exhibit a lower prevalence of this syndrome. Again to date no such data are available. Further support to the argument that there is adaptation to severe illness comes from studies assessing the relative secretion of androgens compared to cortisol. In a group of 23 men, seriously ill for a week or longer compared to controls, the basal serum DHEA and DHEAS concentrations were lower in the ill group and these failed to respond to stimulation with synthetic ACTH (1-24) [85]. Furthermore, the ratio of androstenedione to cortisol, before and after ACTH stimulation, is diminished in critically ill subjects compared to controls who were awaiting cardiac catheterization [86]. The adaptation appears to be established at presentation to the intensive care unit as evidenced by a reduced DHEAS to cortisol ratio and again an elevated plasma cortisol level that correlated with the disease severity [87]. It is, however, unclear from this study exactly how long the patients had been unwell prior to admission to the ITU. Overall these changes are consistent with the shift away from mineralocorticoid and androgen synthesis to favour the production and secretion of cortisol, and suggest a global change in adrenocortical glomerulosa function. Whether this is a dysfunction or a useful adaptation is debatable, since although it should tend to ensure continued secretion of cortisol, the syndrome of hyperreninaemic hypoaldosteronism has been associated with an increased mortality. DHEAS itself has innate immunostimulatory properties, enhancing IL-2 production from cytotoxic T cells [88]. Levels of this hormone are decreased by dopamine infusions [89] and by cortisol through negative feedback on ACTH. Thus not only might the level of cortisol render the individual more susceptible to the problems of sepsis and decreased wound healing, but also a lower DHEAS may contribute to immune paresis. Thus one may speculate that the prolonged use of dopamine in a severely ill individual is potentially liable to result in a divergence of adrenocortical steroidogenesis, and possibly contribute to an increased risk of sepsis.
Adrenal Insufficiency As alluded to above, de novo adrenal insufficiency on the ITU is generally thought to be uncommon [56, 58, 73, 86]. In contrast, other authors report
Newell-Price/Trainer
122
up to 20% of patients with severe sepsis having subnormal responses to the short ACTH stimulation test [90], findings which were also supported by earlier data [91, 92]. More recently, a prospective 14-month study involving 159 patients demonstrated only 2 patients with a picture of adrenocortical insufficiency and a blunted response of cortisol of synthetic ACTH (1-24) 0.25 mg i.v. Thus on balance it would seem that de novo adrenal insufficiency is uncommon as assessed by this test. All studies report the plasma cortisol responses to this dose of intravenous ACTH (1-24) as the means of assessing primary adrenocortical function. However, this dose of ACTH is approximately 1,000-fold physiological, and it is well recognized that nonacutely stressed individuals with poor adrenal reserve may exhibit ‘normal’ cortisol responses to such testing. The potential shortfall of this means of assessment is illustrated by the finding that on the ITU certain patients with a normal response to ACTH (1-24) demonstrate a significant improvement in their cardiovascular indices following the administration of physiological doses of glucocorticoid, and in whom the dose of ionotropic agents could subsequently be reduced [93]. Therefore, although adrenal insufficiency in critical illness would appear uncommon, it at least requires consideration in the hypotensive septic individual unresponsive to other therapies and the 250-g ACTH (1-24) test is a potentially misleading diagnostic aid. Iatrogenic hypoadrenalism may be caused by the use of the intravenously administered imidazole anaesthetic agent etomidate, and its long-term use is documented to be associated with increased mortality and a low plasma cortisol [94, 95]. This is a direct effect on adrenocortical steroidogenesis with enzymatic blockade at several synthetic steps [96]. Indeed this effect has been put to good use since intravenous etomidate infusions can be extremely effective in controlling hypercortisolaemia associated with Cushing’s syndrome for short [97, 98] and prolonged periods on the ITU, even at subhypnotic doses [99]. Clearly, this illustrates the potential for therapeutic interventions to influence the HPA axis and such a possibility should be considered with the use of any new agents.
Therapy Traditionally, pharmacological doses of glucocorticoids have often been administered to patients with adrenal insufficiency during operative procedures in an effort to prevent cardiovascular collapse, haemodynamic instability and death. Despite this, however, non-human adrenalectomized primates appear to tolerate surgical stress just as well if they are given physiological as opposed to supraphysiological replacement doses of glucocorticoid
The Pituitary Adrenal Axis
123
[100, 101]. A sub-physiologically treated group did, however, have a significantly higher mortality rate. These findings suggest that glucocorticoids have a permissive role during surgery and it seems possible that physiological concentrations of glucocorticoid replacement may be sufficient to tolerate surgical stress. In animal models of sepsis there are numerous reports of an increased survival after treatment with high-dose glucocorticoid therapy [102, 103]. An early prospective study in man by Schumer [104] reported a favourable response to very-high-dose systemic glucocorticoid therapy in septic shock. However, two large, randomized placebo-controlled, multicentre trials, involving the recruitment of 605 individuals, failed to demonstrate any benefit of intravenous methylprednisolone at the absolutely massive doses of 30 mg/kg. Furthermore, in both studies there was an excess of secondary infection in those receiving glucocorticoid. It is possible that the beneficial effects seen in the study by Schumer et al. [103] reflected the positive effects of glucocorticoids on circulatory support. Such an improvement in short-term circulatory parameters has been observed by others, but without an overall improvement on mortality [105]. In comatose patients with cerebral malaria, high-dose dexamethasone therapy has also proven deleterious [106]. Thus there is no place for very-high-dose glucocorticoid therapy in management of established septic shock, whilst physiological replacement in cases of deficiency is advantageous. Data is lacking as to whether benefit might be gained by the timely early administration of glucocorticoids prior to the establishment of septic shock, and such studies would be very difficult to adequately perform in man. Conversely, recent data from a randomized, double-blind, placebocontrolled study assessing the effects of hydrocortisone 100 mg i.v. 3 times/ day administered late in septic shock demonstrated a significantly improved rate of reversal of shock and a trend towards an improved 28-day survival [107]. This is a relatively low dose of corticosteroid, and interestingly there was no significant difference in outcome between the responders and nonresponders to the short ACTH (1-24) test. Further studies are needed to establish whether low to moderate dose glucocorticoid administration is advantageous in septic shock.
Conclusions A tight interplay exists between the HPA axis and immune systems that are activated in response to severe illness. This may be perceived as an evolutionary adaptation to respond to stress whilst limiting auto-injury. The degree of stimulation of the HPA axis would appear to reflect the severity of insult in
Newell-Price/Trainer
124
trauma or surgery, but not necessarily in sepsis. A predictable pattern and time course of response may be seen following abdominal surgery, but this is more diverse in sepsis. Mechanisms exist which allow intra-adrenal shuttling of steroidogenesis to favour the continued synthesis and secretion of cortisol, at the expense of androgens and mineralocorticoid. Although adrenocortical failure is probably uncommon, the short ACTH (1-24) stimulation test may exhibit false-negative responses and thus, on occasion, empirical physiological glucocorticoid replacement may be warranted if there is a high enough index of suspicion on clinical grounds. There is no place for massive dose glucocorticoids in the management of severe sepsis. Finally, in the context of severe illness, more study is needed on the interplay between the immune system, the HPA axis, and GR function.
References 1 2 3
4 5
6
7 8
9
10 11
12
13
Plumpton FS, Besser GM: The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg 1969;56:216–219. Van den Berghe G, de Zegher F, Bouillon R: Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827–1834. Norbiato G, Bevilacqua M, Vago T, Baldi G, Chebat E, Bertora P, Moroni M, Galli M, Oldenburg N: Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74: 608–613. Kam JC, Szefler SJ, Surs W, Sher ER, Leung DY: Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 1993;151:3460–3466. Molijn GJ, Koper JW, van Uffelen CJ, de Jong FH, Brinkmann AO, Bruining HA, Lamberts SW: Temperature-induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock. Clin Endocrinol (Oxf) 1995;43:197–203. Miell JP, Taylor AM, Jones J, Buchanan CR, Rennie J, Sherwood R, Leicester R, Ross RJ: Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery. Clin Endocrinol (Oxf) 1992;37:542–551. Cunnah D, Jessop DS, Besser GM, Rees LH: Measurement of circulating corticotrophin-releasing factor in man. J Endocrinol 1987;113:123–131. Linton EA, McLean C, Nieuwenhuyzen Kruseman AC, Tilders FJ, Van der Veen EA, Lowry PJ: Direct measurement of human plasma corticotropin-releasing hormone by ‘two-site’ immunoradiometric assay. J Clin Endocrinol Metab 1987;64:1047–1053. Giuffre KA, Udelsman R, Listwak S, Chrousos GP: Effects of immune neutralization of corticotropin-releasing hormone, adrenocorticotropin, and beta-endorphin in the surgically stressed rat. Endocrinology 1988;122:306–310. Balard PL, Baxter JD, Rousseau GG (eds): Glucocorticoid Hormone Action. Delivery and Transport of Glucocorticoids to Target Cells. New York, Springer, 1979. Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R, McInerney EM, Mullen, TM, Glass CK, Rosenfeld MG: Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 1998;279:703–707. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM: Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997;90:569–580. Fisher GA, Anderson RL, Hahn GM: Glucocorticoid-induced heat resistance in mammalian cells. J Cell Physiol 1986;128:127–132.
The Pituitary Adrenal Axis
125
14
15
16 17 18
19 20 21 22
23 24 25 26
27
28
29
30 31
32 33
34 35 36
Udelsman R, Blake MJ, Holbrook NJ: Molecular response to surgical stress: Specific and simultaneous heat shock protein induction in the adrenal cortex, aorta, and vena cava. Surgery 1991;110: 1125–1131. Blake MJ, Udelsman R, Feulner GJ, Norton DD, Holbrook NJ: Stress-induced heat shock protein 70 expression in adrenal cortex: An adrenocorticotropic hormone-sensitive, age-dependent response. Proc Natl Acad Sci USA 1991;88:9873–9877. Chrousos GP: The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332:1351–1362. Munck A, Naray-Fejes-Toth A: Glucocorticoids and stress: Permissive and suppressive actions. Ann NY Acad Sci 1994;746:115–130. Nakano T, Ohara O, Teraoka H, Arita H: Glucocorticoids suppress group II phospholipase A2 production by blocking mRNA synthesis and post-transcriptional expression. J Biol Chem 1990; 265:12745–12748. Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ: Tumor necrosis factor-alpha and interleukin1-beta enhance the cortisone/cortisol shuttle. J Exp Med 1997;186:189–198. Vishwanath BS, Frey FJ, Bradbury MJ, Dallman MF, Frey BM: Glucocorticoid deficiency increases phospholipase A2 activity in rats. J Clin Invest 1993;92:1974–1980. O’Banion MK, Winn VD, Young DA: cDNA cloning and functional activity of a glucocorticoidregulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA 1992;89:4888–4892. Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E: Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci USA 1992;89:217– 221. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–2012. Besedovsky H, del Rey A, Sorkin E, Dinarello CA: Immunoregulatory feedback between interleukin1 and glucocorticoid hormones. Science 1986;233:652–654. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W: Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987;238:522–524. Uehara A, Gottschall PE, Dahl RR, Arimura A: Interleukin-1 stimulates ACTH release by an indirect action which requires endogenous corticotropin-releasing factor. Endocrinology 1987;121: 1580–1582. Navarra P, Tsagarakis S, Faria MS, Rees LH, Besser GM, Grossman AB: Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 1991;128:37–44. Naitoh Y, Fukata J, Tominaga T, Nakai Y, Tamai S, Mori K, Imura H: Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats. Biochem Biophys Res Commun 1988;155:1459–1463. Perlstein RS, Mougey EH, Jackson WE, Neta R: Interleukin-1 and interleukin-6 act synergistically to stimulate the release of adrenocorticotropic hormone in vivo. Lymphokine Cytokine Res 1991; 10:141–146. van Gool J, van Vugt H, Helle M, Aarden LA: The relation among stress, adrenalin, interleukin6 and acute phase proteins in the rat. Clin Immunol Immunopathol 1990;57:200–210. Perlstein RS, Whitnall MH, Abrams JS, Mougey EH, Neta R: Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology 1993;132:946–952. Mastorakos G, Chrousos GP, Weber JS: Recombinant interleukin-6 activates the hypothalamicpituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993;77:1690–1694. Fischer CP, Bode BP, Takahashi K, Tanabe KK, Souba WW: Glucocorticoid-dependent induction of interleukin-6 receptor expression in human hepatocytes facilitates interleukin-6 stimulation of amino acid transport. Ann Surg 1996;223:610–618. Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE: Glucocorticoid therapy for immunemediated diseases: Basic and clinical correlates. Ann Intern Med 1993;119:1198–1208. Barton BE: The biological effects of interleukin-6. Med Res Rev 1996;16:87–109. Barton BE, Jackson JV: Protective role of interleukin-6 in the lipopolysaccharide-galactosamine septic shock model. Infect Immun 1993;61:1496–1499.
Newell-Price/Trainer
126
37
38 39
40
41
42
43
44 45
46
47
48
49 50 51 52 53 54
55 56
57
Bernier J, Jobin N, Emptoz-Bonneton A, Pugeat MM, Garrel DR: Decreased corticosteroid-binding globulin in burn patients: Relationship with interleukin-6 and fat in nutritional support. Crit Care Med 1998;26:452–460. Doellner H, Arntzen KJ, Haereid PE, Aag S, Austgulen R: Interleukin-6 concentrations in neonates evaluated for sepsis. J Pediatr 1998;132:295–299. Abrahamsson J, Pahlman M, Mellander L: Interleukin-6, but not tumour necrosis factor-alpha, is a good predictor of severe infection in febrile neutropenic and non-neutropenic children with malignancy. Acta Paediatr 1997;86:1059–1064. Brown EA, Dare HA, Marsh CB, Wewers MD: The combination of endotoxin and dexamethasone induces type II interleukin-1 receptor in monocytes: A comparison to interleukin-1-beta and interleukin-1 receptor antagonist. Cytokine 1996;8:828–836. Molijn GJ, Spek JJ, van Uffelen JC, de Jong FH, Brinkmann AO, Bruining HA, Lamberts SW, Koper JW: Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock. J Clin Endocrinol Metab 1995;80:1799–1803. Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, Chrousos GP: Plasma leptin levels are increased in survivors of acute sepsis: Associated loss of diurnal rhythm in cortisol and leptin secretion. J Clin Endocrinol Metab 1998;83:280–283. Licinio J, Mantzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW: Human leptin levels are pulsatile and inversely related to pituitaryadrenal function. Nat Med 1997;3:575–579. Papaspyrou-Rao S, Schneider SH, Petersen RN, Fried SK: Dexamethasone increases leptin expression in humans in vivo. J Clin Endocrinol Metab 1997;82:1635–1637. Janik JE, Curti BD, Considine RV, Rager HC, Powers GC, Alvord WG, Smith JW Jr, Gause BL, Kopp WC: Interleukin-1-alpha increases serum leptin concentrations in humans. J Clin Endocrinol Metab 1997;82:3084–3086. Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, Nicola NA, Alexander WS, Hilton DJ: Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci USA 1996;93:14564–14568. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI: Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998;394: 897–901. Trainer PJ, Eastment C, Grossman AB, Wheeler MJ, Perry L, Besser GM: The relationship between cortisol production rate and serial serum cortisol estimation in patients on medical therapy for Cushing’s syndrome. Clin Endocrinol (Oxf) 1993;39:441–443. Newell-Price JDC, Trainer PJ, Besser GM, Grossman AB: The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 1998;19:647–672. Hume DM, Bell CC, Bartter F: Direct measurement of adrenal secretion during operative trauma and convalescence. Surgery 1962;52:174–187. Cooper CE, Nelson DH: ACTH levels in plasma in preoperative and surgically stressed patients. J Clin Invest 1962;41:1599–1605. Johnston IDA: The endocrine response to trauma. Adv Clin Chem 1972;15:255–285. Gill GV, Prudhoe K, Cook DB, Latner AL: Effect of surgical trauma on plasma concentrations of cyclic AMP and cortisol. Br J Surg 1975;62:441–443. Chopra MP, Thadani U, Aber CP, Portal RW, Parkes J: Plasma cortisol, urinary 17-hydroxycorticoids, and urinary vanilyl mandelic acid after acute myocardial infarction. Br Heart J 1972;34:992– 997. Bailey RR, Abernethy MH, Beaven DW: Adrenocortical response to the stress of an acute myocardial infarction. Lancet 1967;i:970–973. Jurney TH, Cockrell JL Jr, Lindberg JS, Lamiell JM, Wade CE: Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality. Chest 1987;92: 292–295. Span LF, Hermus AR, Bartelink AK, Hoitsma AJ, Gimbrere JS, Smals AG, Kloppenborg PW: Adrenocortical function: An indicator of severity of disease and survival in chronic critically ill patients. Intensive Care Med 1992;18:93–96.
The Pituitary Adrenal Axis
127
58 59
60
61 62 63
64 65
66
67
68 69
70
71 72 73 74
75
76 77
78
Drucker D, Shandling M: Variable adrenocortical function in acute medical illness. Crit Care Med 1985;13:477–479. Reincke M, Allolio B, Wurth G, Winkelmann W: The hypothalamic-pituitary-adrenal axis in critical illness: Response to dexamethasone and corticotropin-releasing hormone. J Clin Endocrinol Metab 1993;77:151–156. Chernow B, Alexander HR, Smallridge RC, Thompson WR, Cook D, Beardsley D, Fink MP, Lake CR, Fletcher JR: Hormonal responses to graded surgical stress. Arch Intern Med 1987;147: 1273–1278. Harris MJ, Baker RT, McRoberts JW, Mohler JL: The adrenal response to trauma, operation and cosyntropin stimulation. Surg Gynecol Obstet 1990;170:513–516. Aun F, McIntosh TK, Lee A, Egdahl RH: The effects of surgery on the circadian rhythms of cortisol. Int Surg 1984;69:101–105. Naito Y, Fukata J, Tamai S, Seo N, Nakai Y, Mori K, Imura H: Biphasic changes in hypothalamopituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab 1991;73:111–117. Penhoat A, Jaillard C, Saez JM: Corticotropin positively regulates its own receptors and cAMP response in cultured bovine adrenal cells. Proc Natl Acad Sci USA 1989;86:4978–4981. Vermes I, Beishuizen A, Hampsink RM, Haanen C: Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: Possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 1995;80:1238–1242. Fink G, Dow RC, Casley D, Johnston CI, Bennie J, Carroll S, Dick H: Atrial natriuretic peptide is involved in the ACTH response to stress and glucocorticoid-negative feedback in the rat. J Endocrinol 1992;135:37–43. Fink G, Dow RC, Casley D, Johnston CI, Lim AT, Copolov DL, Bennie J, Carroll S, Dick H: Atrial natriuretic peptide is a physiological inhibitor of ACTH release: Evidence from immunoneutralization in vivo. J Endocrinol 1991;131:R9–R12. Kellner M, Wiedemann K, Holsboer F: Atrial natriuretic factor inhibits the CRH-stimulated secretion of ACTH and cortisol in man. Life Sci 1992;50:1835–1842. Ur E, Faria M, Tsagarakis S, Anderson JV, Besser GM, Grossman A: Atrial natriuretic peptide in physiological doses does not inhibit the ACTH or cortisol response to corticotrophin-releasing hormone-41 in normal human subjects. J Endocrinol 1991;131:163–167. Hinson JP, Vinson GP, Kapas S, Teja R: The role of endothelin in the control of adrenocortical function: Stimulation of endothelin release by ACTH and the effects of endothelin-1 and endothelin-3 on steroidogenesis in rat and human adrenocortical cells. J Endocrinol 1991;128: 275–280. Parker CR Jr, Baxter CR: Divergence in adrenal steroid secretory pattern after thermal injury in adult patients. J Trauma 1985;25:508–510. Lephart ED, Baxter CR, Parker CR Jr: Effect of burn trauma on adrenal and testicular steroid hormone production. J Clin Endocrinol Metab 1987;64:842–848. Schein RM, Sprung CL, Marcial E, Napolitano L, Chernow B: Plasma cortisol levels in patients with septic shock. Crit Care Med 1990;18:259–263. Voerman HJ, Groeneveld AB, de Boer H, Strack van Schijndel RJ, Nauta JP, van der Veen EA, Thijs LG: Time course and variability of the endocrine and metabolic response to severe sepsis. Surgery 1993;114:951–959. Voerman HJ, Stehouwer CD, van Kamp GJ, Strack van Schijndel RJ, Groeneveld AB, Thijs LG: Plasma endothelin levels are increased during septic shock. Crit Care Med 1992;20:1097– 1101. Weitzberg E, Lundberg JM, Rudehill A: Elevated plasma levels of endothelin in patients with sepsis syndrome. Circ Shock 1991;33:222–227. Zipser RD, Davenport MW, Martin KL, Tuck ML, Warner NE, Swinney RR, Davis CL, Horton R: Hyperreninemic hypoaldosteronism in the critically ill: A new entity. J Clin Endocrinol Metab 1981;53:867–873. Davenport MW, Zipser RD: Association of hypotension with hyperreninemic hypoaldosteronism in the critically ill patient. Arch Intern Med 1983;143:735–737.
Newell-Price/Trainer
128
79 80 81
82
83
84 85 86 87
88 89
90
91 92 93 94 95 96
97 98
99
100 101
Findling JW, Waters VO, Raff H: The dissociation of renin and aldosterone during critical illness. J Clin Endocrinol Metab 1987;64:592–595. Raff H, Findling JW: Aldosterone control in critically ill patients: ACTH, metoclopramide, and atrial natriuretic peptide. Crit Care Med 1990;18:915–920. Stewart PM, Walker BR, Holder G, O’Halloran D, Shackleton CH: 11-Beta-hydroxysteroid dehydrogenase activity in Cushing’s syndrome: Explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1995;80:3617–3620. Carey RM, Thorner MO, Ortt EM: Dopaminergic inhibition of metoclopramide-induced aldosterone secretion in man. Dissociation of responses to dopamine and bromocriptine. J Clin Invest 1980;66:10–18. Beck FW, Sowers JR, Sicca D, Welch BG: Absent aldosterone response to metoclopramide in patients with high spinal cord transection: Evidence that metoclopramide stimulates aldosterone secretion through central pathways. Life Sci 1985;36:2435–2444. Anderson JV, Struthers AD, Payne NN, Slater JD, Bloom SR: Atrial natriuretic peptide inhibits the aldosterone response to angiotensin II in man. Clin Sci (Colch) 1986;70:507–512. Parker LN, Levin ER, Lifrak ET: Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 1985;60:947–952. Drucker D, McLaughlin J: Adrenocortical dysfunction in acute medical illness. Crit Care Med 1986;14:789–791. Wade CE, Lindberg JS, Cockrell JL, Lamiell JM, Hunt MM, Ducey J, Jurney TH: Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients. J Clin Endocrinol Metab 1988;67:223–227. Suzuki T, Suzuki N, Daynes RA, Engleman EG: Dehydroepiandrosterone enhances IL-2 production and cytotoxic effector function of human T cells. Clin Immunol Immunopathol 1991;61:202–211. Van den Berghe G, de Zegher F, Wouters P, Schetz M, Verwaest C, Ferdinande P, Lauwers P: Dehydroepiandrosterone sulphate in critical illness: Effect of dopamine. Clin Endocrinol (Oxf) 1995; 43:457–463. Sibbald WJ, Short A, Cohen MP, Wilson RF: Variations in adrenocortical responsiveness during severe bacterial infections. Unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg 1977;186:29–33. McKee JI, Finlay WE: Cortisol replacement in severely stressed patients (letter). Lancet 1983;i:484 Finlay WE, McKee JI: Serum cortisol levels in severely stressed patients (letter). Lancet 1982;i: 1414–1415. Baldwin WA, Allo M: Occult hypoadrenalism in critically ill patients. Arch Surg 1993;128:673–676. Watt I, Ledingham IM: Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia 1984;39:973–981. Ledingham IM, Watt I: Influence of sedation on mortality in critically ill multiple trauma patients (letter). Lancet 1983;i:1270 Allolio B, Dorr H, Stuttmann R, Knorr D, Engelhardt D, Winkelmann W: Effect of a single bolus of etomidate upon eight major corticosteroid hormones and plasma ACTH. Clin Endocrinol (Oxf) 1985;22:281–286. Allolio B, Stuttmann R, Fischer H, Leonhard W, Winkelmann W: Long-term etomidate and adrenocortical suppression (letter). Lancet 1983;ii:626 Schulte HM, Benker G, Reinwein D, Sippell WG, Allolio B: Infusion of low dose etomidate: Correction of hypercortisolemia in patients with Cushing’s syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 1990;70:1426–1430. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM: Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing’s syndrome and peritonitis. J Clin Endocrinol Metab 1998;83:3542–3544. Udelsman R, Chrousos GP: Hormonal responses to surgical stress. Adv Exp Med Biol 1988;245: 265–272. Udelsman R, Ramp J, Gallucci WT, Gordon A, Lipford E, Norton JA, Loriaux DL, Chrousos GP: Adaptation during surgical stress. A re-evaluation of the role of glucocorticoids. J Clin Invest 1986;77:1377–1381.
The Pituitary Adrenal Axis
129
102
103 104 105
106
107
Hinshaw LB, Beller BK, Chang AC, Passey RB, Lahti RA, Flournoy DJ, Lane MM, Archer LT: Effects of prior administration of steroids upon recovery from lethal sepsis. Surg Gynecol Obstet 1986;163:335–344. Schuler JJ, Erve PR, Schumer W: Glucocorticoid effect on hepatic carbohydrate metabolism in the endotoxin-shocked monkey. Ann Surg 1976;183:345–354. Schumer W: Steroids in the treatment of clinical septic shock. Ann Surg 1976;184:333–341. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M: The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984;311:1137–1143. Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, Harinasuta T: Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med 1982;306:313–319. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A: Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–650.
Dr. Peter J. Trainer, Consultant Endocrinologist, Department of Endocrinology Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX (UK) Tel. +44 161 446 3666, +44 161 446 3772, E-Mail
[email protected] Newell-Price/Trainer
130
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 131–151
............................
The Pituitary Gonadal Axis A.K. Fletcher Department of Medicine, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, UK
Contents Introduction ............................................................................................... Normal Physiology of the Hypothalamo-Pituitary-Gonadal Axis ......................... Men ...................................................................................................... Women .................................................................................................. Diagnosis of Hypogonadism .......................................................................... Laboratory Investigation – Men .................................................................. Laboratory Investigation – Women .............................................................. Acute Systemic Illness and Gonadal Function .................................................. Mechanisms of Hypogonadism in Acute Illness ............................................. Hypogonadism in Specific Conditions ............................................................. Trauma .................................................................................................. Respiratory Disease .................................................................................. Renal Disease .......................................................................................... Gastrointestinal Disease ............................................................................ Liver Disease ........................................................................................... Cancer ................................................................................................... Endocrine Disease .................................................................................... Infectious Disease .................................................................................... Neurological Disease ................................................................................ Other Disease .......................................................................................... Effect of Drugs ........................................................................................ Treatment of Hypogonadism in Acute Illness ................................................... Oestrogen Replacement Therapy ................................................................. Androgen Replacement Therapy ................................................................. Anabolic Steroid Treatment ....................................................................... Complications of Treatment of Hypogonadism in Acute Illness ........................ Summary of Sex Steroid Treatment ............................................................. Summary and Conclusions ............................................................................ References ..................................................................................................
