Nutrition in Gastrointestinal and Liver Diseases (Special Issue: Digestive Diseases 2003, 3)

Nutrition in Gastrointestinal and Liver Diseases Editors Christos Dervenis, Athens Herbert Lochs, Berlin 12 figures, ...

Author: C. G. Dervenis | Herbert Lochs

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Nutrition in Gastrointestinal and Liver Diseases Editors

Christos Dervenis, Athens Herbert Lochs, Berlin

12 figures, 18 tables, 2003

Basel 폷 Freiburg 폷 Paris 폷 London 폷 New York 폷 Bangalore 폷 Bangkok 폷 Singapore 폷 Tokyo 폷 Sydney

S. Karger Medical and Scientific Publishers Basel 폷 Freiburg 폷 Paris 폷 London New York 폷 Bangalore 폷 Bangkok Singapore 폷 Tokyo 폷 Sydney

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2003 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7657–9

Vol. 21, No. 3, 2003

Contents

196 Editorial Lochs, H. (Berlin); Dervenis, C. (Athens)

252 Sugar Intake, Taste Changes and Dental Health

in Crohn’s Disease Schütz, T.; Drude, C.; Paulisch, E.; Lange, K.-P.; Lochs, H. (Berlin)

Review Articles

258 Serum Mineral Levels in Children with Intestinal

198 What We Have Learned about Cachexia in

Gastrointestinal Cancer Palesty, J.A.; Dudrick, S.J. (Waterbury, Conn.) 214 Nutritional Support in Acute Pancreatitis Avgerinos, C.; Delis, S.; Rizos, S.; Dervenis, C. (Athens) 220 Nutrition and Inflammatory Bowel Disease: Its

Relation to Pathophysiology, Outcome and Therapy Gassull, M.A. (Badalona) 228 Factors Enhancing Intestinal Adaptation after

Bowel Compensation Botsios, D.S.; Vasiliadis, K.D. (Thessaloniki) 237 Helicobacter pylori Infection, Vitamin B12 and

Homocysteine. A Review Dierkes, J.; Ebert, M.; Malfertheiner, P.; Luley, C. (Magdeburg)

Parasitic Infection Olivares, J.L.; Fernández, R.; Fleta, J.; Rodríguez, G.; Clavel, A. (Zaragoza) 262 Impact of Body Mass Index on Fasting Blood Glucose

Concentration among Helicobacter pylori Carriers Kyriazanos, I.D.; Sfiniadakis, I.; Dimakos, P.; Gizaris,V.; Datsakis, K.; Dafnopoulou, A. (Athens) 266 Selenium Is Depleted in Crohn’s Disease on Enteral

Nutrition Kuroki, F.; Matsumoto, T.; Iida, M. (Fukuoka City) 271 L-Carnitine in the Treatment of Mild or Moderate

Hepatic Encephalopathy Malaguarnera, M.; Pistone, G.; Astuto, M.; Dell’Arte, S.; Finocchiaro, G.; Lo Giudice, E.; Pennisi, G. (Catania) 276 Fructose Breath Hydrogen Test – Is It Really

a Harmless Diagnostic Procedure? Müller, P. (Leisnig/Leipzig); Meier, C.; Böhme, H.J.; Richter, T. (Leipzig)

Original Papers 245 Prevalence of Malnutrition in Hospitalized Medical

Patients: Impact of Underlying Disease Pirlich, M.; Schütz, T.; Kemps, M.; Luhman, N.; Burmester, G.-R.; Baumann, G. (Berlin); Plauth, M. (Dessau); Lübke, H.J.; Lochs, H. (Berlin)

279 Screening for Iron Overload in the Turkish Population Barut, G.; Balci, H. (Istanbul); Bozdayi, M. (Ankara); Hatemi, I.; Ozcelik, D.; Senturk, H. (Istanbul)

286 Author Index and Subject Index

© 2003 S. Karger AG, Basel Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/ddi_issues

Editorial Dig Dis 2003;21:196–197 DOI: 10.1159/000074105

Malnutrition – The Ignored Risk Factor Herbert Lochs Christos Dervenis

Nutritional therapy, once a cornerstone of medical treatment, has lost its attractivity in favor of drug treatment, molecular genetic interventions or other high-tech therapies. As a consequence, data about nutritional status or dietary habits are missing in many patient charts. This development reflects the opinion of many doctors that nutrition does not greatly affect the course of diseases, and that nutritional intervention is laborious but much less effective than other forms of therapy. In view of this trend, it seems interesting to analyze the importance of nutrition in different dieseases. Of course, it is well accepted that nutrition is an important factor for the therapy and prognosis in several diseases, such as diabetes mellitus, hyperlipidemia, obesity or hemochromatosis. However, the most basic nutritional disturbance – malnutrition – is frequently ignored since it is considered as a complication of the disease process, with little bearing on the prognosis and little possibility for therapeutic intervention. However, an analysis of the literature reveals that malnutrition is an independent risk factor in many disease processes and that treatment of malnutrition can indeed improve the patients’ prognosis. Such an analysis has to address several questions, mainly the prevalence and diagnosis of malnutrition and its impact on the patients’ prognosis. It should set the stage for the papers in this issue of Digestive Diseases, which deals with nutritional questions.

Prevalence and Diagnosis of Malnutrition in Hospitalized Patients An evaluation of the nutritional status of hospitalized patients in different countries shows a prevalence of malnutrition between 20 and 60% of admitted patients (table 1). The prevalence is not different among different countries; however, a subgroup analysis showed that geriatric patients as well as patients with malignant diseases carry the highest risk of becoming malnourished. The parameters used do diagnose malnutrition varied considerably in the different studies. In older studies, usually static parameters of the nutritional status, like body mass index or anthropometric measurements, were used. However, later on, it became clear that body composition reflecting the percentage of lean body mass, water

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Accessible online at: www.karger.com/ddi

and fat, or indices including dynamic parameters, like weight loss or a stress factor, do correlate better with the patients’ prognosis than plain body weight or body mass index. From these studies, several nutritional indices have been developed which allow conclusions about the prognosis and might therefore be used to define patients with an indication for nutritional therapy. The subjective Global Assessment (SGA) is one of the most widely used nutritional indices [1]. It consists of a patient history part (recent weight loss, changes in eating habits, gastrointestinal symptoms, physical fitness and stress factor) and a physical examination (body weight, subcutaneous fat mass, muscle atrophy, edema). The subjective global assessment is easy to calculate and therefore convenient to use in a clinical setting. A similar index (NRS 2002) has recently been developed by the European Society of Parenteral and Enteral Nutrition [2]. It also includes a patient history (weight loss, reduced dietary intake) physical parameters (body mass index) and a disease severity factor. Like the SGA, it can be calculated quickly and is therefore useful in the clinical situation. It is important to mention that malnutrition does not necessarily correlate with a low body mass. Changes in body composition with an increased fat mass and decreased body cell mass pose a similar risk to the patient than overt malnutrition with reduced body mass, as has been shown in a recent investigation [3].

Impact of Malnutrition on Prognosis Malnutrition has a profound impact on a patient’s prognosis. Malnourished patients have a higher risk of postoperative complications when compared to well-nourished patients and a longer hospital stay [3–7]. Furthermore the long-term mortality of malnourished patients is much higher than that of comparable well-nourished patients [8]. This is particularly important since physicians in the hospital usually see the patient only for 7–10 days during his/her hospital stay. As has been shown in several studies, posthospital mortality is significantly increased in malnourished patients. The fact that this complication of malnutrition is developing so late explains why hospital physicians are not more aware of malnutrition-associated risks.

Prof. Dr. Herbert Lochs Universitätsklinikum Charité Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie Schumannstrasse 20/21, DE−10098 Berlin (Germany) Tel. +49 30 450 514021, Fax +49 30 450 514923, E-Mail [email protected]

Table 1. Prevalence of malnutrition in hospitalized patients Authors

n

Country

Bistrian et al. (1974) [12] 131 USA Bistrian et al. (1976) [13] 251 USA Hill et al. (1977) [14] 105 UK Weinsier et al. (1979) [15] 134 USA Coats et al. (1993) [16] 228 USA McWhirter and Pennington (1994) [17] 500 UK Cederholm et al. (1995) [6] 205 S Naber et al. (1997) [5] 155 NL Bruun et al. (1999) [18] 244 USA Edington et al. (2000) [19] 850 UK Waitzberg et al. (2001) [20] 4,000 Brazil Pirlich et al. (2003) [21] 803 Germany

Disease

Malnourished, %

surgery general medicine surgery general medicine general medicine

50 44 48 48 38

multidisciplinary geriatric internal medicine surgery multidisciplinary multidisciplinary multidisciplinary

40 20 45–62 39 20 20 22

However, there are also economic impacts of malnutrition during the hospital stay. Reilly et al. [9] calculated the patient costs of 771 hospitalized patients in Internal Medicine and Surgery. They defined malnourished patients on a history of weight loss, low albumin and total lymphocyte count as well as low body mass index. The median expenditures for malnourished patients amounted to USD 11,217 versus USD 7,660 for well-nourished patients. Robinson et al. [10]

prospectively calculated the expenses for 100 patients. Well-nourished patients had a median stay of 10 days whereas malnourished patients stayed for 16.6 days. The actual cost was USD 7,692 for the well-nourished and USD 16,691 for the malnourished patients. On a DRG basis, payment from well-nourished patients was USD 4,352 and USD 5,124 for malnourished patients. This clearly shows that malnutrition is not just a risk for the patient but also a financial risk for the hospital. A study by Braunschweig et al. [11] who followed the expenses for 404 patients who were hospitalized for more than 7 days is especially interesting. Patients were divided into a reference group which had not lost weight during their hospital stay and a group who lost weight independently of their initial nutritional status. The control group generated an average expenditure of USD 28,631, whereas the group who lost weight generated an average expenditure of USD 45,762. This issue of Digestive Diseases is devoted to nutritional problems. A number of papers deal with problems of malnutrition in different diseases. Besides the prevalence of malnutrition in hospitalized patients, questions concerning the impact of malnutrition in gastrointestinal cancer and acute pancreatitis as well as inflammatory bowel disease are discussed. Furthermore, nutritional therapy has proved to be effective not just as treatment of preexisting malnutrition but also to influence disease processes, as has been shown in inflammatory bowel disease, hepatic encephalopathy and other gastrointestinal diseases. By raising their attention to nutritional problems, doctors will hopefully increasingly again include nutritional therapy in patient care.

References 1 Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeeboy KN: What is subjective global assessment of nutritional status? JPEN J Parenter Enteral Nutr 1987;11:8–13. 2 Kondrup J, Allison SP, Elia M, Vellas B, Plauth M: ESPEN guidelines for nutrition screening 2002. Clin Nutr 2003;22:415–421. 3 Kyle UG, Pirlich M, Morabia A, Lochs H, Schuets T, Pichard C: Abnormal body composition is associated with increased length of hospital stay: A controlled population study in Switzerland and Germany, submitted to Clinical Nutrition. 4 Selberg O, Böttcher J, Tusch G, Pichlmayr R, Henkel E, Müller MJ: Identification of highand low-risk patients before liver transplantation: A prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 1997;25:652–657. 5 Naber TH, Schermer T, de Bree A, Nusteling K, Eggink L, Kruimel JW, Bakkeren J, van Heereveld H, Katan MB: Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications. Am J Clin Nutr 1987;66:1232–1239. 6 Cederholm T, Jagren C, Hellstrom K: Outcome of protein-energy malnutrition in elderly medical patients. Am J Med 1995;98:67–74. 7 Detsky AS, Baker JP, O’Rourke K, Johnston N, Whitwell J, Mendelson RA, Jeejeeboy KN: Predicting nutrition-associated complications

Editorial

8

9

10

11

12

13

14

for patients undergoing gastrointestinal surgery. JPEN J Parenter Enteral Nutr 1987;11: 440–446. Pirlich M, Schütz T, Gastell S, Lochs H: Malnutrition affects long-term prognosis in hospitalized patients. Gastroenterology 2002;122: 363. Reilly JJ Jr, Hull SF, Albert N, Waller A, Bringardener S: Economic impact of malnutrition: A model system for hospitalized patients. JPEN J Parent Enteral Nutr 1988;12:371–376. Robinson G, Goldstein M. Levine GM: Impact of nutritional status on DRG length of stay. JPEN J Parenter Enteral Nutr 1987;11:49–51. Braunschweig C, Gomez S, Sheean PM: Impact of declines in nutritional status on outcomes in adult patients hospitalized for more than 7 days. J Am Diet Assoc 2000;100:1316– 1322. Bistrian BR, Blackburn GL, Hallowell E, Heddle R: Protein status of general surgical patients. JAMA 1974;230:858–860. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Maylor J: Prevalence of malnutrition in general medical patients. JAMA 1976;235:1567– 1570. Hill GL, Blackett RL, Pickford I, Burkinshaw L, Young GA, Warren JV, Schorath CJ, Morgan DB: Malnutrition in surgical patients. An unrecognized problem. Lancet 1977;i:689– 692.

Dig Dis 2003;21:196–197

15 Weinsier RL, Hunker EM, Krumdieck CL, Butterworth CE Jr: Hospital malnutrition. A prospective evaluation of general medical patients during the course of hospitalization. Am J Clin Nutr 1979;32:418–426. 16 Coats KG, Morgan SL, Bartolucci AA, Weinsier RL: Hospital-associated malnutrition: A reevaluation 12 years later. J Am Diet Assoc 1993;93:27–33. 17 McWhirter JP, Pennington CR: Incidence and recognition of malnutrition in hospital. BMJ 1994;308:945–948. 18 Bruun LI, Bosaeus I, Bergstad I, Nygaard K: Prevalence of malnutrition in surgical patients: Evaluation of nutritional support and documentation. Clin Nutr 1999;18:141–147. 19 Edinton J, Boorman J, Durrant ER, Perkins A, Giffin CV, James R, Thomson JM, Oldroyd JC, Smith JC, Torrance AD, Blackshaw V, Green S, Hill CJ, Berry C, McKenzie C, Vicca N, Ward JE, Coles SJ: Prevalance of malnutrition on admission to four hospitals in England. The Malnutrition Prevalance Group. Clin Nutr 2000;19:191–195. 20 Waitzberg DL, Caiaffa WT, Correia MI: Hospital malnutrition: The Brazilian National Survey (IBRANUTRI): A study of 4,000 patients. Nutrition 2001;17:573–580. 21 Pirlich M, Schütz T, Kemps M, Luhman N, Burmester GR, Baumann G, Plauth M, Lübke HJ, Lochs H: Prevalence of malnutrition in hospitalized medical patients: Impact of underlying disease. Dig Dis 2003;21:245–252.

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Review Article Dig Dis 2003;21:198–213 DOI: 10.1159/000073337

What We Have Learned about Cachexia in Gastrointestinal Cancer J.A. Palesty S.J. Dudrick St. Mary’s Hospital, Yale University Affiliate, Department of Surgery, Waterbury, Conn., USA

Key Words Cancer W Cachexia W Cancer cachexia syndrome W Malnutrition W Anorexia W Gastrointestinal cancer

Abstract It is appreciated widely by clinicians that significant malnutrition accompanies malignant processes in approximately 50% of patients and eventually leads to severe wasting which accounts for approximately 30% of cancer-related deaths overall, 30–50% of deaths in patients with gastrointestinal tract cancers, and up to 80% of deaths in patients with advanced pancreatic cancer. The body wasting known as cancer cachexia is a complex syndrome characterized by progressive tissue depletion and decreased nutrient intake that is manifested clinically as inexplicable, recalcitrant anorexia and inexorable host weight loss. Decreased nutritional intake, increased metabolic expenditure and dysfunctional metabolic processes, including hormonal and cytokine-related abnormalities, all appear to play roles in the development of cancer cachexia. Although this condition of advanced protein-calorie malnutrition, sometimes described as the cancer anorexia-cachexia syndrome, is not entirely understood, it appears to be multifactorial, is a major cause of morbidity and mortality in cancer patients, and ulti-

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mately leads to death. Therapeutic interventions have met with little success, and, regardless of tremendous efforts throughout the decades, the exact nature of the mediators responsible for cancer cachexia remain elusive. The pathogenesis of cancer cachexia appears to be related to proinflammatory cytokines, alterations in the neuroendocrine axis and tumor-derived catabolic factors. Despite trials of conventional and/or aggressive nutritional support by a myriad of feeding techniques, patients with cancer cachexia have failed to gain consistent significant benefits in terms of weight gain, functional ability, quality of life or survival. Additionally, attempts to ameliorate the abnormal clinical and metabolic features of cancer cachexia with a variety of pharmacologic agents have met with only limited success. Either until cancer of the gastrointestinal tract can be cured or until it is possible to identify the exact causes and mechanisms of the cancer cachexia syndrome, the most realistic and practical options currently are directed toward minimizing adverse gastrointestinal side effects or complications of the malignant process and/or therapy, as well as increasing appetite, food intake and nutrient utilization in an effort to enhance quality of life and improve survival. Copyright © 2003 S. Karger AG, Basel

Stanley J. Dudrick, MD, FACS St. Mary’s Hospital, Yale University Affiliate Department of Surgery, 56 Franklin Street Waterbury, CT 06706 (USA) Tel. +1 203 5746479, Fax +1 203 5975877, E-Mail [email protected]

Introduction

Cachexia results from the inexorable and recalcitrant progression of nutritional deterioration, which occurs in approximately 50% of patients with malignant disorders, and in about 80% of patients with cancers involving the upper gastrointestinal tract. It is among the most debilitating and life-threatening aspects of cancer, and results in body mass wasting that accounts for up to 30% of cancerrelated deaths [1]. Clinically, the cancer cachexia syndrome is characterized primarily by anorexia, early satiety, wasting, weight loss, weakness, fatigue, poor mental and physical performance, decreased capacity for wound healing, impaired immunologic function, and a compromised quality of life, none of which are resolved by forced nutrient intake [1, 2]. Diminished nutritional intake, increased metabolic expenditure and disordered or malfunctioning metabolic processes, including hormonal and cytokine-related abnormalities, all appear to play roles in the development of cancer cachexia [1, 3]. Although this condition of advanced protein-calorie malnutrition, frequently referred to as the cancer anorexia-cachexia syndrome, is not entirely understood, it appears to be multifactorial, it is a major cause of morbidity and mortality in cancer patients, and it ultimately leads to death [3, 4]. The origin of the word cachexia is both descriptive and incriminating. It is derived from the Greek words kakos, meaning bad, and hexis, meaning condition, habit or state of being [2, 3]. Cancer cachexia was first reported as a commonly occurring syndrome more than 70 years ago, when an autopsy series of 500 cancer patients documented that the immediate cause of death in cancer patients was secondary to inanition in 114 (22%) of the patients, and that up to two-thirds of this cadre of patients exhibited some degree of cachexia [5]. Since then, the scope of malnutrition in the cancer patient has been studied in a wide variety of patient groups. In a series of 3,047 patients enrolled in Eastern Cooperative Oncology Group (ECOG) chemotherapy protocols and who were all assessed for weight loss before initiating chemotherapy, survival was significantly lower in the patients who demonstrated weight loss when compared with those who had not lost any weight prior to starting chemotherapy [6, 7]. In this study group, patients with breast cancer or sarcomas had the lowest frequency of weight loss (31–40%), patients with colon cancer had an intermediate frequency of weight loss (48– 61%), and patients with pancreatic or gastric cancer had the highest frequency of weight loss (83–87%), with about one-third of these patients having presented initially with

What We Have Learned about Cachexia in Gastrointestinal Cancer

greater than 10% weight loss [6, 7]. In a prospective study of 280 cancer patients, malnutrition was related predominantly to tumor type and site, with stomach and esophageal cancer patients demonstrating significantly higher degrees of malnutrition compared with the other groups. Moreover, as expected, malnutrition was shown to increase in severity as the disease advanced [8]. In another study of 365 patients with gastrointestinal cancer, almost 50% were shown to be malnourished. The incidence of malnutrition was related to the site of the disease, and the stage of the disease was identified as a predictor of weight loss, with over 50% of stage III patients manifesting malnutrition [9]. Although nutritional status is usually evaluated by a combination of clinical assessment and anthropometric tests, including body weight, skin-fold thickness and midarm circumference, most clinicians rely on body weight as the major measure of nutritional status, using usual adult body weight as a point of reference [2]. Cachexia should be expected if an involuntary or unexpected weight loss of greater than 5% has occurred within a previous 6-month period, especially when combined with muscle wasting. A weight loss of 10% or more ordinarily indicates severe depletion, but can also be used as a starting criterion for the anorexia-cachexia syndrome in obese patients. Body compartment analysis has shown that patients with cachexia lose approximately equal amounts of fat and fat-free mass. Losses of fat-free mass occur primarily from skeletal muscle and reflect decreases both in cellular mass and intracellular potassium concentration [2, 10]. Cancer patients with documented 5% weight loss have a shorter median survival rate than patients with stable weight, respond poorly to chemotherapy, and experience increased toxicity to chemotherapy [2, 7, 11]. How does cancer cachexia compare with other conditions associated with weight loss, such as the anorexia which may occur in uncomplicated starvation, or that following a major injury or accompanying sepsis? Usually, the non-cancer patient with acute starvation initially develops rapid breakdown of protein from lean body mass, amino acid mobilization, gluconeogenesis and increased excretion of nitrogen in the urine. These early responses to the stressful stimulus are altered subsequently by the body to conserve protein and energy. Addition of a major injury or sepsis to simple starvation, or to the presence of a tumor, compounds the situation by increasing the rate and duration of the catabolic response, and the associated high rate of tissue breakdown may persist for quite some time [12]. The patient with cancer cachexia exhibits fea-

Dig Dis 2003;21:198–213

199

Table 1. Nutritional problems associated with the development of

cancer cachexia (adapted from Shils [14]) 1 Anorexia and early satiety with progressive weight loss and undernutrition 2 Altered taste or dysgeusia causing hypophagia, food aversion or altered food intake 3 Alterations in protein, carbohydrate and fat metabolism 4 Increased energy expenditure despite decreased body mass 5 Impaired food intake secondary to: A. Mechanical obstruction of the gastrointestinal tract at any level B. Intestinal dysmotility induced by various tumors 6 Malabsorption secondary to: A. Deficiency or inactivation of pancreatic digestive enzymes B. Deficiency or inactivation of bile salts C. Failure of ingested food to mix and interact effectively with digestive enzymes D. Intestinal fistulas – internal and/or external E. Infiltration of the small bowel wall or lymphatics and mesentery by malignant cells F. Blind loop syndrome with associated bacterial overgrowth G. Malnutrition-induced villous hypoplasia in the small intestine 7 Protein-losing enteropathy 8 Metabolic abnormalities induced by tumor-derived eutopic hormones or peptides A. Hypoglycemia induced by insulin-secreting tumors B. Hyperglycemia induced by islet glucagonoma or somatostatinoma C. Hypercalcemia and hypophosphatemia with osteomalacia induced by parathyroid hormone-like polypeptides secreted by some tumors D. Anemia secondary to chronic blood loss and/or bone marrow suppression 9 Electrolyte and fluid derangements secondary to: A. Persistent vomiting and intestinal obstruction or intracranial tumors B. Intestinal fluid losses through fistulas or diarrhea C. Intestinal secretory abnormalities with hormone-secreting tumors such as: a) Carcinoid syndrome b) Zollinger-Ellison syndrome (gastrinoma) c) Verner-Morrison syndrome (VIPoma) d) Villous adenoma e) Increased calcitonin D. Inappropriate antidiuretic hormone (ADH) secretion associated with specific tumors such as lung carcinomas E. Hyperadrenalism secondary to tumors producing corticotropins or corticosteroids 10 Miscellaneous organ dysfunction with nutritional complications such as intractable gastric ulcers with gastrinomas, Fanconi’s syndrome with light-chain disease, or coma with brain tumors 11 Tumor products stimulating monocyte production of various interleukins

200

Dig Dis 2003;21:198–213

tures of both starvation and injury. However, in the cancer patient, not only is food intake usually inadequate, but the presence of the malignant tumor may decrease the ability of the patient to regulate the response to starvation. Cancer cachexia is more likely to resemble the condition produced by a major injury or sepsis than cachexia secondary to simple starvation [13]. In addition to the multiple effects of cancer on the nutritional status of the patient, the antineoplastic therapies currently in use can have adverse effects contributing to the cachexia of the patient. Understanding the multiple nutritional, metabolic and physiologic changes that can occur provides the basis for evaluating the requirements for nutritional support in various clinical situations and for planning and providing support as indicated. Although a localized tumor may exert various initial systemic and generalized effects in a patient, as the tumor grows and metastasizes, these effects often become even more obvious as a result of the increased tumor burden and its local and distant invasion. Additionally, some malignant tumors can produce effects at a distance from the original tumor or its metastases, further compounding malnutrition [14]. The nutritional problems associated with neoplastic disease which can cause or contribute to the development of cancer cachexia are outlined in table 1.

Metabolic Pathophysiology of Cancer Cachexia [3]

Inability to gain and/or maintain weight despite seemingly adequate nutrient intake could be due to at least these obvious possibilities: (1) increased metabolic needs generated by the accentuated nutritional demands of the semiautonomous tumor; (2) generalized increased energy expenditure in the cancer patient; (3) maladaptive metabolism, i.e., failure of the cancer patient’s host tissues to utilize the nutrients available efficiently and effectively to satisfy the energy requirements of the body [3]. Although malignant cells do have their own specific nutrient requirements and do expend energy, it has been shown that this fact does not fully explain the cancer cachexiaanorexia syndrome in human cancer patients [15]. Therefore, it is important to differentiate data reported in animal tumors, which tend to represent a much larger proportion of the total body weight of the organism, from data reported with human tumors which generally represent a much smaller proportion of the weight of the host.

Palesty/Dudrick

Many studies of resting energy expenditure (REE) and basal energy expenditure have been performed to establish whether cancer patients are hypermetabolic [15]. These studies have demonstrated that approximately 60% of cancer patients have abnormal REE, of which approximately 35% are hypometabolic, and 25% are hypermetabolic. A confounding aspect of these studies is that lean body mass, rather than total body mass, correlated with alterations found in measured REE. Thus, cancer patients, who ordinarily have early diminished lean body mass, may be expected to have energy expenditure levels which are low for their total weight, and what appears to be hypometabolism, may really represent a eumetabolic state. Despite this non-standard interpretation of REE data in cachectic cancer patients, it appears that although hypermetabolism of the host and/or tumor plays a role in cancer cachexia, hypermetabolism does not suffice as a complete explanation of the cancer cachexia syndrome. For convenience and understanding, maladaptive metabolism may be separated into metabolism of carbohydrate, and fat, which are obviously intimately interrelated [16]. The most apparent precipitating event of maladaptive metabolism in the cachectic cancer patient is decreasing blood glucose or a tendency toward hypoglycemia, which results both from hypermetabolism of the tumor and the host tissues, together with decreased nutrient intake related to anorexia hypophagia or the anatomic or physiologic changes produced by malignant cells of various origins. In normal starving human beings in whom decreased nutrient intake is the principal factor, an immediate increase in glucose production as well as in protein synthesis and breakdown occurs as a compensatory mechanism. This self-preserving adjustment can occur because the body responds with an increase in use of fat-derived calories, primarily ketone bodies for energy production [3]. However, in cancer patients, this conservation of gluconeogenesis does not occur, but rather both protein breakdown and lipolysis occur at increasing rates in the process of maintaining high rates of glucose synthesis. Accordingly, the role of insulin in the cancer patient appears to become paramount at this point as a state of relative insulin resistance develops. The insulin resistance state, in turn, is characterized by a decreased uptake and use of glucose, predominantly in skeletal muscle, and a tendency toward gluconeogenesis and lipolysis [3]. The lipolytic component of insulin resistance is manifested by excess fatty acid oxidation which does not decrease even with increased fat or caloric intake. Additionally, as decreased nutrient intake and absorption occur in the

Table 2. Abnormalities of carbohydrate, protein, and fat metabolism associated with cancer cachexia (adapted from Shils [14])


Dig Dis 2003;21:198–213

Carbohydrate metabolism Glucose intolerance Insulin resistance Abnormal insulin secretion Impaired glucose clearance Increased glucose production Increased glucose turnover Increased Cori cycle activity Protein metabolism Increased whole body protein turnover Increased protein fractional synthesis rates in the liver Decreased fractional synthesis rates in muscle Increased hepatic protein synthesis Recalcitrant muscle protein breakdown Decreased plasma levels of branched-chain amino acids Fat metabolism Excess body fat depletion relative to body protein loss Increased lipolysis Increased free fatty acids Increased glycerol turnover Decreased lipogenesis Hyperlipidemia Failure of glucose to suppress oxidation of free fatty acids Decreased serum lipoprotein lipase activity despite normal insulin availability

cancer patient, increased rates of glycerol and free fatty acid turnover occur which ordinarily does not occur during adaptation in a non-tumor-bearing, otherwise healthy but starving individual. Moreover, in healthy patients, a glucose infusion suppresses lipolysis, but does not suppress lipolysis in cancer patients. Ultimately, the cancer patient depletes fat stores, develops hypertriglyceridemia and manifests decreased lipoprotein lipase levels. This results in failure of production of free fatty acids and monoacylglycerol, and subsequently, decreased adipocyte triglyceride synthesis, which depends upon free fatty acids [3]. A summary of the current status of the understanding of the metabolic maladaptation of the cancer patient to decreased nutrient intake and increased metabolic caloric needs of both the tumor and the host include: increased hepatic glucose production; failure of uptake of the gluconeogenic glucose by muscle, resulting in proteolysis and production of glycogenic amino acids; uptake and use of glucose by tumor cells with resulting lactate production and occasional lactic acidosis; and increased lipolysis with production of fatty acid and glycerol, ultimately used for

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energy and further gluconeogenesis (table 2). Thus, the nutritional requirements of the tumor are selectively favored over those of the host by these aberrant metabolic mandates in the cancer patient [3].

Pathogenic Mechanisms of Anorexia

The intake of energy substrates is significantly reduced among cancer patients who lose weight, and although anorexia is unlikely to be responsible solely for the wasting seen in cancer patients, it may be a substantial contributing factor [3, 16, 17]. Cancer patients, especially those with gastrointestinal cancer, may frequently suffer from physical obstruction of the alimentary tract, pain, constipation, maldigestion, malabsorption, debility, or the side effects of therapy, including opiates, radiotherapy, or chemotherapy, any of which may lead to decreased food intake [19, 20]. Additionally, hypercalcemia associated with cancer is a fairly common condition which can cause nausea, vomiting and weight loss as well as other untoward side effects. Moreover, anorexia is an extremely distressing syndrome because appetite and the ability to eat have been reported to be the most important factors in the physical and psychologic aspects (especially depression) of a patient’s quality of life [12, 21]. However, no clinical cause of reduced food intake is obvious in a large number of patients with cancer and cancer cachexia. The early satiety which accompanies reduced appetite in anorectic cancer patients has been postulated to be caused by the production of tumor cell factors that exert their effects by acting on hypothalamic sensory cells [38]. Possible factors include the satietins which have been purified from human plasma and found to consist of two extensively glycosylated glycoproteins. The larger molecule, satietin D, has been shown to produce a long-lasting anorectic effect when injected into rats, although its role in the development of anorexia has not been established. Another possible cause of anorexia is the increased serotonergic activity within the central nervous system of patients with cancer cachexia, attributed to the enhanced availability of tryptophan to the brain. A close relationship between elevated plasma-free tryptophan and anorexia has been observed in patients with cancer and reduced food intake [22]. The fact that uptake of tryptophan into the brain is competitive with uptake of branched-chain amino acids has suggested the use of BCAA to decrease the incidence of anorexia [22]. Because weight loss is such a potent stimulus to food intake in healthy human beings, the persistence of anorexia in cancer patients implies a failure of

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this adaptive feeding response, which is so impressive in normal human beings [23–26]. A hormone secreted by adipose tissue, leptin, is now known to be an integral component of the mechanism for body weight recognition [19, 27–34]. Because weight loss causes leptin levels to fall in proportion to the loss of body fat, it appears that leptin plays an important role in triggering the adaptive response to starvation [2]. The activity of the hypothalamic orexigenic signals that stimulate feeding and suppress energy expenditure are increased by low leptin levels in the brain, which also decrease the activity of anorexigenic signals that suppress appetite and increase energy expenditure [2, 23–26]. In experimental animals that are fasted, most of the orexigenic signals are known to be up-regulated, suggesting that these signals play an important role in facilitating the recovery of lost weight. It appears that neuropeptide Y (NPY) produced in the hypothalamus binds to a receptor (Y-5) in adjacent hypothalamic cells, which in turn increases the response of additional NPY and stimulates the neuronal basis of appetite [3]. It has further been shown that leptin also binds to Y-5, inhibiting NPY activity and producing satiety [35]. Recently, glucagon-like factor 1 and urocortin have also been shown to be appetite suppressants [3, 36, 37]. The cancer anorexia syndrome may result from circulating factors produced by the tumor or by the host in response to the tumor, and several cytokines have been proposed as possible mediators of the cachectic process [19]. Elevated serum levels of tumor necrosis factor-·, interleukin (IL)-1, and IL-6 have been found in some, but not all cancer patients, and the serum levels of these cytokines appear to correlate with the progression of the tumor [38–40]. Interferon-·, interferon-Á and leukemiainhibitory factor are additional cytokines which have been postulated to play a role in the etiology of cancer cachexia, but which have not been proven to be responsible solely for the induction of cachexia [38]. However, chronic administration of these cytokines, either alone or in combination, is capable of reducing food intake and reproducing the cancer anorexia-cachexia syndrome [19, 38–43]. These cytokines may produce long-term inhibition of appetite and feeding by stimulating the production and release of leptin and/or by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, leading to the normal compensatory mechanisms for decreases in food intake and body weight [18, 19, 23– 29, 34, 39, 44–46]. Thus, the weight loss which occurs in cancer patients obviously differs considerably from that which occurs in simple starvation in otherwise healthy human beings.

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Melanocortins, a family of regulatory peptides, which include adrenocorticotropin (ACTH) and the melanocyte-stimulating hormones, have recently been reported as potential contributory factors in anorexia and cachexia [2, 47–49]. This group of peptides and their receptors are important in memory, behavior and immunity, but also help to regulate appetite and body temperature [19, 31– 33]. In animal studies, the melanocortin system remained active during cancer-induced cachexia, whereas the normal response to marked loss of body weight would have resulted in down-regulation of the anorexigenic melanocortin-signaling system in order to conserve energy stores. Moreover, blockade of the melanocortin receptor reversed the anorexia and cachexia in the animals, suggesting a pathogenetic role for this system [19, 47–49]. The specific roles and the relative importance of the various factors in the cancer anorexia-cachexia syndrome remain to be clarified. It is presumed that anorexia is caused by the same mediator or mediators that also produce the metabolic derangements of cancer cachexia itself. Use of antianorectic agents alone may improve quality of life in the cancer patient, but may not solve the problem of anorexia and its associated morbidity and mortality in cancer patients [16]. The role of hormones in the cancer anorexia-cachexia syndrome must be considered because of the obvious role that hormones play in the intermediary metabolism of carbohydrates [50]. Insulin, epinephrine, ACTH, human growth hormone, and insulin-like growth factor have all been suggested to have a role in the anorexia-cachexia syndrome. During early starvation, decreased insulin levels and increased glucagon and epinephrine result in activation of cyclic adenosine monophosphate and of a protein kinase that activates hormone-sensitive lipase. Failure of this normal mechanism may account for the weight loss in cancer patients who have increased rates of glycerol and free fatty acid turnover compared with starved healthy patients [16]. Recent studies have indicated the presence of an acidic peptide in animal tumors which appears to have lipolytic properties that could lead to some of the characteristics of the cancer cachexia syndrome [16, 51]. This factor appears to be a proteoglycan which has been found in the urine of murine species with tumors as well as in human patients with cancer anorexia-cachexia syndrome involving weight loss of 11.4 kg [16, 52]. In animals, this proteoglycan has been shown to mobilize free fatty acids from adipose tissue, and amino acids from muscle, which prompted the investigators to suggest that the role of these tumor products is to mobilize nutrients for which the

tumor has the greatest affinity and which will result in further increased tumor growth. Investigations are currently underway to determine whether this proteoglycan is widely present in cachectic human cancer patients and whether its pathophysiologic actions mimic those of the cancer anorexia-cachexia syndrome [3]. A potentially clinically useful feature of this research is the discovery of an antagonist (eicosapentaenoic acid) of this proteoglycan which could have a role in the treatment of the human anorexia-cachexia syndrome [16, 53]. It is highly likely that multiple mediators rather than a single mediator probably account for the metabolic and pathophysiologic abnormalities associated with the anorexia-cachexia syndrome. It is possible, indeed likely, that tumor cells produce multiple active peptides or glycopeptides; that they also stimulate the induction of additional cytokines or lymphokines from host immune cells; and that they stimulate abnormal hormonal responses to the metabolic stress induced by the malignancy. It is unlikely that a single factor could account for the hypermetabolism, abnormal glucose metabolism, protein gluconeogenesis and insulin resistance, in addition to the anorexia, anemia and fever that accompany the cancer anorexia-cachexia syndrome.


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Dysfunctional Gastrointestinal Manifestations

As a result of the malignant disease and/or its treatment, abnormalities can occur in the mouth or elsewhere in the gastrointestinal tract and may interfere with ingestion of food [19]. Aberrations of taste and smell have also been documented in cancer patients [54, 55]. Altered capacity to recognize and taste sweetness in foods occurs in more than one-third of patients, whereas bitterness, sourness, and saltiness are less frequently encountered in cancer patients [56, 57]. Decreased threshold for recognition of bitter taste correlates well with meat aversion, and other aversions to specific foods may be learned or developed secondary to unpleasant experiences that coincide with exposure to a particular food [54]. This usually occurs in cancer patients in association with chemotherapy [58]. It appears that these changes in taste and smell correlate with decreased nutrient intake, poor response to therapy, and tumor progression including metastasis [57]. The roles of other factors in the etiology of cachexia require clarification, including zinc deficiency, alterations in brain neurotransmitters, and opioid peptides that affect taste and nutrient selection [2, 39, 54, 58]. Direct involvement in the gastrointestinal tract or its accessory

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Table 3. Nutritional problems secondary to gastrointestinal cancer therapy (adapted from Shils [14])

I. Radiation therapy A. Radiation of the oropharynx 1. Impairment or destruction of taste; xerostomia and odynophagia; loss of teeth B. Radiation of lower neck and mediastinum 1. Esophagitis with dysphagia 2. Fibrosis with esophageal stricture C. Radiation of abdomen and pelvis 1. Acute and chronic intestinal damage with diarrhea, malabsorption, stenosis, obstruction, and fistula formation II. Surgery therapy A. Radical resection of oropharyngeal structures 1. Chewing and swallowing difficulties B. Esophagectomy 1. Gastric stasis and hypochlorhydria secondary to vagotomy 2. Steatorrhea secondary to vagotomy 3. Diarrhea secondary to vagotomy 4. Early satiety 5. Reflux and/or regurgitation C. Gastrectomy (total or near total) 1. Dumping syndrome 2. Malabsorption 3. Achlorhydria and lack of intrinsic factor 4. Hypoglycemia 5. Early satiety D. Intestinal resection 1. Jejunum a) Decreased efficiency of absorption of many nutrients 2. Ileum a) Vitamin B12 deficiency b) Bile salt malabsorption with diarrhea or steatorrhea c) Hyperoxaluria and renal stone formation d) Calcium and magnesium depletion e) Fat and fat-soluble vitamin malabsorption 3. Massive bowel resection a) Life-threatening malabsorption (short bowel syndrome) b) Malnutrition c) Metabolic acidosis d) Dehydration 4. Ileostomy and/or colostomy a) Complications of salt and water balance and homeostasis E. Blind loop syndrome 1. Vitamin B12 malabsorption F. Pancreatectomy 1. Malabsorption 2. Diabetes mellitus

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III. Pharmacologic therapy A. Corticosteroids 1. Fluid and electrolyte imbalance 2. Nitrogen and calcium losses 3. Hyperglycemia B. Sex hormone analogue 1. Fluid retention 2. Nausea 3. Glucocorticoid effects secondary to megestrol acetate C. Immunotherapy 1. Tumor necrosis factor a) Fluid retention b) Hypotension c) Nausea and vomiting d) Diarrhea 2. Interleukin-2 a) Hypotension b) Fluid retention c) Azotemia 3. Interferons a) Anorexia b) Nausea and vomiting c) Diarrhea d) Azotemia D. Cytotoxic chemotherapy 1. Nausea and vomiting 2. Mucositis and stomatitis 3. Diarrhea 4. Abdominal pain or cramping 5. Hepatotoxicity 6. Gastrointestinal bleeding with anemia 7. Anorexia 8. Weight loss 9. Inhibition of protein synthesis 10. Inhibition of purine and pyrimidine synthesis 11. Inhibition of DNA synthesis, replication and transcription 12. Inhibition of various metabolic processes

digestive organs by tumors can cause problems with digestion and nutrient absorption, and subsequently lead to malnutrition and cachexia [2]. Odynophagia and/or dysphagia occur most commonly in patients with cancers of the head and neck and esophagus, and tumors elsewhere in the gastrointestinal tract and the hepatobiliary tract are often complicated by partial or total obstruction of the digestive tract, causing nausea and/or vomiting [55]. Metastatic cancers from other systems to the gastrointestinal tract can also cause, or contribute to, similar problems by extrinsic pressure on the gastrointestinal tract structures. Although satiety signals from the gastrointestinal tract help to regulate appetite and food intake, early satiety is a

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characteristic of cachectic cancer patients, even without direct involvement of the gastrointestinal tract, and may be associated with increased activity of proinflammatory cytokines including IL-1ß, and centrocorticotropic-releasing factor (CRF), which is a potent anorexigenic factor [19, 60, 61]. Changes in gastrointestinal motility observed during stress suggest that CRF may be involved as the triggering signal [2]. CRF may also induce the delayed gastric emptying and gastric stasis observed not only in cancer patients, but in non-neoplastic conditions such as infection and anorexia nervosa [2, 54, 62, 63]. These abnormal gastrointestinal effects may result in early satiety and may have a negative influence on food intake. Another major cause of malnutrition leading to anorexia-cachexia syndrome occurs concomitantly with anticancer therapies [54, 56]. Nausea, vomiting, abdominal cramping, bloating, mucositis and paralytic ileus can all accompany chemotherapy. Fluorouracil, adriamycin, methotrexate and cisplatin are among the many antineoplastic agents that may induce severe gastrointestinal complications [64]. Because enterocytes are rapidly dividing cells, they are more susceptible to the cytotoxic effects of both chemotherapy and radiotherapy than most other cells in the body. Erosive lesions that can occur at various levels of the digestive tract, resulting in the impairment of food intake, digestion and nutrient absorption, can be caused by both chemotherapy and radiotherapy [2]. Consequences of cancer treatment predisposing to nutritional problems are listed in table 3.

Nutritional Support with Cancer Cachexia

Early studies promoted optimism that judicious enteral or parenteral nutritional support might overcome cancer anorexia, and modulate or obviate malnutrition and cancer cachexia [19, 65–67]. However, the failure of aggressive nutritional support to increase lean body mass, especially skeletal muscle mass, in the patient with cancer cachexia has been disappointing. In a meta-analysis of 28 randomized studies of cancer patients receiving total parenteral nutrition (TPN), the use of TPN preoperatively in patients with gastrointestinal cancer helped to reduce major surgical complications and operative mortality significantly, but no significant benefit was shown on survival, tolerance of treatment, toxicity, or tumor response in patients receiving chemotherapy and TPN [68]. A survey analyzing results individually for patients receiving radiation therapy and chemotherapy and for patients undergoing major surgery, concluded that the routine use of pre-


operative intravenous feeding should be limited to patients unable to sustain lean body mass by oral or enteral feeding [69]. The authors stated further that intravenous feeding had not been documented to affect responses either to therapy or survival favorably in patients receiving radiation therapy or chemotherapy. However, they also affirmed that selecting patients for support with TPN remains a matter of clinical judgment, and that when therapy response rates and nutritional morbidity are high, intravenous feeding should be instituted until the host can recover from the effects of antitumor therapy [69]. The authors concluded additionally that there is clear evidence that in individual patients with cancer, intravenous feeding can prevent death from starvation and decrease the morbidity of treatment, but only those patients undergoing surgery for gastrointestinal tract neoplasia have benefited significantly from the addition of adjuvant intravenous feeding [69]. Another subsequent review concluded that chronically malnourished patients given nutritional support often have restoration of a sense of wellbeing and become more physically functional; however, whether this support results in long-term clinical benefits is difficult to evaluate [70]. The authors stated also that it appears that routine application of nutritional support to all patients undergoing treatment for malignancy is not justified, and that the primary indication for nutritional support is for the malnourished patient undergoing a major operation for upper gastrointestinal malignancy, and for the chemotherapy patient with severe gastrointestinal dysfunction [70]. In another analysis of 18 trials in children with cancer, the author acknowledged the clear benefits of nutritional support in patients undergoing a bone marrow transplantation; however, there appeared to be little support for the routine aggressive nutritional support in the non-surgical oncology patient [71]. Nonetheless, the author concluded further that circumstances exist in which aggressive nutritional support by any and all routes should be provided, especially during prolonged inability to eat, when nutrition is secondary to poor intake, when a nutrition support team is available to decrease related complications, and when the tumor present is deemed likely to respond to antineoplastic treatment [71]. Additionally, parenteral nutrition may facilitate administration of complete chemoradiation therapy dosages in esophageal cancer patients and may have beneficial effects for certain patients with decreased food intake because of mechanical obstruction of the gastrointestinal tract [72–74]. Home parenteral nutrition can also be efficacious and rewarding for such patients [2]. If the gastrointestinal tract can be used for nutritional sup-

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port, enteral nutrition has the advantage of maintaining the integrity of the enterocytes, the mucosal barrier, and immunologic function, as well as the advantage of having lower cost and fewer adverse side effects [2, 54, 74]. Some surveys of the effectiveness of ineffectiveness of nutritional support in cancer patients have emphasized survival as an important criterion [14]. On this matter, several points merit consideration. First, most surveys did not include survival data, thus leaving only a relatively small number of patients in this category. Second, if malignancies such as metastatic esophageal, stomach, colon and lung cancers do not respond well to any known antitumor treatments, why should nutritional support be expected to help such patients beyond delaying death and perhaps improving the quality of life in some patients in whom starvation existed to varying degrees? Finally, the clinician or investigator interested in the subject of efficacy of nutritional support in cancer cachexia should review the published meta-analysis and also the original trial reports together with other reviews that provide evidence of the value of many cases of improved nutrition for appropriate patients with cancer cachexia [14, 75, 76]. There is much more to be learned about the metabolism of cancer patients with progressive disease, and such knowledge will likely lead to improvements in nutritional support as more effective antineoplastic therapies are also developed [14]. The effects of aggressive nutritional support on tumor growth and development have been difficult to delineate in cancer patients and are still being debated [2, 77]. However, a clear benefit of nutritional support may be derived in cancer patients with severe malnutrition who may require surgery or may have an obstructing, but potentially responsive tumor to therapy [2, 55, 73, 78]. Experience has also indicated that the cancer patient with a severely dysfunctional alimentary tract resulting from radiation, chemotherapy, surgery or combination thereof, but who is free of residual malignant disease, is entitled to proper management by oral, enteral, and/or parenteral feeding support which can lead to a prolonged life of good quality [14]. Finally, controversy remains regarding the influence of aggressive nutritional support on the quality of life of patients with advanced cancer, and it is very important to consider the risks, benefits and ethical aspects involved before beginning such a regimen. Physician attitudes, patient age and prognosis, and family or patient’s perceptions often play important roles in the decision to administer nutritional support, and these variables will continue as issues during the patient’s course [79].