132 132 132 134 134 135 136 136 136 139 139 139 140 140 141 141 142 142 142 143 143 143 144 145 145 146 146 147 147
Introduction Changes in the delicate inter-relationships that exist in endocrine physiology have been well described in acute illness. The dynamics of the hypothalamo-pituitary-gonadal axis in acute illness have not been studied in the same detail as other endocrine axes, but profound changes have been reported. The majority of studies have been confined to males. In order to appreciate the changes that occur in the hypothalamo-pituitary-gonadal axis in acute illness, it is necessary to understand the normal physiology of this axis, and the first section of this chapter describes this. The diagnosis and consequences of hypogonadism in relation to acute illness and the possible mechanisms for the effects of acute illness are then discussed whilst the final section comprises a review of treatments and the possible role for anabolic steroids in acute illness.
Normal Physiology of the Hypothalamo-Pituitary-Gonadal Axis The physiology of the complicated feedback loops that exist to control sex steroid secretion began to be unravelled when it was established that removal of the pituitary results in diminished testicular function [1]. An overview of the feedback mechanisms that comprise the hypothalamo-pituitarygonadal axis is given in figure 1. Men Testicular function is principally under the control of the hypothalamopituitary axis. The hypothalamus secretes gonadotrophin-releasing hormone (GnRH) in discrete pulses at intervals of 60–90 min [2]. These pulses are modified by negative feedback of testosterone and by cortical stimulation or inhibition by neurotransmitters (e.g. -aminobutyric acid, opioid peptides, serotonin, neuropeptide Y, substance P, corticotrophin releasing factor) [3, 4]. GnRH in turn stimulates the anterior pituitary to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are also secreted in pulses that mimic those of GnRH, with LH showing the greatest pulse amplitude. LH stimulates Leydig cells to produce testosterone whilst FSH predominantly stimulates spermatogenesis through its action on Sertoli cells. Sertoli cells also secrete inhibin, which exerts negative feedback control on FSH secretion, but the exact function of this protein is controversial [5]. Testosterone circulates in the blood mostly bound to either albumin (50%) with weak affinity or to sex hormone-binding globulin (SHBG) (40%) with high affinity [6]. The remaining 10% is bioavailable or free testosterone. The
Fletcher
132
Cerebral cortex
+/s
Hypothalamus
GABA, opioids, serotonin, neuropeptide Y, substance P, CRH s
GnRH s
+/-1
+
-
Corticotrophinreleasing horm one GABA g-Am inobutyric acid GnRH Gonadotrophinreleasing horm one Luteinizing horm one LH Follicle-stim ulating FSH
CRH
s
s s
Pituitary
s
LH FSH +/-1
-
s
Testis
Oestradiol +
s
Testosterone Inhibin +
Ovaries
Fig. 1. Diagram of the hypothalamo-pituitary-gonadal axis. 1 Oestradiol may stimulate or inhibit gonadotrophin secretion depending on its concentration and on the progesterone concentration.
majority of the effects of testosterone are mediated by its active metabolite 5-dihydrotestosterone which has higher affinity for the androgen receptor [7]. The conversion of testosterone to 5-dihydrotestosterone is catalysed by the 5-reductase enzyme. Testosterone may also be converted to oestradiol by the aromatase enzyme complex. The high affinity of SHBG for testosterone ensures it is the principal carrier of testosterone, and therefore SHBG production and levels directly reflect circulating levels of testosterone. The hepatic synthesis of SHBG is stimulated by thyroid hormones and sex steroids, including oestradiol, and is inhibited by insulin and insulin-like growth factor-1. States of protein depletion, as are often seen in catabolic acute illnesses, can result in reduced SHBG concentrations. In addition, an age-dependent diurnal variation in both testosterone and SHBG occurs, with young men having highest levels in the
The Pituitary Gonadal Axis
133
Table 1. Causes of increased or reduced SHBG concentrations Increased SHBG
Decreased SHBG
Oestrogen treatment Androgen deficiency Ageing Thyrotoxicosis Alcohol-induced cirrhosis Hepatitis
Androgen treatment Hyperinsulinaemia Obesity Hypercortisolaemia Nephrotic syndrome Hypothyroidism
morning. Older men have lower concentrations of testosterone and higher concentrations of SHBG and a dampened diurnal variation [8]. Conditions associated with altered SHBG levels are listed in table 1. Women As in men, the gonadal axis in women is under the control of the hypothalamo-pituitary axis. The secretion of GnRH from the hypothalamus is regulated by cortical neurotransmitter stimulation or inhibition and by feedback from sex steroids. GnRH is secreted in pulsatile fashion and stimulates the anterior pituitary to secrete FSH and LH. These, in turn, act on the ovary to promote follicular maturation, luteinization and secretion of oestradiol and progesterone. The modulation of hypothalamic and pituitary hormone secretion is more complex than in men, involving both positive as well as negative feedback loops. Oestradiol can inhibit gonadotrophin secretion or promote it depending on its concentration [9]. In addition, in the presence of high concentrations of progesterone, oestradiol does not stimulate the hypothalamus or pituitary [9]. Only 3% of oestradiol is ‘free’; the rest is either bound to albumin (60%) or to SHBG (37%). The affinity to which SHBG binds oestradiol is only approximately one fifth of that with which it binds testosterone, and oestradiol itself stimulates the hepatic production of SHBG.
Diagnosis of Hypogonadism The symptoms and physical signs that accompany hypogonadism are often subtle, and usually an aspect of the history alerts the clinician to the diagnosis. In both sexes, the clinical findings may be separated into hypogonad-
Fletcher
134
Table 2. Hypogonadism – clinical findings and consequences Males
Females
onset before puberty
onset after puberty
onset before puberty
Micropenis Testes =5 ml
Normal penis size Testes 15 ml and soft
Primary amenorrhoea Reduced breast development
Reduced strength and muscle mass Eunuchoid habitus
Reduced strength and muscle mass Normal skeletal proportions Male escutcheon
Female pubic hair distribution Reduced libido High-pitched voice Delayed bone age
Reduced libido Normal voice Normal bone age
Osteoporosis in later life Osteoporosis in later life
onset after puberty
Secondary amenorrhoea Normal breast development but mammary atrophy Absent pubic and Normal female axillary hair escutcheon Osteoporosis in later life Osteoporosis in later life Underdeveloped internal genitalia Reduced libido Infertility
Vaginal atrophy Reduced libido Infertility Increased incidence of cardiovascular disease Onset of mood disturbance
Increased subcutaneous Increased subcutaneous fat fat Reduced lean body mass Reduced lean body mass
ism occurring before puberty and that occurring after puberty. A summary of these findings is given in table 2. Laboratory Investigation – Men Laboratory investigation is needed to confirm the hypogonadal state. Measurement of serum testosterone in men should be accompanied by estimations of LH and FSH. Morning is the ideal time to measure testosterone so that the affect of diurnal variation of testosterone levels is minimized. Assays for measuring bioavailable testosterone are not widely available, therefore additional measurement of SHBG is useful in enabling a free androgen index to be calculated. This is important in a patient with acute (or chronic) illness, as hypercatabolic states sometimes have an adverse effect on SHBG concentrations. In most instances of acute illness, however, concentrations of SHBG are maintained [10]. Away from the situation of acute illness, it is essential to also measure prolactin if hypogonadotrophic hypogonadism is discovered, as hyperprolactinaemia per se may lower LH [11]. In acute illness, however, the picture of ‘hypogonadotrophic hypogonadism’ is by far the most common
The Pituitary Gonadal Axis
135
[12], and prolactin may be secreted in response to the stress of acute, severe illness. In acute illness, therefore, further evaluation of the pituitary should be deferred if possible until several weeks after recovery. Laboratory Investigation – Women The clinical features of hypogonadism in women are largely those which are recognized after the menopause. Normal practice is to evaluate oestradiol concentrations in the context of FSH and LH levels and the time of sampling in relation to the menstrual cycle. As in men, in the absence of acute illness, it is essential to further fully evaluate the pituitary gland, prolactin levels, adrenal axis and thyroid axis if hypogonadotrophic hypogonadism is found. Few studies have reported the effect of acute illness on SHBG concentrations in women, although it is likely that concentrations are maintained as they are in men.
Acute Systemic Illness and Gonadal Function All acute severe illnesses are capable of producing hypogonadotrophic hypogonadism [13]. This is usually temporary and the picture mimics that of nonthyroidal illness or ‘sick euthyroid syndrome’ with levels of testosterone or oestradiol returning to normal approximately 6 weeks after recovery [12]. Indeed, hypogonadotrophic hypogonadism has been reported to be more common than nonthyroidal illness in a survey of male inpatients [14]. In men, falls in testosterone concentrations of the order of 50% have been reported [12]. In these patients SHBG concentrations are conserved. In addition, the more severe the acute illness, the more profound hypogonadism tends to be [15]. An overview of the effects of acute illness on gonadal function is given in table 3. Mechanisms of Hypogonadism in Acute Illness It is possible to speculate that hypogonadism in the context of acute illness is a deliberate physiological response to prevent an individual from reproduction when this would be disadvantageous. Most studies have demonstrated hypogonadotrophic hypogonadism in acute illness and have postulated that the principal mechanism is that of hypothalamo-pituitary disequilibrium, with suppression of the axis causing a subsequent secondary reduction in gonadal function within 24 h. Further evidence in support of a central mechanism is provided by a study which demonstrated blunted responses to GnRH stimulation in critically ill postmenopausal women [16], although another study involving experimentally induced hypoglycaemia in otherwise fit women showed normal responses to
Fletcher
136
Table 3. The hypothalamo-pituitary-gonadal axis in acute illness Illness
Men
Women
testos- LH terone
FSH
Oestrogen
LH
FSH
!
! or
! or
Trauma1 Respiratory disease Chronic obstructive pulmonary disease Sleep apnoea
Renal disease Renal failure
!
! or
Gastrointestinal disease Coeliac disease Alcohol-induced cirrhosis Cancer
!
2
Endocrine disease Thyrotoxicosis3 Acute pituitary insufficiency Cushing’s syndrome Diabetes mellitus
! ! or ! or
or
! or ! or
! or
! or
! or or
! or or
Infectious disease HIV4 Neurological disease Stroke Epilepsy5 Cardiovascular disease Myocardial infarction >Levels decreased; !>levels increased; >levels normal. Transient increase in LH and FSH has been reported. 2 Effects depend on intercurrent illness and treatment effects. 3 SHBG may rise. 4 Many possible mechanisms exist (e.g. drugs, neoplasia, cytokines). 5 Temporal lobe epilepsy associated with hypogonadotrophic hypogonadism. Anticonvulsant treatment may lower testosterone levels through enzyme induction. 1
The Pituitary Gonadal Axis
137
GnRH [17]. There are many possible factors which could be responsible for central suppression of the hypothalamo-pituitary-gonadal axis. For example, the stress of acute illness is usually associated with a rise in corticotrophinreleasing hormone, pro-opiomelanocortin, adrenocorticotrophic hormone and ultimately cortisol, all of which have been shown to suppress gonadotrophin secretion [18, 19] and cortisol receptors have been found in the rat testis [20]. This is complicated by ‘inappropriately’ low levels of cortisol having been found in some of the most severely ill patients in an intensive care unit [21]. Other factors may also have an important role: opioids used as analgesia may alter hypothalamic gonadotrophin secretion and neurotransmitter control of hypothalamic gonadotrophin secretion may be altered in the cortical response to severe stress associated with acute illness. In one study, dopamine infusion was associated with decreased LH secretory pulse amplitude, mass and frequency in critically ill men [22]. A recent study has cast doubt on the suggestion that central mechanisms are solely responsible for the hypogonadism that accompanies acute illness [23]. Intensive care patients’ gonadotrophin and testosterone levels were measured on successive days after admission. Whilst testosterone levels declined as expected, LH and FSH levels rose transiently in the first 3 days after admission before falling to the low levels normally associated with acute illness. Subsequently, LH and FSH levels returned to the normal range within 14 days irrespective of whether the patients subsequently survived or died (although testosterone concentrations remained low). These results suggest that both central mechanisms and Leydig cell resistance have a role. Relatively preserved inhibin levels in acutely ill patients suggest Sertoli cells are less affected than Leydig cells [24]. Patients with acute illness have high levels of circulating cytokines as part of an acute inflammatory response. These cytokines may also be partly responsible for low testosterone and oestrogen levels in addition to the factors mentioned earlier. A wide range of cytokines have been shown capable of regulating steroid biosynthesis. For example, concentrations of interleukin (IL)-6 have been found to be inversely correlated with testosterone concentrations [25]. In animals, tumour necrosis factor- (TNF-), IL-2 and interferon inhibit enzymes of testosterone synthesis [26]. Infusions of individual cytokines into laboratory Leydig cell preparations have unfortunately not yet implicated one cytokine alone, but macrophage-conditioned media has been shown to reduce testosterone levels in this context [27]. This may mean that the interaction of several cytokines is necessary or that an as yet undiscovered cytokine is responsible. Further evidence for this interaction between cytokines and gonadal function is provided by studies performed in patients with rheumatoid arthritis, in whom testosterone levels are low [28] and IL-1 and IL-6
Fletcher
138
are felt to be important in pathogenesis. In these patients, expression of both cytokines is variably affected by the concentrations of testosterone and oestradiol, but many of these patients are also treated with exogenous glucocorticoids, which also affect sex steroid levels [29]. In summary, no clear single factor has been identified to be responsible for the hypogonadism which accompanies acute illness. It appears that both central effects and Leydig cell resistance coexist. Central effects of drugs, stress and cortisol have been implicated, and cytokines have been shown to interfere with sex steroid biosynthesis.
Hypogonadism in Specific Conditions Trauma Studies of gonadal function in trauma patients have usually been conducted in the setting of intensive care. Almost all severely injured patients, irrespective of gender, show features of hypogonadotrophic hypogonadism at some point in their illness [10]. Only one study, mentioned earlier, showed transient primary hypogonadism [23]. The nature of the trauma appears to be unimportant, as head injury is equally associated with hypogonadism [30] as burn trauma [31], although the mechanism may be different: head injury may disrupt the delicate neural connections around the pituitary through shearing forces, whereas in burn injury cortisol levels rise, very high levels of cytokines are found, and opioid analgesia is required. Two studies, after excluding known potentially confounding coexistent conditions, have demonstrated that the degree of reproductive axis suppression is proportional to the degree of illness and trauma, measured by Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores [15, 32]. Teasing out which of the many potential aetiological factors are responsible for hypogonadism is difficult, and one can speculate that a combination of the effects of drugs, endogenous opioids, direct trauma to the pituitary and/or hypothalamus, cortisol or cytokines is to blame. Respiratory Disease Most studies of the hypothalamo-pituitary-gonadal axis in respiratory disease have focused on chronic rather than acute illness and have usually been performed in men. These studies have found low testosterone levels especially in patients with chronic obstructive pulmonary disease [33, 34]. It is likely that in at least some of these patients, recurrent acute illness is responsible for the low testosterone levels. In a study over 30 years ago, testosterone concentrations rose during acute asthma attacks [35], but then fell to concentrations below the
The Pituitary Gonadal Axis
139
reference range in between attacks. Testosterone has been shown to worsen sleep apnoea in men, possibly by affecting respiratory drive during hypoxia, and low levels of testosterone may therefore have a protective role [36]. Sleep apnoea itself is associated with low testosterone and normal gonadotrophin levels in men [37]. Renal Disease Both acute and chronic renal failure are associated with hypogonadism in men and women [38, 39]. LH levels are usually elevated in both sexes, and the pulses of GnRH release are of reduced amplitude and frequency [40]. Women have low [41] or normal [42] concentrations of oestradiol and the majority are amenorrhoeic [41]. The combination of high levels of LH and low/normal levels of oestrogen suggest primary gonadal failure, but the finding of normal FSH concentrations indicates hypothalamo-pituitary dysregulation is present as well. Hyperprolactinaemia is common in patients with acute and chronic renal disease [42]. Elevated prolactin levels are a well-recognized cause of sexual dysfunction and hypogonadism, although it is not clear whether this is a consequence of a hypothalamo-pituitary effect or a direct gonadal effect. Prolactin clearance in renal failure is only slightly diminished and it seems the likely mechanism for high levels of prolactin is reduced dopaminergic inhibition of pituitary lactotrophs [43]. In women undergoing haemodialysis treatment, menstrual bleeding can be restored with oestrogen/progesterone therapy as in non-uraemic patients. In chronic renal failure, the hypogonadism in men mirrors that of women with low gonadal steroids, high LH and normal/high FSH levels, and possible Leydig cell resistance [44]. Nevertheless, men also have disturbance in the hypothalamo-pituitary regulation of gonadotrophin secretion. Oestradiol concentrations have been reported to be reduced [41], normal [45] or elevated [46] in uraemic men and feedback of oestradiol to the hypothalamic LH pulse generator may result in abnormal activity. In addition, it has been proposed that changes in the concentration and distribution of hypothalamic endogenous opioids (which are involved in the negative feedback control of pulsatile LH release in health) result in disturbed LH release in uraemia [39]. Gastrointestinal Disease Androgen resistance, with clinical features of hypogonadism and low 5dihydrotestosterone but elevated LH and free testosterone, has been described in adult male patients with coeliac disease [47]. This, along with the other manifestations of the disease, improves after instituting a gluten-free diet [47]. Inflammatory bowel disease is associated with reduced fertility in men but not women [48]. Sulphasalazine may cause oligospermia and is the principal
Fletcher
140
reason for infertility in men, which is reversible on discontinuation of the drug [49]. Most patients with inflammatory bowel disease, male or female, do not have hypogonadism unless acute exacerbations supervene. Liver Disease Liver disease is associated with hypogonadism, but different studies have described different patterns of LH release and concentration [50, 51]. In men, the majority of studies have been undertaken in patients with alcohol-induced liver disease. Alcohol appears to inhibit testosterone synthesis, through an effect on alcohol dehydrogenase [50]. This accounts for reports of raised gonadotrophin levels associated with alcohol misuse [51]. Other studies, however, have shown impaired LH secretion and low testosterone levels in chronic liver disease, suggesting a primary testicular defect is not the whole story [50]. In addition, SHBG levels increase in hepatic cirrhosis, with the effect that there is less free or bioavailable testosterone. Oestradiol levels are high in many patients with hepatic cirrhosis and this has the effect of both stimulating hepatic SHBG synthesis and inhibiting gonadotrophin secretion by negative feedback [19]. Prolonged, unopposed oestrogen effects in liver disease can result in either amenorrhoea or menorrhagia [52], and up to 60% of women develop amenorrhoea prior to liver transplantation [53]. Reversal of the menstrual and hormonal irregularities occurred in the great majority of women after successful transplantation [54]. Cancer Cancer may cause acute hypogonadism in men and women alike, as a direct effect of intercurrent acute illness or the debility and poor nutritional state that often accompanies it. Studies have reported primary and hypogonadotrophic hypogonadism in this context, and it is difficult to determine whether these effects are due to the cancer per se or the effects of acute illness, liver involvement, nutritional deficit or advanced age [54–56]. The treatment of cancer may have profound implications for the reproductive axis. In women, infertility may follow ovarian exposure to radiation, and this effect depends on the dose and fractionation of the radiation given and the state of development of the germ cell [57, 58]. Chemotherapy may produce temporary or permanent ovarian failure. The effects of some chemotherapeutic agents and other drugs on the hypothalamo-pituitary-gonadal axis are given in table 4. In addition, the acute effects of radiation and chemotherapy on the bone marrow may result in susceptibility to acute infection and these, along with the acute toxic effect of the treatment itself, are likely to cause hypogonadotrophic
The Pituitary Gonadal Axis
141
hypogonadism. The pituitary-hypothalamic axis may be damaged after craniospinal irradiation given for intracranial malignancy, and hypogonadotrophic hypogonadism is a well-recognized consequence [59]. Endocrine Disease SHBG concentrations often rise in thyrotoxicosis, with only small changes occurring in free testosterone [60]. Thyrotoxicosis is associated with osteopaenia in both sexes, but this appears to be predominantly the effect of thyroid hormones on bone remodelling rather than a direct effect of hypogonadism [61]. Both hypothyroidism and thyrotoxicosis can be associated with anovulatory bleeding, amenorrhoea or anovulation [62]. Testosterone and gonadotrophin levels are often low in Cushing’s syndrome, although this may be a consequence of acute illness on the hypothalamopituitary-gonadal axis or a direct effect of the high circulating cortisol level [63]. Sexual dysfunction has a well-described association with diabetes mellitus. Hypogonadism has a significant role, although the effects of drugs, neurological and vascular factors are profound. Both primary and hypogonadotrophic hypogonadism have been reported [64, 65]. Most studies have been conducted in male patients with chronic stable diabetes mellitus, but one showed reduced testosterone levels in patients with diabetic ketoacidosis, most likely as a result of acute illness [66]. Infectious Disease Any acute infection causing systemic illness has the capacity to cause hypogonadotrophic hypogonadism. Equally, infections of the gonads (e.g. orchitis, leprosy) frequently result in primary hypogonadism with elevated gonadotrophin concentrations. The effect of human immunodeficiency virus (HIV) infection on the reproductive axis has been studied in more detail than other infections but practically all studies have been conducted in men. The reader is referred to a comprehensive recent review of this subject [67]. A wide range of causative mechanisms for gonadal axis disturbance is possible: direct effects of the virus; complicating neoplasia; opportunistic infection or treatment; as a result of illicit drug misuse; or the effects of HIV-induced cytokines. Asymptomatic HIV-infected men usually have normal testosterone levels, but levels fall progressively as the disease develops [68]. Both hypogonadotrophic hypogonadism and primary hypogonadism have been described [69, 70]. Neurological Disease Few patients with acute neurological disease (apart from head trauma mentioned earlier) have been studied with regard to their gonadal function.
Fletcher
142
Patients who have suffered spinal cord injury usually maintain gonadotrophin, oestrogen and testosterone levels [71]. It has been claimed that temporal lobe epilepsy is associated with hypogonadism, with the cause attributable to anticonvulsant treatment and/or abnormal neurotransmitter influence on the hypothalamus [72]. Patients with other forms of epilepsy have normal levels of gonadotrophins and sex steroids [73]. Other Disease Surprisingly there are virtually no data on the effect of acute cardiovascular disease on the hypothalamo-pituitary-gonadal axis. It is probable that hypogonadism occurs as in virtually all other acute severe illness, although this cannot be assumed. One study showed that testosterone levels fell on the fourth day after myocardial infarction with a compensatory increase in LH concentration [74]. Systemic lupus erythematosus is associated with reduced fertility in women with very active disease, but inactive forms do not impair fertility [65]. Many other conditions have well-recognized associations with hypogonadism (e.g. haemochromatosis [75], rheumatoid arthritis [28], myotonic dystrophy [76]) but rarely is acute illness a feature. For this reason, discussion of these conditions has been withheld from this chapter. Effect of Drugs Many drugs used in the treatment of acute illness may result in hypogonadism. A selection of these drugs and their effects is given in table 4. Drugs may cause hypogonadism via a variety of mechanisms. They may have central effects, impair hormone synthesis or influence metabolism (e.g. by aromatization).
Treatment of Hypogonadism in Acute Illness Treatment of the hypogonadism that commonly accompanies acute illness could be thought of as tampering with a normal physiological response, and careful consideration should be given to the advantages and disadvantages of treatment. Several treatment strategies may be employed. First, treatment of the underlying condition or removal of a precipitating cause will often lead to a return of normal gonadal function. Second, specific treatments may be of value. An example is the beneficial effect of dopamine agonist therapy in hyperprolactinaemia, which may result in a return of normal gonadal function [45].
The Pituitary Gonadal Axis
143
Table 4. Effects of drugs on the hypothalamo-pituitary-gonadal axis Drug
Effect
Central nervous system Opioids Phenothiazines Tricyclic antidepressants Phenytoin Carbamazepine
T, LH, FSH !Prolactin1 T, LH, FSH T, !LH2 T, !LH2
Cardiovascular system Digoxin Spironolactone
!E2, T T, !E2
Gastrointestinal system Cimetidine Sulphasalazine
T normal but blocks androgen receptors Reversible oligospermia
Endocrine system Glucocorticoids Cyproterone Finasteride
T, !LH, !FSH T T
Antimicrobial drugs Ketoconazole
T, !LH, !FSH
Anticancer drugs MVPP
3
T, oligospermia
T>Testosterone action; LH>luteinizing hormone; E2>oestradiol; FSH> follicle-stimulating hormone; MVPP>nitrogen mustard, vinblastine, prednisolone, procarbazine. 1 Hyperprolactinaemia subsequently may cause T, LH and FSH levels to fall. 2 Carbamazepine and phenytoin increase testosterone metabolism through enzyme induction. 3 Many other chemotherapeutic agents (e.g. cyclophosphamide, chlorambucil) are toxic to the germinal epithelium and result in oligo- or azoospermia.
Oestrogen Replacement Therapy Specific indications for the use of oestrogens currently include treatment of menopausal symptoms such as vasomotor instability or vaginal atrophy, early menopause, established osteoporosis and those at particular risk of developing osteoporosis [77]. Contraindications to treatment include pregnancy, oestrogen-dependent carcinoma, thromboembolic disease, liver disease, breast feeding and undiagnosed vaginal bleeding [77].
Fletcher
144
Androgen Replacement Therapy Testosterone is licensed for replacement therapy in hypogonadal men, but not for the treatment of impotence or impaired spermatogenesis, for which it has no benefit. Methods of administration include oral, intramuscular, subcutaneous pellet implant and more recently, transdermal. Testosterone has a high first-pass metabolism, and bioavailability after oral administration is therefore variable and limited. Most hypogonadal patients receive intramuscular testosterone esters monthly or more frequently (to limit peaks and troughs) and unwanted effects include pain at the injection site. Many patients learn to administer their own injections. Transdermal delivery systems used to be confined to shaved scrotal skin, but recently patches have been developed which may be applied to other skin sites [78]. This mode of administration minimizes peaks and troughs but sensitivity reactions are common. Transdermal delivery is also more expensive at present. Anabolic Steroid Treatment There are surprisingly few data relating to the use of anabolic steroids in acute illness. In those instances where full and rapid recovery is anticipated, it is unlikely that anabolic agents would have measurable benefit. In circumstances where acute illness leads to severe debility and wasting, the potential for anabolic agents needs to be examined more closely. Indeed, it was to promote growth in treating asthenic or aplastic diseases that these substances were first developed [79]. Testosterone has been shown to increase lean body mass, muscle size and strength and bone density when given in supraphysiological doses in health [80]. It is not possible to separate these anabolic effects from the ability of these substances to stimulate the development of male phenotype and secondary sexual characteristics. It has been suggested that a total cumulative anabolic steroid dose of 3 g is required before an increase in muscle and lean body mass is observed [81]. Such doses are of the order of 10 times the usual therapeutic replacement dose and it is therefore not surprising that side effects from treatment are well described (see below). Limited data exist on the effect of testosterone replacement in men with HIV infection. In one study, whilst improvements in mood and libido were noted, no effects were observed on lean body mass or muscle strength [82]. In another study, testosterone treatment improved HIV wasting [83]. Other studies have described beneficial effects of testosterone in rheumatoid arthritis [84] and myotonic dystrophy [76]. When given with nutritional support, oxandrolone has been shown to improve catabolism in patients with alcoholic hepatitis [85] and nandrolone has benefited patients with multiple trauma [86].