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The best treatment for cancer cachexia, especially that related to cancer of the gastrointestinal tract, is to cure the cancer. Unfortunately, this lofty goal remains an infrequent achievement currently among patients with solid tumors. Since a cure for cancer is still under investigation and forthcoming, the best palliative or therapeutic metabolic options available are to stimulate increased nutritional intake and ameliorate or prevent the catabolism of muscle and fat. This can be accomplished to varying degrees with a multitude of pharmacologic agents. However, a goal as monumental as this would be much easier to achieve if it were possible to identify the exact causes and mechanisms of the cancer anorexia-cachexia syndrome. Currently, only those elements of decreased food intake directly related to the antineoplastic treatment, such as nausea, vomiting, mucositis and dysfunctional gastrointestinal motility, can be somewhat controlled or modulated clinically. The most realistic and practical options at this time are directed toward minimizing adverse gastrointestinal side effects or complications and increasing appetite and nutritional intake in an effort to improve quality of life. Several types of drugs which have been commonly employed in attempts to improve appetite, food intake, sense of well-being and body weight gain, include progestational drugs, corticosteroids and antiserotonergic drugs. Additionally, a newer group of drugs is under investigation primarily because of their effects on tumor necrosis factor-·, or their effects on muscle metabolism. These and other agents now present the possibility of confronting this recalcitrant syndrome from a different approach and an opportunity for combined therapeutic endeavors to improve the quality of life of these patients [80].

Progestational Agents

In many patients who were originally receiving progestational drugs as part of a multimodal antineoplastic treatment regimen, notable increases in appetite and significant body weight gain occurred. These empirically derived findings prompted controlled trials to study these agents specifically regarding their ability to increase appetite in patients with cancer anorexia-cachexia and perhaps promote weight gain as well. Megestrol acetate (Megace) has been the most widely used and studied drug in this category, and its effects on increasing appetite, caloric intake and weight gain has been shown to be dose related, in doses ranging from 160 to 1,600 mg, with an optimal dosage of about 800 mg/day [80, 81]. Generally, patients

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are started on the lowest effective dosage (160 mg/day), and the dose is increased according to the clinical response of the patient to the drug [80, 82]. Studies using medroxyprogesterone acetate have also been associated with a significant increase in appetite together with increases in serum thyroid binding prealbumin (transthyretin) and retinal binding protein without any concomitant changes in body weight, functional performance status, or anthropometric measurements [80, 83]. On the other hand, a controlled multicenter study comparing medroxyprogesterone with a placebo demonstrated significantly approved appetite and body weight (but not quality of life) in the experimental group versus the control group in advanced-stage, non-hormone sensitive cancer [80, 84]. A combination of megestrol and prednisone was shown to improve appetite significantly better, compared with those patients given a placebo while receiving radiation therapy [85]. Moreover, megestrol was significantly better as an appetite stimulant than prednisone or fluoxymesterone [80]. The data comparing megestrol with dexamethasone as appetite stimulant remain to be clarified [80, 86]. The possible mechanisms of action of progestational drugs is unclear, but may be related to their glucocorticoid activity. Currently suggested explanations for their effectiveness include stimulation of NPY, modulation of calcium channels in the ventromedial hypothalamus, and hindrance of the activity of cytokines, including TNF, IL-1 and IL-6 [80, 87–89]. Concerns with the use of either megestrol or medroxyprogesterone are centered on the associated side effects including induction of thromboses and thromboemboli, breakthrough uterine bleeding, hypertension, hyperglycemia, peripheral edema, alopecia, Cushing syndrome, adrenal suppression and adrenal insufficiency [80, 90– 93]. However, these adverse effects have been encountered only rarely in most clinical trials [80, 94–97]. On the other hand, caution must be taken in administering these drugs to patients with known thromboembolic disease, heart disease or high risk for fluid retention [2, 78].

Glucocorticoids

Although appetite stimulants, including corticosteroids, have been of some value in patients with low nutrient intakes, they have not proven to be as useful in patients with major metabolic abnormalities or cancer anorexia-cachexia syndrome. Corticosteroids have been


shown to increase the sense of well-being and to alleviate anorexia and asthenia in cancer patients; however, their effects diminish appreciably after 3–4 weeks. Although several randomized, controlled clinical studies have demonstrated the symptomatic benefits of some of the different corticosteroids, most reports have indicated a limited beneficial effect on appetite, food intake, sense of wellbeing and performance for up to 4 weeks [2, 82, 98–103]. Corticosteroids also have a significant antinausea effect and can improve asthenia and pain control in some patients; however, no lasting positive effect on body weight has been observed. Moreover, prolonged corticosteroid administration has a negative effect on protein synthesis, thus neutralizing potential benefits of increased appetite. Additionally, prolonged corticosteroid treatment may result in weakness, delirium, osteoporosis and immunosuppression, compounding these adverse side effects, which are frequently already present in patients with advanced cancer [2, 104]. Prednisolone and dexamethasone have been shown to improve appetite to a greater extent than a placebo, and methylprednisolone may improve quality of life; however, no compelling evidence exists to indicate the superiority of any one glucocorticoid in stimulating appetite [2, 20, 78, 100]. Although the exact mechanism of action of these drugs on appetite is unclear, some studies indicate that the corticosteroids inhibit prostaglandin metabolism and inhibit the synthesis or release of the cytokines IL-1 and TNF-·, which, in turn, theoretically decrease appetite through their action on NPY, leptin, CRF and serotonin [2, 20, 78, 100]. At this time, no definitive evidence exists to support an explanation for the exact mechanism of action of corticosteroids in stimulating appetite in cancer anorexiacachexia patients.

Anabolic Steroids

Although anabolic steroids have been shown to be effective among athletes and other healthy people in gaining muscle mass, they have not been shown to achieve this benefit in gastrointestinal cancer patients [80, 106]. On the other hand, nandrolone has been shown to increase weight gain in a group of lung cancer patients by increasing protein synthesis via the androgen receptor. However, this is the only study that has demonstrated any usefulness of anabolic steroids in the treatment of cancer patients [2, 107].

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Antiserotonergic Drugs

Cyproheptadine is an antiserotonergic drug with antihistamine actions which have been useful in the symptomatic relief of rhinitis, conjunctivitis and pruritis associated with allergic reactions, which has also been useful as an appetite stimulant in anorexia nervosa [80]. Although cyproheptadine did not prevent progressive weight loss in patients with advanced cancer, it was successful as a mild appetite stimulant in a randomized controlled study [2, 82, 103, 108]. Because evidence suggests that anorexia may be mediated by increased serotonergic activity in the brain, its blockade by cyproheptadine might mediate an antianorexia effect [2, 109, 110]. However, its primary side effect is sedation, which might limit its usefulness in advanced cancer patients [80, 108]. Granisetron and odansetron, which are often used as antiemetics during chemotherapy, are additional serotonin receptor inhibitors that have been used in the cancer anorexia-cachexia patient as antagonists to the satiating effect of serotonin [2, 111]. Although these agents have failed to promote weight gain in trials to date, they have been noted to improve the patients’ ability to enjoy food [2, 112]. Additional investigations in cancer anorexiacachexia patients are required to define the role of these and other antiserotonergic mediators in stimulating appetite.

Metabolic and Physiologic Modulators

Branched-chain amino acids may modulate the peripheral muscle proteolysis which occurs in cancer cachexia by providing protein-sparing substrate for both muscle metabolism and gluconeogenesis [2, 104]. When used in TPN solutions, the branched-chain amino acids have been shown to improve protein accretion and albumin synthesis while improving nitrogen balance [2, 113]. Moreover, oral supplementation of branched-chain amino acids has been used successfully to decrease the severity of anorexia in cancer patients, theoretically, by competing with tryptophan, the precursor of brain serotonin, thus blocking increased hypothalamic activity of serotonin [2, 110, 111]. Following studies in animals, which demonstrated that eicosapentaenoic acid inhibited lipolysis and muscle protein degradation in a cachexia model, patients with pancreatic cancer who received supplements of fish oil exhibited decreased fatigue and a slight body weight gain as well as a reduction of acute-phase proteins during a

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3-month study [115]. In other studies in cachectic cancer patients, the inclusion of eicosapentaenoic acid in the diet significantly increased weight gain, lean body mass, performance status and survival, the latter unexpected result occurring in both the weight-losing and non-weight-losing groups of patients [116, 117]. Gastroparesis and gastrointestinal dyskinesia are recognized complications of cancer cachexia which can cause anorexia, nausea, early satiety and constipation, leading to impaired food intake [2, 118]. Because many patients with advanced cancer have delayed gastric emptying and gastroparesis, prokinetic agents such as metoclopramide have been used in cancer patients to prevent or ameliorate the emesis associated with chemotherapy and may alleviate anorexia and early satiety with minimal side effects [2, 54, 82, 119]. Other prokinetic agents such as domperidone and erythromycin require additional controlled randomized studies to define their roles in treatment of cancer cachexia patients [2, 63, 104].

Other Potentially Useful Drugs

Because hydrazine sulfate inhibits phosphoenol-pyruvate carboxykinase, an integral enzyme in gluconeogenesis, it was hypothesized that by interrupting the Cori cycle and normalizing carbohydrate metabolism, this agent might be useful in improving appetite, caloric intake and nutritional status in cachectic cancer patients [2, 20]. However, several large studies showed that this drug has no significant impact on weight gain or any other benefit in patients with advanced colorectal cancer [120–122]. Increased survival times, improved appetite and increases in caloric intake and serum albumin levels have been reported with the use of hydrazine sulfate in some studies, but these favorable effects have not been confirmed by others [79]. Because of the lack of definitive studies showing consistent efficacy, together with the significant risk of neurotoxicity associated with its use, this drug has not gained popularity with oncologists [2, 80]. Thalidomide has been shown to decrease the activity of TNF-· through cytokine modulation in cancer patients, in addition to improving insomnia, restlessness and nausea in advanced cancer patients, while improving appetite and sense of well-being in the majority of patients studied [2, 80, 123]. Side effects of thalidomide include fever, skin rash and peripheral neuropathy in addition to its well-known teratogenic effects [80, 124, 125]. Melatonin, a hormone produced by the pineal body, has promoted increased weight gain and increased appe-

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tite in patients with advanced cancer in association with its ability to decrease levels of circulating TNF-· [2, 80, 126]. A study of 100 patients with metastatic carcinoma showed that weight loss of more than 10% was a much less common finding among patients receiving melatonin than among the patients receiving a placebo [2, 80, 126]. Pentoxifylline is a methylxanthine-derived phosphodiesterase inhibitor which has been shown to decrease TNF-· synthesis in cancer patients by decreasing gene transcription [80, 127, 128]. However, its use in a controlled trial of cancer patients with solid tumors elicited no increase in appetite or body weight gain compared with the controls [80, 129]. 5-Deoxy-5-fluorouridine, a fluorinated pyrimidine nucleoside, is a cytostatic agent which has been shown to decrease the progression of cachexia in an animal model by inhibiting IL-6 and proteolysis-inducing factor [2, 130, 131]. Although this agent decreased the progression of tumor growth, it did not demonstrate preservation of body weight even though it ameliorated progressive weight loss and hyperglycemia while increasing the production acute phase proteins [2, 130]. Cannabinoids are well-known appetite stimulants which can promote weight gain. Marijuana and its derivatives, dronabinol, marinol and nabilone have shown their effectiveness as antiemetics in cancer patients especially those receiving chemotherapy [2, 78, 102–104]. A number of studies have demonstrated improved appetite after administration of cannabinoids; however, minimal improvement in overall body weight was achieved [2, 132, 133]. Limitations of these agents as potential appetite stimulants include their adverse effects on the central nervous system such as somnolence, confusion and perceptual disturbances which may be augmented further in advanced cancer patients who often already exhibit some cognitive impairment [2, 80, 134, 135]. ß2-Adrenergic receptor agonists have been shown to prevent muscle protein wasting in tumor-bearing rats and to increase muscle mass and function significantly in nontumor-bearing rats [80, 136–140]. Even without changing food intake or rate of tumor growth, a recent study demonstrated that salbutamol, salmeterol and clenbuterol had a positive effect on muscle mass in tumor-bearing rats [141]. Although studies in human beings are limited, this class of drugs has been shown to improve muscle strength significantly following orthopedic surgery, even without the need for exercise. However, to date, no controlled studies have been reported using these agents in cancer patients [2, 142].

Non-steroidal anti-inflammatory drugs (NSAIDS) reduce circulating levels of IL-6, acute phase proteins and cortisol, which renders them useful in treating fever and pain in patients with advanced cancer [2]. In a series of colorectal cancer patients, ibuprofen was shown to normalize protein kinetics in cachectic patients and stabilize weight, while reducing REE and increasing quality of life in patients with pancreatic cancer [2, 143–146]. The main limitation of this class of drugs is their adverse effect on the gastrointestinal tract; however, recent studies into the efficacy of COX-2 inhibitors such as celecoxib and rofecoxib, which appear to have fewer and less severe gastrointestinal side effects, have indicated promising early results in their use as alternatives to the older NSAIDS.


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Commentary

In this review of cachexia associated with gastrointestinal cancer, we have attempted to summarize the more common metabolic abnormalities in the cachectic cancer patient, the theories proposed as explanations of these phenomena and the nutritional and pharmacologic interventions currently in use for amelioration of the severe host tissue depletion caused by this wasting syndrome. The metabolic pathophysiology of cancer cachexia has been reviewed, discussed and summarized, and the current status of the understanding of the metabolic maladaptation of the cancer patient to decreased nutrient intake and increased metabolic needs of both the tumor and the host has been outlined. The nutritional problems associated with the development of cancer cachexia have also been presented comprehensively with particular emphasis on the side effects and complications indigenous to cancers of the gastrointestinal tract. Additionally, the abnormalities of carbohydrate, protein and fat metabolism commonly associated with cancer cachexia have been outlined and discussed from historical, current and future perspectives. Moreover, the nutritional problems secondary to individual forms of antineoplastic therapy in specific regions of the gastrointestinal tract have been delineated extensively. The established and experimental nutritional and pharmacologic support options in the management of patients with cancer cachexia and advanced gastrointestinal cancer have been described briefly in an attempt to update their status as therapeutic adjuncts. The perplexing problem of cancer cachexia and anorexia is compounded in patients with malignancies of the gastrointestinal tract because not only are the usual

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cancer-associated mediators of cachexia and anorexia active in inducing weight loss, wasting and deterioration of functional status, but, the normal means by which nutrient intake is attained by the patient is compromised by direct involvement of the gastrointestinal tract anywhere from the mouth to the anus by tumor, thus interfering with the normal mechanisms favoring appetite, gustatory satisfaction, food intake, digestion, nutrient absorption and substrate assimilation. This ‘double jeopardy’ does not ordinarily occur with malignancies of other organ systems unless or until metastases compromise the gastrointestinal tract and its appendages secondarily. Thus, the increased metabolic expenditure and requirements imposed by the neoplastic process are less likely to be met by the gastrointestinal tract alone. Furthermore, curative and palliative therapies, including surgery, chemotherapy, radiotherapy and immunotherapy alone or in combination, impose an additional burden on an already crippled system.

Attempts to overcome this grave physical and functional handicap initially included parenteral nutritional supplementation and total parenteral nutrition; however, lack of uniform success in achieving optimal nutritional status, improvement of function, and increase in survival has been disappointing and challenging. Currently, the most promising therapeutic possibilities are dependent upon the continuing development of combinations of antineoplastic therapies, unique nutrient formulations, and pharmacologic agents designed to ameliorate the metabolic derangements induced by the tumor and its products. Obviously, the ultimate answer to this vexing situation is to assault the biology of the neoplastic process at its foundation and develop a cure for cancer.

Acknowledgment The authors greatly appreciate the many significant contributions of Joan Reeser in the preparation of the manuscript.

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Nutritional Support in Acute Pancreatitis Costas Avgerinos Spiros Delis Spyros Rizos Christos Dervenis 1st Department of Surgery, Konstantopoulion, Agia Olga Hospital, Athens, Greece

Key Words Acute pancreatitis W Gut barrier W Total parenteral nutrition W Enteral nutrition

Abstract Acute pancreatitis (AP), mainly the severe necrotizing type, results in extreme energy demands which might lead, if prolonged, to severe malnutrition. Besides that, starving during AP contributes to gut barrier dysfunction, the main cause of bacterial translocation and sepsis. The aim of nutritional support in AP is to prevent malnutrition and protect the gut by maintaining mucosal integrity. Traditionally, nutritional support during the acute phase of the disease has been provided through total parenteral nutrition (TPN) solutions. However, recent animal and human studies have identified new patterns of pancreatic secretion and hormonal stimulation during the course of AP, different from those assumed for years. Thus it has become feasible to use the natural enteral route for nutrition with potential benefits compared with TPN.

Acute pancreatitis (AP) is a disease with a wide spectrum of clinical courses, ranging from the mild form with minimum morbidity and almost zero mortality, to the severe form with a high percentage of complications and a high risk for a lethal outcome [1, 2]. The latter form is characterized by various degrees of necrosis of pancreatic parenchyma as well as local and systemic complications such as SIRS and MOF, representing a typical hypermetabolic septic model with high-energy consumption and protein breakdown that leads to severe malnutrition. On the other hand, the mild form of the disease is much less aggressive against body metabolism and is usually selflimited. Patient’s oral intake starts within 3–7 days after disease onset, resulting in minor and usually easily reversible nutritional defects. As a result, nutritional support by enteral feeding or total parenteral nutrition (TPN) should be one of the main therapeutic aims in AP, and nutritional management should depend on the underlying pancreatic disease form.

Malnutrition in Acute Pancreatitis

Copyright © 2003 S. Karger AG, Basel

Malnutrition during the clinical course of AP is a result of a combination of oral food intake restriction, increased energy demands and often preexisting nutritional defects (i.e. alcoholic malnutrition). All AP-pathogenetic factors

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Christos Dervenis, MD 1st Department of Surgery, Konstantopoulion Agia Olga Hospital, 3–5 Ag. Olgas str. GR–14233 Athens (Greece) Tel. +30 1 277 546, Fax +30 1 279 3969, E-Mail [email protected]

meet at a starting point where a common pattern leading to the clinical presentation of the disease begins. This pathway involves activation of trypsinogen to trypsin after which an activation cascade of various enzymes is started leading to pancreatic and peripancreatic tissue autodigestion. At the same time, liberations of acute phase reactants resulted in a hemodynamic response similar to that seen in sepsis syndrome (increased cardiac output, decreased peripheral resistance and increased oxygen consumption). This is accompanied by alterations in the carbohydrates, proteins and lipids metabolism. The disease and its complications are also associated with the release of cytokines (IL-1, IL-6, IL-8, TNF, PAF), activation of the compliment and creation of arachidonic acid metabolic products. These energy-consuming biochemical alterations in parallel with reduction of food intake result in a negative energy balance and a rapid loss of lean body mass which adversely affects the host’s defenses and immune competence [3]. Non-suppressive gluconeogenesis is observed in severe pancreatitis and net protein catabolism can rise to 40 g nitrogen/day as opposed to normal subjects where glucose supply cannot inhibit that phenomenon completely [4, 5]. In 80% with severe AP complicated by sepsis, a marked increase in resting energy expenditure is observed and using the Harris-Benedict equation total energy expenditure is 1.49 times the predicted resting energy expenditure [6, 7].

Under physiologic conditions the entry of nutrients into the duodenum results in a burst of pancreaticobiliary digestive secretions that mix with the nutrients in order to be exposed to the small intestine mucosa. It has been shown that up to 70–80% of nutrients are absorbed from the lumen as proximal as the duodenojejunal junction [12, 13]. The rest remains unabsorbed within the small intestine. This physiologic malabsorption is believed to act as an energy and amino acid supply to the mucosa of small and large intestine [14] with regard to fat, amino acids and carbohydrates in different proportions [14– 17]. Enteral feeding support in AP aims to avert negative nitrogen balance, to protect gut barrier function and therefore prevent secondary pancreatic infection. The rationale behind the concept of enteral feeding is that there is at least some evidence that it is important in restoring and might prevent morphological changes in the intestine associated with starvation. Lack of nutrients in the gut lumen leads to loss of mucosal integrity as a result of a decrease of mucosal thickness [18]. Enteral feeding can also reverse the reduction in hilus height occurring after TPN and theoretically can play an important role in the management of severe AP as it probably prevents sepsis and immune failure.

Pathophysiology of Pancreas in Acute Pancreatitis Pathophysiology of the Gut in Acute Pancreatitis

Contamination of pancreatic necrosis and consequent sepsis is the main cause of death in severe pancreatitis, although in the early period of the disease, SIRS remains the main fatal course [8]. Maintenance of gut integrity is of high priority in severe AP in order to prevent pancreatic necrosis contamination and preserve its immune function. Bacterial translocation through the gut wall is the prominently proposed mechanism for pancreatic necrosis contamination. In normal subjects the gut which represents the largest immune organ of the human body acts as a physiologic barrier against bacteria and endotoxins. Secretory IgA produced by gut lymphoid tissue prevents bacterial and viral adherence to the mucosa [9]. Experimental work in rats has shown that gut barrier function in the small intestine is compromised very early after the onset of AP. This observation has also been documented in humans [10, 11].

For many years to put the pancreas at rest in AP was considered as the best medical practice and the cornerstone of therapeutic manipulations. It was stated that by that way exacerbation of pancreatic inflammation and autodigestion would be avoided as the absence of content in stomach and duodenum diminish further production of pancreatic proteolytic enzymes [19]. The true clinical significance of that belief has been recently disputed. The three phases of exocrine pancreatic secretion (cephalic, gastric, intestinal) and the real pattern of pancreatic output proved to be different in AP. Pancreatic exocrine secretion is severely reduced early after the onset of AP and the cholecystokinin-stimulated secretion is abolished at the time of maximal histological damage to the pancreas [20]. Several experimental and clinical trials have shown that delivery of nutrients into the jejunum does not increase pancreatic secretion and is well tolerated with no increase in complications. More specifically, although administration of lipid in the duodenum is a strong stimula-

Nutritional Support in Acute Pancreatitis

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tory factor for pancreatic exocrine secretion, jejunal delivery of the same amount of lipids causes minimal pancreatic reaction [21–24]. Intravenous lipid infusion has minor effects as has been shown in human studies. Gastric or duodenal protein or carbohydrate administration is also a strong stimulus for pancreatic secretion, while as expected jejunal delivery of the same nutrients is harmless to the pancreas [25–31]. As there is no evidence that putting the pancreas at rest has any clinical benefit, this theory is strongly challenged nowadays [32] and enteral feeding has gained increasing acceptance for nutritional support in AP.

Energy Supply in Acute Pancreatitis

According to the ESPEN guidelines [33], a hypocaloric energy supply of 15–20 kcal/kg/day is more suitable during the early catabolic stage of non-surgical patients with MOF in AP. In non-severely ill patients, nutritional requirements can be resumed at approximately 25– 35 kcal/kg/day with 1.2–1.5 g protein/kg/day. Carbohydrates and lipids should be administered 3–6 and 2 g/kg/ day respectively, but care should be taken to avoid high blood glucose and triglyceride concentrations.

Total Parenteral Nutrition in Acute Pancreatitis

Traditionally, TPN has for many years been the only nutrient providing treatment in patients with AP and prolonged starvation. TPN achieves minimal exocrine pancreatic secretions as well as sufficient energy and protein provision. Since 1974, when Feller et al. [34] showed in an uncontrolled retrospective study a decrease in the mortality rate of patients who received intravenous hyperalimentation while suffering from AP, several other similar retrospective uncontrolled clinical trials have failed to reproduce the same results. On the contrary and despite differences in the parameters of the trials, other authors observed a higher incidence of catheter-related sepsis among TPN groups [35, 36] but no difference in total mortality [35–37]. Two prospective non-randomized trials have been published on that subject. In 1989, Sitzmann et al. [38] divided 73 patients with AP of various severities into three groups depending on their ability to tolerate glucose-free, lipid-based and lipidfree nutrition. Within 15 days, most patients in all groups achieved an improvement in nutritional status. A higher mortality rate was observed in the fat-free group as well as

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among patients with a persistent negative nitrogen balance. A high incidence of catheter sepsis was also documented. In 1991, Kalfarentzos et al. [39] divided 67 patients with severe AP (13 Ranson criteria) into two groups of early (within 72 h after admission) and late (after 72 h) onset of TPN. They noted a significantly lower incidence of complications and mortality in the early group but a high catheter sepsis incidence as well. Sax et al. [40] carried out the only randomized controlled trial on the effects of early parenteral nutrition versus no nutritional support in patients with AP. The two groups of patients (mean Ranson score 1) that received either conventional therapy alone or conventional therapy with TPN had no significant differences in length of hospital stay, number of days of oral intake and number of complications as well as a ninefold increase in the incidence of catheter sepsis in the TPN group. As a conclusion it can be stated that no strong level 1 information regarding the role of TPN in severe AP exists and more trials are needed in order to show any benefit. A trend for improvement of morbidity and mortality though is delineated in patients with severe pancreatitis – those with prolonged starvation and those who achieved a positive nitrogen balance.

Enteral Nutrition in Acute Pancreatitis

More recently, attention has been given to the possible role of the enteral route of delivering the necessary calories and nutrients. The rationale behind the concept of enteral feeding is that there is at least some evidence that is important in restoring and might help in preventing morphological changes in the intestine associated with starvation. As reported already, a lack of nutrients in the gut lumen leads to loss of mucosal integrity as a result of a decrease of mucosal thickness [32]. Enteral feeding also can reverse the reduction in villus height occurring after TPN. In an experimental model, rats with pancreatitis were infused with Ringer’s lactate solution for 48 h followed by parenteral or enteral nutrition until the 7th day. Results showed lower endotoxin levels, a more prominent villus height and T-cell levels in animals that received enteral nutrition compared with those that received TPN [41]. In theory, enteral nutrition could play an important role in the treatment of severe AP, as it probably prevents sepsis and immune failure. Since the mid-1980s, some clinical evidence from critically ill patients, especially those with severe injuries, has

Avgerinos/Delis/Rizos/Dervenis

shown that giving enteral nutrition very early could favorably alter the outcome. Moore et al. [42] studied 32 patients with severe trauma and compared early enteral nutrition with no nutritional intervention. They found a statistically significant difference in septic morbidity (9 vs. 29%). The first retrospective study for the effects of the enteral nutrition in patients with AP was published in 1973 by Voitk et al. [43], who demonstrated good tolerance and even beneficial effects of an elemental diet delivered in the stomach of 6 patients suffering from complicated pancreatitis. Kudsk et al. [44] and Parekh et al. [45] published their experiences on enteral feeding in retrospective studies, the former through feeding jejunostomies and the later through gastric catheters. In general, they demonstrated improvement of the nutritional status accompanied by successful resolution of complications, but in both studies enteral nutrition was commenced after the acute phase of pancreatitis. Simpson et al. [46] in a similar study published favorable results with nasoenteral feeding in 5 patients with acute alcoholic pancreatitis, while Nakad et al. [47] in a prospective uncontrolled study described their experience of early jejunal nutrition starting 36 h after admission. Recently, Eatock et al. [48] in a prospective uncontrolled study revealed the positive effects of gastric delivered nutrients in 26 patients with severe AP. Overall, all of these papers have proved that enteral nutrition can be started in patients with AP since it is a safe method of nutritional support, it is well tolerated and causes no aggravation of the disease. On the contrary, Powell et al. [49] published in 2001 the only randomized controlled study comparing 13 patients that received enteral nutrition within 72 h of disease onset with 14 others treated conventionally (nil by mouth). It was shown in this study that early enteral nutrition did not ameliorate the inflammatory response as demonstrated by a serum concentration of inflammatory response markers (CRP, IL-6, sTNFRI). Furthermore, abnormal intestinal permeability occurred more frequently in patients receiving enteral nutrition. Recently, five randomized controlled studies were published comparing enteral feeding (EN) with TPN. Kalfarentzos et al. [50] randomized 38 patients, all with severe AP, in two groups (EN vs. TPN). They found a significant reduction in total, including septic complications in the enteral feeding group. The cost was three times lower in EN than in TPN and they suggested the preferable use of EN in all patients with severe disease. The other study was from the UK [51], and 34 patients were also randomized in two groups (EN vs. TPN). In that

study, patients with moderate and severe disease were included. Patients who received enteral feeding fared better after 7 days with respect to Apache II score and CRP levels compared with the TPN group. The authors also reported an increase in serum IgM endotoxin core antibodies in the TPN group which remained unchanged in the EN group. The total antioxidant capacity was less in the former group. They concluded that patients on enteral nutrition were exposed to lower endotoxin levels, which was probably related to preserved host defense. More recently, Abou-Assi and O’Keefe [52] demonstrated earlier recovery, shorter hospital stay and shorter duration of nutritional support, better tolerance to restarting oral feeding and much cheaper costs for nutrition in the group of 17 enterally fed patients with AP compared with 16 patients who received TPN. Catheter-related sepsis and hyperglycemia necessitating insulin were significantly more common in the TPN group but overall mortality was no different. Olah et al. [53] compared conventional parenteral nutrition (48 patients) with early jejunal nutrition (41 patients) in 89 patients admitted with AP. The rate of septic complications, need for surgery, multiple organ failure and death was higher in the TPN group but differences were not statistically significant. Finally, another randomized controlled trial was published by a Scottish group [54] that studied the effect of early enteral nutrition on markers of the inflammatory response in predicted severe AP. Serum IL-6, tumor necrosis factor receptor I and CRP were used as inflammatory markers. Despite previous findings, the authors documented that early enteral nutrition did not ameliorate the inflammatory response in patients with severe AP compared with no nutritional intervention. A randomized study is under way by our group to try and identify the role of early enteral nutrition in severe AP compared with standard TPN in reducing the need for surgery in patients with predicted severe AP. We recently reported preliminary results (23 patients) where we showed that early enteral nutrition seems to reduce surgical interventions in the enteral nutrition group by reducing the incidence of sepsis (9 vs. 33%) [55]. Although the current practice is to use nasojejunal tubes, placed endoscopically or under radiographic screening, a recent study by the Glasgow group [48] showed that nasogastric feeding is usually possible in severe AP. They reported that this practice is safe, well tolerated and without any sign of clinical or biochemical deterioration. Another question that needs to be answered is the possible role of immune-enhanced enteral diets in severe AP


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[56]. There are a number of reports, mainly in severely injured patients, dealing with this aspect [56–58]. A metaanalysis [57] including 1,009 patients from 11 trials showed that immune-modulated regimens resulted in a significant reduction of infectious complications and length of hospital stay, but with no effect on survival. Only one study has dealt with the use of glutamine in AP, as a supplement in the standard TPN. They found that glutamine improves leukocyte activity and reduces proinflammatory cytokine release in AP. No conclusions can be drawn from these studies, but as it seems possible that immune-enriched diets could play a role, further trials are needed to clarify this issue.

Conclusions

At present there is no definite evidence that artificial nutrition support – either total parenteral or enteral – alters the outcome in most patients with AP, unless malnutrition is also a problem. Diagnosis of AP is not itself an indication for instituting artificial nutrition, unless severity of the disease is the case. Enteral nutrition support is safe, well tolerated and does not stimulate the pancreas compared with parenteral feeding, and therefore should be used preferably in the treatment or prevention of malnutrition and probably immunosuppression and infection, in patients with AP. Finally, larger, well-conducted trials, recruiting only patients with severe AP and stratifying them for disease severity, nutritional status and etiology of pancreatitis before randomization, are needed before any conclusive statement on the benefits of nutritional support on outcome can be made.

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28 Johnson LR, Schanbacker LM, Dudrick SJ, Copeland EM: Effect of long-term parenteral feeding on pancreatic secretion and serum secretin. Am J Physiol 1977;233:E524–E529. 29 Grant JP, Davey-McCrae J, Snyder PJ: Effect of enteral nutrition on human pancreatic secretions. J Parenter Enteral Nutr 1987;11:302– 304. 30 Vidon N, Hecketsveiler P, Butel J: Effect of continuous jejunal perfusion of elemental and complex nutritional solutions on pancreatic enzyme secretion in human subjects. Gut 1978; 19:194–198. 31 Variyam EP, Fuller RK, Brown FM, Quallich LG: Effect of parenteral amino acids on human pancreatic exocrine secretion. Dig Dis Sci 1985;30:445–455. 32 Saluja AK, Steer M: Pathophysiology of pancreatitis. Role of cytokines and other mediators of inflammation. Digestion 1999;60(suppl 1):27–33. 33 Meier R, Beglinger C, Layer P, Gullo L, Keim V, Laugier R, Friess H, Schweitzer M, Macfie J, Espen Consensus Group: Espen guidelines on nutrition in acute pancreatitis. Clin Nutr 2002;21:173–183. 34 Feller JH, Brown RA, Toussaint GPM, Thompson AG: Changing methods in the treatment of severe pancreatitis. Am J Surg 1974; 127:196–201. 35 Goodgame JT, Fischer JE: Parenteral nutrition in the treatment of acute pancreatitis: Effects on complications and mortality. Ann Surg 1977;186:651–658. 36 Grand JP, James S, Grabowski V, Trexler KM: Total parenteral nutrition in pancreatic disease. Ann Surg 1984;200:627–631. 37 Robin AP, Campbell R, Palini CK, Liu K, Donahue PE, Nyhus LM: Total parenteral nutrition during acute pancreatitis: Clinical experience with 156 patients. World J Surg 1990; 14:572–579. 38 Sitzmann JV, Steinborn PA, Zinner MJ, Cameron JN: Total parenteral nutrition and alternate energy substrates in treatment of severe acute pancreatitis. Surg Gynecol Obstet 1989; 168:311–317.


39 Kalfarentzos FE, Karavias DD, Karatzas TM, Alevizatos BA, Androulakis LA: Total parenteral nutrition in severe acute pancreatitis. J Am Coll Nutr 1991;10:156–164. 40 Sax AC, Warner BW, Talamini MA, Hamilton FN, Bell RH Jr, Fischer JE: Early total parenteral nutrition in acute pancreatitis: Lack of beneficial effects. Am J Surg 1987;153:117– 124. 41 Kotani J, Usami M, Nomura H: Enteral nutrition prevents bacterial translocation but does not improve survival in acute pancreatitis. Arch Surg 1999;134:287–292. 42 Moore F, Moore E, Kudsk K et al: Clinical benefits of an immune enhancing diets for early post-injury feeding. J Trauma 1994;37:607– 615. 43 Voitk A, Brown RA, Echave V, McArdle AH, Gurd FN, Thompson AG: Use of an elemental diet in the treatment of complicated pancreatitis. Am J Surg 1973;125:223–227. 44 Kudsk KA, Campbell SM, O’Brien T, Fuller R: Postoperative jejunal feeding following complicated pancreatitis. Nutr Clin Pract 1990;5:14– 17. 45 Parekh D, Lawson HH, Segal I: The role of total enteral nutrition in pancreatic disease. S Afr J Surg 1993;31:57–61. 46 Simpson WG, Marsano L, Gates L: Enteral nutritional support in acute alcoholic pancreatitis. J Am Coll Nutr 1995;14:662–665. 47 Nakad A, Piessevaux H, Marot JC, Hoang P, Geubel A, Van Steenberger W: Is early enteral nutrition in acute pancreatitis dangerous? About 20 patients fed by endoscopically placed nasogastrojejunal tube. Pancreas 1998;17:187– 193. 48 Eatock F, Brombacher G, Steven A, Imrie C, McKay C, Carter R: Nasogastric feeding in severe acute pancreatitis may be practical and safe. Int J Pancreatol 2000;28:25–31. 49 Powell JJ, Murchison JT, Fearon KC, Ross JA, Siriwardena AK: Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 2000;87: 1357–1381.

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50 Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos C: Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: Results of a randomised prospective trial. Br J Surg 1997;83:349–353. 51 McClave SA, Greene LM, Snider HL, Makk LJ, Cheadle WG, Owens NA et al: Comparison of the safety of early enteral vs. parenteral nutrition in mild acute pancreatitis. J Parenter Enteral Nutr 1997;21:14–20. 52 Abou-Assi S, O’Keefe SJD: Nutrition support during acute pancreatitis. Nutrition 2002;18: 938–943. 53 Olah A, Pardavi G, Belagyi T, Nagy A, Issekutz A, Mohamed GE: Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate. Nutrition 2002;18:259– 262. 54 Powell JJ, Murchison JT, Fearon KCH, Ross JA, Siriwardena AK: Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 2000;87:1375–1381. 55 Paraskeva C, Smailis D, Priovolos A, Sofianou K, Lytras D, Avgerinos C, Rizos S, Karagiannis J, Dervenis C: Early enteral nutrition reduces the need for surgery in severe acute pancreatitis. Pancreatology 2001;1:372. 56 Eckerwall G, Andersson R: Early enteral nutrition in severe acute pancreatitis: A way of providing nutrients, gut barrier protection, immunomodulation or all of them? Scand J Gastroenterol 2001;5:449–458. 57 Heys S, Walker L, Smith I, Eremin O: Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer. Ann Surg 1999;229:467–477. 58 Olah A, Belagyi T, Issekutz A, Gamal ME, Bengmark S: Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br J Surg 2002;89:1103–1107.

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Nutrition and Inflammatory Bowel Disease: Its Relation to Pathophysiology, Outcome and Therapy Miquel A. Gassull Department of Gastroenterology and Hepatology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain

Key Words Ulcerative colitis W Crohn’s disease W Inflammatory bowel disease W Malnutrition W Enteral nutrition W Dietary fat W Unabsorbable dietary carbohydrates W Colonic fermentation

Abstract Nutritional deficiencies are frequent in patients with ulcerative colitis and Crohn’s disease, and negatively influence the outcome of the disease. Growth retardation, osteopenia and thromboembolic phenomena are some of the inflammatory bowel disease complications in which nutritional deficits are involved. Moreover, nutrients can play a role in the pathogenesis of the disease and, in some cases, can be a primary therapeutic tool. Enteral nutrition has proven to play a therapeutic role in Crohn’s disease. The nutrient(s) responsible for this effect are not well identified but dietary fat appears to be a major factor. In ulcerative colitis, unabsorbable carbohydrates can modulate the intestinal microbial environment, thus contributing to improve colonic inflammation. Copyright © 2003 S. Karger AG, Basel

Several facts relate nutrition and inflammatory bowel disease (IBD) and many features even support the existence of a bidirectional relationship between them. In this sense, a high prevalence of nutritional derangement (macro- and micronutrients), both in ulcerative colitis (UC) and Crohn’s disease (CD), has been reported [1–5]. In addition, qualitative differences in diet composition have been suggested as being the cause of the low incidence of IBD and other immune-based diseases in specific populations [6]. Finally, it has been shown that changes in some components of the diet are able to downregulate the inflammatory response in vitro, in animals and in humans [7–14]. In this paper the above-mentioned aspects will be reviewed, with special emphasis on data relating to nutritional deficiencies, IBD pathophysiology, clinical outcome and the changes of incidence in some geographical areas. Also the evidence about the role of nutritional manipulation in inducing and maintaining clinical disease remission will be discussed.

Protein Energy Malnutrition and Micronutrient Deficit in IBD: Their Effect on Disease Outcome

Various degrees of protein energy malnutrition, vitamin, mineral and trace element deficiencies may develop in UC and CD [1–5]. Anorexia has been blamed for many

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Miquel A. Gassull MD, PhD, Assoc. Prof. Med. Head, Department of Gastroenterology and Hepatology Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n ES–08916 Badalona, Catalonia (Spain) Tel./Fax +34 93 4978951, E-Mail [email protected]

years as being one of the main causes of IBD-associated malnutrition, growth failure and sexual development retardation in children and adolescents. The cause of these derangements is multifactorial and related to the existence of active inflammation. In animals with experimental colitis, this clinical situation has been reproduced and found to be especially related to the release of IL-1 by the inflamed mucosa [13–15]. Other causes of malnutrition in IBD include a hypermetabolic state, due to inflammation, extensive intestinal involvement or surgical resection of the small intestine, interfering with nutrient absorption, or an increase of nutrient losses through the inflamed and ulcerated gut (small and large bowel). In addition, the existence of fistulas and/or strictures in the small intestine facilitates bacterial overgrowth. The excess of bacteria results in an increased production of bacterial metabolites of nutrients through fermentation and hydroxylation processes. Some of the products such as folate may have a beneficial effect, however an excess of short-chain fatty acids and especially fatty acid hydroxylation results in increased diarrhea and hence nutrient wasting. Bacterial overgrowth also induces vitamin B12 deficiency. Finally, medical treatment (therapeutic fasting, steroids, cholestyramine) [16, 17] and self- or medically-recommended dietary restrictions may also contribute the development of nutritional deficiencies in IBD patients [10, 17]. Nutritional derangement may influence adult IBD outcome, since it may increase the need for surgical treatment [1] and its complications [17]. However, it has been in children and adolescents where malnutrition, in its wider sense, together with steroid treatment (by IGF-1 suppression) have been blamed as inducing one of the most severe IBD complications in this population – linear growth and sexual maturation failure [18–20]. Experiments in rats with colitis have shown the important impact of the excessive release of proinflammatory cytokines by the inflamed mucosa on growth retardation [21]. However, nutritional deterioration can also be blamed for causing more than 50% of the delayed growth observed in these experimental animals, because it is associated with a low IGF-1 synthesis. Feeding properly colitic rats partially reversed the linear growth deficit, but it never reached that of the control animals [21]. These studies strongly support the fact that decreasing the inflammatory process and feeding patients may adequately improve linear growth in the infant and adolescent IBD population. These objectives could be reached by using concomitantly immunomodulatory therapy and nutritional support. There is also the possibility that especially designed nutri-

tional formulas may achieve both goals; this aspect will be dealt with later in this article. Suboptimal levels of micronutrients are often found both in children and adults with IBD, but except for iron and folate, it is unusual to discover symptoms attributable to these deficits [3–5]. In spite of this, subclinical deficits may have a pathophysiological significance since they may favor self-perpetuation of the disease (because of defects in the mechanisms of tissue repair), defective defense against damage produced by oxygen free radical and can facilitate lipid peroxidation [22, 23], even in clinically inactive or mildly active disease [24], as well as the development of dysplasia in the intestinal mucosa [25]. However, the potential therapeutic role of antioxidant micronutrients, both in inducing disease remission and in the prevention of disease relapse, has scarcely been investigated. Recently, it was shown that the administration of vitamins E and C for 4 weeks in mild to moderate cases of CD induced a significant reduction of oxidative stress as measured by breath pentane and ethane output, plasma lipid peroxides and F-2 isoprostane, suggesting increased requirements of such micronutrients [26]. One of the most risky situations in patients with acute IBD is the appearance of thromboembolic complications, related in part to the existence of nutritional imbalances, resulting in excessive plasma homocysteine. Increased homocysteine levels have proved to be thrombogenic and an independent risk factor for cardiovascular disease [27, 28] and deep-vein thrombosis [29]. This sulfur-containing amino acid is formed during the demethylation of methionine. Hyperhomocysteinemia has been reported to be prevalent in patients with IBD [28, 29] and related to both low folate [30] and vitamin B12 [31] levels. However, only a small amount of homocysteine is cleared via a remethylation pathway dependent on vitamin B12 and folate, but most of the homocysteine is converted to cystothione by cystothione ß-synthase which is a vitamin B6-dependent enzyme. Although low vitamin B6 levels were reported in IBD patients many years ago [3], it is only recently that they have been related to the high homocysteine levels in IBD and the risk of thrombosis [32]. Osteopenia associated with IBD is an area of increasing concern, especially in CD [33–37]. Nutritional deficiencies, inflammatory cytokines and treatment with corticosteroids have been incriminated in its pathogenesis [38, 39]. The disease itself seems to exert a direct effect in inducing osteopenia in these patients. This was shown in an in vitro experiment in which the serum of patients with CD impaired osteoblastic function [40]. In 36 new cases of pediatric CD, a dual X-ray absorptiometry study dem-

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onstrated osteopenia and osteoporosis in 17 and 25% respectively [41]. A bone fracture rate as high as 40% has been reported in a population-based cohort study [42]. It is noteworthy that low bone mineral density has been described in adult CD patient populations as distant as Puerto Rico, The Netherlands and Korea [43–45]. In some cases, this abnormality is detected in newly diagnosed cases in both adults [45] and children [46]. Supporting the fact that inflammation is an important factor in inducing osteopenia in IBD is that TNF-·, IL-1ß and IL11 (proinflammatory cytokines) promote the secretion of a ligand able to stimulate receptors in osteoclast precursors, inducing osteoclast maturation and bone resorption [47]. Glucocorticoids, the gold standard treatment in IBD, are associated with side effects including permanent damage such as cataracts, growth failure, sexual development retardation, and osteopenia. In fact, glucocorticoids are an important factor aggravating bone loss in IBD, because they decrease intestinal calcium absorption, increase renal calcium excretion and induce parathyroid hormone secretion. The result is decreased bone formation and enhanced bone resorption [46, 47]. These data should be enough to restrict their use in the treatment of IBD, both as long-term therapy (even at low doses) and in patients with frequent relapses (steroid-dependent) [48–51]. Bone loss induced by steroid therapy is dose- and durationdependent. In addition, growth and sexual development retardation in children and adolescents may be aggravated by glucocorticoid treatment due to its suppressive effect on IGF-1, which mediates the effect of growth hormone on the growth of plate bones [21]. Then it is highly recommendable in this population to use steroids only when strictly necessary, in short treatments, avoid repeated treatments (use other immunosuppressors) and especially try nutrition as primary treatment.

Possible Role of Nutrition in the Incidence of IBD in Some Geographical Areas

The low incidence of IBD and other immune-based diseases in some communities like Greenland Eskimos, as compared to western populations, has been attributed to differences in lifestyle and the type of diet [52, 53]. It has been hypothesized that components of the Eskimo’s diet (abundant in n-3 fatty acid-rich marine oils) produce changes in cell membrane composition (including that of the immune-competent cells) [53]. This would result in a downregulated expression of certain cytokines, adhesion

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molecules, lymphocyte chemotactic activity and an increased synthesis of eicosapentaenoic (n-3) acid-derived eicosanoids with attenuated proinflammatory activity [8, 9, 54–57]. The hypothesis is supported both by in vitro and in vivo studies [53–59]. Moreover, increases in the annual incidence in both UC and CD have been observed in countries where qualitative changes in dietary fat were established because of public health reasons [60–62] or when hit by western dietary influences as in Japan [63]. The major dietary changes in these countries were the substitution of butter by margarine in Sweden [62] and the decrease in intake of fish while increasing that of meat and seed oils in Japan [63]. These changes, as mentioned, were followed by increases in the incidence of IBD in these countries.

Is Diet a Factor in the Etiopathogenesis of IBD? Does It Explain the Therapeutic Effect of Enteral Nutrition?