The Pituitary Gonadal Axis
145
The prevalence of misuse of anabolic steroids is high [87]. A recent survey of 30,000 randomly selected people in the USA reported 0.9% of males and 0.1% females over 12 years of age had taken anabolic steroids at some time in their lives [88]. The clandestine use of anabolic steroids means few controlled trials have been performed to evaluate their effects, although several reports of adverse effects exist. Complications of Treatment of Hypogonadism in Acute Illness Adverse effects of androgen treatment may be divided into two categories: those associated with replacement therapy and those associated with supraphysiological doses. First, with replacement therapy, mild gynaecomastia (due to aromatization to oestradiol) may occur. In addition, testosterone has been shown to cause or worsen sleep apnoea when given for hypogonadism in these patients [36]. Testosterone treatment has resulted in a fall of highdensity lipoprotein cholesterol through its action on hepatic lipoprotein lipase activity, but the long-term effect of this on the incidence of cardiovascular disease is not clear [89, 90]. Treatment with alkylated androgens has been associated with development of hepatocellular carcinoma and peliosis hepatis (haemorrhagic liver cysts) [91, 92]. Suppression of the hypothalamo-pituitary-testicular axis with testicular atrophy occurs if supraphysiological doses of anabolic steroids are used. In women, virilization may occur. There are anecdotal reports of adverse cardiovascular events: for example, a myocardial infarction occurred in a 22year-old man [93] and a stroke occurred in a 34-year-old, both of whom misused anabolic steroids [94]. Insulin resistance during anabolic steroid use has been described, but clinical diabetes mellitus has not [95]. Psychosis, mood swings and psychological dependence have been widely reported [96]. Prostatic carcinoma associated with the use of anabolic steroids has been reported once [97], and it should be noted that their use is contraindicated in patients with carcinoma of the prostate. Adverse effects of oestrogen treatment include features of premenstrual syndrome, with weight gain, mood changes and fluid retention. In addition, gallstones, thromboembolism, migraine and hepatocellular carcinoma have been associated [77]. Summary of Sex Steroid Treatment Androgen and oestrogen replacement therapy is indicated for the treatment of hypogonadism, providing appropriate precautions to minimize risks. There is little evidence to support the use of replacement therapy or the use of anabolic steroids in hypogonadism associated with acute illness and further work needs to be done before their use is justified. Beneficial effects of
Fletcher
146
anabolic steroids have been reported in HIV wasting, alcoholic hepatitis, multiple trauma and rheumatoid arthritis, but there are significant adverse effects associated with their use.
Summary and Conclusions Virtually all acute illness can be associated with hypogonadism, which often persists for many months after recovery. Primary and hypogonadotrophic hypogonadism may occur. The aetiology is likely to be multifactorial, involving central effects of drugs, neurotransmitter action, and high circulating levels of cortisol and cytokines. In the future, it is likely that further mechanisms will be elucidated. Oestrogens and androgens are needed for normal sexual differentiation, growth and development, and the maintenance of secondary sexual characteristics in women and men. Deficiencies of these hormones can have serious sequelae and replacement is indicated if the deficiency is permanent. There are insufficient data at present to recommend hormone replacement for hypogonadism associated with acute illness, but further study is required in order that potential benefits for such patients are not overlooked. In addition, the use of anabolic steroids in the context of acute illness has not yet been properly evaluated, and the potentially serious adverse effects associated with supraphysiological doses of these substances mean that their use cannot at present be recommended.
References 1 2 3 4 5 6
7 8
Medvei VC: 1900–1940 Part 1; in The History of Clinical Endocrinology. Carnforth, Parthenon, 1993, pp 218–226. Wang C, Swerdloff RS: Evaluation of testicular function. Baillie`res Clin Endocrinol Metab 1992; 6:405–408. Halasz B, Kiss J, Molnar J: Regulation of the gonadotropin-releasing hormone (GnRH) neuronal system: Morphological aspects. J Steroid Biochem Mol Biol 1989;33:663–668. Rasmussen DD: New concepts in the regulation of hypothalamic gonadotropin releasing hormone (GnRH). J Endocrinol Invest 1986;9:427–437. Plymate SR, Paulsen CA, McLachlan RI: Relationship of serum inhibin levels to FSH and sperm production in normal men and men with a varicocele. J Clin Endocrinol Metab 1992;74:859–864. Dunn JF, Nisula BC, Rodbard D: Transport of steroid hormones: Binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981;53:58–68. Winters SJ: Endocrine evaluation of testicular function. Endocrinol Metab Clin North Am 1994; 23:709–723. Bremner WJ, Vitello MV, Prinz PN, Zumoff B, Strain GW, Kreak J, O’Connor J, Rosenfield RS, Levin J, Fukushima DK: Loss of circadian rhythmicity in blood testosterone levels with ageing in
The Pituitary Gonadal Axis
147
9 10 11 12 13 14 15 16
17 18 19 20 21 22 23
24
25
26 27 28 29 30 31 32 33
normal men. J Clin Endocrinol Metab 1983;56:1278–1281. Jacobs HS: The ovary; in Weatherall DJ, Ledingham JGG, Warrell DA (eds): Oxford Textbook of Medicine. Oxford, Oxford University Press, 1996, vol 2, pp 1669–1679. Woolf PD, Hamill RW, McDonald JV, Lee LA, Kelly M: Transient hypogonadotropic hypogonadism caused by critical illness. J Clin Endocrinol Metab 1985;60:444–450. Winters SJ, Troen P: Altered pulsatile secretion of luteinising hormone in hypogonadal men with hyperprolactinaemia. Clin Endocrinol 1984;21:257–263. Turner HE, Wass JAH. Gonadal function in chronic illness. Clin Endocrinol 1997;47:379–403. Semple CG, Gray CE, Beastall GH: Male hypogonadism – A non-specific consequence of illness. Q J Med 1987;64:601–607. Jarek MJ, Legare EJ, McDermott MT: Endocrine profiles for outcome prediction on an intensive care unit. Crit Care Med 1996;21:543–550. Spratt DI, Cox P, Orav J, Moloney J, Bigos T: Reproductive axis suppression in acute illness is related to disease severity. J Clin Endocrinol Metab 1993;76:1548–1554. Gebhart SSP, Watts NB, Clark RV, Umpierez G, Sgoutas D: Reversible impairment of gonadotropin secretion in critical illness. Observations in postmenopausal women. Arch Intern Med 1989;149: 1637–1641. Bing-You RG, Spratt DI: Serum estradiol but not gonadotropin levels decrease acutely after insulininduced hypoglycemia in cycling women. J Clin Endocrinol Metab 1992;75:1054–1059. Cumming DC, Quigley ME, Yen SSC: Acute suppression of circulating testosterone levels by cortisol in men. J Clin Endocrinol Metab 1983;57:671–673. Plymate SR, Jones RE: Testicular function in critical illness; in Ober KP (ed): Contemporary Endocrinology: Endocrinology of Critical Disease. Totowa, Humana Press, 1997, pp 271–283. Ulisse S, Fabbri A, Tinajero JC, Dufau ML: A novel mechanism of action of corticotrophin releasing factor in rat Leydig cells. J Biol Chem 1990;265:1964–1971. Rothwell PM, Udwadia ZF, Lawler PG: Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582–583. Van den Berghe G, de Zegher F, Lauwers P, Veldhuis JD: Luteinizing hormone secretion and hypoandrogenaemia in critically ill men: Effect of dopamine. Clin Endocrinol 1994;41:563–569. Spratt DI, Bigos ST, Beilins I, Cox P, Longcope C, Orav J: Both hyper- and hypogonadotrophic hypogonadism occur transiently in acute illness: Bio- and immunoreactive gonadotropins. J Clin Endocrinol Metab 1992;75:1562–1570. Dong Q, Hawker F, McWilliam D, Bangah M, Burger H, Handelsman DJ: Circulating immunoreactive inhibin and testosterone levels in men with critical illness. Clin Endocrinol 1992;36:399– 404. Amado JA, Lopez-Espadas F, Vazquez-Barquero A, Salas J, Rianch JA, Lopez-Cordovilla JJ, Garcia-Unzueta M: Blood levels of cytokines in brain-dead patients: Relationship with circulating hormones and acute-phase reactants. Metabolism 1995;44:812–816. Nadin L, Butler AM, Farrell GC, Murray M: Pretranslational downregulation of cytokines P450 2C11 and 3A2 in male rat livers by tumor necrosis factor alpha. Gastroenterology 1995;109:198–205. Watson ME, Newman RJ, Payne AM, Abdelrahim M, Francis G: The effect of macrophage conditioned media on Leydig cell function. Ann Clin Lab Sci 1994;24:84–95. Gordon D, Beastall GH, Thomson JA, Sturrock RD: Androgenic status and sexual function in males with rheumatoid arthritis. Q J Med 1986;231:671–679. Li ZG, Danis VA, Brooks PM: Effect of gonadal steroids on the production of IL-1 and IL-6 by blood mononuclear cells in vitro. Clin Exp Rheumatol 1993;11:157–162. Clark JDA, Raggatt PR, Edwards OM: Hypothalamic hypogonadism following major head injury. Clin Endocrinol 1988;29:153–156. Lephart ED, Baxter CR, Parker CR Jr: Effect of burn trauma on adrenal and testicular steroid hormone production. J Clin Endocrinol Metab 1987;64:842–848. Luppa P, Munker R, Nagel D, Weber M, Engelhardt D: Serum androgens in intensive-care patients: Correlations with clinical findings. Clin Endocrinol 1991;34:305–310. Semple Pd’A, Beastall GH, Brown TM, Stirling KW, Mills RJ, Watson WS: Sex hormone suppression and sexual impotence in hypoxic pulmonary fibrosis. Thorax 1984;39:46–51.
Fletcher
148
34
35 36
37 38 39 40
41 42 43
44 45
46 47 48 49 50 51
52 53 54 55
56 57 58
Aasebo U, Gyltnes A, Bremnes RM, Aakvaag A, Slordal L: Reversal of sexual impotence in male patients with chronic obstructive pulmonary disease and hypoxemia with long-term oxygen therapy. J Steroid Biochem Mol Biol 1993;46:799–803. Trethewie ER: Asthma and testosterone. Nature 1966;209:1136. Matsumoto AM, Sandbloom RE, Schoene RB, Lee KA, Giblin EC, Pierson DJ, Bremner WJ: Testosterone replacement in hypogonadal men: Effects on obstructive sleep apnoea, respiratory drive and sleep. Clin Endocrinol 1985;22:713–721. Santamaria JD, Prior JC, Fleetham JA: Reversible reproductive dysfunction in men with obstructive sleep apnoea. Clin Endocrinol 1988;28:461–470. Lim VS: Reproductive endocrinology in uraemia. Baillie`res Clin Obstet Gynaecol 1994;8:469–480. Handelsman DJ, Dong Q: Hypothalamo-pituitary-gonadal axis in chronic renal failure. Endocrinol Metab Clin North Am 1993;22:145–161. Veldhuis JD, Wilkowski MJ, Zwart AD, Urban RJ, Lizarralde G, Iranmanesh A, Bolton WK: Evidence for attenuation of hypothalamic gonadotropin-releasing hormone (GnRH) impulse strength with preservation of GnRH pulse frequency in men with chronic renal failure. J Clin Endocrinol Metab 1993;76:648–654. Baumann G, Reza P, Chatterton R, Green D, Krumlovsky F: Plasma estrogens, androgens and von Willebrand factor in men on chronic hemodialysis. Int J Artif Organs 1988;11:449–453. Gomez F, de la Cuerva R, Wauters J, Lemarchan-Berand T: Endocrine abnormalities in patients undergoing long-term hemodialysis. The role of prolactin. Am J Med 1980;68:522–530. Lim VS, Kathpalia SC, Frohman LA: Hyperprolactinemia and impaired pituitary response to suppression and stimulation in chronic renal failure: Reversal after transplantation. J Clin Endocinol Metab 1979;48:101–107. Mastrogiocomo I, de Besi L, Zuchetta P, Serafini E, la Greca G, Gasparotto ML, Lorenzi S, Dean P: Male hypogonadism of uremic patients on hemodialysis. Arch Androl 1988;20:171–175. Muir JW, Besser GM, Edwards CR, Rees LH, Cattell WH, Ackrill P, Baker LR: Bromocriptine improves reduced libido and potency in men receiving maintenance hemodialysis. Clin Nephrol 1983;20:308–314. Rodger RSC, Morrison L, Dewar JH, Wilkinson R, Ward MK, Kerr DNS: Loss of pulsatile luteinising hormone secretion in men with chronic renal failure. Br Med J 1985;291:1598–1600. Green RJB, Goble HL, Edwards CRW, Dawson AM: Reversible insensitivity to androgens in men with untreated gluten enteropathy. Lancet 1977;i:280–282. Levi AM, Fisher AM, Hughes L, Hendry WF: Male infertility due to sulphasalazine. Lancet 1979; ii:276–278. Birnie GG, McCleod TIF, Watkinson G: Incidence of sulphasalazine-induced male infertility. Gut 1981;22:452–455. Bannister P, Handley T, Chapman C, Losowsky MS: Hypogonadism in chronic liver disease: Impaired release of luteinising hormone. Br Med J 1986;293:1191–1193. Baker HWG, Burger HG, de Kretser DM, Dulmanis A, Hudson B, O’Connor S, Paulson CA, Purcell N, Rennie GC, Seah CS, Taft HP, Wang C: A study of the endocrine manifestations of hepatic cirrhosis. Q J Med 1979;177:145–178. Stellon AJ, Williams R: Increased incidence of menstrual abnormalities and hysterectomy preceding primary biliary cirrhosis. Br Med J 1986;293:297–298. Cundy TF, O’Grady JG, Williams R: Recovery of menstruation and pregnancy after liver transplantation. Gut 1990;31:337–338. Chlebowski RT, Heber D: Hypogonadism in male patients with metastatic cancer prior to chemotherapy. Cancer Res 1982;42:2495–2498. Blackmann MR, Weintraub BD, Rosen SW, Harman SM: Comparison of the effects of lung cancer, benign lung disease and normal ageing on pituitary-gonadal function in men. J Clin Endocrinol Metab 1988;66:88–95. Todd BD: Pancreatic carcinoma and low serum testosterone: A correlation secondary to cancer cachexia? Eur J Surg Oncol 1988;14:199–202. Ash P: The influence of radiation on fertility in man. Br J Radiol 1980;53:271–278. Madsen BL, Guidice L, Donaldson SS: Radiation-induced premature menopause: A misconception.
The Pituitary Gonadal Axis
149
59 60 61 62 63 64
65 66 67 68 69
70 71 72 73
74 75 76 77 78
79 80
81 82 83 84
Int J Radiat Oncol Biol Phys 1995;32:1461–1464. Constine LS, Woolf PD, Cann D, Mick G, McCormick K, Raubertas RF, Rubin P: Hypothalamicpituitary function after irradiation for brain tumors. N Engl J Med 1993;328:87–92. Ford HC, Cooke RR, Keighley EA, Feek CM: Serum levels of free and bound testosterone in hyperthyroidism. Clin Endocrinol 1992;36:187–192. Swartz CM, Young MA: Male hypogonadism and bone fracture. N Engl J Med 1988;318:996 Becks GP, Burrow GN: Thyroid disease and pregnancy. Med Clin North Am 1991;75:121–150. Luton JP, Thieblot P, Valcke JC, Mahoudeau JA, Bricaire H: Reversible gonadotropin deficiency in male Cushing’s disease. J Clin Endocrinol Metab 1977;45:488–495. Ali ST, Shaikh RN, Ashfaqsiddiqi N, Siddiqi PQR: Serum and urinary levels of pituitary-gonadal hormones in insulin-dependent and non-insulin-dependent diabetic males with and without neuropathy. Arch Androl 1993;30:117–123. Nixon MD, Rebar RW: The female gonadal response to critical disease; in Ober KP (ed): Contemporary Endocrinology: Endocrinology of Critical Disease. Totowa, Humana Press, 1997, pp 285–298. Semple CG, Gray CE, Beastall GH: Androgen levels in men with diabetes mellitus. Diabetic Med 1988;5:122–125. Maggi M, Forti G: Gonadal function in AIDS. Baillie`res Clin Endocrinol Metab 1994;8:849–857. Poretsky L, Can S, Zumoff B: Testicular dysfunction in human immunodeficiency virus-infected homosexual men. Metabolism 1995;44:946–953. Croxson TS, Chapman WE, Miller LK, Levitt CD, Senie R, Zumoff B: Changes in the hypothalamicpituitary-gonadal axis in human immunodeficiency virus-infected homosexual men. J Clin Endocrinol Metab 1989;68:317–321. Dobs AS, Dempsey MA, Ladenson PW, Polk F: Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 1988;84:611–616. Linsenmeyer TA, Perkash I: Infertility in men with spinal cord injury. Arch Phys Med Rehabil 1991;72:747. Spark RF, Wills CA, Royal H: Hypogonadism, hyperprolactinaemia and temporal lobe epilepsy in hyposexual men. Lancet 1984;i:413–417. Macphee GJA, Larkin JG, Butler E, Beastall GH, Brodie MJ: Circulating hormones and pituitary responsiveness in young epileptic men receiving long-term anti-epileptic medication. Epilepsia 1988; 29:468–475. Wang C, Chan V, Tse TF, Yeung RTT: Effect of acute myocardial infarction on pituitary-testicular function. Clin Endocrinol 1978;9:249–253. Cundy T, Butler J, Bomford A, Williams R: Reversilbility of hypogonadotrophic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol 1993;38:617–620. Barreca T, Rossi B, Magnani G, Sartucci F, Arena R, Rolandi E: Nyctohemeral pattern of serum LH, FSH and PRL in patients with myotonic dystrophy. Clin Endocrinol 1983;18:319–325. British National Formulary: Drugs used in the treatment of disorders of the endocrine system; in British National Formulary. London, British Medical Association, 1996, vol 32, pp 304–312. Arver S, Dobs AS, Meikle AW, Allen RP, Sanders SW, Mazer NA: Improvement of sexual function in testosterone deficient men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Urol 1996;155:1604–1608. Wu FCW: Testicular steroidogenesis and androgen use and abuse. Baillie`res Clin Endocrinol Metab 1994;6:373–403. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R: The effects of supra-physiological doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996;335:1–7. Forbes GB: The effects of anabolic steroids on lean body mass: The dose response curve. Metabolism 1985;34:571–573. Rabkin JG, Rabkin R, Wagner G: Testosterone replacement therapy in HIV illness. Gen Hosp Psychiatry 1995;17:37–42. Raffi F, Brisseau J, Planchon B, Remi J, Barrier JH, Grolleau J: Endocrine function in 98 HIVinfected patients: A prospective study. AIDS 1991;5:729–733. Cutolo M, Balleari E, Giusti M, Intra E, Accardo S: Androgen replacement therapy in male patients
Fletcher
150
85
86
87 88 89 90 91 92 93 94 95 96 97
with rheumatoid arthritis. Arthritis Rheum 1991;34:1–5. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT: A randomized controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200–1208. Hausmann DF, Nutz V, Rommelsheim K, Caspari R, Mosebach KO: Anabolic steroids in polytrauma patients: influence on renal nitrogen and amino acid losses: A double-blind study. J Parenteral Enteral Nutr 1990;14:111–114. Bagatell CJ, Bremner WJ: Androgens in men – Uses and abuses. N Engl J Med 1996;334:707–714. Yesalis CE, Kennedy NK, Kopstein AN, Bahrke MS: Anabolic-androgenic steroid use in the United States. JAMA 1993;270:1217–1221. Bagatell CJ, Heiman JR, Matsumoto AM, Rivier JE, Bremner WJ: Metabolic and behavioral effects of high dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab 1994;74:561–567. Friedl KE, Hannan CJ Jr, Jones RE, Plymate SR: High-density lipoprotein is not decreased if an aromatizable androgen is administered. Metabolism 1990;39:69–74. Ishak KG, Zimmerman HJ: Hepatotoxic effects of the anabolic/androgenic steroids. Semin Liver Dis 1987;7:230–236. Soe KL, Soe M, Gluud C: Liver pathology associated with the use of anabolic-androgenic steroids. Liver 1992;12:73–79. McNutt RA, Ferenchik GS, Kirlin PC, Hamlin NJ: Acute myocardial infarction in a 22-year-old world class weight lifter using anabolic steroids. Am J Cardiol 1988;62:164. Frankle MA, Eichberg R, Zachariah SB: Anabolic androgenic steroids and a stroke in an athlete: Case report: Arch Phys Med Rehabil 1988;69:632–633. Cohen JC, Hickman R: Insulin resistance and diminished glucose tolerance in power lifters ingesting anabolic steroids. J Clin Endocrinol Metab 1987;64:960–963. Pope HG Jr, Katz DL: Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 1988;145:487–490. Roberts JT, Essenhigh DM: Adenocarcinoma of prostate in 40-year-old body-builder. Lancet 1986; ii:742.
Dr. A.K. Fletcher, Department of Medicine, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU (UK) Tel. +44 114 271 4160, Fax +44 114 256 0458
The Pituitary Gonadal Axis
151
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 152–175
............................
The Regulation of Growth Hormone Secretion E. Ghigo, E. Arvat, L. Gianotti, M. Maccario, F. Camanni Division of Endocrinology, Department of Internal Medicine, University of Turin, Italy
Contents Introduction ............................................................................................... Biochemical Aspects and Biological Activities of GH ......................................... GH Secretion: Influence of Age, Gender and Nutrition ...................................... Neural Control of GH Secretion .................................................................... Hormonal and Metabolic Control of GH Secretion ........................................... GH Secretion in Pathophysiological Conditions ................................................ Conclusions ................................................................................................ References ..................................................................................................
152 152 156 161 165 168 170 171
Introduction The growth hormone (GH) story began in 1886 when Pierre Marie described pituitary enlargement in an acromegalic patient. During the early 1900s, other workers demonstrated the linkage between pituitary function and growth in animals and humans, and in 1944 Li and Evans first isolated the peptide hormone now known as GH. More than 100 years later, after countless further studies, the interest in GH is not satisfied but is rather increasing. The aim of this chapter is to give a clinically oriented overview of GH secretion in humans in order to provide a better understanding of the endocrine and metabolic responses to critical illness.
Biochemical Aspects and Biological Activities of GH The pituitary GH gene is expressed primarily in the anterior pituitary gland by somatotropic and somatomammotropic cells and is responsible for
the major circulating form of human GH. It is synthesized as a prohormone containing a 26-amino acid signal sequence, which is cleaved as the hormone is transferred across the rough endoplasmic reticulum into storage granules. The processed protein product of the pituitary GH-N gene is a single-chain, 22-kDa, 191-amino acid peptide, the biologically active conformation of which is maintained by two disulfide bridges [1, 2]. The RNA product of the GH-N gene undergoes alternative splicing, resulting in a second GH translation product of 20 kDa which lacks 15 internal amino acids in comparison with the 22-kDa form. Approximately 5–15% of circulating immunoreactive human GH is the 20-kDa form. Interestingly, the 22- and 20-kDa forms of human GH may have some different biological activities. In fact, although both forms are capable of stimulating growth in animals, there is evidence that the 20-kDa form does not bind with high affinity to GH receptors in human liver. On the other hand, the GH-N gene is also expressed in human lymphoid cells where it may modulate immune function via activation of specific receptors which have higher affinity for the 20-kDa GH form [1, 2]. When GH from within the human pituitary is analyzed immunologically, a complex mixture of peptides is revealed which derive from posttranslational modification. In fact, approximately 75% of the GH in human pituitary glands occurs in the unmodified 22-kDa form; for circulating GH this percentage is reduced to 43%. Approximately 5% of the physiological forms of modified GH in the circulation are acidic forms of the monomeric 22kDa GH, about 20% occurs as dimers and 7% as oligomeric forms of the 22-kDa GH. The majority of the remaining modified forms of GH in the circulation consists of monomeric, dimeric or oligomeric forms of the 20kDa gene product. The physiological function of the modified GH forms is unknown [1, 2]. GH messenger RNA (mRNA) in somatotrope cells is under the regulation of general and tissue-specific transcriptional factors, hormones and cAMP [2, 3]. Among pituitary-specific transcription factors, the role of Pit-1 has to be emphasized. It is a homeodomain protein that is essential for pituitary differentiation and GH expression in humans as well as in rodents. Some patients with growth retardation due to GH deficiency have been found to have inactivating mutations of the Pit-1 gene. Pit-1 mediates the stimulatory effect of cAMP on GH secretion and both Pit-1 and cAMP are involved in the stimulation of GH mRNA synthesis by GH-releasing hormone (GHRH) in somatotroph cells [3–5]. Glucocorticoids and thyroid hormones also play a major role in the control of GH mRNA production [2, 5]. In humans, GH has a monocomponent half-life of approximately 19 min but it has been estimated that this is decreased in aging, obesity and hypothy-
Regulation of Growth Hormone Secretion
153
roidism and increased in chronic renal failure and liver disease. After secretion into the bloodstream by anterior pituitary somatotrope cells, GH is capable of binding to specific GH-binding proteins (GHBPs) [6–9]. The GH half-life is putatively influenced by the amount and the avidity of these high-affinity binding proteins. The high-affinity GHBP is very similar to the extracellular domain of the GH receptor (GHR) and the GHR gene codes for both receptor and high-affinity GHBP. In man the GHBP is believed to arise from the receptor by proteolytic cleavage although data in some animal species indicates that alternative splicing of a single primary transcript can give rise to distinct mRNAs for the GHR and GHBP. Recently, an alternative splice of the human GHR mRNA has been described which generates large amounts of binding proteins. It is now generally assumed that GHBP levels reflect the tissue concentration of the GHR. The relevance of low-affinity GHBP is unclear [2, 8, 9]. The presence of GHBP modifies the in vivo kinetics of GH (approximately 40–50% of GH is bound to GHBP). In fact, the GH-GHBP complex represents a hormone reservoir and, during GH secretory pulses, the presence of GHBP modifies the amount of hormone which has access to the receptors [8]. The human GHR cDNA encodes a 638-amino acid polypeptide which includes an 18-amino acid signal peptide and a mature full-length receptor of 620-amino acids. The human receptor has a high degree of homology with that of other species, has a 30% of homology with the prolactin receptor and is part of a much larger cytokine receptor family which includes erythropoietin and the interleukins [2, 10]. The expression of the GHR is mainly in liver, kidney, heart and muscle tissue but is also in the central nervous system. Interestingly, GHR levels are low at birth and increase in the postnatal period. The regulation of the GHR and GHBP is complex but may be modulated by GH, peripheral hormones and nutritional factors. Some studies have demonstrated that there is marked inter-individual, but limited intra-individual, variability in GHBP levels. Thus, it has been hypothesized that the GHR/GHBP level is genetically fixed and GH secretion is the regulated entity. The likely mediator of this regulation is IGF-I which is known to inhibit GH secretion [8, 11, 12]. The consequence of GH binding to its receptors in various target tissues is the generation of an insulin-like growth factor, first known as somatomedin C and now as IGF-I. Another growth factor structurally related to insulin is somatomedin A or IGF-II [12]. The human IGFs are single-chain peptides of 7.5 kDa composed of 70and 67-amino acid residues for IGF-I and IGF-II, respectively. In contrast to most peptide hormones, the IGFs are secreted as they are produced and there is no organ in which IGFs are stored. The liver is the principal source of
Ghigo/Arvat/Gianotti/Maccario/Camanni
154
GH-dependent circulating IGF-I but the highest concentrations of IGFs are observed in blood. In fact, IGFs are produced in most organs and exert biological effects on most cell types. The ubiquity of sites of production and action has led to the concept that these peptides act by autocrine and paracrine mechanisms as well as by classical endocrine mechanisms [12]. IGFs in serum and most body fluids are complexed with high-affinity binding proteins (IGFBPs). Six distinct IGFBPs have been characterized (IGFBP1 to -6) and four of them are found in serum in significant quantities. Less than 5% of the IGF-I in the circulation is free and most (?90%) is bound in a 150kDa complex with IGFBP-3 and an acid-labile subunit. This complex is believed to be the principal carrier form for IGFs. The remainder of the IGFs in the circulation is bound to IGFBP-1, -2 or -4. The binding proteins are each regulated differently and are believed to exert different functions [12, 13]. Receptors for IGFs are present on virtually all cell types. IGF-I is bound principally by the type 1 IGF receptor, which has 40% structural homology with the insulin receptor. In fact, IGF receptor type 1 exhibits a hierarchy of binding affinities which favors IGF-I?IGF-II?insulin. The type 2 IGF receptor binds preferentially to IGF-II rather than IGF-I and does not bind insulin. On the other hand, both IGF-I and -II bind to the insulin receptor but with only 1% of the affinity of insulin. Whilst insulin receptors predominate in hepatocytes, adipocytes and muscle cells, type 1 IGF receptor are located mainly in cells of mesenchymal origin such as fibroblasts, chondrocytes and osteoblasts [12]. The most important hormonal stimulus of IGF-I synthesis and release is GH, which also stimulates the synthesis of IGFBP-3 and the acid-labile subunit. There is clear evidence showing that in conditions of normal nutrition IGF-I, more than IGFBP-3, is the best peripheral marker of GH status; for example, mean IGF-I levels are elevated in acromegalic patients and reduced in hypopituitary patients with GH deficiency. However, it has to be emphasized that IGF-I synthesis depends on nutrition as well as on GH. In particular, amino acids and glucose are critical regulators of IGF-I and IGFBP synthesis and are needed for the activity of GH receptor and postreceptor mechanisms [2, 14–16]. The linkage between the GH/IGF-I axis and nutrition has important clinical implications, as impaired nutritional status leads to GH insensitivity, characterized by reduced secretion of IGF-I and increased GH secretion which is not sufficient to override peripheral resistance [12, 16, 17]. GH regulates somatic and tissue growth, stimulates tissue differentiation and cell proliferation, and has a major role in the control of protein, lipid, glucose and electrolyte metabolism. GH can exert its effects either directly or indirectly through the actions of IGF-I [2, 12, 15, 18–20].