Nutrients in the form of chemically and physicochemically complex food products are one of the main components of the intestinal environment. As such, the possibility that the food antigenic load may be one of the triggering factors initiating and perpetuating the abnormal intestinal inflammatory response has been frequently invocated. This has been the basis for using therapeutic fasting in acute UC and CD (bowel rest), amino acid-base elemental diets (low antigenic power) for treating acute CD and excluding the suspected offending food (exclusion diets) in the treatment of active or maintenance of remission in CD. Various studies have shown that withholding nutrients from the intestinal lumen does not influence disease outcome [64–66], even in acute disease. Elemental diets have shown to offer no advantage as compared to whole protein-based polymeric diets (higher antigenic load) in inducing remission in active CD, at least in three meta-analyses summarizing the findings of several trials [67–69]. The effect of exclusion diets in inducing or maintaining remission is still doubtful, since the reintroduction of the offensive food frequently is not accompanied by disease relapse [70]. Recently, experimental work in vitro (human peripheral blood lymphocytes) and humans (skin and rectal mucosa) has tried to ascertain whether or not intestinal epithelium and immune cells have an increased sensitivity to different components of the diet. Although peripheral blood lymphocytes and rectal mucosa are not, under normal circumstances, exposed to intact food, the results

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showed increased sensitivity in CD compared to healthy individuals [71, 72]. The true value in etiopathogenic and therapeutic terms of these findings needs to be further explored. Several years ago, Gonzalez-Huix et al. [73] first suggested that fat composition of the diet, rather than the nitrogen source, may explain why enteral nutrition may have an anti-inflammatory effect in active CD. This was based on the fact that in a randomized clinical trial a polymeric enteral diet (higher antigenic load than elemental) containing 30% of the calories as lipids (65% olive oil, 10% milk fat and 25% MCT) was as effective as 1 mg/kg b.w. of prednisolone. These authors hypothesized that the key factor for the therapeutic effectiveness of enteral nutrition in CD was the amount (elemental low fat) or the type of fat used in the design of the formula diet. This hypothesis has been reinforced in a recent paper [74]. In the literature a great deal of data supports the immunomodulatory role of dietary fat. The effect that fatty acids have from different sources in modifying cell membrane composition and hence the influence on the function of the proteins embedded in it, has already been mentioned. The consequences of this are relevant in terms not only on the type of eicosanoids and other second messengers synthesized [9], but also in the cell signaling system, influencing the activity of nuclear transcription factors and hence the genes expressing proteins involved in the inflammatory process (cytokines, adhesion molecules, iNOS, etc.) [75–83]. It is worth emphasizing that usually there is a tendency, especially by clinical nutritionists, in using the words fat and fatty acids synonymously. Mammals do not eat single fatty acids in the diet but different fat sources with mixtures of fatty acids. The predominance of one or some of them give to the fat source not only its physicochemical properties, but also its nutritional and metabolic value. In this sense it is worth mentioning that different fat sources with different predominant fatty acids have different effects on the expression of different cytokines in an elegant experimental setting in mice [84]. It may not be the effect of a single fatty acid but the combination of several that exerts the immunomodulatory action. An example of this possibility is fish oil, which has been made synonymous of a fat source rich in n-3 eicosapentanoic (EPA) and docosahexaenoic acid (DHA). In fact, fish oil contains no more than 25% of EPA and DHA together, the larger component being saturated fatty acids (LCT + MCT) 45%, with 16% of monounsaturated and 10% of n-6 fatty acids [84]. It is then plausible that the antiinflammatory effect would be related more to an adequate mixture of fatty acids (fat source) than to a single

one. In this sense, a recent paper showed that the use in an enteral formula diet of an artificially made mixture with a highly predominant (70%) synthetic fatty acid, did not obtain any therapeutic effect as compared to one using a natural source [74]. This fact also raises the question of the role of the non-fatty acid component of the lipid sources, since many compounds are found, at least in some oil sources that may have, through their antioxidant effect, immune regulatory properties [85, 86]. This possibility has to be further explored. An interesting but seldom mentioned aspect is the potential anti-inflammatory role of MCT. These compounds have always been regarded as energy providers in malabsorptive states or easy sources of energy for malnourished individuals. However, it has been shown experimentally [84, 87–89] that MCT modulates the expression of adhesion molecules and cytokines and the metabolism of linoleic acid (precursor of potent proinflammatory eicosanoids). Also, a polymeric enteral diet containing high amounts of MCT is as effective as a very low fat elemental diet in inducing remission in active CD [90]. In fact, when the composition of the diets reported as highly effective in inducing remission in active CD are carefully analyzed, it can be observed that those with a higher remission rate are those with very low fat content and those where one third of the fat source was MCT [73, 91]. A further aspect related to dietary fat is its influence in the cell cycle. A feature in CD is the resistance of T lymphocytes to the natural apoptotic process, leading to its accumulation in the bowel wall and hence contributing to perpetuate the inflammatory process [92]. Some lipid sources (fish oil or olive oil, but not corn oil) induce apoptosis in intestinal cell lines cultures by, at least, inhibiting the expression of the antiapoptotic mitochondrial protein Bcl-2 [93]. This may be a further mechanism explaining why some fat sources show a positive therapeutic effect in active CD while others do not. To summarize this part, it can be said that although T lymphocytes and rectal mucosa have shown sensitization to some food products, the therapeutic effect of exclusion diets is still not well established and there is no difference in the rate of remission achieved by whole protein or amino acid formula diets when used as primary treatment in CD. Nutrients as components of cell structures: Changes in dietary components can influence numerous cell functions and the cell cycle. Fat is, up to now, the best studied nutrient and has been shown to influence immune cell response, although many other aspects of these com-


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pounds need to be explored. So far, changes in the composition of dietary fat have been shown to be able to influence disease outcome in CD and some data relate major qualitative changes in fat intake in geographically distant populations (Sweden and Japan) with an increase in the incidence of CD, suggesting a possible role as trigger in genetically susceptible individuals. Little is known about the potential effect of changes in dietary fat on intestinal bacterial populations.

Nutrition and Ulcerative Colitis

Up to now in this review, the relationship between nutrition and UC has seldom been mentioned, except for its capacity of inducing nutritional derangement. When dealing with the role of enteral nutrition, the effect of different dietary fat composition in primary therapy, its influence in disease etiopathogenesis and incidence, mostly CD has been mentioned. In fact the enteral formula diets used as primary treatment in CD have proven not to be effective in UC, although improve patients’ nutritional status and prevent complications related to surgery, when compared to parenteral nutrition [94]. One of the different possible explanations is that while CD is an antiapoptotic disease, UC is not [92]. Moreover, there are major differences in the etiopathogenesis of both diseases, as far as the environmental factors are concerned. The most obvious is the effect of smoking, being protective in UC and inductor in CD. More is known about the relationship between the intestinal environment and the colonic mucosa. Finally, the concentration of bacteria in the colon is much higher than that in the small intestine and, even though endogenous bacteria play a crucial role in the pathogenesis of CD, little is known about the relationship between small intestinal bacteria and nutrients present in the intestinal lumen in such a condition. The colon is highly dependent of the environment in its lumen to maintain its structure and function. Almost 80% of the energy required for such a task is obtained from nutrients reaching the large bowel. Several substrates enter the colon every day, these include nonabsorbed carbohydrates, proteins and a few others. In short, anaerobic bacteria deal with these substrates through a fermentation process producing branchedchain fatty acids from proteins and short-chain fatty acids plus a large volume gas (H2 and CO2) from carbohydrates. The gas volume is reduced by the action of methanogenic and sulfate-reducing bacteria producing CH4 and SH2 respectively. Short-chain fatty acids (acetate, propionate

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and butyrate) are involved in the maintenance of colonic structure (butyrate is the preferred fuel for the colonocyte) and immune homeostasis. The first consequence of shortchain fatty acid synthesis is the decrease of intraluminal pH in the colon [95]. This fact favors the development of Lactobacilli, Bifidobacteria strains (probiotics) and a decrease of those of Clostridia, Bacteroides, Escherichia coli. This is known as the ‘prebiotic effect’ effect of fiber. As mentioned, short-chain fatty acid, especially butyrate, is oxidized by the colonic mucosa and used mainly as an energy provider. In recent years it has been postulated that butyrate oxidation is incomplete or defective in both UC and pouchitis, suggesting that this defect may be implicated in the pathogenesis of both conditions [96– 103]. Rectally administered 13C-labelled butyrate was significantly less oxidized by active UC patients than by healthy controls, whereas patients with inactive disease showed a trend towards a lower oxidation than healthy subjects [104]. These findings in non-active UC are supported by other studies [105]. Recent work suggests that in active UC there is an excess of SH2 synthesis by sulfate-reducing bacteria in the colon [103]. This excessive SH2 contributes to the inefficient butyrate oxidation in the colonic mucosa [100]. In patients with proctitis refractory to treatment with topical steroids and 5-aminosalicylic acid (5-ASA), the nutritional approach, by intrarectally administering butyrate as maintenance treatment for such a type of UC, has produced significantly positive results as compared to placebo [99, 106]. Moreover, the relapse rate of quiescent UC treated with soluble dietary fiber (Plantago ovata seeds), substrate precursor for the production of butyrate in the colon (prebiotic), was not different than that of patients given 5-ASA at the usual maintenance doses [107], although there was a non-significant trend towards a lower relapse rate in those patients on combined therapy. Interestingly enough, patients on treatment with this fiber preparation increased butyrate production in the colon (as measured by stool analysis) as compared to those on 5-ASA alone [107]. This nutritional approach in the maintenance therapy of UC supports the role of butyrate in the pathogenesis of the UC. However, butyrate is not only an energy provider, but a true anti-inflammatory substance, since it prevents the activation of the nuclear transcription factor NFÎB and through this mechanism prevents the expression of cytokines and other molecules involved in the inflammatory process [108–110]. This is achieved by the inhibition of the phosphorylation or degradation of the inhibitory protein IÎB that holds NFÎB in the cell cytoplasm. Butyrate

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would be a dietary factor regulating the inflammatory process from the intestinal lumen. Its therapeutic possibilities as primary therapy in active UC are currently under investigation. Its anti-inflammatory properties, together with its prebiotic action, strongly suggest the possibility of using a combined prebiotic-probiotic approach (symbiotic) in the treatment of UC and pouchitis. The UC nutritional approach both in terms of pathogenesis and therapy seems to follow a different route than

that of CD, with a more clear interaction in the intestinal ecosystem in the former. Thus a nutritional therapeutic approach may also be possible in UC. The interest in the knowledge of the possible role of nutritional imbalances in IBD relies on its potential usefulness of nutritional manipulation as a preventive measure in genetically susceptible individuals and as its use as a true biological therapy, free of side effects, in certain groups or subgroups of patients with IBD.

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Factors Enhancing Intestinal Adaptation after Bowel Compensation D.S. Botsios K.D. Vasiliadis 4th Surgical Clinic, Aristotle University of Thessaloniki, Thessaloniki, Greece

Key Words Gut adaptation W Intestinal failure W Growth factors

trition, in a shorter period of time, which reduce the rate of adverse effects caused by artificial nutrition and improve quality of life. Copyright © 2003 S. Karger AG, Basel

Abstract Intestinal failure (IF) refers to the condition in which certain causes lead to derangements in nutrient absorption capacity. Gut adaptation occurs in response to IF and it is both morphologic and physiologic in nature and can be mediated by growth factors and nutrients. Our paper reviews certain trophic growth factors that have important interactions relevant for intestinal growth, function and adaptation. Data Source: The literature was reviewed (data from both animal and human studies) and certain trophic factors that modulate intestinal adaptation are summarized. The factors reviewed are: epidermal growth factor, insulin-like growth factor I and II, transforming growth factor · and ß, neurotensin, interleukin-11, glucagon-like peptide-2, keratinocyte growth factor, human growth hormone, short-chain fatty acids, and glutamine. Conclusions: Growth factors augment intestinal proliferation, diminish programmed apoptosis, and modulate the adaptive process. They also have the potential to improve nutrient absorption in some bowel disease. The enhancement of gut adaptation may allow patients to transition of parenteral/enteral to normal nu-

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0213–0228$19.50/0



Introduction

Intestinal failure (IF) refers to the condition in which the functioning bowel is insufficient to allow for the absorption of an adequate amount of nutrients. Considerable progress in the understanding and treatment of IF has been made over the last years. Fleming and Remington [1] defined IF as ‘the reduction in functioning gut mass below the amount necessary for adequate digestion and absorption of food’. According to this definition, IF can be present in patients with a normal, yet dysfunctional, length of bowel. IF may be divided into two types: the first is characterized by an absolute reduction in normally functioning gut mass (short bowel syndrome – SBS), and the second featured by an intestine with extensive lesions or functional insufficiency (intestinal dysfunction). In addition, IF can be complete (total small bowel enterectomy) or partial (partial resection). The condition can be acute and temporary, as seen with recoverable motility disorders such as

D. Botsios, Assoc. Prof. Surg. Kaukasou 64 GR–55133 Thessaloniki (Greece) Tel. +30 2392051560, Fax +30 2310358000 E-Mail [email protected]

ileus and obstruction, or chronic and permanent. Although a wide spectrum of conditions can be associated with IF, four principal underlying causes can be identified – these are (a) the SBS, (b) total parenchymal bowel disease (e.g. Crohn’s disease), (c) motility disorders, such as visceral myopathy and chronic intestinal obstruction, and (d) small bowel fistulation which leads to premature loss of enteric content. The major resulting nutritional disorders are starvation and dehydration, but loss of body mass is frequently made worse by catabolism from associated sepsis [2]. SBS is the best-known form of IF. It usually results from extensive small bowel resection for the consequences of superior mesenteric artery or vein thrombosis or volvulus. SBS can also result from repeated resection of small bowel strictures due to Crohn’s disease. In addition, SBS is associated with many aftereffects, such as gastric hypersecretion, gallstone formation, renal calculi, liver disease and metabolic bone disease. Chronic motility disorders, such as those characterized, as intestinal pseudoobstruction or visceral myopathy, are rare causes of IF. Regarding survival following massive bowel resection in humans, a review made by Wilmore [3] documented that in infants with an intact ileocecal valve, none with small intestinal length !15 cm survived, while, in infants receiving ileocecal resection, this length is extended to 40 cm. However, patients with an even shorter length of remaining intestine can nowadays be successfully weaned from parenteral nutrition (PN), if certain nutrients are administered in combination. The lower limit of remaining gut length compatible with successful weaning from enteral feeding is estimated to be ^30 cm in children. In adults, on the other hand, the extent of compensatory hypertrophy is becoming very limited (the lower limit of remaining intestinal length is said to be at least 50–70 cm) [4]. Recovery of intestinal function can be expected from efficient use of certain factors stimulating regeneration and hypertrophy of the remnant intestinal mucosa, in addition to prolonged nutritional management with enteral and parenteral nutritional regimens. It should be noted that both SBS and IF are associated with the loss of the gut barrier function. Resolution of IF can occur spontaneously by the process of intestinal adaptation, a process that is stimulated by enteral nutrition, or in the case of intestinal fistula can be resolved surgically. In those cases where resolution does not take place, recourse has to be made to permanent PN. The increased use of long-term total parenteral nutrition (TPN) revealed numerous adverse effects that were

not recognized previously. These are problems related to (a) intravenous catheter care, (b) supply of micronutrients and (c) the occurrence of irreversible hepatic failure.

Factors Enhancing Intestinal Adaptation after Bowel Compensation

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Small Bowel Adaptation in Intestinal Failure

Where IF is the result of the SBS, it is the hope that compensatory mechanisms may reduce dependence on PN. Several mechanisms are available: (a) Spontaneous adaptation, which results from cellular hyperplasia, villous enlargement, intestinal lengthening and dilatation, altered motility, increased absorptive capacity and increased activity of brush-border enzymes. Alimentary secretions, ingested nutrients and hormones stimulate the changes. (b) Bowel-lengthening procedures: over the past 16 years, Bianchi has pioneered bowel-lengthening procedures in neonates and infants with SBS [5]. (c) Reserved small bowel segments: segmental bowel reversal in patients with SBS aims to slow intestinal transit time, thereby theoretically enhancing absorption. (d) Intestinal transplantation, and (e) Pharmacological stimulation of adaptation-growth factors and other modulators.

Growth Factors and Other Modulators

A number of specific factors that enhance the proliferation response of the enterocyte have been identified and their effect was demonstrated mainly in animal studies. Epidermal Growth Factor (EGF) EGF, extracted from the mucous gland and Brunner’s glands, is a low-molecular-weight polypeptide that is known to enhance the growth of the intestinal mucosa. It has been shown to be involved in the maturation of a number of developing tissues. Several studies have demonstrated the trophic effects of EGF on intestinal mucosa in a variety of experimental models [6–11]. Some of the effects of exogenous EGF on the gastrointestinal mucosa are notably similar to the compensatory changes observed after massive small bowel (SB) resection [12–14]. EGF receptors are present throughout the intestinal tract and located on both basolateral and brush-border membranes. In experimental studies continuous administration of the EGF resulted in significant increases in body weight, intestinal weight (SB and colon), SB length, and ileal mucosal mass following massive SB resection [15]. In addition, the mucosal DNA and protein contents in-

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creased after EGF administration, suggesting an augmentation of the usual mucosal hyperplasia observed after massive SB resection. Goodlad et al. documented that EGF administration increased colon weight, which resulted from intestinal epithelial proliferation. In addition, they observed an increase in pancreatic weight after EGF administration, which raised the possibility that EGF mediates some of its trophic effects through increases in pancreatic growth or secretion [16]. In normal mature intestinal mucosa, administration of EGF has been reported to increase intestinal weight, lactase-specific activity, net calcium transport [8], and galactose and glycine absorption [17]. Similar trophic effects of EGF on atrophic mucosa (caused by lack of enteral nutrition while on TPN [7, 18, 19] or by administration of an elemental diet) have also been reported [10]. Chaet et al. showed in 1994 that administration of EGF after massive SB loss can by of nutritional benefit through its enhancement of the normal post-resection intestinal response [15]. In a series of studies, Thomson et al. [9, 20–22] showed that EGF stimulates neomucosal growth on serosal patches created in the rabbit intestine. In their studies, maximal stimulation was achieved through intravenous [10] administration of EGF. EGF given enterally does not stimulate cell proliferation in the colon, whereas intravenous recombinant EGF reverses the marked intestinal hypoplasia characteristically found in TPN-fed rats. In a study of EGF administration after massive SB resection, Read et al. [23] reported increased intestinal net weight and sucrase activity after 7 days of oral EGF administration. Furthermore, EGF upregulates electrolytes and nutrient absorption in the small bowel and thus mediates the absorptive capacities of various nutrients. Read et al. [23], in an experimental study, administrated EGF orally and documented that there were no positive synergistic effects of EGF and intestinal resection, nor did EGF fully compensate for the lack of luminal contents. Because post-resection adaptation may begin immediately after resection and continue for several weeks [12], further studies are needed to evaluate EGF’s effect on the residual SB after massive resection, when administrated throughout the period of expected adaptation. Although EGF had multiple trophic effects in experimental models, EGF’s safety and utility for human therapy are presently under research.

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Insulin-Like Growth Factors I and II (IGF-I and II) IGF-I and II are growth factors similar in structure to insulin, which is primarily involved in the regulation of normal growth and development. The major source of circulating IGF-I and II is the liver, and their effects are more direct than that of growth hormone (GH). Several studies have demonstrated the trophic effects of IGF-I and II on intestinal mucosa in a variety of experimental models [24]. IGF-I is produced in the liver in response to GH, and leads to an increase in crypt cell production rate, with a consequent increase in villus high and nutrient absorptive capability [25, 26]. IGF-I enhances DNA and protein synthesis in intestinal crypt cells in vitro, maintains intestinal integrity, and enhances intestinal mucosal adaptation after intestinal resection. Localization of IGF receptors in the intestinal epithelium suggests a functional role of IGF-I in intestinal epithelial cell growth and differentiation and thus a possible role of IGF-I in gut repair [27]. A recent experimental study demonstrated that administration of IGF-I enhanced epithelial restitution after intestinal mucosal injury. In this model, increased thymidine uptake, cell migration and increased TGF-ß mRNA expression were noted in intestinal epithelial cells [27]. Sigalet and Martin [28] showed that IGF-I could improve weight gain in a rat model of severe bowel syndrome (SBS). This improvement in weight gain was associated with an increase in nutrient transport at the cellular level and variable increases in villus size. IGF-I has the greatest effect on weight gain, which should be the guide to further studies regarding the mechanisms underlying effects. IGF-I probably acts directly by improving nutrient absorption at the enterocyte level or by an effect on adaptation. According to other similar studies [12, 29, 30], it is assumed that an increase in villus height accompanies any significant improvement in nutrient absorption characteristics. It is possible that IGF-I is acting through endocrine pathways and only indirectly affecting nutrient transport characteristics. Although markedly beneficial effects of IGF-I and II have been observed in animal studies, its clinical effects on protein metabolism and gut integrity have not yet been clearly demonstrated and further analysis is required. Transforming Growth Factor (TGF)-· and ß TGF-· is a 5.5-kDa protein containing 50-amino-acid residues that share 35% structural homology with EGF, a common membrane receptor with a similar spectrum of biological activity [31]. TGF-· has been reported to stimulate proliferation of a wide range of epidermal and epi-

Botsios/Vasiliadis

thelial cells and is important in intestinal cell proliferation [32]. In a recent study, Falcone et al. [33] have shown that in a mouse model of SBS, normal adaptation resulted in 30% increase in ileal TGF-· mRNA levels by post-operative day 3. Additionally, it has been shown that exogenous TGF-· given within the first 3 days significantly enhanced enterocyte proliferation and stimulated intestinal adaptation. TGFs were isolated for the first time in 1978 from culture medium conditioned by Rous sarcoma virus-transformed fibroblasts [34] and include two proteins, now designated TGF-· and TGF-ß. Both proteins have a different structure and a different spectrum of biological activity. Since its isolation from transformed cell lines, TGF-· has been identified in a wide spectrum of epithelial cells, including gastrointestinal epithelium [35]. TGF-· has recently been found to promote proliferation in established cell lines and to exert a trophic effect on intact gastric, intestinal and colonic mucosa. TGF-· is considered important in epithelial cell proliferation in digestive tissues during the developmental period [36], in the promotion of cell migration and motivation of fluid and electrolyte transport in the enterocyte [37], in the inhibition of gastric acid secretion and promotion of gastric ulcer healing [38] and gastric mucosal repair [39] and in intestinal mucosal repair [40] following acute epithelial injury. Several lines of evidence have implicated TGF-· as a potential modulator of intestinal adaptation in an animal model of SBS. In a recent study the potential effects of exogenous TGF-· as a gut-trophic agent after small bowel resection in the rat was investigated. It was shown that exogenous TGF-· given at high doses (75 Ìg/kg/day) stimulated intestinal adaptation in the remaining gut. This was evident from increased bowel and mucosal weights, mucosal DNA and protein, villus height and crypt depth. Exogenous TGF-· has been showed to accelerate the proliferation of intestinal cells. In addition, the administration of TGF-· reduced cell death via apoptosis. Both increased cell production and decreased cell death may indicate an adaptive mechanism to increase enterocyte mass following TGF-· administration [41]. These observations suggest that TGF-· may have clinical utility for the patient with SBS. TGF-ß inhibits cell proliferation in vitro and in vivo. No clinical studies have been performed to demonstrate clinical efficacy.

Neurotensin Neurotensin is a tridecapeptide originally isolated from bovine hypothalamus and subsequently found to be widely distributed in the gastrointestinal tract. Neurotensin-like immunoreactivity has been localized to a specific mucosal endocrine cell type (N-cell) that is found in highest density in the ileum [42]. Neurotensin-like immunoreactivity in plasma increases two- to threefold after meals [43]. Thus, potential physiological actions of neurotensin on gastric and pancreatic secretion, gastrointestinal motility, and gastrointestinal growth may be mediated by a hormonal mechanism with release of neurotensin from N cells of the intestinal mucosa, as well as paracrine and neurocrine mechanisms involving local release from N cells and nerve fibers. Neurotensin increases contractile activity of the colon [44] and disrupts the interdigestive myoelectric complex of the small intestine [45]. Neurotensin also increases intestinal blood flow and capillary permeability [42] and stimulates net fluid secretion by small intestine in vitro [47]. Wood et al. [48] showed that neurotensin had trophic effects on the small intestine in rats. Neurotensin produced increases in weight, DNA and protein content of the small intestine. There were also increases in total content of three brush-border enzymes measured in this study, namely sucrase, maltase and leucine aminopeptidase. The potential action of neurotensin on small intestinal growth is not due solely to an endocrine mechanism. High doses of neurotensin may result in high concentrations within the intestine, similar to those expected after local release of neurotensin from endocrine cells or neurons. By this reasoning, neurotensin could exert paracrine or neurocrine effects on intestinal growth. It is not yet established whether neurotensin acts directly on the small intestine or indirectly through effects on other growth factors. Neurotensin has been reported to stimulate release of thyrotropin in rats [49] and insulin and glucagon in dogs [50]. Other similar studies showed that neurotensin prevents atrophy of the intestinal mucosa associated with TPN and promotes the release of secretory IgA and IgM into the bile [51].


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Interleukin-11 (IL-11) IL-11, a 19-kDa bone marrow-derived growth factor, is a multifunctional peptide that uses the gp130 receptor common subunit for receptor function [52]. It was first cloned in 1990 from an immortalized primate bone marrow stromal cell line, PU-34 [53]. Its hematopoietic effects include increases in peripheral blood neutrophils

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and platelets, and stimulation of erythroid elements, megakaryocytes, and B-cell differentiation in vivo and in vitro [54]. IL-11 also improves survival rate and decreases bacterial translocation in burned mice [55]. Recent studies suggest that IL-11 enhances a small intestine mucosal mass after massive small bowel resection [56, 57]. However, these studies did not determine if there were changes in the function at the remnant small intestine. The current findings show that exogenous administration of IL-11 increases mucosal mass, as noted by enhanced DNA content, in a dose-dependent manner. These data corroborate the results of previously described in vivo studies and further strengthen the assertion that IL-11 has a trophic effect on intestinal epithelial cells. The systemic infusion IL-11 had significantly enhanced galactose and glycine absorption. [58]. Glucagon-Like Peptide-2 (GLP-2) GLP-2 is a 33-amino-acid peptide known to enhance mucosal integrity in normal intestine and in intestine that has undergone adaptation after massive small bowel resection (MSBR) [59]. GLP-2 is liberated from the carboxy-terminus of proglucagon in small and large intestine L cells by the action of tissue-specific proteases. GLP-2 belongs to a specific class of compounds referred to as proglucagon-derived peptides (PGDPs), products of the posttranslational processing of proglucagon. A role for PGDPs as intestinal hyperplasia and hypertrophy were noted in 2 patients with PGDP-secreting tumors [60, 61]. It was shown subsequently that nude mice carrying subcutaneous PGDP-producing tumors had a significant increase in small intestinal weight [62]. The PGDP responsible for the intestinal epithelial proliferation in these mice was identified as GLP-2. Subsequent studies confirmed that the naturally occurring form of GLP-2 induces growth in normal intestine [63–65]. Drucker et al. [66] further showed that a synthetic, protease-resistant form of GLP-2 was a potent agent for increasing small and large intestine mass in normal rats. Findings in other similar studies showed that GLP-2 increases mucosal mass and absorptive function in intestine after MSBR [67]. In experiments on massive bowel resection or ischemia/reperfusion injury, administration of GLP-2 significantly increased DNA and protein content of the intestinal mucosa [59]. However, such effects have not been confirmed in humans. Keratinocyte Growth Factor (KGF) KGF, synthesized and secreted by stromal fibroblasts, is expressed predominantly in the dermis [68]. However,

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expression of KGF receptor and KGF messenger RNA (mRNA) has been detected throughout the gastrointestinal tract [69]. Recent studies support a role for KGF in tissue repair [70, 71]. In inflammatory bowel disease, increased expression of KGF has been described in the mucosa, suggesting a potential role for KGF in mediating mucosal repair mechanisms [72, 73]. The role for KGF as an endogenous mediator of growth and differentiation in the gastrointestinal tract is supported by the isolation of mRNA for KGF and its receptor in both the small and large intestine of rodents [69, 74]. Recently it has been demonstrated that exogenous fulllength KGF significantly reduces the severity and extent of mucosal injury in different experimental models of colitis in rats and mice [75, 76]. KGF induces proliferation of colonic epithelium (or alternatively decreased apoptosis) and quantitatively increases the mucin content [75, 77]. KGF has also been demonstrated to increase the number of goblet cells as well as mucin production throughout the gastrointestinal tract of rats and mice [69, 75, 76]. Housley et al. [69] showed that KGF enhanced the growth of the intestinal mucosa. An animal study by Estivarez et al. [78] showed that KGF inhibits atrophy of the duodenal and ileal mucosa induced by fasting. Johnson et al. [79] evaluated the effects of KGF on intestinal adaptation after resection of 85% of the small intestine. It was concluded that KGF enhances gut growth, differentiation and gene regulation during adaptation in rat small intestine after massive resection. The clinical relevance was that KGF might be beneficial in the management of patients undergoing massive intestinal resection. In a recent experimental study in mice, Yang et al. [80] showed that KGF administration improved epithelial absorptive function and stimulated intestinal proliferation after SBS. They concluded that KGF improved intestinal adaptation after small bowel syndrome and may have clinical applicability. Human Growth Hormone (hGH) hGH belongs to anabolic hormones. In 1974, Wilmore et al. [81] first reported the clinical effects of hGH. They reported that administration of hGH to burn patients resulted in an improvement of nitrogen and potassium balance and enhanced wound healing. Based on initial observations showing GH can increase nutrient and electrolyte absorption in hypophysectemized animals [82], Byrne et al. [83] reported in a nonrandomized, open study that GH and dietary modification improved nutrient absorption in patients with small bowel syndrome. Subse-

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quent studies using more rigorous techniques have shown no effect on nutrient absorption with GH treatment in human patients [84, 85], whereas a variety of animal studies have shown conflicting results [86–88]. Kissmeyer-Nielsen et al. [89] administrated GH to TPN patients with gastrointestinal diseases and reported its protein-sparing effect, a reduced incidence of infection, and a decrease in malaise. Concerning the proliferating effect of GH on intestinal mucosa, a number of animal studies have demonstrated its beneficial effect on structural maintenance, adaptation and wound healing [90]. If GH does affect the adaptive process, it is likely this effect is mediated through IGF-I [24]. Sigalet and Martin [28], in their experimental study, documented that GH administration improved weight gain which resulted as a consequence in nutrient absorption characteristics [12, 29, 30]. Their experimental evidence raises the hypothesis that GH is acting indirectly through endocrine pathways, enhancing nutrient transport. Gu et al. showed, in a rat model, that GH enhanced small bowel adaptation. This result indicated that application of GH could alleviate mucosal atrophy of the remnant small intestine caused by PN and improve intestinal adaptation significantly in short bowel rats [91]. Short-Chain Fatty Acids (SCFAs) SCFAs are formed in the gastrointestinal tract of mammals by microbial fermentation of carbohydrates, and readily absorbed by intestinal and colonic mucosa, and are trophic to intestinal mucosa. Acetate, propinate and butyrate account for about 85% of SCFAs and are produced in a nearly constant molar ratio of 60:25:15 [92]. One week of SCFA supplementation has been shown to retard TPN-associated atrophy in rats with intact bowels [93] and after 80% intestinal resection [94]. Recent studies have reported that SCFA-supplemented TPN enhanced both structural [95] and functional [96] adaptation to 80% intestinal resection as early as 3 days after surgery. SCFAs may influence small intestinal mucosal proliferation by stimulating secretion of PGDPs. Intestinal proglucagon mRNA abundance and plasma concentrations of PGDPs are strongly correlated with cellular proliferation during intestinal adaptation [97–100]. Precise physiologic roles for each of the PGDPs continue to be elucidated, however, it was shown recently that GLP-2 modulates basolateral membrane glucose transport in rats [101]. Other studies showed that SCFA-supplemented TPN increases proglucagon gene expression 3 and 7 days after intestinal resection [95]. Physiologically,


SCFAs are a logical mediator of trophic gastrointestinal hormones (i.e., PGDPs) and ileal adaptation because they are produced distally within the gastrointestinal tract in response to malabsorbed substrate. Many studies have established a strong relation between cellular proliferation and elevated amounts of proglucagon mRNA and PGDPs [97, 98, 102–104]. Taylor et al. [100] reported that after intestinal resection, proglucagon expression increased threefold, peaking 2 days after surgery and declining thereafter. In a recent study it was shown that SCFA-supplemented TPN increased proglucagon mRNA abundance [95]. Tappenden et al. [105] showed that SCFA-supplemented TPN rapidly upregulated jejunal GLUT-2 mRNA (glucose transporter 2) and ileal GLUT-2 abundance and ileal proglucagon mRNA. Within the intestinal resection model, SCFAs may exert their trophic effect by extending the duration of increased proglucagon expression. Glutamine (Gln) Gln is the most abundant nonessential amino acid in the body. The most important function of Gln lies in its metabolic role as a nitrogen carrier between major organs. Gln prevents the degeneration of muscle protein, maintains body protein levels at the time of surgical stress and is involved in the maintenance of intestinal epithelial cell function as an energy source. A number of studies suggest that Gln is conditionally essential for gut metabolism, structure and function in the stressed animal [106, 107]. Gln has therefore been postulated to be of crucial importance for the integrity and growth of small intestinal mucosa [108, 109]. Wiren et al. [110] were not able to show better adaptation using Gln supplementation to the diet compared to chow feeding, whereas several studies confirmed that a dipeptive alanyl-Gln-enriched TPN solution could increase the growth of the intestinal mucosa in animals with intestinal atrophy due to TPN [111] and massive bowel resection [112]. Dipeptive alanyl-Glnenriched TPN solution could also have a protective effect on the mucus covering the surface of the intestinal mucosa [113]. For the clinical efficacy of Gln, several studies have been performed demonstrating conflicting results [114– 116]. Specifically, concerning the effect of Gln on intestinal function, Wilmore et al. [117] treated 300 short bowel patients with a combination of GH, Gln and high carbohydrate diet, and reported that 60% of the patients could be weaned from TPN, in 30% TPN could be reduced, and the remaining 10% still required the same quantity of

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TPN. This result shows the importance of such a combination therapy in the adaptive process of SBS. On the contrary, Scolapio et al. [84] reported no improvements in small bowel morphology (villus height, crypt depth), stool losses and macronutrient absorption in response to active treatment with GH, Gln and high-carbohydrate, low-fat diet when compared with placebo carbohydrate in a randomized, crossover study in 8 patients with well-established SBS. Additionally, Mandir and Goodlad [118] also found there was no effect of Gln supplementation on mitotic activity in the small intestine. Alavi et al. [119] have also demonstrated that enteral Gln does not promote adaptation either alone or in combination with hepatocyte growth factor in resected rats. However, further clinical studies need to be conducted to confirm the efficacy of Gln-enriched TPN formulas in the treatment of intestinal failure.

Conclusions

Growth factors augment intestinal proliferation, diminish programmed apoptosis, and modulate the adaptive process. They also have the potential to improve nutrient absorption in some bowel diseases. The enhancement of gut adaptation may allow the patient’s transition from parenteral/enteral to normal nutrition in a shorter period of time, which reduces the rate of adverse effects caused by artificial nutrition and improves quality of life. These data confirm that gut-trophic agent administration may be of benefit to patients with IF during adaptation. In addition, bowel adaptation enhancement could be useful in the therapeutic management of patients with malabsorption syndromes. Although beneficial effects of these trophic agents have been observed in human and animal studies, further research and analysis is required for their clinical applicability.

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Helicobacter pylori Infection, Vitamin B12 and Homocysteine A Review

Jutta Dierkes a Matthias Ebert b Peter Malfertheiner b Claus Luley a a Institute

of Clinical Chemistry and Biochemistry, and b Department of Gastroenterology and Hepatology, University Hospital Magdeburg, Magdeburg, Germany

Key Words Helicobacter pylori infection W Vitamin B12 deficiency W Homocysteine W Pernicious anemia

Abstract It has been suggested that there is an association between Helicobacter pylori infection, reduced cobalamin absorption and cobalamin status and, consequently, elevated homocysteine levels. This would offer an explanation why H. pylori infection is associated with coronary heart disease. To date, more than 25 studies have been published that either deal with H. pylori infection and homocysteine, H. pylori infection and cobalamin status, or both. The design of these studies differs widely in terms of definition of H. pylori status, measuring cobalamin status, selection of study cohorts and geographical study areas. Therefore, results are fairly inconclusive at present and do not suggest a major role of H. pylori infection in the development of cobalamin deficiency and elevated homocysteine levels. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0213–0237$19.50/0



Introduction

The aetiology of atrophic gastritis and gastric cancer has been rewritten since the detection of Helicobacter pylori during the 1980s. It is now known that the major cause of atrophic gastritis is an infection with H. pylori, which normally occurs in early childhood and persists lifelong if left untreated. Prevalence rates of H. pylori infection vary by age, country of origin, socioeconomic status and are typically about 20–50% in healthy adults in Western Europe and 80% in adults in economically less developed countries [1]. Although the infection will cause gastric inflammation in virtually all infected subjects, the majority of infected subjects will remain asymptomatic, while others develop atrophic gastritis and subsequently gastric ulcer which can further develop to gastric cancer [2]. One severe consequence of atrophic gastritis is the malabsorption of cobalamin (vitamin B12), which is frequent in the elderly due to hypo- or achlorhydria with subsequent bacterial overgrowth, and reduced production and secretion of intrinsic factor [3]. It has been suggested that H. pylori infection may play an important role in the reduction of acid production, reduced intrinsic factor secretion and therefore the development of vitamin B12 deficiency. However, development of vitamin B12 defi-

Dr. Jutta Dierkes Institute of Clinical Chemistry and Biochemistry Leipziger Strasse 44, DE–39120 Magdeburg (Germany) Tel. +49 391 6713900, Fax +49 391 6713902 E-Mail [email protected]

Table 1. Studies on H. pylori and cobalamin, pernicious anemia and homocysteine

Group (first author) Cobalamin Van Asselt, 1998 [21] Pilott, 1996 [22] Cenerelli, 2002 [23] Bloemenkamp, 2001 [24] Shuval-Sudai, 2003 [25] Tamura, 2002 [26]

Patients

Effect with H. pylori

Mild cobalamin deficiency in healthy elderly Serum cobalamin and folate in elderly Serum cobalamin and folate in diabetes mellitus type 2 Serum cobalamin and folate women with peripheral artery disease Serum cobalamin in outpatients

No association No association No association No association Higher frequency of low serum cobalamin in H.pyloripositive patients Lower serum cobalamin and folate in patient with H. pylori Lower food cobalamin absorption in H.pylori-positive patients Serum cobalamin related to atrophy and inflammation and H.pylori density

Serin, 2002 [29]

Serum cobalamin and folate in patients with coronary artery disease Food cobalamin malabsorption in patients with low cobalamin Gastric histology and serum cobalamin

Pernicious anemia Fong, 1991 [11] Haruma, 1995 [12] Marignani, 1999 [13] Annibale, 2001 [14] Andres, 2003 [15] Annibale, 2000 [16] Kaptan, 2000 [17] Avcu, 2001 [18] Ma, 1994 [19]

Pernicious anemia, case-control study Pernicious anemia, case-control study Patients with macrocytic anemia Pernicious anemia Cobalamin-deficient elderly Pernicious anemia Vitamin B12-related anemia Vitamin B12 deficiency Pernicious anemia

No association No association No association No association No association Frequency of H. pylori-positive patients: 60% Frequency of H. pylori-positive patients: 56% Frequency of H. pylori-positive patients: 57% Frequency of H.pylori-positive patients: 83%

Homocysteine Saxena, 1997 [30] Leung, 2001 [31] Yoshino, 2002 [32] Bloemenkamp, 2001 [24] Tamura, 2002 [26] Whincup, 2000 [33] Cenerelli, 2002 [23]

Patients Dyspeptic patients Case-control H. pylori-positive vs. -negative Women with peripheral artery disease and controls Patients with coronary artery disease Prospective study on CVD Patients with diabetes mellitus type 2 and controls

No association No association No association No association Higher homocysteine in H. pylori-positive patients Higher homocysteine in H. pylori-positive patients Higher homocysteine in H. pylori-positive patients

Effect of eradication therapy Leung, 2001 [31] Kaptan, 2000 [17]

Dyspeptic patients Patients with low vitamin B12 and anemia

Avcu, 2001 [18]

Vitamin B12 deficiency anemia

Serin, 2002 [29]

Low serum cobalamin, no anemia

No change in homocysteine Increase in serum cobalamin and improvement in haematological variables Increase in serum cobalamin and improvement in haematological variables Increase in serum cobalamin

Carmel, 2001 [28]

ciency occurs slowly due to the low requirement (2 Ìg/ day), the enterohepatic cycle of cobalamin and the liver stores of the vitamin that have been built up during life and that are about 2–3 mg of cobalamin by the age of 60 [3]. The classical sign of vitamin B12 deficiency is megaloblastic anaemia which, however, occurs in only 50% of vitamin B12-deficient subjects. Other signs of vitamin B12

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deficiency which are often overlooked are psychiatric and neurodegenerative changes [4]. Diagnosis of vitamin B12 deficiency is usually made by low serum cobalamin concentrations which, however, has an only low diagnostic sensitivity [5]. Other diagnostic tools to detect vitamin B12 deficiency are the measurement of specific metabolites such as homocysteine and methylmalonic acid [6, 7]. With the exception of homocysteine, these diagnostic

Dierkes/Ebert/Malfertheiner/Luley

tools require specialized equipment and are not offered routinely. Lack of intrinsic factor causing pernicious anaemia is classically diagnosed by the Schilling test. This test, however, will not detect malabsorption of food-bound cobalamin, since free, crystalline vitamin B12 is used during the Schilling test. Therefore, another test, the egg yolk cobalamin absorption test (EYCAT) has been introduced for the diagnosis of malabsorption of food-bound cobalamin [8]. However, this test is not widely used. The interest in the association of H. pylori infection with cobalamin status is further triggered by the association of low cobalamin status with hyperhomocysteinaemia which is a widely acknowledged risk factor of atherosclerosis [9]. The association between H. pylori – low cobalamin – elevated homocysteine offers a metabolic explanation why H. pylori infection is associated with increased risk for cardiovascular disease, especially coronary heart disease [10]. This review summarizes the present knowledge of the association of H. pylori, cobalamin and homocysteine concentrations. It considers studies published in English until April 2003 (table 1).

Helicobacter and Pernicious Anaemia

If H. pylori indeed causes cobalamin deficiency, an association of H. pylori with pernicious anaemia could also be expected. This issue was investigated by a number of studies in patients with pernicious anaemia which, however, could not prove this hypothesis and even showed a lower prevalence of H. pylori infection in patients with pernicious anaemia. Fong et al. [11] studied the frequency of H. pylori infection in 28 patients with pernicious anaemia and 28 agematched control subjects (mean age 59 B 14 years). Diagnosis of H. pylori infection was made by gastric biopsy and serology. Positive biopsies were found in 3 of 28 patients with pernicious anaemia (11%) in contrast to 20 of 28 control subjects (71%). A similar result was reported by Haruma et al. [12], who investigated 24 patients with pernicious anaemia and 24 age-matched control subjects. H. pylori status was diagnosed by biopsies and IgG antibodies. No patient with pernicious anaemia but 67% of control subjects were H. pylori-positive. A low frequency of H. pylori infection in patients with macrocytic anaemia in comparison to microcytic anaemia was also reported by Marignani et al. [13]. H. pylori status was diagnosed by biopsy and IgG antibodies. Patients with macrocytic

H. pylori Infection, Vitamin B12 and Homocysteine

anaemia were older than those with microcytic anaemia, had lower vitamin B12 levels and higher gastrin levels, but only 2 of 44 patients were H. pylori-positive in contrast to 22 of 36 patients with microcytic anaemia. Annibale et al. [14] investigated 150 patients with atrophic body gastritis. Patients were grouped according to their H. pylori status and the prevalence of pernicious anaemia. 37 patients were H. pylori-negative by both serology and histology; 79 patients were negative by histology but positive by serology and 34 patients were positive by both serology and histology. The lowest frequency of pernicious anaemia was found in patients being positive by serology and histology (12%), an intermediate frequency was found in the group with negative histology but positive serology (46%) and the highest frequency of pernicious anaemia was found in the group negative for H. pylori (76%). Andres et al. [15] investigated the H. pylori infection status in 60 elderly patients who had been selected by cobalamin deficiency due to food-cobalamin malabsorption and who presented with polyneuropathy (35%), dementia and confusion (30%) and anaemia (27%). Gastric atrophy was documented in 19 out of 32 investigated patients, but infection with H. pylori was documented in only 1 of the patients. The above cited studies suggest that the hypothesis that H. pylori is a causative factor in pernicious anaemia does not hold true and that H. pylori infection is even protective in the development of cobalamin-associated anaemia. However, some other studies report that patients with pernicious anaemia have H. pylori infection rates comparable to the normal population. Annibale et al. [16] reported that 49 of 81 patients with pernicious anaemia were positive for H. pylori infection (60%), although only 8 showed a positive histological H. pylori status and 41 were positive by serological investigation. A Turkish study revealed comparable results [17]. They investigated 138 patients with vitamin B12 deficiency and anaemia which was not due to intrinsic factor deficiency or gastrectomy. Diagnosis of H. pylori infection was confirmed by rapid urease testing and gastric biopsies in 77 of 138 patients (56%). Another study from Turkey [18] reported that among 421 patients with vitamin B12 deficiency, H. pylori infection was detected in 241 of them (57%). A small Swedish study [19] involving 30 patients with pernicious anaemia reported that 25 of them had antibodies against H. pylori (83%). Thus, so far, studies revealed heterogeneous data on the association of H. pylori infection and cobalamin-related anaemia. However, it has been suggested that the low

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frequency of H. pylori infection in total gastric atrophy can be explained by the fact that infected subjects become Helicobacter-negative as a result of the virtual absence of acid production which inhibits survival of H. pylori [20]. This would mean that the low frequency of H. pylori infection reported by some of the studies reflects a falsenegative result. As all studies on this issue had a crosssectional design, a definitive answer cannot be given at present. Longitudinal studies, however, are difficult to perform and are ethically questionable.