Regulation of Growth Hormone Secretion
155
IGF-I-mediated actions of GH are predominantly the effects on the proliferation and/or maturation of many tissues including bone, cartilage and skeletal muscle in concert with many other hormones and growth factors. Both liver and tissue IGF-I can mediate GH effects on proliferation and maturation [2, 21–24]. Particularly, at bone and cartilage levels, GH stimulates the multiplication and differentiation of germinal cells while IGF-I acts on the proliferation of chondrocytes. GH is also able to make chondrocytes responsive to IGF-I produced either locally or in the liver [2, 21–24]. GH also plays an important role in the differentiation and growth of adipose tissue and muscle cells and regulates the expression of a variety of proteins in the liver [2, 25–27]. Recently, evidence has been provided for independent effects of GH and IGF-I on protein metabolism; GH stimulates protein synthesis and IGF-I reduces protein breakdown. In fact, the effect of GH and IGF-I on protein metabolism has been shown to be synergistic in humans [17, 20, 28]. The actions of GH on carbohydrate metabolism are complex, having both acute and delayed effects and both direct and IGF-I-mediated actions. Acutely, GH can stimulate insulin release but is also able to enhance glucose oxidation. The delayed effects of GH are antagonistic to those of insulin and GH hypersecretion in acromegaly is a cause of secondary diabetes mellitus. However, long-term GH replacement in GH-deficient adults improves insulin sensitivity and this seems to be an IGF-I-mediated effect [15, 18, 29, 30]. The actions of GH on lipid metabolism include its well-known direct lipolytic effect. However, recent data demonstrates that GH also possesses clear stimulatory actions on the low-density lipoprotein (LDL) receptor leading to removal of cholesterol from the circulation; in fact, GH treatment reduces circulating LDL levels. A stimulatory effect of GH on high-density lipoprotein has also been demonstrated. These effects may explain the increased incidence of cardiovascular disease in GH-deficient adults [15, 26, 31].
GH Secretion: Influence of Age, Gender and Nutrition GH is secreted in pulses occurring approximately every 3 h with clear amplification during sleep. Between pulses the GH nadir values are frequently below the limit of detection of conventional radioimmunoassays. Recent advances in assay techniques have increased the sensitivity of the GH assay and allowed detection of GH concentrations up to 50–200 times lower than previously possible. It has been demonstrated that it is possible to quantify GH concentrations at all time points of a GH profile thereby allowing GH secretion to be studied more meaningfully in healthy subjects and those with pathophysiology. In fact, significant, although reduced, GH pulsatility has
Ghigo/Arvat/Gianotti/Maccario/Camanni
156
Fig. 1. Representative profiles of pulsatile GH release in 3 women and 3 men. The upper panels show the serum GH concentrations, with the deconvolution-predicted fits. The lower panels show the calculated GH secretory rates [from 6, with permission].
been shown even in hypopituitary patients with severe GH deficiency [7, 32] (fig. 1, 2). Among physiological events which affect GH secretion, particular mention has to be given to sleep, physical exercise, food intake and age-related variations [7, 19, 32–36]. A prominent physiologic correlate of GH secretion in healthy
Regulation of Growth Hormone Secretion
157
Norm al young m en Norm al m iddle-aged m en Norm al older m en Hyperthyroid m iddle-aged m en Obese m iddle-aged m en Prepubertal boys Late pubertal boys Pubertal delay (- T) Pubertal delay (+ T) 0.0
0.2
0.4 0.6 0.8 1.0 1.6 Daily GH secretory rates (m g)
1.8
2.0
Fig. 2. Daily GH secretion rates over the human lifespan as predicted by deconvolution analysis [from 6, with permission].
adults is sleep and particularly slow wave sleep (stages III and IV). Recent studies in normal young men, with sampling blood every 30 s and polysomnographic recordings, have demonstrated that about 50–60% of the variability of GH concentrations during the night is accounted for by an association of GH release with episodes of deep sleep. On the other hand, sleep associated with rapid-eye movement is accompanied by relative suppression of GH secretion and ‘fully awake sleep’ is associated with a further decrease in GH secretion [7, 32, 37, 38]. The exact basis for the temporal association between slow wave sleep and GH secretion is not known but it probably involves neuroendocrine mechanisms such as variations in central catecholaminergic and cholinergic activities leading to hyperactivation of GHRH-secreting neurons and concomitant reduction of somatostatin activity [39]. Another well-known physiological, stimulatory influence on somatotroph secretion is physical exercise. GH increases after acute exercise and mean GH secretion is enhanced in highly trained subjects who also show increased IGF-I levels. The mechanisms underlying the stimulatory effect of physical exercise on somatotroph function are still largely unclear though there are data suggesting that neuroendocrine and/or metabolic factors have a crucial role [34]. It has been demonstrated that a greater than 3-fold increase in GH release is present within 2–5 days of fasting in healthy men and women. This augmentation of GH secretion is characterized by the combined amplification of GH
Ghigo/Arvat/Gianotti/Maccario/Camanni
158
secretory burst frequency and amplitude without any change in estimated GH half-life. During fasting, despite increased GH secretion, IGF-I levels fall pointing to the major role of nutrition in the control of IGF-I synthesis and release; in addition, impairment of GH receptor and postreceptor mechanisms is induced by insufficient nutritional support [7, 16, 40, 41]. Fastinginduced GH hypersecretion occurs before IGF-I reduction, indicating that the lack of IGF-I negative feedback is not the cause of this early amplification of GH pulsatility. Moreover, GH hypersecretion during fasting is inhibited by IGF-I administration but also when eating is resumed well before normalization of IGF-I levels. Thus, it is clear that central mechanisms are involved in the amplification of GH secretion induced by fasting. Prolonged fasting and chronic caloric restriction lead to peripheral GH insensitivity, marked decrease of IGF-I synthesis and release, and to lack of negative IGF-I feedback [7, 42–45]. While fasting and caloric restriction stimulate GH secretion, the effect of food intake on GH secretion depends on the timing and the specific nutrients. Generally, after a mixed meal, a late increase of GH secretion occurs while early refractoriness to stimuli has been reported. On the other hand, while protein intake has a prompt stimulatory effect, carbohydrate intake has a prompt inhibitory effect on GH secretion followed by a late rebound. The mechanisms underlying the influence of nutrients on GH secretion are discussed later [16]. GH secretion undergoes clear age-related variations both in animals and in humans [7, 19, 35, 36, 46–49]. Under physiological conditions, IGF-I levels generally follow the age-related variations of GH secretion, the notable exception being in the neonatal period [35, 50]. GH synthesis is detectable in human pituitary tissue as early as 12 weeks’ gestation when the levels in the fetal circulation are about 20 g/l; they increase to about 100 g/l at 22 weeks’ gestation and are normally 10–40 g/l at term. Thus, spontaneous pulsatile GH secretion is exaggerated in newborns, then decreasing to constant levels until the onset of puberty when it is clearly amplified, particularly in term of pulse amplitude. Mean 24-hour GH secretion reduces in adulthood and is greater in women than in men; in fact, women have clearly greater burst mass than men. A progressive fall in 24-hour GH secretory rates occurs with increasing age (approximately 14% per decade); this is due to a decline in both daytime and nighttime GH secretory burst number and amplitude, particularly in women, so that the gender-related difference in GH secretion disappears with age [50–53]. In contrast, IGF-I levels are low at birth despite GH hypersecretion which likely reflects peripheral GH insensitivity. Subsequently, in fed subjects, IGF-I levels reflect age-related variations of GH secretion, i.e. increasing at puberty
Regulation of Growth Hormone Secretion
159
and decreasing thereafter up to low levels in aging. Interestingly, in adulthood no gender-related difference in IGF-I level is present, in spite of enhanced GH secretion in women. Age-related variations in IGFBP-3 levels, a less sensitive marker of GH status than IGF-I, parallel those of IGF-I [35, 36, 50, 51]. The mechanisms underlying the age-related variations in GH secretion certainly include the influence of gonadal steroids and adiposity; in fact, daily GH secretion is negatively correlated with body mass index and percentage body fat, and positively correlated with estrogen and testosterone concentrations [7, 19, 52–54]. The impact of adiposity on GH secretion is of great importance. Mean GH concentrations over 24 h, as well as spontaneous GH secretion, are reduced in obese and increased in anorectic patients and inversely correlate with body mass even in normal weight subjects (mean GH secretion is reduced approximately 6% for each unit increase in body mass index). Nevertheless, there is evidence indicating that age and body mass are independently correlated with age-related variations in somatotrope secretion [7, 54, 55]. Gonadal steroids, particularly estradiol, have an important positive influence on GH secretion, as is clearly demonstrated by evidence that estrogens, as well as testosterone, but not dihydrotestosterone, increase GH pulsatility in peripubertal children and hypogonadal subjects; moreover, estrogen replacement enhances GH pulsatility in postmenopausal women in the presence of a concomitant reduction of IGF-I levels [51–54]. While the influence of gonadal steroids on GH secretion plays a major role in the amplification of GH secretion at puberty, there is also evidence that the age-related decrease of GH secretion reflects age-related variations in the neural control of somatotrope secretion. Data in animals and in humans demonstrate that the pituitary GH-releasable pool is not reduced with advancing age. In humans, the GH response to many provocative stimuli, including GHRH, is reduced in aging and this evidence suggests impairment of pituitary GHRH receptor or postreceptor mechanisms. However, in elderly subjects, GH pulsatility and IGF-I levels have been found to be restored by GHRH treatment and the GH response to GHRH is fully restored by administration of arginine to the levels recorded in young adults and normally growing children [35, 36, 48]. As arginine probably acts via inhibition of hypothalamic somatostatin (SS) release, these data agree with in vitro and in vivo evidence in animals, pointing to the existence of both decreased GHRH activity and somatostatinergic hyperactivity in aging. Somatostatinergic activity seems increased at least in comparison to the decreased activity of GHRH-secreting neurones. Among the possible causes of SS hyperactivity, the well-known agerelated decrease of central cholinergic activity seems to play a major role; in
Ghigo/Arvat/Gianotti/Maccario/Camanni
160
fact, the inhibitory influence of hypothalamic tuberoinfundibular cholinergic pathways on somatostatinergic neurons has been clearly demonstrated in animals and in humans. On the other hand, it is well known that brain aging affects the majority of neural pathways; in this context, the age-related reduction of catecholaminergic activity could also play a role in GHRH hypoactivity and SS hyperactivity [36, 47]. When considering aging of GH/IGF-I axis, one should also take into account the possible impairment of peripheral GH sensitivity. In fact, the acute IGF-I response to stimulation with GH has been reported to be reduced in elderly subjects. Interestingly, GHBP levels, which could reflect GHR number, have also been found to be reduced in some but not all studies. Thus, the existence of peripheral GH resistance cannot be ruled out in aging. Nevertheless, it has to be emphasized that IGF-I levels in the elderly have been restored to young levels by treatment with GH, GHRH and orally active GH secretagogues [8, 35, 36, 45, 56]. Improvement of IGF-I levels in elderly subjects has been found to counteract the age-related changes in body composition, thus reinforcing the hypothesis that at least some of the effects of aging may reflect the decreased activity of GH/IGH-I axis. Although aging is a physiological condition, attention is now being given to the possibility that restoration of the activity of GH/IGF-I axis with GH, GHRH or GH secretagogues may have useful anabolic effects in some catabolic elderly subjects [35, 36, 57, 58].
Neural Control of GH Secretion It has been clearly demonstrated that GH secretion is primarily under the control of the central nervous system (fig. 3). In fact, in animals and in humans there is clear evidence that GH secretion is mainly regulated by the tight interplay between the hypothalamic neurohormones GHRH, which stimulates GH synthesis and release, and SS, which inhibits GH release; both GHRH and SS have specific receptors in the pituitary [19, 33, 39, 59–61]. It has been demonstrated that GH pulses reflect GHRH pulses occurring at times of reduced SS release. Reduced SS release in turn, seems to trigger the firing of GHRH neurons. During increased SS release, GHRH is unable to activate GH release but is probably needed to activate its synthesis. Closely integrated communication between SSergic and GHRHergic neurons via intrahypothalamic synaptic interaction is also needed for modulation of GH secretion [59, 61]. It has to be emphasized that GH secretion is mainly dependent on the GHRH activity; this has been demonstrated in animals and in humans using
Regulation of Growth Hormone Secretion
161
3
Ghigo/Arvat/Gianotti/Maccario/Camanni
162
experimental models such as passive immunization against GHRH, the use of GHRH antagonists or transgenic animals. It is now widely accepted that SS is devoted more to modulating than inhibiting GH secretion. In fact, a prompt inhibitory and a late stimulatory effect of SS on GH secretion has been demonstrated in animals and in humans. In GH-deficient animals, hypothalamic SS activity has been found to be reduced and can be restored by GH replacement [59–61]. In addition to GHRH and SS, several other neurotransmitters and neuropeptides play an important role in the control of GH secretion. Their influence may be exerted directly on somatotrope cells but, more frequently, is at the hypothalamic level and is mediated by GHRH and/or SS modulation [19, 33, 39, 60, 62]. Among the various neurotransmitters and neuropeptides, particular attention has to be given to GH secretagogues (GHS). These are synthetic, small peptides or nonpeptide analogues derived from metenkephalin but devoid of opioid activity; recently, a specific GHS receptor from human pituitary and hypothalamus has been cloned [63–70]. Evidence that this receptor has no significant similarity with any other known G-protein coupled receptor, strongly points towards the existence of a yet unknown endogenous GHS-like ligand. GHS have marked, dose-dependent, age-related stimulatory effects on GH secretion after intravenous and oral administration; they are more potent than GHRH and in vivo in humans, have a synergistic effect with GHRH and are somewhat refractory to inhibition by exogenous SS. At present there is evidence showing that their action is exerted both at the pituitary level and more importantly at the hypothalamus. Among various mechanisms underlying the GH-releasing effect of GHS, there is evidence showing that it is dependent on the integrity of GHRH activity and could also be due to functional antagonism of SS activity, both at the pituitary and the hypothalamic level. However, some studies point to the existence of an unidentified hypothalamic factor which could mediate GHS activity. Basically, it can be stated that GHS represent a turning point in our understanding of the control of GH secretion. Their exact physiological role has still to be clarified but GHS antagonist administration can abolish spontaneous GH secretion in animals [63, 64, 66, 68]. Of the classical neurotransmitters and neuropeptides involved in the neural control of GH secretion, catecholamines, acetylcholine, amino acids and galanin deserve to be considered with particular attention. Clear evidence has Fig. 3. Neural and metabolic regulation of GH secretion in humans. GHRH>GHreleasing hormone; GHRPs>GH-releasing peptides; SRIF>somatotrophin release-inhibiting factor; FFA>free fatty acids.
Regulation of Growth Hormone Secretion
163
now been accumulated showing that age-related variations in the activity of these neural pathways underly the age-related functional changes of GH/IGF-I axis [19, 33, 35, 36, 39, 47, 60, 62]. Both in animals and in humans the catecholaminergic system regulates somatotropic function with dual action mediated by different receptors. The stimulatory effect of catecholamines is mediated by 2-adrenergic receptor activation which, in turn, stimulates the activity of GHRH-secreting neurons and inhibits somatostatinergic neurons. In fact, clonidine and guamfacine, two 2-adrenergic agonists, stimulate basal and GHRH-stimulated GH secretion and their effect is specifically abolished by 2-antagonists, such as yohimbine and idazoxan. On the other hand, the activation of -adrenergic receptors mediates the inhibitory effect of catecholamines by stimulating hypothalamic SS release. -Adrenergic blockade, by propranolol or atenolol, although unable to stimulate basal GH secretion, potentiates somatotrope responsiveness to several secretagogues including GHRH, whilst 2-adrenergic agonists, such as salbutamol, exert marked inhibitory effects on both basal and GHRH-induced GH secretion. Interestingly, it has been demonstrated that the inhibitory adrenergic influence on somatotropic function is not operative under basal conditions but is triggered by GH increase, possibly to prevent the exhaustion of the pituitary pool [19, 33, 39, 60, 62]. Acetylcholine plays a major stimulatory role on somatotropic function through inhibition of hypothalamic SS release both in animals and in humans. In fact, muscarinic antagonists, such as atropine and pirenzepine, strongly inhibit spontaneous GH secretion as well as somatotrope responsiveness to several stimuli including GHRH. In contrast, cholinergic agonists such as pyridostigmine, a cholinesterase inhibitor, potentiate both basal and GHRHinduced GH secretion [19, 33, 39, 60, 62]. Galanin is a neuropeptide which has a potentiating effect on GH secretion, both basally and stimulated by GHRH; it has been hypothesized to concomitantly influence GHRH- and SS-secreting neurons. The involvement of galanin in the control of somatotropic function is clearly demonstrated by evidence that it is cosecreted by GHRH-secreting neurons and that passive immunization against galanin or administration of galanin antagonists abolishes somatotrope pulsatility in animals [39, 71]. Amino acids play a major stimulatory role in GH secretion. In humans, arginine strongly stimulates GH secretion, potentiates the GH response to GHRH and fully restores the somatotrope responsiveness to GHRH in aging. When combined with arginine, GHRH becomes the most potent and reproducible, age-independent stimulus of GH secretion in clinical practice [39]. Arginine probably acts via inhibition of hypothalamic SS release [39, 60]. As it is the precursor of nitric oxide (NO) and hypothalamic NO-secreting pathways
Ghigo/Arvat/Gianotti/Maccario/Camanni
164
have been demonstrated, it has now to be considered as a neurotransmitter. Other amino acids have stimulatory effects on GH secretion but this is generally mediated by independent mechanisms, the notable exception being methionine which, like arginine, may act via inhibition of hypothalamic SS release [33, 39, 60, 72]. Many other neurotransmitters and neuropeptides play a role in the control of somatotropic function. However, those discussed in this section seem at present, to be the most important in the neural mechanisms governing the activity of GH/IGF-I axis. In addition, they are commonly used in basic and clinical studies in neuroendocrinology [39, 60].
Hormonal and Metabolic Control of GH Secretion Among peripheral hormones, it is widely accepted that IGF-I, the GHdependent hormone which mediates the majority of GH metabolic actions, plays a major role in the control of GH secretion (fig. 3). Extensive studies have shown the powerful negative feedback effects of IGF-I on GH secretion at both pituitary and hypothalamic levels. At the pituitary level, IGF-I exerts important actions to inhibit GH synthesis and release. At the hypothalamic level a stimulatory effect of IGF-I on SS release has been shown; this action could contribute to the prompt negative feedback control of GH secretion although IGF-I also has a negative influence on the activity of GHRH-secreting neurons [12, 73, 74]. It is noteworthy that the acute SS-mediated negative GH autofeedback mechanisms are probably independent of IGF-I and are mediated by neurotransmitters. In fact, the acute GH response to GHRH is inhibited by recent GH or GHRH administration regardless of any variation in IGF-I levels; somatotrope responsiveness is fully restored by neurotransmitters which negatively modulate hypothalamic SS release [39]. In considering the negative IGF-I feedback on GH secretion, attention has to be given to the effects of variations in free IGF-I levels and/or by local IGF-I production [12]. Insulin has been shown to inhibit GH synthesis and release from the pituitary in vitro, as well as in vivo, in humans; as insulin binds to IGF-I receptors, these could mediate its inhibitory action. Among the other pancreatic hormones, it has to be emphasized that glucagon per se is not a true GH secretagogue, in fact it stimulates GH levels after intramuscular but not after intravenous administration and the exact mechanism of action is obscure [12, 75, 76]. It is well known that chronically elevated glucocorticoid levels block spontaneous and stimulated GH secretion as well as somatic growth. As gluco-
Regulation of Growth Hormone Secretion
165
corticoids are able to strongly stimulate the transcription of the human GH gene in vitro, it appears that chronic exposure to glucocorticoids inhibits GH secretion via hypothalamic mechanisms. In addition, GHRH-induced GH secretion is also impaired in hypocortisolemic patients in whom it is restored by glucocorticoid replacement. Similarly, glucocorticoids given acutely to normal subjects stimulate GH secretion which is, in turn, blunted 12 h after administration. Thus, glucocorticoids have a dual action on somatotrope function. It is also noteworthy to mention that glucocorticoids are able to stimulate IGF-I levels but also to inhibit their biological activity [2, 19, 77, 78]. It has been clearly demonstrated that GH secretion shows sexual dimorphism in humans. While there are contrasting data about the greater somatotrope responsiveness to provocative stimuli in women than in men, there is no doubt that spontaneous GH secretion over the day exhibits gender differences. Higher mean GH concentrations, due to greater GH secretory bursts mass, in women than in men have been shown. Estrogen replacement restores GH secretion in postmenopausal women and amplifies GH pulsatility in peripubertal children; in the latter group, testosterone, which can be aromatized to estradiol, has a similar effect [51–53]. At present the mechanisms underlying the gonadal modulation of somatotrope function are unclear. Actions at both the pituitary and the hypothalamic levels have been hypothesized for both estrogens and androgens, but are still controversial. Whilst androgens stimulate IGF-I levels, estrogens reduce the stimulatory effect of GH on IGF-I synthesis. In fact, it has been demonstrated that estrogens impair the stimulatory effect of GH on IGF-I by acting at a postreceptor level. Taking into account evidence that despite higher mean GH concentrations, women have IGF-I levels which overlap with those in men, it could be hypothesized that the enhanced GH secretion in females overrides the estrogen-induced decrease in peripheral GH sensitivity [51–53]. Thyroid hormones play a well-known stimulatory effect on somatotrope secretion and have a major role in the initiation and maintenance of somatic growth. Spontaneous GH secretion is reduced in hypothyroidism and is enhanced in hyperthyroidism although surprisingly both conditions exhibit reduced somatotrope responsiveness to provocative stimuli [79, 80]. The most important influence of thyroid hormones on somatotrope function is probably exerted at the pituitary level. In fact, it has been demonstrated that thyroid hormones are needed for GH gene transcription, translation and GH secretion. Thyroid hormones also affect the activity of GHRH-secreting neurons and could influence SS release at the hypothalamic level. The influence of thyroid hormones on the activity of the GH/IGF-I axis also takes place at the peripheral level and is needed for normal IGF-I synthesis and release [2, 79–81].
Ghigo/Arvat/Gianotti/Maccario/Camanni
166
Glucose plays an important inhibitory role on GH secretion in humans. In fact, insulin-induced hypoglycemia and oral glucose load are considered classical stimulatory and inhibitory tests of GH secretion, respectively. However, the actual role of glucose in the control of somatotrope function is more complicated [46, 82]. The stimulatory effect of hypoglycemia on GH secretion has to be considered as a counter-regulatory response to glucopenia. The GH response to hypoglycemia is robust and largely refractory to inhibitory influences. In contrast, glucose load-induced hyperglycemia has a prompt inhibitory effect on both basal and GHRH-stimulated GH secretion although it has a late stimulatory effect. About 3–4 h after glucose load, a rebound increase of GH secretion and increased somatotrope responsiveness to GHRH have been clearly demonstrated [46, 82]. The inhibitory effect of glucose load on GH secretion is frequently lost in pathophysiological conditions such as acromegaly, diabetes, liver cirrhosis, malnutrition, anorexia nervosa, psychosis and even obesity, as well as in physiological conditions such as in newborns [50, 55, 82]; generally, this is not the case for the stimulatory effect of hypoglycemia and this evidence leads to the concept of the so-called paradoxical GH response to glucose load. It remains that GH secretion is exaggerated in chronic hyperglycemia associated with diabetes mellitus and that this probably worsens metabolic control and favors vascular complications [45, 83]. The understanding of the mechanisms by which glucose influences GH secretion has been complicated by species-related differences. Although a direct pituitary action of glucose is unlikely, there is now some evidence favoring the hypothesis that glucose plays its stimulatory role at this level. Its inhibitory role is more likely mediated at the hypothalamic level via stimulation of SS release [19, 46]. The influence of glucose on the activity of GH/IGF-I axis also works at the peripheral level; in fact, together with amino acids, glucose plays the most important role in allowing peripheral GH sensitivity and, thus, IGF-I synthesis and release. This has again clear clinical implications in malnutrition states as well as in diabetes which have both to be considered as conditions of acquired resistance to GH actions [16]. GH has a lipolytic action and, in turn, there is evidence that free fatty acids (FFA) have an inhibitory effect on GH secretion. In fact, in humans as well as in animals it has been demonstrated that the administration of lipidheparin emulsions (to increase FFA) inhibits both basal and stimulated GH secretion; on the other hand, pharmacological reductions of FFA levels, by nicotinic acid or acipimox, are able to enhance both basal and GHRH-stimulated GH release. While early studies favored an SS-mediated hypothalamic action, there is now convincing evidence that FFA exert their inhibitory role
Regulation of Growth Hormone Secretion
167
on somatotrope function directly at the pituitary level, possibly by directly inhibiting GH synthesis. Exaggerated FFA levels may have a key role in the pathogenesis of GH hyposecretion in obesity and acipimox treatment is able to restore GH secretion in obese patients. On the other hand, GH secretion is generally elevated in catabolic conditions in spite of elevated FFA levels [7, 17, 19, 40, 42, 46].
GH Secretion in Pathophysiological Conditions Acromegaly and GH deficiency (GHD) are paradigmatic conditions of GH hyper- and hyposecretion respectively. Increased GH secretion in acromegaly and gigantism is characterized by an increase in basal (interpulse) GH levels as well as in the number of detectable GH pulses, which are generally of short duration and low amplitude. It has been suggested that GH fluctuations in acromegalics could reflect variations in hypothalamic SS tone while high-frequency GHRH release has also been demonstrated. Evidence of hypothalamic regulation of pituitary GH secretion in acromegaly derives from the finding that GHRH is frequently able to stimulate GH secretion. However, it has to be emphasized that the responsiveness of GH-secreting adenomas to secretagogues is frequently abnormal and often paradoxical; for example, a glucose load is unable to suppress GH levels while TRH, LHRH and CRH, which do not stimulate GH secretion in normal subjects, frequently do so in patients with GH-secreting adenomas. Moreover, dopaminergic agonists such as levodopa and bromocriptine, which generally stimulate GH secretion in normal subjects, frequently inhibit it in acromegalics. A hypothalamic pathogenesis of acromegaly has been hypothesized and is supported by evidence that it can be due to ectopic GHRH hypersecretion. Pituitary pathogenesis of GH-secreting adenomas is most frequent and mutations of somatotrope G proteins can lead to GH hypersecretion [7, 55, 84–88]. GHD frequently has a hypothalamic pathogenesis. In fact, children with idiopathic GHD and absent GH response to classical provocative tests (such as hypoglycemia, levodopa, arginine or clonidine) generally respond to GHRH; moreover, some short children with normal GH response to classical provocative tests have reduced mean GH secretion over 24 h with impaired frequency and amplitude of GH pulses. Thus, in addition to idiopathic pituitary GHD and acquired pituitary GHD, impaired activity of GHRHsecreting neurons or neurotransmitter pathways may also be a frequent cause of GHD or GH insufficiency. GHD leads to impairment of somatic growth in children while in adults severe GHD impairs body composition and metabolism [89].
Ghigo/Arvat/Gianotti/Maccario/Camanni
168
The diagnosis of GHD, and particularly of GH insufficiency, is still a matter of debate both in childhood and in adulthood. Normal IGF-I and IGFBP-3 levels do not rule out the diagnosis. In childhood, within the appropriate auxological context, the combined evaluation of spontaneous mean GH secretion and the somatotrope response to provocative tests is probably the most reliable approach. In adulthood the study of spontaneous mean GH secretion fails to distinguish even severe GHD from normal subjects partly due to the physiological age-related reduction of GH secretion. Thus, the diagnosis of severe GHD in adults relies on provocative tests of which insulininduced hypoglycemia is still considered the gold standard. However, classical provocative tests have very low limits of normality and are not reproducible in children or in adults and this reduces their reliability. On the other hand, GHRH when combined with substances such as pyridostigmine or arginine, which likely act via inhibition of SS release, becomes the most powerful and reproducible stimulus to evaluate the maximal secretory capacity of somatotrope cells. These tests are equally reliable up to adulthood but not in the elderly when the potentiating effect of arginine, but not of pyridostigmine, is preserved. The GHRH plus arginine test has been recently proposed as the most promising alternative to insulin-induced hypoglycemia for the diagnosis of GHD. The possibility that GHS, alone or combined with GHRH, may be a reliable stimulus for the diagnosis of GHD is promising but has still to be demonstrated [90–96]. Besides acromegaly and GHD, GH secretion is exaggerated or reduced in several other pathological conditions. Generally, these alterations of GH secretion are normalized by curing the underlying disease and do not represent a diagnostic or therapeutic problem. Both spontaneous and stimulated GH secretion are severely impaired in obesity and although a hypothalamic pathogenesis has been hypothesized, there is now convincing evidence pointing to exaggerated FFA levels as the major cause of GH insufficiency in obese patients. Increased FFA levels could be also responsible for GH hyposecretion in hypercortisolism, although chronic elevation of glucocorticoids per se could impair hypothalamic control of somatotrope function [2, 19, 33, 77, 78]. Transient GHD is induced by chronic administration of drugs which possess an inhibitory effect on somatotrope function; in this context it is likely that GH suppression heightens the catabolic effects of chronic treatment with glucocorticoids. GH secretion, as assessed by the somatotrope responsiveness to GHRH, is also impaired in hypocortisolemic states and is restored by cortisol replacement [33, 97]. GH synthesis and secretion is also impaired in hypothyroidism with markedly depressed GH pulsatility and preserved but reduced somatotrope respon-
Regulation of Growth Hormone Secretion
169
siveness to provocative stimuli [46, 79]. GH hypersecretion has been shown in hyperthyroidism. Spontaneous GH pulsatility has been shown to be increased 2- to 3-fold but despite this, the somatotrope response to provocative stimuli is generally impaired, possibly reflecting exhaustion of the GH releasable pool [46, 79]. Elevated GH levels are seen in patients with chronic renal failure. It is likely that this is due to prolonged GH half-life while impaired IGF-I activity probably accounts for low growth velocity in children [45, 98]. GH hypersecretion also occurs in many other pathophysiological conditions in which GH insensitivity is present. GH insensitivity can be genetic or acquired. Among the genetic causes of resistance to GH, mutations have been identified that involve the molecular structure of GH, the function of the GH receptor and the synthesis of IGF-I. GH hypersecretion in these conditions is likely due to a lack of negative IGF-I feedback and in support of this notion, GH secretion is normalized by IGF-I replacement. Partial GH insensitivity has recently been reported in children previously classified as having idiopathic short stature [99, 100]. The most frequent causes of GH insensitivity are acquired and include malnutrition, sepsis, trauma, liver cirrhosis and diabetes [17, 40, 42–45]. A common feature of genetic and acquired GH insensitivity is the reduction of both basal and GH-stimulated IGF-I levels; this is generally coupled with reduction of high-affinity GHBP levels and elevated GH secretion. GH hypersecretion is clear in malnutrition, liver cirrhosis and diabetes, but is not always coupled to IGF-I hyposecretion in critically ill patients. Pathophysiological conditions of GH insensitivity generally show loss of the inhibitory effect of a glucose load on GH secretion, reduced sensitivity to somatostatin and a paradoxical response to TRH. Acquired GH insensitivity is partial and high GH doses can lead to clear-cut increases of IGF-I release and an anabolic effect on protein metabolism in catabolic patients. Biosynthetic IGF-I alone or in combination with GH has been proposed for the treatment of both genetic and acquired conditions of GH insensitivity. Many studies indicate that short children with genetic GH insensitivity benefit from treatment with IGF-I [17, 40, 42, 43, 100–103].
Conclusions The knowledge accumulated about the GH/IGF-I axis in the last 10 years is impressive; it has increased our understanding in many different fields of endocrinology, metabolism and internal medicine and has crucial clinical implications from both a therapeutic and a diagnostic point of view.
Ghigo/Arvat/Gianotti/Maccario/Camanni
170
As well as the diagnosis and treatment of classical endocrinopathies, such as acromegaly and GHD, at present the most interesting aspect of the GH field is the metabolic actions of GH. These have been well known for many years but until recently most physicians considered GH to have no major biological relevance following the cessation of linear growth. The availability of biosynthetic GH and intensive investigation of the effects of GH replacement in GH-deficient adults has unequivocally clarified the importance of GH throughout life in controlling body composition, organ function and protein, lipid and carbohydrate metabolism. Based on this evidence, potential therapeutic indications for the use of GH or GHS are catabolic states and possibly critical illness.
References 1 2 3 4 5 6
7
8 9 10 11 12 13 14 15 16 17
Bauman G: Growth hormone heterogeneity genes, isohormones, variants, and binding proteins. Endocr Rev 1991;12:424–449. Strobl JS, Thomas MJ: Human growth hormone. Pharmacol Rev 1994;46:1–34. Parks JS, Abdul-Latif H, Kinoshita E, Meacham LR, Pfaffle RW, Brown MR: Genetics of growth hormone gene expression. Horm Res 1993;40:54–61. Vila V, Jimenez O, Guell A, Castrillo JL: Pit-1 and Pit-2 role in growth hormone gene regulation. J Pediatr Endocrinol 1993;6:225–228. Theill LE, Karin M: Transcriptional control of GH expression and anterior pituitary development. Endocr Rev 1993;14:670–689. Veldhuis JD: New modalities for understanding dynamic regulation of the somatotropic (GH) axis: Explication of gender differences in GH neuroregulation in the human. J Pediatr Endocrinol Metab 1996;9:237–253. Iranmanesh A, Veldhuis JD: Clinical pathophysiology of the somatotropic (GH) axis in adults; in Veldhuis JD (ed): Neuroendocrinology. I. Endocrinol Metab Clin North Am. Philadelphia, Saunders, 1992, vol 21, pp 783–817. Bauman G, Shaw MA, Amburn K: Circulating growth hormone binding proteins. J Endocrinol Invest 1994;17:67–81. Postel-Vinay MC: Regulation of the growth hormone-binding proteins in human plasma. Acta Endocrinol 1991;124:10–13. Kelly PA, Ali S, Rozakis M, Goujon L, Nagano M, Pellegrini I, Gould D, Djiane J, Edery M, Finidori J: The growth hormone/prolactin receptor family. Recent Prog Horm Res 1993;48:123–164. Herington AC: Growth hormone receptor and binding protein: Distribution and function. J Pediatr Endocrinol 1993;6:235–240. Jones J, Clemmons DR: Insulin-like growth factors and their binding proteins: Biological actions. Endocr Rev 1995;16:3–34. Zapf J: Physiological role of the insulin-like growth factor binding proteins. Eur J Endocrinol 1995; 132:645–654. Furlanetto RW: Insulin-like growth factor measurements in the evaluation of growth hormone secretion. Horm Res 1990;33(suppl 4):25–30. de Boer H, Block GJ, van der Veen EA: Clinical aspects of growth hormone deficiency in adults. Endocr Rev 1995;16:63–86. Thissen JP, Ketesleger JM, Underwood LE: Nutritional regulation of insulin-like-growth-factors. Endocr Rev 1994;15:80–85. Ross RJM, Chew SL: Acquired growth hormone resistance. Eur J Endocrinol 1995;132:655–660.
Regulation of Growth Hormone Secretion
171
18 19 20 21 22 23 24 25 26 27 28
29
30 31 32 33 34 35 36 37 38 39 40
41 42 43
Davidson MB: Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 1987; 8:115–131. Casanueva FF: Physiology of growth hormone secretion and action; in Melmed S (ed): Endocrinol Metab Clin North Am. Philadelphia, Saunders, 1992, vol 21, pp 483–492. De Feo PP: Hormonal regulation of human protein metabolism. Eur J Endocrinol 1996;135:7–18. Johansson AG, Lindh E, Ljunghall S: Growth hormone, insulin-like growth factor I, and bone: A clinical review. J Intern Med 1993;234:553–560. Eriksen EF, Kassem M, Langdahl B: Growth hormone, insulin-like growth factors and bone remodelling. Eur J Clin Invest 1996;26:525–534. Holmes SJ, Shalet SM: Role of growth hormone and sex steroids in achieving and maintaining normal bone mass. Horm Res 1996;45:86–93. Isaksson OGP, Lindhal A, Nilsson AL: Mechanisms of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr Rev 1987;8:426–438. Wabitsch M, Hauner H, Heinze E, Teller W: In vitro effects of growth hormone in adipose tissue. Acta Pediatr 1994;406:48–53. Angelin B, Rudling M: Growth hormone and hepatic lipoprotein metabolism. Curr Opin Lipidol 1994;5:160–165. Florini JR, Ewton DZ, Coolican SA: Growth hormone and the insulin-like growth factor system in myogenesis. Endocr Rev 1996;17:481–517. Wolf SE, Barrow RE, Herndon DN: Growth hormone and IGF-I therapy in the hypercatabolic patient; in Ross RJM, Savage MO (eds): Growth Hormone Resistance. Clin Endocrinol Metab. London, Baillie`re Tindall, 1996, vol 10, pp 447–458. Juul A, Jorgensen JO, Christiansen JS, Muller J, Skakkeboek NE: Metabolic effects of GH: A rationale for continued GH treatment of GH-deficient adults after cessation of linear growth. Horm Res 1995;44:64–72. Moller N, Jorgensen JO, Moller J, Orskov L, Ovesen P, Schmitz O, Christiansen JS, Orskov H: Metabolic effects of growth hormone in humans. Metabolism 1995;44:33–36. Marcus C, Margery V, Kamel A, Bronnegard M: Effects of growth hormone on lipolysis in humans. Acta Pediatr 1994;406:54–59. Thorner MO, Hartman ML, Vance ML, Pezzoli S, Ampleford EJ: Neuroendocrine regulation of growth hormone secretion. Neurosci Biobehav Rev 1995;19:465–468. Dieguez C, Page MD, Scanlon MF: Growth regulation and its alteration in disease states. Clin Endocrinol 1988;28:109–143. Cuneo RC, Wallace JD: Growth hormone, insulin-like growth factors and sport. Endocrinol Metab 1994;1:3–13. Corpas E, Harman SM, Blackman S: Human growth hormone and human aging. Endocr Rev 1993;14:20–39. Ghigo E, Arvat E, Gianotti L, Ramunni J, Di Vito L, Maccagno B, Grottoli S, Camanni F: Human aging and the GH/IGF-I axis. J Pediatr Endocrinol Metab 1996;9:271–278. Takahashi Y, Kipnis DM, Daughday WH: Growth hormone secretion during sleep. J Clin Invest 1968;47:2079–2090. Koella WP: The organization and regulation of sleep. A review of the experimental evidence and a novel integrated model of organizing and regulating apparatus. Experientia 1984;40:309–338. Ghigo E: Neurotransmitter control of growth hormone secretion; in De la Cruz (ed): Regulation of Growth Hormone and Somatic Growth. Amsterdam, Elsevier Science, 1992, pp 103–136. Jenkins RC, Ross RJM: Acquired growth hormone resistance in catabolic states; in Ross RJM, Savage MO (eds): Growth Hormone Resistance. Clin Endocrinol Metab. London, Baillie`re Tindall, 1996, vol 10, pp 411–419. Hartman ML: Physiological regulators of growth hormone secretion; in Juul A, Jorgensen JOL (eds): Growth Hormone in Adults. Cambridge, Cambridge University Press, 1996, pp 5–35. Jenkins RC, Ross RJM: The endocrinology of the critically ill. Curr Opin Endocrinol Diabetes 1996;3:138–145. Bentham J, Rodriguez-Arnao J, Ross RJM: Acquired growth hormone resistance in patients with hypercatabolism. Horm Res 1993;40:87–91.
Ghigo/Arvat/Gianotti/Maccario/Camanni
172
44 45
46 47 48 49
50 51 52 53 54
55
56 57
58
59 60 61 62 63
64
65 66 67
Van den Berghe G, de Zegher F: Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med 1996;24:1580–1590. Donaghy AJ, Baxter RC: Insulin-like growth factor bioactivity and its modification in growth hormone-resistant states; in Ross RJM, Savage MO (eds): Growth Hormone Resistance. Clin Endocrinol Metab. London, Baillie`re Tindall, 1996, vol 10, pp 421–447. Scanlon MF, Issa BG, Dieguez C: Regulation of growth hormone secretion. Neuroendocrinology 1996;46:149–154. Muller EE, Cocchi D, Ghigo E, Arvat E, Locatelli V, Camanni F: Growth hormone response to GHRH during lifespan. J Pediatr Endocrinol 1993;6:5–13. Keljiman M: Age-related alterations of the growth hormone/insulin-like-growth-factor I axis. JAGS Geriatr Biosci 1991;39:295–307. Hoffman AR, Pyka G, Lieberman SA, Ceda GP, Marcus R: The somatopause; in Muller EE, Cocchi D, Locatelli V (eds): Growth Hormone and Somatomedins during Lifespan. Berlin, Springer, 1993, pp 265–274. Chatelain P, Claris O, Lapillone A, Dimayo M, Salle B: Fetal and neonatal somatotrope function. Front Paediatr Neuroendocrinol 1994;20:127–130. Ho KK, Weissberger AJ: Secretory patterns of growth hormone according to sex and age. Horm Res 1990;33:7–11. Kerrigan JR, Rogol AD: The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence. Endocr Rev 1992;13:281–298. Wehrenberg WB, Giustina A: Mechanisms and pathways of gonadal steroid modulation of growth hormone secretion. Endocr Rev 1992;13:299–308. Veldhuis JD: New modalities for understanding dynamic regulation of the somatotropic (GH) axis: Explication of gender differences in GH neuroregulation in the human. J Pediatr Endocrinol Metab 1996;9:237–253. Muller EE, Rolla M, Ghigo E, Belliti D, Arvat E, Andreoni A, Torsello A, Locatelli V, Camanni F: Involvement of brain catecholamines and acetylcholine in growth hormone hypersecretory states. Pathophysiological, diagnostic and therapeutic implications. Drugs 1995;50:805–837. Shetty KR, Duthie EHJ: Anterior pituitary function and growth hormone use in the elderly; in Melmed S (ed): Endocrinol Metab Clin North Am. Philadelphia, Saunders, 1995, vol 24, pp 213–231. Rudman D, Rao UMP: The hypothalamic-growth hormone-somatomedin C: The effect of aging; in Morley JE, Korenman SG (eds): Endocrinology and Metabolism in the Elderly. Boston, Blackewell Scientific, 1991, pp 35–57. Ghigo E, Arvat E, Gianotti L, Grottoli S, Rizzi G, Ceda GP, Camanni F: Aging and GH-releasing peptides; in Bercu B, Walker R (eds): Growth Hormone Secretagogues. New York, Serono Symposia, 1996, pp 415–431. Frohman LA, Jansson JO: Growth hormone-releasing hormone. Endocr Rev 1986;7:223–231. Muller EE, Nistico` G: Neurotransmitter regulation of the anterior pituitary; in Muller EE, Nistico` G (eds): Brain Messengers and the Pituitary. San Diego, Academic Press, 1989, pp 404–537. Tannembaum GS: Genesis of episodic growth hormone secretion. J Pediatr Endocrinol 1993;6: 273–282. Hartman ML, Veldhuis JD, Thorner MO: Normal control of growth hormone secretion. Horm Res 1993;40:37–47. Bowers CY, Veeraragavan K, Sethumadhavan K: Atypical growth hormone-releasing peptides; in Bercu B, Walker R (eds): Growth Hormone. II. Basic and Clinical Aspects. New York, Springer, 1993, pp 205–222. Micic D, Mallo F, Peino R, Cordido F, Leal-Cerro A, Garcia-Mayor RV, Casanueva FF: Regulation of growth hormone secretion by the growth hormone-releasing hexapeptide (GHRP-6). J Pediatr Endocrinol 1993;6:283–289. Deghenghi R, Boutignon F, Luoni M, Grilli R, Guidi M, Locatelli V: Small peptides as potent releasers of growth hormone. J Pediatr Endocrinol Metab 1995;8:311–313. Korbonits M, Grossman AB: Growth hormone-releasing peptide and its analogs. Novel stimuli to growth hormone release. Trends Endocrinol Metabol 1995;6:43–49. DeVita RJ, Wyratt MJ: Benzolactam growth hormone secretagogues. Drugs Future 1996;21:273–281.
Regulation of Growth Hormone Secretion
173
68 69
70 71 72 73 74 75 76
77
78
79 80 81 82 83 84 85 86 87 88 89
90
91 92
Ghigo E, Arvat E, Muccioli G, Camanni F: Growth hormone-releasing peptides. Eur J Endocrinol 1997;136:445–460. Casanueva FF, Micic D, Pombo M, Leal A, Bokser L, Zugaza JL, Dieguez C: Role of the new growth hormone-releasing secretagogues in the diagnosis of some hypothalamo-pituitary pathologies. Metabolism 1996;45(suppl 1):123–126. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI: A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273:974–977. Vrontakis ME, Torsello A, Friesen HG: Galanin. J Endocrinol Invest 1981;14:785–794. Moncada S, Highs A: The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–2012. Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L, Hintz RL: Somatomedin C effects on both the hypothalamus and the pituitary. Science 1981;212:1279–1288. Ceda GP: IGFs in the feedback control of GH secretion: Hypothalamic and/or pituitary action? J Endocrinol Invest 1995;18:734–737. Melmed S: Insulin suppresses growth hormone secretion by rat pituitary cells. J Clin Invest 1984; 73:1425–1433. Ghigo E, Bartolotta E, Imperiale E, Bellone J, Cardinale G, Aimaretti G, Valetto MR, Cherubini V, Maccario M, Cocchi D, Camanni F: Glucagon stimulates GH secretion after intramuscular but not intravenous administration. Evidence against the assumption that glucagon per se has a GHreleasing activity. J Endocrinol Invest 1994;17:849–854. Dieguez C, Mallo F, Senaris R, Pineda J, Martul P, Leal-Cerro A, Pombo M, Casanueva FF: Role of glucocorticoids in the neuroregulation of growth hormone secretion. J Pediatr Endocrinol Metab 1996;9:255–260. Wajchenberg BL, Liberman B, Giannella Neto D, Morozimato MY, Semer M, Bracco LO, Salgado LR, Knoepfelmacher M, Borges MH, Pinto AC, Kater CE, Lengyel AM: Growth hormone axis in Cushing’s syndrome. Horm Res 1996;45:99–107. Valcavi R, Zini M, Portioli I: Thyroid hormones and growth hormone secretion. J Endocrinol Invest 1992;14:313–330. Giustina A, Wehrenberg WB: Influence of thyroid hormones on the regulation of growth hormone secretion. Eur J Endocrinol 1995;133:646–653. Gaspard T, Wondergen R, Hamamdzic M, Klitgaard HM: Serum somatomedin stimulation in thyroxine-treated hypophysectomized rats. Endocrinology 1978;102:606–610. Valcavi R: Oral glucose tolerance test: An inhibitory or a stimulatory input to growth hormone secretion? J Endocrinol Invest 1996;19:253–255. Mercado M, Baumann G: Characteristics of the somatotropic axis in insulin-dependent diabetes mellitus. Arch Med Res 1995;26:101–109. Melmed S: Acromegaly. Metabolism 1996;45(suppl 1):51–52. Lamberts SW, de Herder W, Kwekkedom DJ, van der Lely AJ, Nobels FR, Krenning EP: Current tools in the diagnosis of pituitary tumours. Acta Endocrinol 1993;12:6–12. Ezzat S, Forster MJ, Berchtold P, Rederlmeier DA, Boerling V, Harris AG: Acromegaly. Clinical and biochemical features in 500 patients. Medicine 1994;73:233–240. Faglia G, Arosio M, Spada A: GS protein mutations and pituitary tumours: Functional correlates and possible therapeutic implications. Metabolism 1996;45:117–119. Liuzzi A, Oppizzi G, Cozzi R, Dallabonzana D, Petroncini M, Orlandi P, Chiodini PG: GH regulation in acromegaly. J Pediatr Endocrinol 1993;6:339–343. Zadik Z, Chalew SA, Kowarsky AA: The definition of a spontaneous growth hormone (GH) peak: Studies in normally growing and GH-deficient children. J Clin Endocrinol Metab 1992;74:801– 805. Camanni F, Ghigo E, Aimaretti G, Gianotti L, Bellone J, Imperiale E: Diagnosis of growth hormone deficiency; in Andreoli M, Shields M (eds): Highlights in Molecular and Clinical Endocrinology. Frontiers in Endocrinology. New York, Ares-Serono Symposia, 1994, vol 9, pp 211–217. de Boer H, Block GJ, Poo-Synders C, van der Veen EA: Diagnosis of growth hormone deficiency in adults. Lancet 1994;343:1645–1646. Ho KK, Hoffman DM: Defining growth hormone deficiency in adults. Metabolism 1995;44(suppl 4): 91–96.
Ghigo/Arvat/Gianotti/Maccario/Camanni
174
93 94 95
96 97
98 99 100 101
102 103
Laron Z, Buternandt O: Optimum use of growth hormone in children. Drugs 1991;42:1–8. Casanueva FF: Diagnosis of growth hormone deficiency in adulthood. Eur J Endocrinol 1996;135: 168–170. Thorner MO, Bengtsson BA, Ho KY, Albertsson-Wikland K, Christiansen JS, Faglia G, Irie M, Isaksson O, Jorgensen JO, Ranke M: The diagnosis of growth hormone deficiency in adults. J Clin Endocrinol Metab 1995;80:3097–3098. The Growth Hormone Research Society Group: Consensus guidelines for diagnosis and treatment of adults with GH deficiency. J Clin Endocrinol Metab 1998;83(2):382–395. Giustina A, Romanelli G, Candrina R, Giustina G: Growth hormone deficiency in patients with idiopathic adrenocorticotrophin deficiency resolves during glucocorticoid replacement. J Clin Endocrinol Metab 1989;68:120–124. Mehls O, Blum WF, Schaefer F, Tonshoff B, Scharer K: Growth failure in renal disease; in Bierich JR (ed): Growth Disorders. Clin Endocrinol Metab. London, Baillie`re Tindall, 1992, vol 6, pp 665–685. Laron Z, Klinger B: Laron syndrome: Clinical features, molecular pathology and treatment. Horm Res 1994;42:198–202. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J: Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 1994;15:369–390. Underwood LE, Backeljauw P: Therapy with recombinant human insulin-like growth factor I in children with insensitivity to growth hormone and in catabolic conditions. J Intern Med 1993;234: 571–577. Sassolas G: Potential therapeutic applications of GH in adults. Horm Res 1994;42:72–78. Wilmore DW: Growth hormone and growth factors in catabolic illness. Endocrinol Metab 1995; 2(suppl B):77–84.
Ezio Ghigo, MD, Division of Endocrinology, Department of Internal Medicine, University of Turin, Cso Dogliotti, 14, I–10126 Turin (Italy) Tel. +39 11 6335601, Fax +39 11 6647421
Regulation of Growth Hormone Secretion
175
Jenkins RC, Ross RJM (eds): The Endocrine Response to Acute Illness. Front Horm Res. Basel, Karger, 1999, vol 24, pp 176–200
............................
Growth Hormone and IGF-I as Anabolic Therapy C. Botfield, C.J. Hinds Department of Anaesthetics, St. Bartholomew’s Hospital, London, UK
Contents Introduction ............................................................................................... Growth Hormone and Insulin-Like Growth Factor-I Physiology .......................... The GH/IGF-I Axis ..................................................................................... IGF Receptors ............................................................................................ IGF-Binding Proteins ................................................................................... IGFBP-3 .................................................................................................... IGFBP-1 .................................................................................................... Acquired GH Resistance ............................................................................... The Anabolic Properties of GH ..................................................................... Dose, Frequency and Route of GH Administration ........................................... Side Effects of GH Administration ................................................................. The Anabolic Properties of IGF-I ................................................................... The Anabolic Effects of GH and IGF-I Compared ............................................ GH and IGF-I Given in Combination ............................................................. Are the Anabolic Actions of Growth Factors Accompanied by Functional Improvements ...................................................................... Editor’s Note in Proof .................................................................................. Conclusions ................................................................................................ Acknowledgement ....................................................................................... References ..................................................................................................
176 177 177 178 178 178 179 179 180 182 182 185 187 190 191 192 192 193 193
Introduction The hypermetabolic response to trauma, burns, sepsis and major surgical procedures is characterized by severe protein and fat wasting, a negative nitrogen balance and weight loss [1] which is resistant to nutritional support [2].