Helicobacter and Subclinical Cobalamin Deficiency

Vitamin B12 deficiency is rare in young adults and has an increasing prevalence in the elderly. Development of vitamin B12 requires years and depends mainly on presence of achlorhydria and on whether intrinsic factor is present or absent, since the intrinsic factor is necessary to maintain the enterohepatic circle of cobalamin. Thus, hypo- and achlorhydria which compromise food-cobalamin absorption must be present for long time before vitamin B12 deficiency occurs. Furthermore, subclinical vitamin B12 deficiency is difficult to diagnose as haematological changes are rare in this stage. Therefore, it is mainly diagnosed by low serum cobalamin or metabolic changes as elevated concentrations of the metabolites homocysteine or methylmalonic acid. Studies have also investigated whether food-cobalamin malabsorption is associated with H. pylori infection and whether the degree of gastric atrophy can be linked to cobalamin deficiency. Van Asselt et al. [21] investigated the determinants of cobalamin deficiency in healthy elderly, but did not find a statistically significant association of H. pylori infection with mild cobalamin deficiency. The study included 105 healthy elderly Dutch subjects (age range 74–80 years) who were classified according to cobalamin and methylmalonic acid concentrations as ‘cobalamin-deficient’ (n = 25), ‘possibly cobalamin-deficient’ (n = 53) or ‘not cobalamin-deficient’ (n = 27). H. pylori IgG antibodies were found in 54, 68 and 44% of the respective groups. Thus, it was concluded that both H. pylori infection and mild cobalamin deficiency was common in this cohort, but H. pylori infection did not contribute significantly to cobalamin deficiency. Also, other studies did not find a difference in cobalamin levels between H pylori-positive and -negative patients. Pilott et al. [22] reported no effect of H. pylori infection on nutritional indices including serum cobala-

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min and folate in 102 elderly. H. pylori antibodies were found in 84% of the elderly. Cenerelli et al. [23] investigated patients with diabetes mellitus type 2 and controls and found no effect of H. pylori infection on the level of cobalamin. Even higher cobalamin levels were reported by Bloemenkamp et al. [24] in H. pylori-positive subjects in a study including women with peripheral artery disease and controls. Since the latter two studies also investigated homocysteine, they are described in detail below. On the other hand, a significant association of H. pylori infection and prevalence of low cobalamin concentrations was reported by Shuval-Sudai and Granot [25]. 133 patients were investigated in Israel for H. pylori infection and cobalamin and folate status. Patients were enrolled in a community primary care clinic, were between 18 and 90 years of age, and were eligible for the study if they had no history of H. pylori eradication, previous gastrointestinal disease or surgery, vegetarian diet or multivitamin use. H. pylori status was assessed by IgG antibodies. A significantly higher frequency of low cobalamin levels (cut-off !250 pg/ml) was found in H. pylori-positive patients (n = 96). Similar results were obtained with the lower cut-off level of 180 or 145 pg/ml. Interestingly, lower folate levels were observed in the H. pylori-positive patients. A similar result was reported by Tamura et al. [26] who investigated 93 patients with coronary artery disease and observed both lower cobalamin and folate levels in patients positive for H. pylori. H. pylori infection was diagnosed by biopsies. In this study, homocysteine was also investigated (see below). Reasons for differences in cobalamin status due to H. pylori infection may be that H. pylori infection affects the absorption of either food-cobalamin or free cobalamin which can be studied employing the EYCAT test or the Schilling test, respectively. In particular, food-cobalamin malabsorption has been investigated with respect to H. pylori infection. The contribution of different factors to food-cobalamin malabsorption was studied in a small group of 19 volunteers by Cohen et al. [27]. Volunteers had been selected on the basis of age and their cobalamin levels to ensure a wide range of deficient and replete subjects. Food-cobalamin absorption was tested using the EYCAT. H. pylori status was determined by biopsies and 13C-urea breath tests. Gastric function was investigated by basal and pentagastrin-stimulated gastric aspirates, and gastric inflammation and atrophy were scored on scales ranging from 0 to 3 and 1 to 4, respectively. Six of the 19 patients had severe food cobalamin malabsorption. Three of them also


had H. pylori infection and antral gastritis while the other 3 patients did not have H. pylori infection but corpus atrophy with achlorhydria. The issue whether H. pylori infection affects food-cobalamin malabsorption was further studied by Carmel et al. [28]. Data of 202 subjects who underwent the EYCAT test in their clinic, among them 43 healthy volunteers and 159 patients with low cobalamin levels, were analysed retrospectively. H. pylori infection was confirmed either by the presence of IgG antibodies or the 13C-urea breath test. Determination of H. pylori status was done in 167 subjects and in 133 subjects, serum pepsinogen I and II were measured, while serum gastrin and parietal cell antibodies were assayed in 158 subjects. Severe food-cobalamin malabsorption was found in 24% of the patients with low cobalamin levels and in 9% of the healthy volunteers. The mean excretion rate of radiolabelled cobalamin during the EYCAT was significantly lower in H. pylori-positive subjects than in H. pylori-negative subjects (2.26 B 1.90% vs. 3.43 B 2.22%). H. pylori infection was associated with presence of severe food-cobalamin malabsorption (78% H. pylori-positive subjects vs. 50% H. pylori-positive subjects in mild food-cobalamin malabsorption and 44% H. pylori-positive subjects with normal absorption). In a multivariate regression analysis using data of 136 subjects, ethnic origin, age, H. pylori status, and serum gastrin contributed independently to the EYCAT result. Thus, present studies support the view that H. pylori infection interferes with food-cobalamin absorption, although results by Cohen et al. [27] suggest that different mechanisms may be involved. Further studies investigated whether cobalamin status is related to gastric atrophy or inflammation. Serin et al. [29] selected 145 patients from a gastroenterological clinic who did not show signs of atrophy, erosions, or ulcers. Biopsy specimen of the gastric antrum and corpus were taken and analysed for signs of inflammation, gastritis and H. pylori density. Vitamin B12 was measured in serum. Histopathological scores for both antral and corpus H. pylori density and inflammation were significantly inversely associated with serum vitamin B12 levels. In multivariate analyses, only H. pylori density was associated with vitamin B12 levels.

Is Helicobacter Infection Related to Hyperhomocysteinaemia?

Although the role for H. pylori in the development of cobalamin deficiency is not clear, it offers an attractive explanation why H. pylori infection could be associated


with hyperhomocysteinaemia. A further link may exist due to the observed effect of H. pylori on folate status. Both vitamin B12 and folate status are important for maintenance of low homocysteine concentrations. Present evidence suggests that elevated homocysteine concentrations are independently associated with increased risk for cardiovascular disease. Thus, hyperhomocysteinaemia in patients with H. pylori infection may be one mechanism by which H. pylori is associated with coronary heart disease. However, an association of H. pylori infection and homocysteine concentrations was not reported in a number of studies. Saxena et al. [30] investigated homocysteine in 220 subjects (mean age 66 B 10 years). They reported no differences in homocysteine levels in patients with positive serology for H. pylori (n = 122) compared to those with no antibodies against H. pylori. The result remained the same after analyzing men and women separately. Interestingly, the values reported by the authors are remarkably high with a mean homocysteine value of 22.7 B 11 Ìmol/l. A similar result was reported by Leung et al. [31] who investigated the association between H. pylori and homocysteine in 49 patients with dyspepsia referred for endoscopy. Patients were relatively young (median age 43 years), and 37 were found to be H. pylori-positive by gastric biopsies. There was no difference in homocysteine in infected compared to non-infected subjects and no association of homocysteine to gastric histology or H. pylori density. A Japanese study [32] included 45 healthy middleaged subjects infected with H. pylori and 45 age-matched controls without infection. The mean age was 39 years in both groups. H. pylori infection was diagnosed by 13Curea breath test and serology. No difference was found in plasma homocysteine between patients and controls. None of these studies investigated cobalamin or folate status. No difference in homocysteine according to H. pylori status was found in 150 women with peripheral artery disease and 412 control women [24]. H. pylori was diagnosed by positive IgG antibody test. The frequency of H. pylori infection in PAD patients was 42% in comparison to 27% in control subjects, resulting in an odds ratio for PAD of 2.0 (1.3–2.9). Homocysteine was significantly higher in patients than in controls, however, adjustment for homocysteine did not alter substantially the association between H. pylori and PAD. In this study, folate and vitamin B12 levels were also measured. No difference was found in homocysteine and folate levels between H. pylo-

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ri-positive and -negative patients and even higher cobalamin levels were measured in H. pylori-positive subjects. The authors conclude that homocysteine cannot explain the association between H. pylori infection and atherosclerosis. It has to be noted that the blood sample for analyses was taken between 1998 and 2000, while the diagnosis of PAD was made between 1990 and 1999. In contrast to the above-mentioned reports on lack of association between H. pylori and homocysteine concentrations, other investigators reported significantly higher levels of homocysteine in H. pylori-positive patients. Tamura et al. [26] studied homocysteine, related vitamins and H. pylori infection in 93 Japanese patients who underwent coronary arteriography. The mean age of the patients was 64 B 9 years, and 57 of them were found to be H. pylori-positive as diagnosed by stomach biopsies. Significantly lower cobalamin and folate levels and higher levels of homocysteine were found in H. pylori-positive patients than in H. pylori-negative patients. Homocysteine was weakly, but significantly related to the atrophic score of the stomach of the patients. Whincup et al. [33] reported higher homocysteine levels both in H. pylori-positive patients with coronary heart disease and in healthy controls which have been prospectively investigated in the British Regional Heart Study. However, the effect of H. pylori infection was, although significantly, not very strong and increased the homocysteine modestly. No vitamin levels were reported in this study. Cenerelli et al. [23] investigated homocysteine in patients with diabetes type 2 and healthy controls (n = 30 and 43, respectively) and found no difference between patients and controls. However, subjects with H. pylori infection showed significantly higher homocysteine concentrations. The diagnosis of H. pylori was made by 13Curea breath test. There was no difference in folate or cobalamin between H. pylori-positive and -negative subjects.

change in homocysteine concentration after eradication (10.5 vs. 10.2 Ìmol/l). A number of studies reported a spontaneous improvement of vitamin B12 status after H. pylori eradication, without specific treatment with cobalamin. Serin et al. [29] investigated 65 of 145 patients after eradication therapy. At baseline, 145 patients with no gastric atrophy, erosion or ulcers were included. Patients were then given an eradication therapy and 65 of the patients were re-analyzed 2–3 months later. Baseline cobalamin levels were indicative for cobalamin deficiency although no anaemia was present. In 33 of these 65 patients, eradication therapy was successful. The authors observed a significant increase in vitamin B12 after eradication therapy with a more pronounced increase in those with complete eradication. Avcu et al. [18] investigated 108 H. pylori-infected patients where H. pylori was also present in dental plaques and who suffered from vitamin B12 deficiency and from signs of anaemia. Mean patient age was 44 years. After eradication therapy, gastric biopsies were repeated in 61 patients and confirmed the successful eradication therapy. Haematological parameters (red blood cell count, haemoglobin, haematocrit and MCV) improved significantly as well as vitamin B12 levels which increased from 71 B 11 to 293 B 11 pg/ml. Mean follow-up time was 15 B 1 months and no treatment for vitamin B12 deficiency was given. A similar effect of eradication therapy was observed by Kaptan et al. [17]. Eradication therapy was given to 77 patients with a positive H. pylori biopsy who were also anaemic and had low cobalamin levels. In 31 patients, H. pylori eradication therapy was successful and the cobalamin level and the blood count were re-investigated after a mean follow-up time of 42 B 19 months. There was a significant improvement in haematocrit, and MCV, and a significant increase in serum cobalamin at re-investigation (63 B 30 to 223 B 38 pmol/l). Patients with unsuccessful eradication therapy received cyanocobalamin therapy, but results were not reported.

Does H. pylori Eradication Affect Cobalamin Status and Homocysteine? Discussion

There are a few studies that investigate the effect of H. pylori eradication therapy on homocysteine or cobalamin levels. The only study that investigated homocysteine was reported by Leung et al. [31] who treated 37 dyspeptic patients. Eradication was confirmed by a negative 13Curea breath test. After 24 weeks, homocysteine was measured again in these patients. There was no significant

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Although the hypothesis on the association of H. pylori infection, cobalamin and homocysteine status is clear and intriguing, the results of the clinical studies on this association revealed highly disparate results and do not clearly support the hypothesis. On the other hand, there is evidence that cobalamin status improves after H. pylori erad-


ication suggesting a causal effect of H. pylori in the development of cobalamin deficiency. The different results on H. pylori and cobalamin status may depend on study design, selection of patients and variables measured. Cobalamin status in the studies varies widely with pernicious anaemia as the ‘tip of the iceberg’ in cobalamin deficiency, and milder forms of cobalamin deficiency that are not always clearly defined. It has to be considered that many patients with cobalamin malabsorption do not develop pernicious anaemia at all or only after decades. H. pylori infection obviously is associated with food-cobalamin malabsorption, but the association with cobalamin deficiency due to intrinsic factor deficiency was not demonstrated. Furthermore, the low prevalence of H. pylori infection in pernicious anaemia is a striking phenomenon that may be explained by the possibility that infected subjects become Helicobacter-negative as a result of the virtual absence of acid production which inhibits survival of H. pylori [20]. Most studies investigated the effect of H. pylori on serum cobalamin levels. However, serum cobalamin has been shown to have limited sensitivity to detect deficiency since many patients still have low-to-normal serum concentrations [6]. Instead, diagnosis of subclinical cobalamin deficiency should be based on metabolic markers like methylmalonic acid or homocysteine [5]. Most studies, however, did not use these additional diagnostic tools. How can the increase of vitamin B12 after eradication therapy be explained? The only study that also measured homocysteine after eradication did not find an effect of eradication on homocysteine [31]. Three studies reported on vitamin B12 response to eradication therapy. None of these studies reported individual data and in each case, a substantial portion of patients was missed during followup. Thus, it can be questioned whether the effect may be influenced by regression to the mean or selection bias. However, it is possible that there is a real effect since reversal of food-cobalamin malabsorption in atrophic gastritis after tetracycline therapy was reported earlier [34]. A likely mechanism is the reduction of bacteria in the stomach and small intestine in hypo- or achlorhydria. This finding supports the view that H. pylori infection may also play a role in food-cobalamin malabsorption. In addition to the association of H. pylori to cobalamin, studies on the association of H. pylori to homocysteine revealed also inconsistent results. A significant effect of H. pylori infection on plasma homocysteine was found in three of six studies. Besides cobalamin deficiency, folate deficiency is also associated to higher homocys-

teine concentrations. Lower folate concentrations in H. pylori-positive patients have been shown in two of four studies that also reported folate concentrations. Diminished folate absorption has been shown in patients with atrophic gastritis [35], but the effect of H. pylori infection has not been investigated in particular. In conclusion, clinical studies do not show a uniform association of H. pylori infection with cobalamin or folate deficiency or elevated homocysteine concentrations. Therefore, routine determination of cobalamin or homocysteine in H. pylori-infected patients as a means of prevention of deficiency or with respect to atherosclerotic risk cannot be recommended at present. On the other hand, the studies do suggest that H. pylori infection has a role in atrophic gastritis and food-cobalamin malabsorption. Subgroups of infected patients are obviously at risk of developing cobalamin deficiency and hyperhomocysteinaemia, who are not identified at present. Before a concise recommendation can be given, more data in patient groups with a well-defined cobalamin status are needed.


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Acknowledgement M. Ebert is supported by the Heisenberg-Programme of the DFG (Eb 187/5-1).

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25 Shuval-Sudai O, Granot E: An association between Helicobacter pylori infection and serum vitamin B12 levels in healthy adults. J Clin Gastroenterol 2003;36:130–133. 26 Tamura A, Fujioka T, Nasu M: Relation of Helicobacter pylori infection to plasma vitamin B12, folic acid and homocysteine levels in patients who underwent diagnostic coronary arteriography. Am J Gastroenterol 2002;97:861– 866. 27 Cohen H, Weinstein WM, Carmel R: Heterogeneity of gastric histology and function in food cobalamin malabsorption: Absence of atrophic gastritis and achlorhydria in some patients with severe malabsorption. Gut 2000;47:638– 645. 28 Carmel R, Aurangzeb I, Qian D: Associations of food-cobalamin malabsorption with ethnic origin, age, Helicobacter pylori infection, and serum markers of gastritis. Am J Gastroenterol 2001;96:63–70. 29 Serin E, Gumurdulu Y, Ozer B, Kayaselcuk F, Yilmaz U, Kocak R: Impact of Helicobacter pylori on the development of vitamin B12 deficiency in the absence of gastric atrophy. Helicobacter 2002;7:337–341. 30 Saxena V, Markus H, Swaminathan S, Mendall ME: Hyperhomocysteinaemia, Helicobacter pylori and coronary heart disease. Heart 1997; 78:524. 31 Leung WK, Ma PK, Choi PC, Ching JY, Ng AC, Poon P, Woo KS, Sung JJ: Correlation between Helicobacter pylori infection, gastric inflammation and serum homocysteine concentration. Helicobacter 2001;6:146–150. 32 Yoshino N, Adachi K, Takashima T, Miyaoka Y, Yuki T, Ishihara S, Kinoshita Y: Helicobacter pylori infection does not affect the serum level of homocysteine. Am J Gastroenterol 2002;97:2927–2928. 33 Whincup P, Danesh J, Walker M, Lennon L, Thomson A, Appleby P, Hawkey C, Atherton J: Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation 2000; 101:1647–1652. 34 Suter PM, Golner BB, Goldin BR, Morrow FD, Russell RM: Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 1991;101: 1039–1045. 35 Russell RM, Krasinski SD, Samloff IM, Jacob RA, Hartz SC, Brovender SR: Folic acid malabsorption in atrophic gastritis. Possible compensation by bacterial folate synthesis. Gastroenterology 1986;91:1476–1482.


Original Paper Dig Dis 2003;21:245–251 DOI: 10.1159/000073342

Prevalence of Malnutrition in Hospitalized Medical Patients: Impact of Underlying Disease Matthias Pirlich a Tatjana Schütz a Martin Kemps a Niklas Luhman a Gerd-Rüdiger Burmester b Gert Baumann c Mathias Plauth d Heinrich Josef Lübke e Herbert Lochs a a Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie, b Rheumatologie und klinische Immunologie, c Kardiologie, Pulmonologie und Angiologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin; d Klinik für Innere Medizin, Städtisches Klinikum Dessau und e Medizinische Klinik I, Krankenhaus Zehlendorf, Berlin, Deutschland

Key Words Malnutrition, prevalence W Malnourished hospitalized patients W Subjective global assessment W Gastrointestinal diseases W Malnutrition, diagnoses

Abstract Background/Aims: Malnutrition is common among hospitalized patients. We investigated whether certain diseases predispose more frequently for malnutrition than others. Methods: Nutritional state was assessed by clinical scores, anthropometry and bioimpedance analysis in 502 consecutively admitted patients in the departments of internal medicine in two hospitals in Berlin (n = 300, university hospital; n = 202, district hospital). The prevalence of malnutrition was compared in patient groups with a different diagnosis. Results: Malnutrition was present in 24.2% of all patients. A clear association between diagnoses and malnutrition was found: the prevalence of malnutrition was significantly higher in malignant than in non-malignant diseases (50.9 vs. 21.0%, p ! 0.0001). High prevalence rates 1 30% were observed in subgroups of patients with inflammatory bowel diseases, chronic heart failure and benign lung

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0213–0245$19.50/0



diseases. Patients with gastrointestinal diseases, however, were not more frequently malnourished than other medical patients (28.8 vs. 22.0%). Malnourished patients were significantly older (70.0 B 13.6 vs. 58.3 B 15.6 years, p ! 0.0001) and had a 40% longer hospital stay (13.1 B 8.1 vs. 9.3 B 6.8 days, p ! 0.0001) than wellnourished patients. Conclusions: Patients with malignancies, inflammatory bowel disease, chronic heart failure and benign lung diseases need special attention due to the high prevalence of malnutrition. Copyright © 2003 S. Karger AG, Basel

Introduction

Malnutrition is a frequent finding in hospitalized patients [1–7]. Data on the prevalence of malnutrition in these patients, however, differ considerably according to the population investigated and the definitions used. From a number of studies performed during the last 30 years, predominantly in the US and UK, it can be estimated that about 20–50% of all medical and surgical patients admitted to hospitals show signs of malnutrition [8]. Malnutrition has been found to be associated with

Dr. med. Matthias Pirlich Medizinische Klinik und Poliklinik Universitätsklinikum Charité, Humboldt-Universität zu Berlin DE–10098 Berlin (Germany) Tel. +49 30 450 514006, Fax +49 30 450 514923, E-Mail [email protected]

Table 1. Participating specialities

University hospital Gastroenterology Cardiology Rheumatology Community hospital Gastroenterology Cardiology All patients

Table 2. Distribution of diagnoses

n

Gender, m/f Age (mean B SD)

100 100 100

48/52 74/26 37/63

56.9B16.3 62.0B12.0 52.2B15.5

101 101 502

38/63 39/62 236/266

65.0B15.7 69.6B14.4 61.2B16.0

increased morbidity [2, 4], with prolonged hospital stay at substantial extra cost of health care [7, 9, 10], and with increased mortality especially in elderly patients [3, 5, 11]. The association between malnutrition and poor survival is especially established in cancer patients [7, 8, 12]. However, despite an increasing number of studies in other countries, the influence of diagnoses on the development of malnutrition in medical patients is unclear. It has been suggested that patients with digestive diseases are at higher risk of developing malnutrition than patients with other internal diseases [4, 7]. The primary objectives of this study were (1) to estimate the overall prevalence of malnutrition among medical patients and (2) to evaluate the impact of diagnoses on the prevalence of malnutrition. The study was performed in two hospitals with different settings (one university hospital and one community hospital) in the city of Berlin, Germany.

Diagnoses

n

%

Gastrointestinal diseases Chronic liver disease Malignancies of liver, pancreas or bile ducts Gastrointestinal malignancies Gastrointestinal bleeding Benign pancreatic or biliary diseases Inflammatory bowel disease Reflux disease Other gastroenterology Gastroenteritis (without salmonella infection) Other benign intestinal diseases (colonic polyps, IBS, diverticulosis) All gastrointestinal diseases

45 22 17 16 13 10 10 8 7

9.0 4.4 3.4 3.2 2.6 2.0 2.0 1.6 1.4

8 156

1.6 31.1

Other internal diseases Coronary heart disease Arrhythmia Rheumatoid arthritis Heart failure Systemic infection Valvular defect Vasculitis/myositis Extraintestinal malignancies Systemic lupus erythematodes Cerebral ischemia All other diseases Benign lung diseases Other rheumatology Other cardiology Dermatosclerosis Diabetes mellitus Urology/kidney diseases Other collagenoses All other internal diseases

85 40 25 24 20 16 15 15 13 13 13 13 12 11 9 9 7 6 346

16.9 8.0 5.0 4.8 4.0 3.2 3.0 3.0 2.6 2.6 2.6 2.6 2.4 2.2 1.8 1.8 1.4 1.2 68.9

Patients and Methods Patients The study protocol was approved by the Ethics Committee of the Universitätsklinikum Charité. The nutritional state of 502 patients consecutively admitted to different specialities of internal medicine was studied in two different hospitals: 300 patients were included in the University Hospital Charité (specialities: gastroenterology (n = 100), cardiology (n = 100), and rheumatology (n = 100)), and 202 patients were included in the District Hospital of Zehlendorf (specialities: gastroenterology (n = 101) and cardiology (n = 101)). Patients were considered eligible for entry if they were over the age of 18, were assumed to stay longer than 2 days, and were willing and able to give written informed consent. Patients admitted to day care units or for observation after endoscopic or other invasive treatment and those admitted to intensive care units were excluded. The number of patients in each speciality, the distribution of gender and the mean age are given in table 1. Patients in the community hospital were slightly older than patients in the university hospital.

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For further classification of patients according to the different diseases, the main diagnoses determined at the time of discharge or referral from the speciality were used. Since there was an overlap of diagnoses between the different specialities, the data analysis of the nutritional state was not performed according to the speciality but to the main diagnoses of the patients. The distribution of diagnoses is given in table 2. 156 patients (31.1%) had diseases of the gastrointestinal tract, and 346 patients (68.9% of all patients) had other internal diseases. Assessment of Nutritional State Two investigators (N.L. and M.K) were trained by the principle investigator (M.P.) in performing the nutritional assessment. The nutritional state of the patients was assessed on the day of hospital admission according to clinical scores, anthropometric measurements, and to the results of bioelectrical impedance analysis. The subjective global assessment was used as the main criterion for the classification of malnutrition.

Pirlich/Schütz/Kemps/Luhman/Burmester/ Baumann/Plauth/Lübke/Lochs

Subjective Global Assessment (SGA) The SGA was established by Detsky et al. [13] and relies primarily on physical signs of malnutrition (loss of subcutaneous fat or muscle mass, edema, ascites) and the patient’s history regarding weight loss, dietary intake, gastrointestinal symptoms, functional capacity, and the disease and its relation to nutritional requirements. Each patient was classified as either well nourished (SGA A), moderately or suspected of being malnourished (SGA B) and severely malnourished (SGA C). The SGA requires only a few minutes by a trained clinician. Its validity to indicate malnutrition-associated risks of poor outcome has been proven in a number of studies [4, 5, 7, 12, 14]. Since subgroups of patients classified as SGA C were too small, comparative analyses were performed between malnourished patients classified as either SGA B or C and well-nourished patients classified as SGA A. Nutritional Risk Index (NRI) The NRI was developed by Buzby et al. [15] and is based on the serum albumin concentration and the ratio of actual to usual weight: NRI = 1.489 ! serum albumin (g/l) ! 41.7 ! (present weight/usual weight). Calculated values 1 100 indicate good nutritional state, 97.5–100 mild malnourishment, 83.5 to ! 97.5 moderate malnourishment, and ! 83.5 severe malnourishment. In our analysis, we used values ! 97.5 for classification of malnutrition. Bioelectrical Impedance Analysis (BIA) BIA was performed by the whole-body tetrapolar contact electrode approach applying an alternating electric current of 800 ÌA at 50 kHz (BIA 2000-M, Data Input GmbH, Frankfurt am Main, Germany). Two pairs of current-introducing and voltage-sensing electrodes were attached to the dorsum of hand and foot of the dominant side of the body [16]. Resistance (R), reactance (Xc) and the phase angle (·) were measured. All impedance measurements were taken under standardized conditions [17]. Patients with implanted cardiac pacemaker or defibrillator were excluded from BIA measurements because of possible interactions with even small electrical currents. Total body water was calculated as 0.69 ! H2/R + 0.8 [16] and fat free mass = total body water/0.732. Body cell mass (BCM) was calculated [18] as BCM = fat free mass ! 0.29 ! ln (·). According to Süttmann [19], a BCM ! 30% of body weight was considered as an indicator of protein malnutrition.