The negative nitrogen balance is attributable to a large increase in protein breakdown which is only partially counteracted by a minor increase in protein synthesis [3], and its magnitude is closely related to outcome [4]. Short-lived hypercatabolism may be advantageous insofar as muscle protein breakdown increases the availability of amino acids such as glutamine for protein synthesis in rapidly dividing cells (e.g. gut mucosa and immune system) and for wound healing. When illness is prolonged however, severe protein loss may lead to weakness and wasting of skeletal and respiratory muscles, impaired immune responses, an increased incidence of infection, poor wound healing and delayed recovery [5]. Although the precise mechanisms responsible for protein catabolism in the critically ill are still unclear, derangement of the growth hormone/ insulin-like growth factor-I (GH/IGF-I) axis is thought to be partly responsible [6, 7].
Growth Hormone and Insulin-Like Growth Factor-I Physiology The GH/IGF-I Axis Pituitary derived GH is released in pulses every 180–200 min [8], the largest peaks occurring about an hour after the onset of deep sleep. Its release is regulated by the dynamic equilibrium between stimulatory hypothalamic growth hormone-releasing hormone (GHRH) and inhibitory somatostatin. Between 40 and 50% of circulating GH is bound to a high-affinity growth hormone-binding protein (GHBP) [9] which is identical to the extracellular domain of the GH receptor and is probably derived from it by proteolytic cleavage [10]. Serum GHBP concentrations may therefore reflect GH receptor density [11]. The binding of GH to its binding protein appears to protect GH from elimination and degradation [12] and may also inhibit binding of GH to tissue receptors [13], as well as enhancing GH activity in the blood [14]. GHBP also regulates GH receptor gene transcription [15]. In addition to its direct actions (lipolysis and insulin antagonism), binding of GH to its receptor stimulates the production of IGF-I within target tissues [16]. IGF-I in turn participates in a negative feedback loop inhibiting further pituitary GH release [17]. The effects of IGF-I in various tissues are mediated by both autocrine and paracrine modes of action [16] and are influenced by its interaction with circulating and locally produced binding proteins and proteases. IGF-I is produced in a wide variety of organs (including liver and muscle) and tissue concentrations may play a more important role in mediating its anabolic effects than circulating levels [16]. Hepatic production of IGF-I is also stimulated by insulin [18] and in turn, IGF-I suppresses insulin secretion [19].
Growth Hormone and IGF-I as Anabolic Therapy
177
IGF Receptors Two types of IGF-I receptor have been identified. The type 1 receptor is similar in structure to the insulin receptor and binds IGF-I, IGF-II and insulin, and the type 2 receptor which is structurally identical to the mannose-6phosphate receptor and binds both IGF-I and -II but not insulin. The insulin receptor will also bind both growth factors although the ligand-binding domains of each receptor remain sufficiently different for each to bind its cognitive hormone with about 10 times more affinity than it does the related ligand [20]. The signal-transducing tyrosine kinase domains of the two receptors are however very similar [20] and activate common intracellular pathways [21]. IGF-I can mimic insulin’s effects on glucose metabolism by acting through its own receptor but rodents with a lethal phenotype associated with insulin receptor deficiency still die within 3–4 days despite IGF-I therapy, suggesting that IGF-I receptors cannot efficiently mediate all the metabolic actions of the insulin receptor [22]. Down-regulation of IGF-I receptors occurs with increasing age [23]. IGF-Binding Proteins The vast majority of circulating IGF-I is reversibly bound to a family of at least six binding proteins (IGFBP 1–6) [24] which may either enhance [25] or diminish [26] the metabolic and cellular actions of IGF-I by regulating its transport, receptor binding, bioavailability, half-life and tissue distribution. IGFBPs also have intrinsic biological activity independent of IGF [27]. IGFBP-3 IGFBP-3 is the major carrier protein for IGF-I and is synthesized in many tissues [28]. Its production is regulated by age, nutritional status and GH [29]. Circulating levels of IGFBP-3 are present in amounts that are equimolar to the sum of IGF-I and IGF-II concentrations [29]. Either of these growth factors can associate with IGFBP-3 and an acid-labile subunit (ALS) to form a high-molecular-weight ternary complex in which the IGF is relatively inert [30]. Formation of the complex increases the half-life of its components by some 50-fold [31]. Since the complex has only limited ability to cross capillary endothelium [32] it remains mainly within the circulation where proteolytic enzymes act directly on IGFBP-3 to alter the affinity with which it binds IGF-I [33], thereby increasing the bioavailability of IGF-I. GH administration induces IGFBP-3 [34] and ALS synthesis [35] stabilizing a greater proportion of circulating IGF-I in the bound form. In contrast, IGF-I infusion inhibits IGFBP-3 and ALS production, possibly because of suppression of GH secretion.
Botfield/Hinds
178
IGFBP-1 IGFBP-1 is a GH-independent binding protein with a relatively short half-life. The effects of IGFBP-1 are mainly inhibitory [36], for example diminishing the actions of IGF-I when insulin levels are low. IGFBP-1 levels, along with the plasma concentration of the other small-molecular-weight IGFBPs (-2, -4) rise in endotoxaemia, possibly allowing increased transfer of IGF-I across the vascular endothelium into the interstitial space where it can elicit a biological response [37].
Acquired GH Resistance In critically ill patients, basal GH secretion increases but oscillatory activity is lost and is not restored immediately with feeding [6]. Pulsatile GH administration has been shown to have a greater effect on IGF-I gene expression than continuous infusion [38] and loss of pulsatility may partly explain the GH resistance associated with critical illness. Reduced production of GHBP may also be important since catabolic conditions seem to be associated with low levels of GHBP [39, 40], although in diet-restricted rodents with GH resistance there is no change in GH binding [41] implying that the defect is at the postreceptor level. Catabolic states also appear to be associated with reduced transcription of some of the alternatively spliced variants of IGF-I [42], as well as changes in circulating levels of IGFBPs. For example, IGFBP-3 levels fall in parallel with IGF-I whereas IGFBP-1 levels are very high [43], but fall to control levels after the introduction of feeding, with concomitant rises in insulin and glucose. Therefore in fasted catabolic patients, any exogenously administered IGF-I might bind to inhibitory IGFBP-1 and be rendered ineffective. In addition to absolute reductions in circulating IGFBP-3 concentrations, critical illness is associated with induction of a protease which reduces the affinity of IGFBP-3 for IGF-I [44]. This protease could exacerbate catabolism by reducing the half-life of IGF-I in the circulation [45] and at the cellular level [46–48]. Recovery is associated with cessation of protease activity and a rise in circulating levels of IGFBP-3 and IGF-I (fig. 1) [44]. Finally, down-regulation of the IGF-I receptor is known to occur in severely catabolic states, particularly when IGF-I levels are high [49] and IGFBP-3 levels are low [50]. Thus it appears that the metabolic actions of the GH/IGF-I axis undergo adaptive change during sickness and fasting such that the indirect anabolic actions of GH are reduced while raised basal GH concentrations promote increased lipolysis and insulin antagonism in order to provide metabolic fuels at the expense of muscle protein loss. Administration of either GH or IGF-I or
Growth Hormone and IGF-I as Anabolic Therapy
179
5.0
500
IGFBP-3
(Low er lim it of norm al range IGFBP-3) 4.0
400 ]
(Low er lim it of norm al range IGF- I ) 3.0
300
200
2.0
]
IGFBP-3 (m g/l) ( , )
IGF- I (mg/l) ( , )
IGF- I
] ] ] ]
100
]
(Low er lim it of norm al range IGF- I ) ] ]
1.0
IGF- I
]
]
IGFBP-3 0
0 0
5
10
15
20 25 30 35 Days follow ing adm ission
40
45
50
Fig. 1. Insulin-like growth factor-1 (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and protease activity in 2 patients studied for a prolonged period. W>IGF-I levels in a survivor; X>IGF-I in a nonsurvivor; Q>IGFB-3 survivor; T>IGFBP-3 nonsurvivor; * protease activity. [From 44, with permission.]
both factors in combination might therefore partially reverse this GH resistance and improve nitrogen economy.
The Anabolic Properties of GH GH administration increases transcription of the IGF-I gene and is associated with retention of nitrogen and intracellular minerals, fluid retention and a gradual increase in lean body mass. The uptake of amino acids from ileum and jejunum is stimulated, possibly due to an increase in the number of functional carriers in the brush border membrane [51]. The anti-insulin-like
Botfield/Hinds
180
effects of GH result in stimulation of lipolysis, hyperglycaemia and increased insulin production, with concomitant loss of body fat. Administration of GH to hypophysectomized rats causes a dose-dependent increase in muscle mass and likewise skeletal muscle hypertrophy occurs in animals with GH-producing tumours [52]. Although initial animal studies indicated that in order for GH to attenuate the catabolic response to stress, adequate nutrition was required [53], more recent work has suggested that dietary protein content may be the most important factor [54–56]. GH treatment has also been shown to stimulate food intake [57]. Normal adults [58] and those with GH deficiency [59] respond to longterm GH treatment with an increase in lean body mass, due to stimulation of protein synthesis, and a decrease in fat mass. Although nitrogen and carbohydrate availability, and in particular the proportion of glucose to fat [60, 61], are important determinants of the anabolic effect of GH, nitrogen retention leading to a positive nitrogen balance has been shown to occur even in those receiving a hypocaloric diet [62]. When healthy male volunteers were randomized to receive GH or placebo during 7 days of normocaloric, hyponitrogenous diet, the treatment group had lower urinary urea excretion and lower serum urea than the control group. Skeletal muscle polyribosome concentration (an indicator of muscle protein synthesis), and amino acid concentrations all decreased in the control group but not in the treatment group [63]. There are now a large number of studies demonstrating that supraphysiological doses of GH can promote positive nitrogen balance in humans who are catabolic secondary to surgery [64, 65], overproduction of glucocorticoids [66], pulmonary disease [67, 68], burns injury [69], trauma [70, 71], short bowel syndrome [72] and AIDS [73]. These effects can be seen within 24 h [74–76] and may be sustained over several weeks of treatment [70]. It was initially thought that GH therapy would only exert a significant effect during the convalescent phase of acute illness but GH administration (0.1 mg/kg/day) has been shown to improve nitrogen balance even in the early phase of severe sepsis [77] and trauma [70]. Administration of GH to patients who had undergone elective cholecystectomy resulted in neutral nitrogen balance with maintenance of skeletal muscle ribosome concentration and attenuation of the postoperative fall in muscle-free glutamine whilst controls, who received TPN alone, remained in negative nitrogen balance with significantly decreased muscle protein synthetic ability and loss of up to 40% of muscle-free glutamine [78]. In a placebo-controlled, randomized study of 180 patients undergoing elective cholecystectomy treated with hypocaloric parenteral nutrition, albumin levels were maintained in those given a small dose of GH (8 IU/day) whereas they fell in the controls [76]. This was associated with a significant rise in plasma GH, IGF-I and insulin concentrations in the treatment group. Moreover, the incidence of wound infec-
Growth Hormone and IGF-I as Anabolic Therapy
181
tion was 17.2% in the control group compared with only 3.4% in the treatment group, possibly contributing to the significantly shorter length of hospital stay in those given GH (p=0.05). A caveat to this study is that the rate of wound infection and the length of hospital stay were greater in the control group than is usually seen in surgical practice. In some studies, however, either nitrogen balance was not improved by GH [79, 80] or GH treatment failed to prevent muscle breakdown [81] despite increased serum levels of GH, insulin, IGF-I and IGFBP-3. In trauma victims, however, serum albumin levels can be significantly increased by GH treatment [82]. Dose, Frequency and Route of GH Administration Catabolic patients require supraphysiological doses of GH to overcome the relative GH insensitivity. A multicentre study of the dose response of GH on cumulative nitrogen balance in postoperative patients suggested that the optimal dose is in the region of 0.3 IU/kg/day [83]. This is about 5–20 times the dose required for GH replacement. A number of studies have investigated the influence of the route, frequency and mode of administration on the anabolic effect of GH. It has been shown for example, that giving GH in the evening leads to greater retention of nitrogen than administration at other times of the day [84]. Because GH stimulates protein synthesis acutely [85] it has been suggested that the effectiveness of GH as an anabolic agent might be enhanced by giving multiple daily doses, attempting to match the normal circadian rhythm. Also, pulsatile GH administration has been shown to stimulate IGF-I gene expression to a greater extent than continuous exposure [38]. Nevertheless, although Moller et al. [86] demonstrated that alanine release from forearm muscle fell by 55% in response to a pulsatile infusion of GH, a similar effect was demonstrated by Fryburg et al. [85] when administering GH as a continuous infusion, suggesting that in terms of protein synthesis the effects of a continuous infusion are broadly similar to those of ‘physiological’ pulses. This is supported by a review of the literature which concluded that pulsatile administration and continuous infusions of GH produced identical increases in serum IGF-I concentrations when used as replacement therapy [84]. Subcutaneous administration of GH results in slower absorption, lower peak concentration and an extended duration of action. Other studies have reported that bioavailability is reduced with this route of administration [84]. Side Effects of GH Administration Dose-related increases in extracellular water associated with sodium retention and decreased body cell mass and intracellular water have been observed
Botfield/Hinds
182
during GH treatment [87]. Cessation of GH therapy is followed by a prompt diuresis [88]. Although usually of little significance, carpal tunnel syndrome and parotid gland tenderness have both been reported, as has a case of papilloedema, in a study of patients with renal impairment treated with GH [89]. On the other hand, GH treatment has been shown to normalize fluid distribution in a group of critically ill surgical patients [90] suggesting that it may stabilize membranes by promoting the synthesis of structural and functional proteins. GH therapy may also lead to electrolyte disturbances, most commonly a decreased serum potassium secondary to potassium movement into the cells, whilst in other studies potassium and phosphate retention have both been reported [65, 74]. Pharmacological doses of GH can produce hypercalaemia and hypercalciuria in critically ill patients [91] especially when treatment is prolonged and renal function impaired. GH is thought to enhance vitaminD-mediated intestinal absorption of calcium and to potentiate parathyroidhormone-mediated renal calcium resorption. Parathyroid and thyroid function were not impaired in these patients and vitamin D levels were within the normal range. Hypercalcaemia during short-term GH therapy is probably clinically unimportant. The anti-insulin effects of GH are well documented [92] and it seems that the mechanism may be defective translocation of glucose transporters rather than a decrease in transporter numbers [93]. GH is also known to mobilize free fatty acids [94, 95]. This could result in fatty infiltration of the liver, microembolism, hypercoagulability, altered membrane function, increased production of eicosanoids and increased susceptibility to cardiac arrhythmias. The insulin resistance induced by GH could deprive cells of glucose, further increase free fatty acid levels, and reduce the availability of amino acids for gluconeogenesis. When GH is given to hypopituitary GH-deficient adults receiving hydrocortisone replacement therapy, there is a significant reduction in mean peak cortisol levels and cortisol-binding globulin (CBG) concentrations [96]. The alterations in circulating cortisol are probably largely a result of the fall in CBG levels as there was no change in calculated levels of unbound cortisol. It has also been postulated that GH may act directly to reduce the availability of administered hydrocortisone or may indirectly modulate activity of 11 hydroxysteroid dehydrogenase [97]. GH and IGF-I have a number of immunomodulatory effects on both lymphocytes and macrophages and may function as phagocyte-activating factors [98, 99], enhancing the production of reactive oxygen intermediates and increasing lymphocyte activity. The experimental findings are, however, often conflicting. For example, whilst GH administration has been shown to enhance the interferon- response to burns injuries and reduce mortality in mice infected
Growth Hormone and IGF-I as Anabolic Therapy
183
with the herpes simplex virus [100], in the rat prior administration of GH, but not IGF-I, increases susceptibility to endotoxaemia [101, 102]. In vitro studies have shown that treatment of mononuclear cells with GH inhibits endotoxin-induced production of TNF and IL-1 [103] and GH treatment has been shown to blunt the increase in circulating TNF in response to endotoxin in calves [104] and bacterial challenge in mice [100]. In another study, GH worsened metabolic acidosis and bleeding tendency in traumatized, septic piglets [105] in association with reductions in portal blood flow, possibly combined with increased metabolic oxygen requirements [105]. These latter changes might lead to increased translocation of bacteria and their cell wall components from the gut lumen. These findings suggest that, depending on the precise circumstances, the effects of GH administration to patients with, or at risk from, sepsis could be either beneficial or detrimental. GH has been shown to increase the peripheral deiodination of thyroxine (T4) to triiodothyronine (T3) [106]. During catabolic illness there is generally a decrease in T3 and an increase in reverse T3 due to decreased conversion of T4 to T3 [107]. This ‘sick euthyroid syndrome’ is thought by some to be protective and it is therefore possible that the effects of GH on thyroid function could be detrimental. Glutamine requirements are markedly increased in critical illness because of the need to supply fuel and precursors for metabolically active tissues such as the immune system and the gut. Consequently, both plasma and muscle levels of this conditionally essential amino acid may be profoundly depleted in catabolic states [108]. The nitrogen-sparing effect of GH, and the preservation of lean muscle mass, is associated with preservation of muscle glutamine levels [78] and GH treatment prior to trauma in piglets has been shown to increase intestinal glutamine uptake [109]. It is unclear however whether the preservation of muscle glutamine in humans given GH is due to decreased efflux, increased synthesis or repletion of glutamine in the plasma pool by increased hepatic or pulmonary release. If glutamine mobilization from muscle is prevented, less may be available to the immune system and other rapidly dividing cells and this could be detrimental. Glutamine is also a substrate for the production of glutathione, a free radical scavenger and phase 2 detoxication enzyme. Gluthathione-S-transferases (GSTs) detoxify a diverse range of electrophilic chemicals. Studies in rodents have indicated that treatment with GH decreases GST isoenzyme activity [110]. Furthermore, male and female rodents differ in their GST isoenzyme pattern and continuous GH infusion given to male rodents has been shown to feminize the isoenzyme pattern [111]. Despite concerns that GH therapy might promote tumour growth, no significant increase in somatic cell mutation frequency has been noted with long-term GH therapy [112]. In fact, GH supplementation has been shown to
Botfield/Hinds
184
inhibit tumour growth in protein-deprived rodents [113], possibly by indirectly limiting the amino acid substrate available to the tumour. However, GH and IGF-I are both important for cell differentiation and proliferation, and malignant cells require a smaller amount of exogenous growth factor for their proliferation than do normal cells [114]. Because these side effects are likely to be more frequent and serious when large doses of GH are given in an attempt to overcome GH resistance in critically ill patients, there has been considerable interest in the potential of IGF-I treatment, either alone or in combination with smaller doses of GH, to attenuate the catabolic response.
The Anabolic Properties of IGF-I Although both GH and IGF-I stimulate growth in GH-deficient animals [115] this can be prevented by infusing IGF-I antibodies together with the GH [116]. Similarly, exogenous GH fails to stimulate growth in diabetic animals with impaired IGF-I production [117]. Moreover, immunizing sheep with IGF-I antiserum causes an increase in net protein catabolism [118] and administration of an interleukin-1 receptor antagonist to septic rats attenuates the sepsis-induced decrease in plasma IGF-I levels, which themselves are linearly related to the rate of muscle protein synthesis [119]. IGF-I rapidly elicits insulin-like effects on classical insulin target tissues, as well as enhancing proliferation and differentiation of cells. Its growthpromoting activity has been demonstrated in both animals and humans. In animals, IGF-I enhances glucose transport, mainly in skeletal muscle [120], increases glycolysis and glycogenolysis, and inhibits gluconeogenesis and protein breakdown [121, 122]. In diabetic rats, IGF-I reduces blood glucose levels and restores growth [123], mimicking the anabolic effects of insulin, and can lower blood glucose in insulin-resistant, septic rats [124]. IGF-I has also been shown to ameliorate weight loss induced by starvation, to increase weight gain after burns injury and to reduce protein losses in fasted rodents [121, 122]. However, not all studies have shown a beneficial effect of IGF-I administration in rodents [125] despite normalization of serum IGF-I concentrations. Also rodents with chronic renal failure are resistant to the anabolic effects of IGF-I and have low serum IGF-I accompanied by low levels of muscle IGF-I mRNA, despite an increase in IGF-I receptor numbers. Receptor tyrosine kinase activity is, however, impaired [126] and this postreceptor defect may explain IGF-I’s lack of anabolic effect under these circumstances. IGF-I has been administered to healthy volunteers [127–129], GH-deficient patients [130], patients with Laron syndrome [131], insulin-dependent
Growth Hormone and IGF-I as Anabolic Therapy
185
diabetics [132], postoperative patients [48, 133] and critically ill patients with the systemic inflammatory response syndrome [47]. When administered intravenously to healthy adults, IGF-I increases glucose uptake 3-fold, reduces hepatic glucose output by 60–70% [127, 128] and lowers blood glucose acutely. Subcutaneous administration, however, has not been associated with hypoglycaemia [48], except in those with Laron syndrome who are prone to developing hypoglycaemia even when not receiving treatment. This difference may be explained by the sudden increase in the proportion of unbound IGF-I which follows intravenous administration and which could precipitate hypoglycaemia by cross-reacting with the insulin receptor. IGF-I administration also suppresses plasma insulin, C-peptide and glucagon concentrations, thereby inhibiting lipolysis with corresponding decreases in free fatty acid and ketone body concentrations. Plasma amino acid concentrations may also fall markedly, secondary to decreased proteolysis [134] whilst protein synthesis is unaffected. In another study in which plasma amino acid concentrations were maintained, however, IGF-I increased protein synthesis [135]. Administration of IGF-I can also attenuate the proteolysis caused by dietary restriction and reduce weight loss to the same extent as GH [129]. On the other hand, Mauras et al. [136] failed to demonstrate any anabolic or glucose-lowering effect of a low-dose IGF-I infusion in fasted subjects rendered catabolic by pharmacological doses of glucocorticoids, despite significantly increased serum IGF-I concentrations. In this study the serum IGF-I concentrations were significantly lower than those achieved by other investigators [127–129]. Interestingly, when GH was administered to similarly catabolic subjects in a dose that achieved comparable IGF-I concentrations, protein synthesis was clearly induced (although the effect on protein breakdown was minimal) suggesting that GH may have anabolic effects not directly attributable to increases in circulating IGF-I [137]. In normally fed volunteers [138] leucine oxidation was decreased by IGF-I alone but increased in those given IGF-I and prednisone, although not to the same extent as those receiving prednisone alone. It would seem therefore, that IGF-I diminishes the protein catabolic response to glucocorticoids in normally fed, but not in starved subjects. Turkalj et al. [134] gave 20% dextrose whilst administering different intravenous infusion rates of IGF-I (5–30 g/kg/h). Glucose consumption increased as the dose of IGF-I increased and dose-dependent decreases in free fatty acids and triglycerides were also seen; at the higher dose IGF-I decreased protein breakdown. Protein synthesis was not altered in any treatment group. Thus, the inhibitory effect of IGF-I on protein breakdown may be dependent on achieving adequate plasma levels, on the relative concentrations of free and bound IGF-I, and on a simultaneous supply of calories.
Botfield/Hinds
186
Disappointingly, three randomized, placebo-controlled, double-blind studies have failed to demonstrate a protein-sparing effect of IGF-I in postoperative patients [133, 139, 140]. Sandstrom et al. [133] concluded that the failure to achieve nitrogen-sparing could be due in part to the absence of supplemental amino acids in their patients who received only intravenous dextrose and in both the other studies patients were receiving total parenteral nutrition. More recently a single, low dose of IGF-I has been given subcutaneously to a small group of critically ill patients with the systemic inflammatory response syndrome [47]. Baseline circulating IGF-I concentrations were extremely low but increased 3-fold after injection, although the levels achieved only approached the fifth percentile of the normal reference range (fig. 2). The elimination half-life of IGF-I was shorter than in less seriously ill patients. There was considerable inter-patient variability, suggesting that dosage would have to be carefully adjusted to the individual patient. An attenuated response tended to occur in the more severely ill patients in association with high levels of IGFBP–1, low levels of IGFBP–3 and the presence of protease activity. Some negative feedback was evident, as endogenous GH levels fell significantly 4–6 h following IGF-I administration. There were, however, no adverse effects attributable to IGF-I administration. The potential synergistic effect of combining IGF-I with glutamine administration on postresection ileal hyperplasia has been investigated in rats who had undergone an 80% small bowel resection [141]. Rodents given the combination therapy showed enhanced ileal DNA and protein content. Interestingly, this effect was not reproduced when glutamine was combined with GH [142]. More studies investigating synergism between glutamine supplementation and growth factors are required.
The Anabolic Effects of GH and IGF-I Compared There is evidence to suggest that GH and IGF-I may exert their anabolic effects via different pathways and that GH may be the more potent of the two agents (table 1). When IGF-I is infused into rats, plasma amino acid concentrations fall rapidly [121] although they are not subsequently incorporated into skeletal muscle, heart or liver, suggesting that IGF-I inhibits proteolysis without stimulating protein synthesis. GH, on the other hand, has been shown to increase protein synthesis without suppressing proteolysis [64, 85] and without any measurable increase in serum IGF-I concentration (although tissue concentrations were not measured) [85]. Indeed serum total IGF-I remained unchanged in animals treated with either GH or GH antiserum [143] although those
Growth Hormone and IGF-I as Anabolic Therapy
187
2 Botfield/Hinds
188
Table 1. Summary of the differences between GH and IGF-I Growth hormone
IGF-I
Tissue growth
Sustained with continued administration Balanced
Mode of action IGFBP-3 ALS Plasma amino acids Protein Insulin C-peptide Glucagon Glucose Lipolysis Extracellular water Calcium
Endocrine Increased production Increased production Maintained or increased Stimulates synthesis Enhanced secretion Raised (Unknown) Raised Increased Increased Increased
Lost despite continued administration Disproportionate effects on spleen, thymus and kidney Endocrine/autocrine/paracrine Significant suppression Significant suppression Decreased Primarily inhibits breakdown Suppressed secretion Lowered Lowered Lowered Inhibited No effect No effect
Duration of effect
treated with GH showed increased muscle mass and those treated with antiserum showed a decrease in muscle mass. In this experiment, the amount of hepatic IGF-I mRNA was also unaffected by GH antiserum implying that GH’s action is not mediated by IGF-I. In hypophysectomized rats, 8–10 times more IGF-I is required to obtain equivalent responses to those produced by GH [144]. Likewise, nitrogen balance improves to the same degree in calorically restricted humans given either GH or IGF-I [129] even though IGF-I levels were 3-fold greater in subjects given IGF-I than in those who received GH. In this instance, GH may be altering IGFBP-3 and ALS concentrations in such a way as to facilitate IGF-I activity [137]. Furthermore, because IGF-I is believed to act by autocrine or paracrine mechanisms [16] relatively large amounts of exogenously administered IGF-I may be required to achieve the same tissue concentrations as those achieved by GH administration. One obvious difference between the actions of GH and IGF-I is the ability of GH to enhance insulin secretion [62], and, as insulin is more effective than IGF-I Fig. 2. Serum concentrations of insulin-like growth factor-I (IGF-I, top), insulin-like growth factor binding protein-3 (IGFBP-3, middle), and insulin-like growth factor binding protein-1 (IGFBP-1, bottom) before and after subcutaneous injection of recombinant human insulin-like growth factor-1 (rhIGF-I, 40 g/kg) in 9 patients. X>Patients 1–5; >patient 6; p>patient 7; Q>patient 8; T>patient 9. [From 47, with permission.]
Growth Hormone and IGF-I as Anabolic Therapy
189
at promoting glucose uptake into the cells, this may help to explain the additional anabolic effect of GH. A further study in postoperative patients has indicated that GH improves nitrogen balance independently of its ability to increase either insulin or IGF-I concentrations [65], while following unilateral nephrectomy IGF-I expression in the kidney is enhanced without an increase in GH secretion [145].
GH and IGF-I Given in Combination The ability of GH to promote lipolysis and insulin resistance may counteract the hypoglycaemic effect of IGF-I when both drugs are given in combination, whilst the two peptides may have synergistic effects on protein anabolism [146]. The combination of GH and IGF-I given to uraemic [57] or surgically stressed rats receiving parenteral nutrition, led to greater weight gain than when either drug were administered alone [147, 148]. The combination also ameliorates the metabolic acidosis induced by surgical stress in intravenously fed rats [147]. More recently, GH and IGF-I given together increased diaphragmatic strength more than did either individual treatment in normally fed young rats [149], but not in nutritionally deprived rats [150]. In the nutritional deprivation model, neither growth factor given alone nor the combination altered the contractile or fatigue properties of the diaphragm [150] although IGF-I alone and in combination with GH did limit the reduction in the cross-sectional area of diaphragmatic fibres. This implies that in nutritional deprivation there is a degree of peripheral resistance to GH which can be bypassed by the administration of IGF-I. In normally fed volunteers, combination therapy induces a significant increase in whole body protein synthesis associated with increased circulating IGF-I levels [151]. However, when absolute changes in markers of protein synthesis were compared with results from previous reports in subjects treated with either growth factor alone, there appeared to be no additive effect of the combination. It may be that the body has a saturatable capacity to accumulate protein even in the presence of adequate substrate. In contrast, combination treatment leads to a greater degree of nitrogen retention than either peptide given alone to volunteers rendered catabolic secondary to calorie deprivation [146] or glucocorticoid administration [152]. Furthermore, all those who received the combination had positive nitrogen balance whereas nitrogen balance remained negative with single therapy. Protein accumulation also appeared to occur within muscle and connective tissue as indicated by significantly increased urinary potassium conservation [153].
Botfield/Hinds
190
There may be several explanations for the enhanced efficacy of combination treatment. The anabolic properties of insulin are well documented but may differ in mechanism of action to those of GH. GH administered with IGF-I counteracts the hypoglycaemic and insulin-lowering effects of IGF-I and thus maintains plasma insulin concentrations, which may augment the anabolic effects by allowing greater inhibition of proteolysis [121, 154]. Moreover, substantially higher serum IGF-I concentrations are achieved with the combination whilst circulating levels of IGFBP-3 and ALS are stabilized. In summary, the enhanced anabolic effect of combination therapy may be due to: (1) higher serum IGF-I levels; (2) increased stability of IGF-I in the ternary complex, perhaps promoting a sustained metabolic action; (3) altered IGF-I clearance with IGF-I interacting with its receptor for a greater length of time; (4) improved tissue IGF-I levels; (5) additive effect of differing mechanisms of action of GH (predominantly increasing protein synthesis) and IGF-I (predominantly inhibiting proteolysis), and (6) substantially greater insulin concentrations.
Are the Anabolic Actions of Growth Factors Accompanied by Functional Improvements Low doses of GH given to healthy elderly subjects increase lean body mass and decrease fat, but may [155] or may not [156] increase muscle strength. Improvements in clinically measurable end points have been demonstrated in some conditions: (1) GH administration maintained hand-grip strength in patients who underwent elective laparotomy whilst controls lost up to 10% of preoperative strength [65]. (2) Fifteen times the normal adult replacement dose of GH led to a reduction of hospital stay in severely burnt children, probably by decreasing donor site healing time [157]. (3) GH improved maximal inspiratory capacity, assumed to be related to improved respiratory muscle strength in a group of 7 malnourished patients suffering from chronic airflow limitation [67]. (4) GH replacement therapy led to increased muscle strength with enhanced muscle mass in a group of adults with hypopituitarism [158]. (5) An average of 38 days’ treatment with GH allowed 81% of previously unweanable ICU patients with postoperative respiratory failure to be weaned from mechanical ventilation [159]. (6) Extubation was achieved within 5–11 days of commencing GH treatment in 3 heart-lung and double lung transplant patients who were difficult to wean from mechanical ventilation [160]. (7) GH treatment reduced hospital stay and wound infection rate in a group of patients who had undergone cholecystectomy [76].
Growth Hormone and IGF-I as Anabolic Therapy
191
In all of the above studies the response to GH was accompanied by a rise in the serum concentration of IGF-I. However, other studies have shown little or no functional improvement: (1) Patients with chronic airflow limitation on mechanical ventilators did not appear to benefit from GH treatment despite a 250% increase in circulating IGF-I levels and improved nitrogen balance [68]. (2) Administration of GH to patients requiring prolonged mechanical ventilation did not improve peripheral muscle function or respiratory muscle strength and there was no evidence that weaning times were reduced despite producing a positive cumulative nitrogen balance, an increase in fat-free mass and a significant increase in serum IGF-I concentration [161]. (3) IGF-I and low-dose GH in combination resulted in a transient increase in body weight but no improvement in isokinetic muscle strength, endurance or quality of life in patients with HIV-associated wasting [162, 163].
Editor’s Note in Proof GH treatment in critical illness: Recently, two large multicentre trials using GH as anabolic therapy in critically ill patients have been terminated due to an increased mortality in patients treated with GH versus placebo (41.7 vs. 18.2%) (Pharmacia and Upjohn, personal commun.). The analysis of these trials is yet to be published, but the studies included 532 patients with either open-heart surgery, abdominal surgery, multiple trauma or acute respiratory failure and used GH doses of either 16 or 24 IU/day. In response to this preliminary communication analysis of a large group (n>450) with AIDSrelated wasting treated with a similar dose of GH showed no increase in mortality (Serono, personal commun.) and the same is true for a group of 166 patients treated for hip fracture, liver transplant and burns (Lilly, personal commun.). Firm conclusions will be possible only when these trials have been fully analysed and published, but it is possible that GH at high dose may be beneficial in some groups and harmful in others.
Conclusions There are theoretical reasons for believing that administration of growth factors could ameliorate many of the adverse effects of catabolic illness and there is no doubt that such treatment is usually associated with an improvement in nitrogen balance. It remains unclear, however, whether the reduction in nitrogen losses translates into clinically important functional improvements.
Botfield/Hinds
192
Some have also been concerned that the supraphysiological doses required to overcome growth hormone resistance may be associated with potentially deleterious side effects, although there is no suggestion in the 90 or more studies in catabolic patients published since the 1950s that morbidity or mortality is increased by the administration of GH. However, the recent disturbing reports that GH increases mortality in critically ill patients needs to be taken into consideration. Further studies examining the potential of combined treatment with lower doses of GH and IGF-I, as well as with nutritional supplements such as glutamine and/or carrier proteins, such as GHBP and IGFBP-3/ALS, are required.
Acknowledgement Dr. Botfield was supported by a grant from Pharmacia and Upjohn.
References 1 2 3
4 5 6
7 8
9 10 11
12 13
Herndon DN, Wilmore DW, Mason AD: Development and analysis of a small animal model simulating the human post-burn hypermetabolic response. J Surg Res 1978;25:394–403. Shaw JHF, Wildbore M, Rolfe RR: Whole body protein kinetics in severely septic patients: The response to glucose infusion and TPN. Ann Surg 1987;205:288–294. Arnold J, Campbell IT, Samuels TA, Devlin JC, Green CJ, Hipkin LJ, MacDonald IA, Scrimgeour CM, Smith K, Rennie MJ: Increased whole body protein breakdown predominates over whole body protein synthesis in multiple organ failure. Clin Sci 1993;84:655–661. Herndon DN, Curreri PW, Abston S, Rutan TC, Barrow RE: Treatment of burns. Curr Probl Surg 1987;24:341–397. Alexander JW: Nutrition and infection – A new perspective for an old problem. Arch Surg 1986; 121:966–972. Ross RJ, Miell JP, Freeman E, Jones J, Matthews D, Preece M, Buchanan C: Critically ill patients have high basal GH levels with attenuated oscillatory activity associated with low levels of IGF-I. Clin Endocrinol 1991;35:47–54. Ross RJ, Chew SL: Acquired growth hormone resistance. Eur J Endocrinol 1995;132:655–660. Hindmarsh PC, Fall CH, Pringle PJ, Osmond C, Brook CG: Peak and trough GH concentrations have different associations with the IGF axis, body composition and metabolic parameters. J Clin Endocrinol Metab 1997;82:2172–2176. Herington AC, Ymer S, Stevenson J: Identification and characterisation of specific binding proteins for growth hormone in normal human sera. J Clin Invest 1986;77:1817–1823. Harrison SM, Barnard R, Ho KY, Rajkovic I, Waters MJ: Control of GHBP release from human hepatoma cells expressing full-length growth hormone receptor. Endocrinology 1995;136:651–659. Bick T, Amit T, Barkey RJ, Hertz P, Youdim MB, Hochberg Z: The interrelationship of GH, liver membrane GHR, serum GHBP activity and IGF-I in the male rat. Endocrinology 1990;126: 1914–1920. Fairhall KM, Carmignac DF, Robinson IC, Marshall NJ: GHBP and GH interactions in vivo in the guinea pig. Endocrinology 1992;131:1963–1969. Dattani MT, Hindmarsh PC, Brook CG, Robinson IC, Marshall NJ: Inhibition of GH bioactivity by GHBP in the eluted stain assay system. J Endocrinol 1994;140:445–453.
Growth Hormone and IGF-I as Anabolic Therapy
193
14
15 16
17 18 19 20
21
22 23 24 25 26
27 28 29 30 31 32 33
34
35
36
Clark RG, Mortensen DL, Carlsson LM, Spencer SA, McKay P, Mulkerrin M, Moore J, Cunningham BC: RhGHBP enhances the growth-promoting activity of GH in the rat. Endocrinology 1996;137:4308–4315. Mullis PE, Wagner JK, Eble A, Nuoffer JM, Postel-Vinay MC: Regulation of hGH receptor gene transcription by hGHBP. Mol Cell Endocrinol 1997;131:89–96. D’Ercole AJ, Stiles AD, Underwood LE: Tissue concentration of somatomedin-C: Further evidence for multiple sites of synthesis and paracrine of autocrine mechanisms of action. Proc Natl Acad Sci USA 1984;81:935–939. Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L, Hintz RL: Somatomedin C mediates GH negative feedback by effects on both the hypothalamus and pituitary. Science 1981;212:1279–1281. Daughayday WH, Phillips LS, Mueller MC: The effects of insulin and GH on the release of somatomedin by the isolated rat liver. Endocrinology 1976;98:1214–1219. Zhao AZ, Zhao H, Teague J, Fujimoto W, Beavo JA: Attenuation of insulin secretion by IGF-I is mediated through activation of phosphodiesterase-3. Proc Natl Acad Sci USA 1997;94:3223–3228. Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E: IGF-I receptor primary structure: Comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J 1986;5:2503–2512. Myers MG Jr, Sun XJ, Cheatham B, Jachna BR, Glasheen EM, Backer JM, White MF: IRS-1 is a common element in insulin and insulin-like growth factor-1 signalling to the phosphatidylinositol 3-kinase. Endocrinology 1993;132:1421–1430. Di Cola G, Cool MH, Accili D: Hypoglycaemic effect of IGF-I in mice lacking insulin receptors. J Clin Invest 1997;99:2538–2544. Dardevet D, Sornet C, Attaix D, Baracos VE, Grizard J: IGF-I and insulin resistance in skeletal muscle of adults and old rats. Endocrinology 1994;134:1475–1484. Baxter RC: IGFBPs in the human circulation: A review. Horm Res 1994;42:140–144. Elgin RG, Busby WH Jr, Clemmons DR: IGFBP enhances the biologic response to IGF-I. Proc Natl Acad Sci USA 1987;84:3254–3258. Ritvos O, Ranta T, Jalkanen J, Suikkari AM, Voutilainen R, Bohn H, Rutanen EM: IGFBP from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells. Endocrinology 1988;122:2150–2157. Kelley KM, Oh Y, Gargosky SE, Gucer Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfield RG: IGFBPs and their regulatory dynamics. Int J Biochem Cell Biol 1996;28:619–637. Blum WF, Ranke MB: Insulin-like growth factor binding proteins (IGFBPs) with special reference to IGFBP-3. Acta Paediatr Scand 1990;367(suppl):55–62. Baxter RC, Martin JL: Binding proteins for IGFs: Structure, regulation and function. Review. Prog Growth Factor Res 1989;1:49–68. Holly JMP, Wass JAH: IGFs: Autocrine, paracrine or endocrine? New perspectives of the somatomedin hypothesis in the light of recent developments. J Endocrinol 1989;122:611–618. Guler HP, Zapf J, Schmid C, Froesch ER: IGF-I and -II in healthy man: Estimations of half-lives and production rates. Acta Endocrinol (Copenh) 1989;121:753–758. Binoux M, Hossenlopp P: IGF and IGFBPs: Comparison of human serum and lymph. J Clin Endocrinol Metab 1988;67:509–514. Clemmons DR, Underwood LE, Chatelain PG, Van Wyk JJ: Liberation of immunoreactive somatomedin-C from its binding proteins by proteolytic enzymes and heparin. J Clin Endocrinol Metab 1983; 56:384–389. Lemmey AB, Glassford J, Flick-Smith HC, Holly JM, Pell JM: Differential regulation of tissue IGFBP-3, IGF-I and IGF type-1 receptor mRNA levels, and serum IGF-I and IGFBP concentrations by GH and IGF-I. J Endocrinol 1997;154:319–328. Ooi GT, Cohen FJ, Tseng LY, Rechler MM, Boisclair YR: GH stimulates transcription of the gene encoding the ALS of the circulating IGFBP complex and ALS promotor activity in rat liver. Mol Endocrinol 1997;11:997–1007. Taylor AM, Dunger DB, Preece MA, Holly JM, Smith CP, Wass JA, Patel S, Tate VE: The GH independent insulin-like growth factor binding protein BP–28 is associated with serum IGF-I inhibitory bioactivity in adolescent insulin dependent diabetics. Clin Endocrinol 1990;32:229–239.
Botfield/Hinds
194
37 38
39 40 41 42
43
44
45 46
47 48
49 50 51 52 53 54
55
56
57 58
Fan J, Molina PE, Gelato MC, Lang CH: Differential tissue regulation of IGF-I content and binding proteins after endotoxin. Endocrinology 1994; 134:1685–1692. Maiter D, Walker JL, Adam E, Moatsstaats B, Mulumba N, Ketelslegers JM, Underwood LE: Differential regulation by GH or IGF-I and GH receptor/binding protein gene expression in rat liver. Endocrinology 1992;130:3257–3264. Mercado M, Molitch ME, Baumann G: Low plasma GHBP in IDDM. Diabetes 1992;41:605– 609. Baruch Y, Amit T, Hertz P, Enat R, Youdim MB, Hochberg Z: Decreased serum GHBP in patients with liver cirrhosis. J Clin Endocrinol Metab 1991;73:777–780. Maes M, Underwood LE, Ketelslegers JM: Low serum somatomedin-C in insulin-dependent diabetes: Evidence for a post-receptor mechanism. Endocrinology 1986;118:377–382. Adamo ML, Ben-Hur H, Roberts CT, Le Roith D: Regulation of start site usage in the leader exons of the rat IGF-I gene by development, fasting and diabetes. Mol Endocrinol 1991;5:1677– 1686. Ross RJ, Miell JP, Holly JMP, Maheshwari H, Norman M, Abdulla AF, Buchanan CR: Levels of GH binding activity, IGFBPs, insulin, blood glucose and cortisol in intensive care patients. Clin Endocrinol 1991;35:361–367. Timmins AC, Cotterill AM, Hughes SC, Holly JM, Ross RJ, Blum W, Hinds CJ: Critical illness is associated with low circulating concentrations of IGF-I and -II, alterations in IGFBPs and induction of an IGFBP-3 protease. Crit Care Med 1996;24:1460–1466. Blat C, Villaudy J, Binoux M: In vivo proteolysis of serum IGFBP-3 results in increased availability of IGF to target cells. J Clin Invest 1994;93:2286–2290. Lamson G, Giudice LC, Cohen P, Lui F, Gargosky S, Muller HL, Oh Y, Wilson KF, Hintz RL, Rosenberg RG: Proteolysis of IGFBP-3 may be a common regulatory mechanism of IGF action in vivo. Growth Regul 1993;3:91–95. Yarwood GD, Ross RJM, Medbak S, Coakley J, Hinds CJ: Administration of human recombinant IGF-I in critically ill patients. Crit Care Med 1997;25:1352–1361. Miell JP, Taylor AM, Jones J, Buchanan CR, Rennie J, Sherwood R, Leicester R, Ross RJ: Administration of human recombinant IGF-I to patients following major gastrointestinal surgery. Clin Endocrinol 1992;37:542–551. Lieberman SA, Butterfield GE, Harrison D, Hoffman AR: Anabolic effects of rIGF-I in cachectic patients with AIDS. J Clin Endocrinol Metab 1994;78:404–410. Conover CA, Powell DR: IGFBP-3 blocks IGF-I induced receptor down regulation and cell desensitisation in cultured bovine fibroblasts. Endocrinology 1991;129:710–716. Inoue Y, Copeland EM, Souba WW: GH enhances amino acid uptake by the human small intestine. Ann Surg 1994;219:715–722. Riss TJ, Novakofski J, Bechtel PJ: Skeletal muscle hypertrophy in rats having growth hormone secreting tumours. J Appl Physiol 1986;61:1732–1735. Gump FE, Schwartz MS, Prudden JF: Studies on GH – iv, dependence of anabolism on intake. Am J Med Sci 1960;239:27–30. MacRae JC, Bruce LA, Hovell FD, Hart IC, Inkster J, Walker A, Atkinson T: Influence of protein nutrition on the response of growing lambs to exogenous bovine growth hormone. J Endocrinol 1991;130:53–61. Caperna TJ, Steele NC, Komarek DR, McMurtry JP, Rosebrough RW, Solomon MB, Mitchell AD: Influence of dietary protein and recombinant porcine somatotropin administration in young pigs: Growth composition and hormone status. J Anim Sci 1990;68:4243–4252. Campbell RG, Johnson RJ, King RH, Taverner MR, Meisinger DJ: Interaction of dietary protein content and exogenous porcine GH administration on protein and lipid accretion rates in growing pigs. J Anim Sci 1990;68:3217–3225. Hazel SJ, Gillaspie CM, Moore RJ, Clark RG, Jureidini KF, Martin AA: Enhanced body growth in uraemic rats treated with IGF-I and GH in combination. Kidney Int 1994;46:58–68. Rudman D, Feller AG, Nagaraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE: Effects of human growth hormone in men over 60 years old. N Engl J Med 1990;323:1–6.
Growth Hormone and IGF-I as Anabolic Therapy
195
59
60
61 62 63
64 65
66
67 68
69 70 71 72 73
74
75
76
77
78
79
Russell-Jones DL, Weissberger AJ, Bowes SB, Kelly JM, Thomason M, Umpleby AM, Jones RH, Sonksen PH: The effects of GH on protein metabolism in adult GH deficient patients. Clin Endocrinol 1993;38:427–431. Isley WL, Underwood LE, Clemmons DR: Changes in plasma somatomedin-C in response to ingestion of diets with variable protein and energy content. J Parenter Enter Nutr 1984;8:407– 411. Snyder DK, Clemmons DR, Underwood LE: Dietary carbohydrate content determines responsiveness to GH in energy restricted humans. J Clin Endocrinol Metab 1989;69:745–752. Manson JM, Wilmore DW: Positive nitrogen balance with hGH and hypocaloric intravenous feeding. Surgery 1986;100:188–197. Lundeberg S, Belfrange M, Wernerman J, von der Decken A, Thunell S, Vinnars E: Growth hormone improves muscle protein metabolism and whole body nitrogen economy in man during a hyponitrogenous diet. Metabolism 1991;40:315–322. Ward HC, Halliday D, Sim AJW: Protein and energy metabolism with biosynthetic hGH after gastrointestinal surgery. Ann Surg 1987;206:56–61. Jiang ZM, He GZ, Zhang SY, Wang XR, Yang NF, Zhu Y, Wilmore DW: Low dose GH and hypocaloric nutrition attenuate the protein catabolic response after major operation. Ann Surg 1989;210:513–525. Bowes SB, Umpleby M, Cummings MH, Jackson NC, Carroll PV, Lowy C, Sonksen PH, RusselJones DL: The effect of recombinant human GH on glucose and leucine metabolism in Cushing’s syndrome. J Clin Endocrinol Metab 1997;82:243–246. Pape GS, Friedman M, Underwood LE, Clemmons DR: The effect of GH on weight gain and pulmonary function in patients with chronic obstructive lung disease. Chest 1991;99:1495–1500. Suchner U, Rothkopf MM, Stanislaus G, Elwyn DH, Kvetan V, Askanazi J: GH and pulmonary disease. Metabolic effects in patients receiving parenteral nutrition. Arch Intern Med 1990;150: 1125–1230. Wilmore DW, Moyland JA, Bristow BF, Mason AD, Pruitt BA: Anabolic effects of hGH and high caloric feedings following thermal injury. Surg Gynaecol Obstet 1974;138:875–884. Ziegler TR, Young LS, Ferrari-Baliviera E, Demling RH, Wilmore DW: Use of hGH combined with nutritional support in a critical care unit. J Parenter Enter Nutr 1990;14:574–581. Jeevanandam M, Ali MR, Holaday NJ, Petersen SR: Adjuvant GH normalizes plasma amino acids in parenterally fed trauma patients. J Parenter Enter Nutr 1995:19;137–144. Ellegard L, Bosaeus I, Nordgren S, Bengtsson BA: Low dose GH increases body weight and lean body mass in patients with short bowel syndrome. Ann Surg 1997;225:88–96. Krentz AJ, Koster FT, Crist DM, Finn K, Johnson LZ, Boyle PJ, Schade DS: Anthropometric, metabolic and immunological effects of GH in AIDS and AIDS-related complex. J Acquir Immune Defic Syndr 1993;6:245–251. Ziegler TR, Rombeau JL, Young LS, Fong Y, Marano M, Lowry SF, Wilmore DW: Recombinant human GH enhances the metabolic efficacy of parenteral nutrition: A double-blind randomized controlled study. J Clin Endocrinol Metab 1992;74:865–873. Voerman BJ, Strack van Schijndel RJ, Groeneveld AB, de Boer H, Nauta JP, Thijs LG: Effects of human GH in critically ill non-septic patients: Results from a prospective randomised placebo controlled trial. Crit Care Med 1995;23:665–673. Vara-Thorbeck R, Guerrero JA, Rosell J, Ruiz-Requena E, Capitan JM: Exogenous growth hormone: Effects on the catabolic response to surgically produced acute stress and on postoperative immune function. World J Surg 1993;17:530–538. Voerman BJ, Strack van Schijndel RJM, Groeneveld ABJ, de Boer H, Nauta JP, van der Veen EA, Thijs LG: Effects of recombinant human GH in patients with severe sepsis. Ann Surg 1992;216:648– 655. Hammarqvist F, Stomberg C, von der Decken A, Vinnars E, Wernerman J: Biosynthetic hGH preserves both muscle protein synthesis and prevents the decrease in muscle free glutamine, and improves whole body nitrogen economy after operation. Ann Surg 1992;216:184–191. Belcher HJ, Mercer D, Judkins KC, Shalaby S, Wise S, Marks V, Tanner NS: Biosynthetic hGH in burned patients: A pilot study. Burns 1989;15:99–107.
Botfield/Hinds
196
80
81 82 83
84 85 86 87 88 89 90 91 92 93 94
95
96
97
98
99 100
101 102
Roth E, Valentini L, Semsroth M, Holzenbein T, Winkler S, Blum WF, Ranke MB, Schemper M, Hammerle A, Karner J: Resistance of nitrogen metabolism to GH treatment in the early phase after injury of patients with multiple injuries. J Trauma 1995;38:136–41. Manson JM, Smith RJ, Wilmore DW: GH stimulates protein synthesis during hypocaloric parenteral nutrition. Ann Surg 1988;208:136–142. Behrman SW, Kudsk KA, Brown RO, Vehe KL, Wojtysiak SL: The effect of GH on nutritional markers in enterally fed immobilized trauma patients. J Parenter Enter Nutr 1995;19:41–46. Lehner JH, Jauch KW, Berger G, Tacke J, Savic B: A multicentre study of dose response effect of GH on cumulative nitrogen balance in patients after major abdominal surgery. Ann Surg 1992;208: 6–16. Jorgensen JOL, Moller J, Moller N, Lauritzen T, Christiansen JS: Pharmacological aspects of GH replacement therapy. Route, frequency and timing of administration. Horm Res 1990;33:77–82. Fryburg DA, Gelfand RA, Barrett EJ: GH acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol 1991;260:E499-E504. Moller N, Jorgensen JOL, Schmitz O, Moller J, Christiansen JS, Alberti KGMM, Orskov H: Effects of a GH pulse on total and forearm substrate fluxes in humans. Am J Physiol 1990;258:F86-F91. Ho KY, Weissberger AJ: The antinatriuretic action of biosynthetic hGH in man involves activation of the renin-angiotensin system. Metabolism 1990;39:133–137. Ziegler TR, Young LS, Manson JM, Wilmore DW: Metabolic effects of GH in patients receiving parenteral nutrition. Ann Surg 1988;208:6–16. Koller EA, Stadel BV, Malozowski SN: Papilledema in 15 renally compromised patients treated with GH. Paediatr Nephrol 1997;11:451–454. Gatzen C, Scheltinga MR, Kimbrough TD, Jacobs DO, Wilmore DW: GH attenuates the abnormal distribution of body water in critically ill surgical patients. Surgery 1992;112:181–187. Knox JB, Demling RH, Wilmore DW, Sarraf P, Santos AA: Hypercalaemia associated with the use of hGH in an adult surgical intensive care unit. Arch Surg 1995;130:442–445. Sherwin RS, Schulman GA, Hendler R, Walesky AB, Belous A, Tamborlane W: Effect of GH on oral glucose tolerance and circulating metabolic fuels in man. Diabetologia 1983;24:155–161. Cartee GD, Bohn EE: Growth hormone reduces glucose transport but not GLUT-1 or GLUT-4 in adult and old rats. Am J Physiol 1995;268:E902–E909. Snyder DK, Clemmons DR, Underwood LE: Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: Effects on anabolism, lipolysis and body composition. J Clin Endocrinol Metab 1988;67:54–61. Lo HC, Hirvonen MD, Kritsch KR, Keesey RE, Ney DM: Growth hormone or IGF-I increases fat oxidation and decreases protein oxidation without altering energy expenditure in parenterally fed rats. Am J Clin Nutr 1997;65:1384–1390. Rodriguez-Arnao J, Perry L, Besser GM, Ross RJ: GH treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy. Clin Endocrinol 1996;45:33–37. Weaver JU, Thaventhiran L, Noonan K, Burrin JM, Taylor NF, Norman MR, Monson JP: The effect of GH replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults. Clin Endocrinol 1994;41:639–648. Edwards CK, Lorence RM, Dunham DM, Arkins S, Yunger LM, Greager JA, Walter RJ, Dantzer R, Kelley KW: Hypophysectomy inhibits the synthesis of tumour necrosis factor alpha by rat macrophages: Partial restoration by exogenous GH or interferon gamma. Endocrinology 1991;128:989–996. Inoue T, Saito H, Fukushima R, Inaba T, Lin MT, Fukatsu K, Muto T: GH and IGF-I enhance host defence in a murine sepsis model. Arch Surg 1995;130:1115–1122. Takagi K, Suzuki F, Barrow RE, Wolf SE, Kobayashi M, Herndon DN: GH improves immune function and survival in burned mice infected with herpes simplex virus type 1. J Surg Res 1997; 69:166–170. Liao W, Rudling M, Angelin B: Growth hormone potentiates the in vivo biological activities of endotoxin in the rat. Eur J Clin Invest 1996;26:254–258. Liao W, Rudling M, Angelin B: Contrasting effects of GH and IGF-I on the biological activities of endotoxin in the rat. Endocrinology 1997;138:289–295.
Growth Hormone and IGF-I as Anabolic Therapy
197
103
104
105 106
107 108 109 110 111
112
113 114 115 116 117 118
119 120
121
122 123 124 125
Kappel M, Hansen MB, Diamant M, Pedersen BK: In vitro effects of human GH on the proliferative responses and cytokine production of blood mononuclear cells. Horm Metab Res 1994;26:612– 614. Elsasser TH, Fayer R, Rumsey TS, Hartnell GF: Recombinant bovine somatotropin blunts plasma tumour necrosis factor alpha, cortisol and thromboxane-2 responses to endotoxin in vivo. Endocrinology 1994;134:1082–1088. Unneberg K, Balteskard L, Mjaaland M, Revhaug A: Growth hormone impaired compensation of haemorrhagic shock after trauma and sepsis in swine. J Trauma 1996;41:775–780. Hussain MA, Schmite O, Jorgensen JO, Christansen JS, Weeke J, Schmid C, Froesch ER: IGF-I alters peripheral thyroid hormone metabolism in humans: Comparison with GH. Eur J Endocrinol 1996;134:563–567. Chopra IJ, Hershman JM, Partridge WM, Nicoloff JT: Thyroid function in non-thyroidal illnesses. Ann Intern Med 1983;98:946–957. Hall JC, Heel K, McCauley R: Glutamine (review). Br J Surg 1996;83:305–312. Mjaaland M, Unneberg K, Jenssen TG, Revhaug A: Experimental study to show that GH treatment before trauma increases glutamine uptake in the intestinal tract. Br J Surg 1995;82:1076–1079. Grgurevich S, Greene FE: Selective suppression of glutathione-S-transferase activities in rat primary hepatocytes by GH. Pharmacology 1995;51:13–23. Staffas L, Mankowitz L, Sonderstrom M, Blank A, Porsch-Hallstrom I, Sundberg C, Mannervik B, Olin B, Rydstrom J, De Pierre JW: Further characterization of hormonal regulation of glutathione transferase in rat liver and adrenal glands. Sex differences and demonstration that GH regulates the hepatic levels. Biochem J 1992;286:65–72. Lin YW, Kubota M, Wakazono Y, Hirota H, Okuda A, Bessho R, Usami I, Kataoka A, Yamanaka C, Akiyama Y, Furusho K: Normal mutation frequencies of somatic cells in patients receiving GH therapy. Mutat Res 1996;362:97–103. Bartlett DL, Stein TP, Torosian MH: Effect of GH and protein intake on tumour growth and host cachexia. Surgery 1995;117:260–267. Moses HL, Robinson AR: Growth factors, growth factor receptors, and cell cycle control mechanism in chemically transformed cells. Fed Proc 1982;41:3008–3011. Guler HP, Zapf J, Scheiwiller E, Froesch ER: rhIGF-I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc Natl Acad Sci USA 1988;85:4889–4893. Isaksson OG, Lindahl A, Nilsson A, Isgaard J: Mechanism of the stimulatory effect of GH on longitudinal bone growth. Endocr Rev 1987;8:426–438. Fagin JA, Roberts CT, LeRoith D, Brown AT: Co-ordinate decrease of tissue IGF-I post-transcriptional alternative mRNA transcripts in diabetes mellitus. Diabetes 1989;38:428–434. Koea JB, Gallaher BW, Breier BH, Douglas RG, Hodgkinson S, Shaw JH, Gluckman PD: Passive immunisation against circulating levels of IGF-I increases protein catabolism in lambs: Evidence for a physiological role for circulating IGF-I. J Endocrinol 1992;135:279–284. Lang CH, Fan J, Cooney R, Vary TC: IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF-I system and protein synthesis. Am J Physiol 1996;270:E430-E437. Valentini L, Holzenbein T, Winkler S, Sautner T, Ollenschlager G, Hortnagl H, Karner J, Roth E: Acute effects of IGF-I on interorgan glucose and lactate flux in protein catabolic dogs. J Surg Res 1995;59:606–613. Jacob R, Barrett E, Plewe G, Fagin KD, Sherwin RS: Acute effects of IGF-I on glucose and amino acid metabolism in the awake fasted rat. Comparison with insulin. J Clin Invest 1989;83:1717– 1723. O’Sullivan U, Gluckman PD, Breier BH, Woodall S, Siddiqui RA, McCutcheon SN: IGF-I in mice reduces weight loss associated with starvation. Endocrinology 1989;125:2793–2794. Binz K, Zapf J, Froesch ER: The role of IGF-I in growth of diabetic rats. Acta Endocrinol (Copenh) 1989;121:628–632. Lang CH: IGF-I stimulates muscle glucose uptake during sepsis. Shock 1996;5:22–27. Thissen JP, Underwood LE, Maiter D, Maes M, Clemmons DR, Keterslegers JM: Failure of IGF-I infusion to promote growth in protein restricted rats despite normalization of serum IGF-I concentrations. Endocrinology 1991;128:885–890.
Botfield/Hinds
198
126
127 128 129 130 131 132 133
134 135
136 137 138
139
140 141 142
143
144 145
146 147 148
Ding H, Gao XL, Hirschberg R, Vadgama JV, Kopple JD: Impaired actions of IGF-I on protein synthesis and degradation in skeletal muscle of rats with CRF. Evidence of a post-receptor defect. J Clin Invest 1996;97:1064–1075. Guler HP, Zapf J, Froesch ER: Short term metabolic effects of rhIGF-I in healthy adults. N Engl J Med 1987;317:137–140. Guler HP, Schmid C, Zapf J, Froesch ER: Effect of rhIGF-I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci USA 1989;86:2868–2872. Clemmons DR, Smith-Banks A, Underwood ER: Reversal of diet-induced catabolism by infusion of recombinant IGF-I in humans. J Clin Endocrinol Metab 1992;75:234–238. Takano K, Hizuka N, Shizume K, Asakawa K, Fukuda I, Demura H: Repeated subcutaneous administration of rhIGF-I to human subjects for 7 days. Growth Regul 1991;1:23–28. Backeljauw PF, Underwood LE: Prolonged treatment with rIGF-I in children with GH-insensitivity syndrome – A clinical research centers study. J Clin Endocrinol Metab 1996;81:3312–3317. Cheetham TD, Holly JM, Clayton K, Cwyfan-Hughes S, Dunger DB: The effects of repeated daily rhIGF-I administration in adolescents with type-1 diabetes. Diabetic Med 1995;12:885–892. Sandstrom R, Svanberg E, Hyltander A, Haglind E, Ohlsson C, Zachrisson H, Berglund B, Undholm E, Breringe H, Lundholm K: The effect of rhIGF-I on protein metabolism in post-operative patients without nutrition compared to effects in experimental animals. Eur J Clin Invest 1995;25:784–792. Turkalj I, Keller U, Ninnis R, Vosmeer S, Stauffacher W: Effect of increasing doses of rIGF-I on glucose, lipid and leucine metabolism in man. J Clin Endocrinol Metab 1992;75:1186–1191. Russell-Jones DL, Umpleby AM, Hennessey TR, Bowes SB, Shojaee-Mordie F, Hopkins KD, Jackson NC, Kelly JM, Jones RH, Sonksen PH: Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans. Am J Physiol 1994;267:E591–E598. Mauras N, Horber FF, Haymond MV: Low dose rhIGF-I fails to alter protein anabolism but inhibits islet cell secretion in humans. J Clin Endocrinol Metab 1992;75:1183–1185. Horber FF, Haymond MW: Human GH prevents protein catabolic side effects of prednisolone in humans. J Clin Invest 1990;86:265–272. Mauras N, Beaufrere B: rhIGF-I enhances whole body protein anabolism and significantly diminishes the protein catabolic effects of prednisone in humans without a diabetogenic effect. J Clin Endocrinol Metab 1995;80:869–874. Goeters C, Mertes N, Tacke J, Bolder U, Kuhmann M, Lowin P, Lohlern D: Repeated administration of recombinant human insulin-like growth factor-1 in patients after gastric surgery. Ann Surg 1995; 222:646–653. Leinskold T, Permert J, Olalson G, Larsson J: Effect of postoperative IGF-I supplementation on protein metabolism in humans. Br J Surg 1995;82:921–925. Ziegler TR, Mantell MP, Chow JC, Rombeau JL, Smith RJ: Gut adaptation and the IGF system: Regulation by glutamine and IGF-I administration. Am J Physiol 1996;271:G866–G875. Vanderhoof JA, Kollman KA, Griffins S, Adrian TE: GH and glutamine do not stimulate intestinal adaptation following massive small bowel resection in the rat. J Pediatr Gastroenterol Nutr 1997; 25:327–331. Palmer RM, Flint DJ, MacRae JC, Fairhurst FE, Bruce LA, Mackie SC, Lobley GE: Effects of GH and an antiserum to rat GH on serum IGF-I and muscle protein synthesis and accretion in the rat. J Endocrinol 1993;139:395–401. Schoenle E, Zapf J, Hauri C, Steiner T, Froesch ER: Comparison of the in vivo effects of IGF-I and -II and of GH in hypophysectomized rats. Acta Endocrinol (Copenh) 1985;108:167–174. Mulroney SE, Lumpkin MD, Roberts CT, LeRoith D, Haramati A: Effect of a GH releasing factor antagonist on compensatory renal growth, IGF-I and IGF receptor gene expression after unilateral nephrectomy in immature rats. Endocrinology 1992;130:2697–2702. Kupfer SR, Underwood LE, Baxter RC, Clemmons DR: Enhancement of the anabolic effects of GH and IGF-I by use of both agents simultaneously. J Clin Invest 1993;91:391–396. Evans SJ, Lo HC, Ney DM, Welbourne TC: Acid-base homeostasis parallels anabolism in surgically stressed rats treated with GH and IGF-I. Am J Physiol 1996;270:E968–E974. Lo HC, Hinton PS, Peterson CA, Ney DM: Simultaneous treatment with IGF-I and GH additively increases anabolism in parenterally fed rats. Am J Physiol 1995;269:E368–E376.
Growth Hormone and IGF-I as Anabolic Therapy
199
149 150 151
152
153
154
155 156
157 158 159 160 161
162
163
Lewis MI, LoRusso TJ, Fournier M: Anabolic influences of IGF-I and/or GH on the diaphragm of young rats. J Appl Physiol 1997;82:1972–1978. Lewis MI, LoRusso TJ, Fournier M: Effect of IGF-I and/or GH on diaphragm of malnourished, adolescent rats. J Appl Physiol 1997;82:1064–1070. Mauras N: Combined recombinant human growth hormone and recombinant human insulin-like growth factor–1: Lack of synergy on whole body protein anabolism in normally fed subjects. J Clin Endocrinol Metab 1995;80:2633–2637. Berneis K, Ninnis R, Girard J, Frey BM, Keuer U: Effects of IGF-I combined with GH on glucocorticoid induced whole body protein catabolism in man. J Clin Endocrinol Metab 1997;82: 2528–2534. Cohn SH, Vartsky D, Yasumura S, Sawitsky A, Zanzi I, Vaswani A, Ellis KJ: Compartmental body composition based on total body nitrogen, potassium and calcium. Am J Physiol 1980;239: E524–E530. Fukagawa NK, Minaker KL, Rowe JW, Goodman MN, Matthews DE, Bier DM, Young VR: Insulin-mediated reduction of whole body protein breakdown. Dose-response effects on leucine metabolism in postabsorptive men. J Clin Invest 1985;76:2306–2311. Cuttica CM, Castoldi L, Gorrini GP, Peluffo F, Delitala G, Filippa P, Fanciulli G, Giusti M: Effect of six month administration of GH to healthy elderly subjects. Ageing 1997;9:193–197. Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M, Grunfeld C: Growth hormone replacement in healthy elderly men improves body composition but not functional ability. Ann Intern Med 1996;124:708–716. Herndon DN, Barrow RE, Kunkel KR, Broemeling L, Rutan RL: Effects of recombinant human GH on donor-site healing in severely burnt children. Ann Surg 1990;212:424–431. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH: GH treatment in GH-deficient adults. 1. Effects on muscle mass and strength. J Appl Physiol 1991;70:688–694. Knox JB, Wilmore DW, Demling RH, Sarrat P, Santos AA: Use of GH for postoperative respiratory failure. Am J Surg 1996;171:576–580. Van den Berghe G, de Zegher F, Vanhaecke J, Verleden G, Lauwers P: GH as a rescue treatment after heart-lung or double lung transplantation. Endocrinol Metab 1994;1:187–190. Pichard C, Kyle U, Chevrolet J-C, Jollier P, Slosman D, Mensi N, Temler E, Ricou B: Lack of effects of recombinant GH on muscle function in patients requiring prolonged mechanical ventilation: A prospective, randomized, controlled study. Crit Care Med 1996;24:403–413. Lee PD, Pivavnik JM, Bukar JG, Muurahainen N, Berry PS, Skolnik PR, Nerad JL, Kudsk KA, Jackson L, Ellis KJ, Gesundheit N: A randomized, placebo-controlled trial, of combined IGF-I and low dose GH therapy for wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 1996;81:2968–2975. Waters D, Danska J, Hardy K, Koster F, Qualls C, Nickell D, Nightingale S, Gesundheit N, Watson D, Schade D: GH, IGF-I and combination therapy in AIDS-associated wasting. A randomized, double blind placebo controlled trial. Ann Intern Med 1996;125:865–872.
C. Botfield, MD, Department of Anaesthetics, St. Bartholomew’s Hospital, London EC1A 7BE (UK) Tel. +44 171 601 7525, Fax +44 171 601 7526
Botfield/Hinds
200
............................
Subject Index Acquired immunodeficiency syndrome hypogonadism 142 hyponatremia and management 49 Acromegaly, see Growth hormone Adrenocorticotropic hormone cytokine regulation 113, 114 immune system integration 113–115 stress response acute stress 116, 117 adrenal steroidal adaptation 120–122 biphasic changes following surgical intervention 117–119 overview 112, 113 sepsis 120, 125 Alanine, gluconeogenesis 8 Androgens, see also Dihydroepiandrosterone sulfate, Testosterone brain adaptation to hyponatremia 37 replacement therapy in hypogonadism 145, 146 Angiotensin II, thirst regulation 32, 33 Antidiuretic hormone cerebral effects 35, 36 diabetes insipidus pathogenesis 40–43 receptors 35 secretion 35 stimuli for release 36, 37 syndrome of inappropriate secretion of antidiuretic hormone 36, 37, 50 thirst regulation 32, 33 Atrial natriuretic peptide, brain adaptation to hyponatremia 37 Brain cell volume regulation, sodium and water roles 38, 39
hypernatremia adaptation 53, 54 hyperosmolality response 39, 40 hyponatremia brain damage 43, 51, 52 hormone roles in adaptation androgens 37 antidiuretic hormone 36, 37 atrial natriuretic peptide 37 estrogen 37 progesterone 37 Burns cortisol response 120 dihydroepiandrosterone sulfate response 119, 120 glucose metabolism response 16–19 Calcitonin calcium metabolism role 68, 82, 83 procalcitonin levels in critically ill patients 82, 83 Calcium growth hormone therapy effects on metabolism 183 intracellular levels and signal transduction 68, 69 measurements of metabolism direct 69 parathyroid hormone 69, 70, 74–76 prognostic markers in critically ill patients 76, 77 serum levels, see also Hypercalcemia, Hypocalcemia albumin binding 68, 69 hormonal regulation calcitonin 68, 82, 83 parathyroid hormone 68
201
Calcium, serum levels (continued) stability 67, 68 supplementation in critically ill patients 77, 78 Citrate blood transfusion, hypocalcemia association 72 Congestive heart failure, hyponatremia and management 48 Cori cycle, lactate recycling 7, 8 Corticotrophin-releasing hormone cytokine regulation 113, 114 hypogonadism role 136, 138 immune system integration 113–115 stress response acute stress 116, 117 biphasic changes following surgical intervention 117–119 overview 112, 113 sepis 120, 125 Cortisol, see Glucocorticoid 5-Deiodinase type I assay 95 cofactor availability in nonthyroid illness and starvation 95, 96 cytokine regulation 97 drug effects on activity 97, 98 synthesis in nonthyroid illness and starvation 97 Diabetes insipidus antidiuretic hormone deficiency 40–43 causes 42, 43 diagnosis 40, 41 thirst response 41 types 41, 42 Dihydroepiandrosterone sulfate adrenal steroidal adaptation to stress 122 burn response 119, 120 Donnan equilibrium, solute distribution in body fluids 30 Estrogen brain adaptation to hyponatremia 37 replacement therapy in hypogonadism 144, 146 sex hormone-binding globulin association 134
Subject Index
Euthyroid sick syndrome, see Thyroid hormone Extracellular fluid electrolyte concentrations 29, 30 homeostasis 28, 29 volume estimation 29 Follicle-stimulating hormone hypogonadism diagnosis men 135 women 136 levels in critically ill patients 138, 140 normal physiology men 132 women 134 Free fatty acids, growth hormone regulation 167–169 Free water clearance, overview 31 Glucocorticoid cortisol stress response acute stress 116, 117 adrenal steroidal adaptation 120–122 biphasic changes following surgical intervention 117, 118 burns 120 direct measurement 115, 116 overview 112, 113 sepsis 120, 125 dose response trials 2 growth hormone regulation 165, 166 therapy effects 183 levels in disease 111 receptors modulation in disease 111, 115 signaling 112, 113 therapy in critical illness 123, 124 Glucose metabolism critical illness response burn injury 16–19 glucose oxidation 13 hepatic glucose output glycerol contribution 12 lactate recycling role 11, 12 overview 10, 11, 17 insulin and glucose infusion 20, 21
202
mediators cytokines 15, 16, 18, 22 hormones 14, 15, 20, 23 microcirculation alterations 16 models for study 21, 22 nutritional therapy 19–21 overview 13, 14 peripheral glucose uptake 12, 13 phentolamine therapy 20 sepsis 16–19 fasting response amino acid gluconeogenesis 8 glucose uptake, peripheral decrease 6, 7 glycerol gluconeogenesis 9 hepatic glucose output 7 lactate metabolism 7 feeding response 6 growth hormone regulation 167 therapy effects 183 hormonal control 10 ketone body production 9 normal fast/feed cycle 5, 6 Glutamate, gluconeogenesis 8 Glycerol gluconeogenesis 9 hepatic glucose output contribution in critical illness 12 Growth hormone binding protein 154, 177 forms 153 half-life 153, 154 history of study 152 insulin-like growth factor mediation of effects 155, 156 levels in disease acromegaly 168,169 critical illness and acquired resistance 111, 170, 179, 180 growth hormone deficiency 168, 169 resistance 170 processing 153 pulsatile secretion 156, 157, 177 receptor 154
Subject Index
regulation of levels aging effects 159–161 cyclic AMP 153 developmental regulation 159, 160 exercise 158 free fatty acids 167–169 glucocorticoids 165, 166 glucose 167 insulin-like growth factor I 165, 166, 177 neural control 161, 163–165 nutrition effects 159 obesity effects 160 Pit-1 153 releasing hormone 161, 163, 164 sex differences 166 sleep 157, 158 thyroid hormone 166, 169, 170 therapy anabolic properties 180–182 combination therapy with IGF-I 187, 189–191 dose and frequency of administration 182 functional improvement assessment 191, 192 indications 171 route of administration 182 side effects 182–185 Hypercalcemia, late development in intensive care unit 78, 79 Hypernatremia aging effects 40, 55 brain adaptation 53, 54 causes 54 clinical manifestations 54, 55 definition 52, 53 essential hypernatremia 55, 56 liver disease association 56 morbidity and mortality 55 postoperative hypernatremia 58 treatment 56–58 Hypocalcemia etiology citrate blood transfusion 72 magnesium abnormalities 72, 73
203
Hypocalcemia, etiology (continued) parathyroid hormone deficiency or resistance 72–74 sepsis 73 vitamin D deficiency or resistance 72–74 natural course in critically ill patients 70, 71 parathyroid hormone levels in critically ill patients 74–77 prevalence 70 Hypodipsia, diagnosis 34 Hypogonadism causes acquired immunodeficiency syndrome 142 cancer 141, 142 cardiovascular disease 143 drug induction 143, 144 endocrine disease 142 gastrointestinal disease 140, 141 liver disease 141 neurological disease 142, 143 renal disease 140 respiratory disease 139, 140 systemic lupus erythematosus 143 trauma 139 diagnosis clinical manifestations 134, 135 men 135 women 136 mechanisms in acute illness 136, 138, 139 treatment anabolic steroid treatment 145, 146 androgen replacement therapy 145, 146 complications 146 estrogen replacement therapy 144, 146 overview 143 Hyponatremia brain damage 43, 51, 52 causes acquired immunodeficiency syndrome 49 congestive heart failure 48 hepatic insufficiency 49, 50 malignancies 50 pharmacologic agents 48
Subject Index
polydipsia-hyponatremia syndrome 46–48 postoperative hyponatremia 44–46, 58 clinical manifestations 43, 44 free water clearance relationship 30, 31 hormonal roles androgens 37 antidiuretic hormone 36, 37, 50 atrial natriuretic peptide 37 estrogen 37 progesterone 37 incidence and prevalence 43 management 50–52 physical factors in brain adaptation 38 Hypothalamic-pituitary-adrenal axis, see also specific hormones adrenal insufficiency in critical illness 122, 123 clinical assessment 115, 116 glucocorticoid therapy in critical illness 123, 124 immune system integration 113–115 overview of function 110 stress response acute stress 116, 117 adrenal steroidal adaptation 120–122 biphasic changes following surgical intervention 117–119 burns 119, 120 overview 112, 113 sepsis 120, 125 Hypothalamo-pituitary-gonadal axis, see also specific hormones hypogonadism causes acquired immunodeficiency syndrome 142 cancer 141, 142 cardiovascular disease 143 drug induction 143, 144 endocrine disease 142 gastrointestinal disease 140, 141 liver disease 141 neurological disease 142, 143 renal disease 140 respiratory disease 139, 140 systemic lupus erythematosus 143
204
trauma 139 diagnosis clinical manifestations 134, 135 men 135 women 136 mechanisms in acute illness 136, 138, 139 treatment anabolic steroid treatment 145, 146 androgen replacement therapy 145, 146 complications 146 estrogen replacement therapy 144, 146 overview 143 normal physiology men 132–134 women 134 Hypothyroidism, see Thyroid hormone Insulin, see Glucose metabolism Insulin-like growth factors aging effects on levels 161 binding proteins IGFBP-1 179 IGFBP-3 178 overview 155, 178 growth hormone mediation of actions 155, 156 regulation of levels 165, 166, 177 receptors 155, 178 synthesis 155 types 154 Insulin-like growth factor-I therapy anabolic properties 185–187 combination therapy with growth hormone 187, 189–191 functional improvement assessment 191, 192 Interleukin-1, hypothalamic-pituitaryadrenal axis regulation in disease 113–115 Interleukin-6, hypothalamic-pituitaryadrenal axis regulation in disease 113–115 Intracellular fluid electrolyte concentrations 30 homeostasis 28, 29 volume estimation 29
Subject Index
Lactic acid Cori cycle 7, 8 fasting response 7 recycling in critical illness 11, 12 Leptin, levels in acute sepsis 115 Luteinizing hormone hypogonadism diagnosis men 135 women 136 levels in critically ill patients 138, 140, 141 normal physiology men 132 women 134 Magnesium abnormalities in hypocalcemia 72, 73 levels in critical illness 81, 82 measurement 70 supplementation in critically ill patients 82 Osmolality definition 31 effective osmolality, see Tonicity effective vs ineffective osmoles 31, 32 Parathyroid hormone calcium metabolism marker 69, 70, 74–76 role 68 deficiency or resistance in hypocalcemia 72–74 levels in critically ill patients 74–77 prognostic marker in critically ill patients 76, 77 Phentolamine, therapy during surgery 20 Phosphate levels in critical illness 79–81 measurement 70 supplementation in critically ill patients 81 Plasma, electrolyte concentrations 29, 30 Polydipsia-hyponatremia syndrome, causes and management 46–48 Progesterone, brain adaptation to hyponatremia 37
205
Protein catabolism critically ill patients 176, 177 growth hormone therapy effects 184 Pulmonary edema etiology 58, 59 incidence 58, 59 postoperative 59 Replacement therapy, see Androgens, Estrogen, Growth hormone, Insulin-like growth factors, Thyroid hormone Sepsis glucose metabolism response 16–19 hypocalcemia 73 leptin levels 115 Sex hormone-binding globulin estrogen binding 134 regulation of expression 133, 134 testosterone association 132, 133 Sodium, see Hypernatremia, Hyponatremia Systemic lupus erythematosus, hypogonadism 143 T3, see Thyroid hormone T4, see Thyroid hormone Testosterone sex hormone-binding globulin association 132, 133 therapy in hypogonadism 145, 146 3,3,55-Tetraiodothyronine (T4), see Thyroid hormone Thirst afferent stimuli 32 diabetes insipidus 41 hormone regulation angiotensin II 32, 33 antidiuretic hormone 32, 33 impaired regulation and diagnosis 34 Thyroid hormone growth hormone regulation 166, 169, 170 therapy effects 184 hypothyroidism tests Achilles reflex half-relaxation time 101 electrocardiogram 101 measurement 89, 90
Subject Index
serum binding proteins, alterations in disease 88, 89 supplementation in low T3 syndrome 102–104 T3 disease response 87, 88, 90 euthyroid sick syndrome 88 kinetics in nonthyroid illness and starvation 90, 91 pathophysiology of low levels in nonthyroid illness and starvation T4 to T3 conversion, inhibition 95–98 T4 uptake in liver, inhibition 93–95 receptors in disease 101 reverse kinetics and pathophysiology in nonthyroid illness and starvation 91, 92, 98 tissue effects of low T3 syndrome 99, 101 T4 disease response 87–89 kinetics in nonthyroid illness and starvation 90, 91 pathophysiology of abnormalities in nonthyroid illness and starvation 92, 93 thyroid-stimulating hormone, role in abnormalities of nonthyroid illness and starvation 98, 99 Thyroxine (T4), see Thyroid hormone Tonicity homeostasis 31, 32 hypotonic vs hypertonic 32 Total body water, factors affecting 29 3,3,5-Triiodothyronine (T3), see Thyroid hormone Tumor necrosis factor-, hypothalamicpituitary-adrenal axis regulation in disease 113–115 Uremia, brain volume response 39, 40 Vasopressin, see Antidiuretic hormone Vitamin D, deficiency or resistance in hypocalcemia 72–74
206