Table 3. Clinical characterization of the study population

Gender, m/f (%) Age, years Height, m Weight, kg BMI, kg/m2 Length of stay, days1

Gastrointestinal diseases (n = 156)

Other internal diseases (n = 346)

71/85 (45.5/54.5) 60.3B16.3 1.68B0.09 69.5B15.8** 24.6B4.5* 9.7B7.6 (n = 139)

165/181 (47.7/52.3) 61.6B15.9 1.69B0.09 74.4B15.0 25.9B4.6 9.8B6.7 (n = 299)

* p ! 0.01; ** p ! 0.001. 64/502 (12.7%) patients were transferred and are therefore not included.

1

Statistical Analysis All data are given as mean B SD. Comparison of mean values between two groups was performed by Mann-Whitney U-test, and differences in frequencies were compared by ¯2 test. p ! 0.05 was considered to be significant.

Results

Albumin Serum albumin was measured in the clinical chemistry laboratory by an automated analyzer using standard procedures, and values ! 3.5 g/dl were considered as indicators of impaired protein synthesis.

Age and gender distribution as well as body height were not different between patients with digestive diseases and patients with other internal diseases (table 3). Body weight and, thus, body mass index (BMI) were significantly lower in patients with digestive than in patients with other internal diseases (p ! 0.01). The average length of hospital stay was not different between both patient groups. Assessment of malnutrition by the SGA demonstrated that almost every fourth patient was malnourished (table 4). A similar result was obtained by using the NRI or the body cell mass (!30% of body weight) as criteria for malnutrition. Other parameters frequently used for the diagnosis of malnutrition such as BMI, upper arm anthropometry or albumin resulted in lower incidence values of malnutrition ranging from 3.8% for BMI to 14.5% for albumin. The incidence of malnutrition as defined by SGA was not significantly different between patients with gastrointestinal diseases and other medical patients. In contrast, the NRI indicated a significantly higher prevalence of malnutrition among patients with digestive diseases when compared with the other patients. Since the NRI includes serum albumin, it is not surprising that low serum albumin levels were also more frequently observed in gastrointestinal patients. Regarding BMI and weight loss 110% during the last 6 months prior to admission, there were no

Hospital Malnutrition

Dig Dis 2003;21:245–251

Anthropometry Body height was measured without shoes to the nearest 0.5 cm with a stadiometer. Weight was measured using calibrated Seca chair scales and compared with the body weight 6 months prior to admission to calculate weight loss. Midarm circumference was measured with a tape measure. Triceps skinfold thickness was measured using a Lange caliper (Holtain Ltd, Crymych, Dyfed, UK). The average of three measurements at each site was used for the calculation of arm muscle area and arm fat area according to Gurney and Jelliffe [20]. Measured arm muscle and arm fat area were compared with reference data [21], and values below the 10th percentile were considered as an indicator of malnutrition.

247

Table 4. Prevalence of malnutrition in all patients and in subgroups of patients with gastrointestinal vs. other internal diseases (% values in parentheses)

Nutritional scores SGA B+C Nutritional risk index ! 97.5 Albumin ! 3.5 g/dl Anthropometry BMI ! 18.5 kg/m2 Weight loss 1 10% body weight AMA ! 10th percentile AFA ! 10th percentile Impedance analysis BCM ! 30% body weight

All patients (n = 502)

Gastrointestinal diseases (n = 156)

Other internal diseases (n = 346)

121/501 (24.2) 107/435 (24.6) 63/434 (14.5)

45/156 (28.8) 52/138 (37.7) 34/138 (24.6)

76/345 (22.0) 55/297 (18.5) 29/296 (9.8)

ns p ! 0.001 p ! 0.001

19/501 (3.8) 48/501 (9.6) 51/496 (10.3) 55/495 (11.1)

8/156 (5.1) 17/156 (10.9) 23/153 (15.0) 22/153 (14.4)

11/345 (3.2) 31/345 (9.0) 28/343 (8.2) 33/342 (9.6)

ns ns p = 0.020 ns

123/453 (27.2)

43/147 (29.3)

80/306 (26.1)

ns

Prevalence of malnutrition (%)

SGA = Subjective global assessment; AMA = arm muscle area; AFA = arm fat area; BCM = body cell mass. Statistics: ¯2 test, gastrointestinal diseases compared to other diseases.

60

***

50 40 30 20 10 0

nt nt na es na es g i as g l i a al as m ise m ise d n d no

ga

s

al tin es s s te in sea tro di

rs he ot

Fig. 1. Prevalence of malnutrition as diagnosed by SGA in malignant (n = 54) vs. non-malignant (n = 448) diseases, and in gastrointestinal diseases vs. other internal diseases; *** p ! 0.0001.

differences observed between gastrointestinal patients and other medical patients. Regarding the results of upper arm anthropometry, we found that significantly more patients with gastrointestinal disease had a low arm muscle area than the other patients, but frequencies for arm fat area were not significantly different. When all patients were classified according to malignant (n = 54) and non-malignant disease (n = 448), we found that significantly more patients with malignancies

248

Dig Dis 2003;21:245–251

were classified as SGA B or C than patients with nonmalignant diseases (fig. 1). Patients with malignancies were then divided into three subgroups: malignancies of liver, pancreas or bile ducts (n = 22), malignancies of the gastrointestinal tract (n = 17), and extraintestinal malignancies (n = 15). According to the SGA, the highest prevalence of malnutrition of 63.6% was observed in patients with malignancies of the liver, pancreas or bile ducts, while patients with gastrointestinal or extraintestinal malignancies had a similar prevalence of 41.2 and 40.0%, respectively (fig. 2). Among patients with benign diseases (table 5) the highest prevalence of malnutrition was observed in patients with chronic inflammatory bowel disease (40%), chronic heart failure (37.5%), benign lung diseases (30.8%), chronic liver diseases (28.9%) and rheumatoid arthritis (28%). In contrast, a rather low percentage of patients with benign digestive diseases was classified as malnourished (ranging from 10 to 15.4%). Finally, all patients were classified into two groups with either good nutritional state or malnutrition according to SGA (table 6). There were no differences between both groups regarding the gender distribution. However, malnourished patients were significantly older than wellnourished patients. Malnutrition was also associated with a significantly higher length of hospital stay. Further analysis demonstrated that NRI, albumin, BMI and parameters of body composition obtained either by anthropometry or BIA all yielded significantly lower values in patients with malnutrition than in well-nourished subjects.


Table 5. Frequency of malnutrition in

Total

selected benign diseases Inflammatory bowel disease Heart failure Benign lung diseases Chronic liver disease Rheumatoid arthritis Valvular defect Systemic lupus erythematodes Cerebral ischemia Arrhythmia Systemic infection Vasculitis/myositis Coronary heart disease Benign pancreatic or biliary diseases Gastrointestinal bleeding Other benign gastrointestinal diseases Reflux disease Other cardiology All other diseases Other rheumatology

10 24 13 45 25 16 13 13 40 20 15 85 13 16 16 10 11 13 12

SGA B+C 4 9 4 13 7 4 3 3 9 4 3 14 2 2 2 1 1 1 0

SGA B+C, % 40.0 37.5 30.8 28.9 28.0 25.0 23.1 23.1 22.5 20.0 20.0 16.5 15.4 12.5 12.5 10.0 9.1 7.7 0

Note: This table includes only disease groups with n 6 10.

Discussion

Table 6. Clinical characteristics and body composition in patients

with SGA A compared to SGA B+C

In this study the nutritional state of 502 hospitalized medical patients with a wide variety of disease states was prospectively assessed. Using the SGA as the main criterion, we found that almost every fourth patient admitted to hospital was malnourished. This prevalence rate appears to be high, especially if one considers the fact that overbut not undernutrition is the main nutrition-related health problem in Germany, indicated by a high and obviously increasing average BMI in the healthy population, especially in the age group over 50 years [22]. Prevalence rates for malnutrition from other countries reported during the last 15 years ranged from 20% [3, 6] up to 62% [4]. The majority of studies on medical patients, however, reported malnutrition rates around 40% [1, 2, 5, 7, 9]. However, there are no representative data from Germany. Therefore, we cannot answer the question whether or not the nutritional state of hospitalized patients in Germany might have changed along with changes of medical care or the demographic transition during the last decades. Differences in prevalence data on malnutrition among different studies not only depend on the population selected or on the institutional setting, but also on the different diagnostic criteria used for the definition [11]. This was highlighted in a very detailed study on 155 non-surgical


Age, years Gender, m/f Nutritional score Nutritional risk index Albumin, g/d Anthropometry BMI, kg/m2 Body weight, kg AMA, mm2 AFA, mm2 Impedance analysis BCM, kg Outcome LOS, days LOS, median (range)

SGA A (n = 380)

SGA B+C (n = 121)

p value

58.3B15.6 184/196

70.0B13.6 52/69

0.000 ns

105.8B7.6 l4.3B0.5

93.6B9.9 3.7B0.6

0.000 0.000

26.6B4.3 76.2B14.8 5,584B1,499 2,829B1,320

22.1B3.6 62.21B12.0 4,421B1,121 1,650B854

0.000 0.000 0.000 0.000

26.1B6.4

19.3B4.7

0.000

13.1B8.1 12.0 (3–49)

0.000

9.3B6.8 7.0 (2–55)

SGA = Subjective global assessment; AMA = arm muscle area; AFA = arm fat area; BCM = body cell mass; LOS = length of hospital stay.

Dig Dis 2003;21:245–251

249

Malignancies: liver, pancreas, bile ducts n=22

63.6

Extraintestinal malignancies n=15

42.9

Gastrointestinal malignancies n=17

41.2

Inflammatory bowel disease n=10

40.0

Heart failure n=24

37.5

Benign lung diseases n=13

30.8

Chronic liver disease n=45

28.9

Rheumatoid arthritis n=25

28.0 23.1

Cerebral ischemia n=13

20.0

Systemic infection n=20 Benign pancreatic or biliary disease n=13

0

Fig. 2. Prevalence of malnutrition in selected diagnoses.

patients applying four different established clinical scores to the same patients [4]. The authors found that depending on the instrument used for diagnosis, between 40 and 62% of their patients were classified as malnourished. The question, however, which score or which diagnostic instrument might provide the best description of the nutritional state, is still open [23]. We decided to choose the SGA as the primary diagnostic criterion in our study because this score is simple, inexpensive, non-invasive and can be performed at the bedside in a very short period of time. The SGA has also been proven to be of prognostic relevance in a number of different clinical settings, especially indicating an increased mortality of patients with internal diseases [4, 5, 12, 14, 24]. In our study, the SGA yielded results similar to the NRI, and patients who were classified as malnourished according to SGA also had significantly impaired body composition and plasma albumin compared to patients classified as well nourished. We also found that malnourished patients were on average 12 years older and had a 40% longer hospital stay than well-nourished patients. This is in accordance with studies in other countries [7, 9] and further supports the assumptions that increasing age is a risk factor for the development of malnutrition [11], and that malnutrition, on the other hand, is associated with an impaired clinical course and extra costs of health care [4, 7–9]. Two more recent studies from the Netherlands [4] and from Brazil [7] also using the SGA for diagnosis suggested that malnutrition might show a stronger association to

250

Dig Dis 2003;21:245–251

15.4

10

20

30

40

50

60

70

Prevalence of malnutrition: SGA B+C (%)

diseases of the digestive system than to some other medical conditions. This assumption appears plausible, since impaired digestion per se can be expected to influence the nutritional state. In fact, Naber et al. [4] found that 61% of their gastrointestinal patients but only 30% of other medical patients were malnourished. ln the study of Waitzberg et al. [7], 61% of all patients with gastrointestinal disorders were also found to be malnourished while on average 48% of the patients were found to be malnourished. In contrast, we found a much lower frequency of malnutrition of 29% in gastrointestinal patients. Furthermore, our gastrointestinal patients as a whole group were not different from patients with other internal diseases, so that our data obviously do not support the assumption of patients with digestive diseases being at higher risk for malnutrition. To better understand possible reasons for these contradictory results, we performed more detailed analyses in subgroups of patients. Not unexpectedly, we found that the malnutrition rate in patients with malignancies was more than twice as high as in benign medical conditions. The highest prevalence of 64% was seen among patients with malignancies of the liver, pancreas or bile ducts. A subgroup analysis of benign diseases demonstrated high prevalence rates of 130% in patients with inflammatory bowel disease, heart failure and benign lung disease (fig. 2). In contrast, benign pancreatic or biliary diseases, gastrointestinal bleeding, reflux disease or other benign digestive diseases were not associated with higher malnutrition rates, but – compared with other medical


conditions – demonstrated rather under average prevalence values. In the cited studies from the Netherlands [4] and Brazil [7], the gastrointestinal patients were not subclassified. Therefore, we can only speculate that the higher malnutrition rates of gastrointestinal patients in these studies compared with our results might be caused by the inclusion of more severely sick patients with inflammatory bowel diseases, more patients with maldigestion or malabsorption, or by inclusion of a higher percentage of malignancies of the digestive system. From previous studies we know that malnutrition in hospitalized patients is frequently underestimated by the medical staff [2], and even simple diagnostic procedures such as the body weight are not performed in a relevant number if not in the majority of patients [2, 7]. Since the health system in Germany is currently under high economic pressure it can be expected that in the future more sick patients will be hospitalized and a number of patients included in the present study will no longer be subjected

to hospitalization but more frequently directed to ambulatory treatment. Therefore, one can expect that in the next years the prevalence of malnourished hospitalized patients will increase in our country. Moreover, our data show that some patient groups like malignancies, inflammatory bowel disease, chronic heart failure, or benign pulmonary diseases have a specifically high prevalence of malnutrition. In these patient groups, special care has to be taken in the evaluation of the nutritional state and nutritional support. It is, therefore, important to improve the awareness of physicians, nurses and other professionals for this problem by better education in nutritional assessment.

Acknowledgement Dr. M. Pirlich was supported by the Else Kröner-Fresenius-Stiftung, Bad Homburg, Germany.

References 1 Coats KG, Morgan SL, Bartolucci AA, Weinsier RL: Hospital-associated malnutrition: A reevaluation 12 years later. J Am Diet Assoc 1993;93:27–33. 2 McWhirter JP, Pennington CR: Incidence and recognition of malnutrition in hospital. BMJ 1994;308:945–948. 3 Cederholm T, Jägrén C, Hellström K: Outcome of protein-energy malnutrition in elderly medical patients. Am J Med 1995;98:67–74. 4 Naber THJ, Schermer T, de Bree A, Nusteling K, Eggink L, Kruimel JW, Bakkeren J, van Heereveld H, Katan MB: Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications. Am J Clin Nutr 1997;66:1232–1239. 5 Sacks GS, Dearman K, Replogle WH, Cora VL, Meeks M, Canada T: Use of subjective global assessment to identify nutrition-associated complications and death in geriatric longterm care facility residents. J Am Coll Nutr 2000;19:570–577. 6 Malnutrition Prevalence Group: Prevalence of malnutrition on admission to four hospitals in England. Clin Nutr 2000;19:191–195. 7 Waitzberg DL, Caiaffa WT, Correia MITD: Hospital malnutrition: the Brazilian National Survey (IBRANUTRI): A study of 4,000 patients. Nutrition 2001;17:573–580. 8 Pirlich M, Luhmann N, Schütz T, Plauth M, Lochs H: Mangelernährung bei Klinikpatienten: Diagnostik und klinische Bedeutung. Akt Ernähr Med 1999;24:260–266. 9 Robinson G, Goldstein M, Levine GM: Impact of nutritional status on DRG length of stay. J Parenter Enteral Nutr 1987;11:49–51.


10 Tucker HN, Miguel SG: Cost containment through nutrition intervention. Nutr Rev 1996; 54:111–121. 11 Pirlich M, Lochs H: Nutrition in the elderly. Best Pract Res Clin Gastroenterol 2001;15: 869–884. 12 Persson C, Sjöden PO, Glimelius B: The Swedish version of the patient-generated global assessment of nutritional status: Gastrointestinal vs. urological cancers. Clin Nutr 1999;18:71– 77. 13 Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeebhoy KN: What is subjective global assessment of nutritional status? J Parenter Enteral Nutr 1987;11:8–13. 14 Lawson JA, Lazarus R, Kelly JJ: Prevalence and prognostic significance of malnutrition in chronic renal insufficiency. J Ren Nutr 2001; 11:16–22. 15 Buzby GP, Knox LS, Crosby LO, Eisenber JM, Haakenson C, McNeal GE, Page CP, Peterson OL, Reinhardt GF, Williford W: Study protocol: A randomized clinical trial of total parenteral nutrition in malnourished surgical patients. Am J Clin Nutr 1988;47:357–365. 16 Kushner RF, Schoeller DA: Estimation of total body water by bioelectrical impedance analysis. Am J Clin Nutr 1986;44:417–424. 17 Pirlich M, Biering H, Gerl H, Ventz M, Schmidt B, Ertl S, Lochs H: Loss of body cell mass in Cushing’s syndrome: Effect of treatment. J Clin Endocrinol Metab 2002;87:1078– 1084.

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18 Pirlich M, Schütz T, Spachos T, Ertl S, Weiss M-L, Lochs H, Plauth M: Bioelectrical impedance analysis is a useful bedside technique to assess malnutrition in cirrhotic patients with and without ascites. Hepatology 2000;32: 1208–1215. 19 Süttmann U, Ockenga J, Selberg O, Hoogestraat L, Deicher H, Müller MJ: Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:239–246. 20 Gurney JM, Jelliffe DB: Arm anthropometry in nutritional assessment: nomogram for rapid calculation of muscle circumference and crosssectional muscle and fat mass. Am J Nutr 1973; 26:912–915. 21 Frisancho AR: New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 1981;34:2540–2545. 22 Pirlich M, Schwenk A, Müller M, Ockenga J, Schmidt S, Schütz T, Selberg O, Volkert D: Leitlinie enterale Ernährung, Ernährungsstatus. Akt Ernähr Med 2003;28(suppl 1):10–25. 23 Klein S, Kinney J, Jeejeebhoy K, Alpers D, Hellerstein M, Murray M, Twomey P: Nutrition support in clinical practice: Review of published data and recommendations for future research directions. Am J Clin Nutr 1997; 66:683–706. 24 Pirlich M, Schütz T, Gastell S, Lochs H: Malnutrition affects long-term prognosis in hospitalized patients. Gastroenterology 2002;122 (suppl 1):A363.

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Sugar Intake, Taste Changes and Dental Health in Crohn’s Disease Tatjana Schütz a Clemens Drude b Erika Paulisch b Klaus-Peter Lange b Herbert Lochs a a Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie, Universitätsklinikum Charité Campus Mitte, Berlin und b Zentrum für Zahnmedizin, Abteilung für zahnärztliche Prothetik und Alterszahnmedizin, Universitätsklinikum Charité Campus-Virchow, Berlin, Deutschland

Key Words Crohn’s disease W Taste changes W Sugar intake W Zinc W Dental caries

ar consumption and insufficient oral hygiene seem to cause the higher caries prevalence. Obviously, patients with CD belong to a high-risk group, and preventive measures should be taken early in the course of the disease. Copyright © 2003 S. Karger AG, Basel

Abstract Background: An increased intake of sucrose has been reported in patients with Crohn’s disease (CD). Since subclinical zinc deficiency reduces taste perception for sweet, we investigated taste perception, sucrose intake and plasma zinc levels as well as dental status in CD patients. Methods: Carbohydrate intake and plasma zinc levels were assessed in 24 CD patients and 24 agematched controls (Con). Taste threshold for sucrose, oral hygiene and caries prevalence were evaluated. Results: In CD a higher sucrose intake (CD 107.1 B 27.7 vs. Con 71.9 B 13.7 g/day; p ! 0.001), a higher taste threshold for sweet (CD 7.31 vs. Con 2.91 g/l; p ! 0.001) and lower plasma zinc levels (CD 11.5 B 1.5 vs. Con 13.5 B 2.0 Ìmol/l; p ! 0.001) were found. API was poor (CD 85.4 B 23.6, Con 31.8 B 24.1, p ! 0.001) and correlated with sucrose intake (p ! 0.01). Caries prevalence was increased in patients with longer disease (1 3 years) (DMFT index: 13 years 15.6 B 5.7 vs. ! 3 years 9.5 B 4.3; p ! 0.05). Conclusion: Dental status in CD patients is poor. Both increased sug-

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0213–0252$19.50/0



Introduction

Malnutrition is frequently observed in patients with Crohn’s disease (CD) and manifests itself in weight loss and nutrient deficiencies [1]. Special importance is attached to zinc and its role in taste perception. In this context, Henkin et al. [2] and Solomons et al. [3] described that reducing zinc triggers a reversible hypogeusia. In the 1970s, studies on the dietary habits of CD patients drew attention to higher intakes of carbohydrates, sugar or added sugar before or after the onset of the disease compared to patients with ulcerative colitis [4] or healthy controls [5–11]. As one possible cause for the increased sugar consumption, an impaired gustatory function for the sweet taste has been discussed. However, the hypothesis that an excessive intake of refined carbohydrates may be the result of a higher taste threshold for sweet was refuted by three studies [12–14]. A higher threshold for sweet was only observed in patients with

Dr. Tatjana Schütz Universitätsklinikum Charité Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie Schumannstrasse 20/21, DE–10098 Berlin (Germany) Tel. +49 30 450 514059, Fax +49 30 450 514923, E-Mail [email protected]

active disease (Crohn’s disease activity index – CDAI 1200) and patients with CD for more than 2 years [15]. Studies on dental status imply that CD patients have a high caries frequency and activity [16, 17]. The reason for the increased caries prevalence is unclear but as the most likely link the dietary regimen can be suggested. In this overlapping field of gastroenterology, otorhinolaryngology and dentistry this interdisciplinary study was conducted to examine the association between serum zinc concentrations and the taste threshold for sweet, as well as the intake of sucrose and carbohydrates and its effect on the risk of caries and caries prevalence in CD patients compared to healthy controls.

Table 1. Characteristics of CD patients and healthy controls (mean

B SD)

Number Gender, m/f Age, years Smoker/non-smoker Crohn’s disease activity index Disease duration, years

CD patients

Controls

24 10/14 36.2B15.0 13/11 153B98 5.0B3.9

24 12/12 35.4B10.8 12/12 – –

Table 2. Mono-, di- and polysaccharide intake (mean B SD) in CD patients and healthy controls

Methods Patients Twenty-four CD diagnosed by generally accepted criteria [18] and 24 age-matched healthy subjects participated in the study (table 1). Disease activity was assessed according to the CDAI [19]. Disease was active (CDAI 1 150) in 50% of the patients. The duration of disease ranged between 1 and 18 years with a median of 4 years. Eleven patients were current smokers. Patients received standard medical treatment including corticosteroids (n = 11), mesalazine (n = 17), azathioprine (n = 2), and metronidazole (n = 1) as mono- or combination therapy. Two patients were irregularly supplemented with vitamin A (n = 1) or zinc (n = 1). Patients with severe secondary diseases, otorhinolaryngologic and neurologic disorders, or diseases of the oral cavity as well as patients taking medication that influences taste perception (diuretics, antidiabetics, antihypertensives, antirheumatics, psychoactive drugs) were excluded from the study. The study protocol was approved by the local ethical committee and all patients and healthy subjects gave their written informed consent. Procedure Sucrose and carbohydrate intake of the present daily diet were assessed by a food-frequency questionnaire in which the intake of 64 food items and 9 beverages was documented in three categories: regularly (once to several times a day), rarely (once a week to once a month), and never. Standard portion sizes were applied to the food categories and glucose and carbohydrate content was then calculated using the EBIS software (Forschungszentrum für Ernährung in Prävention und Therapie, Hohenheim GmbH, Stuttgart, Germany), which is based on the German Food and Nutrition Database (BLS, version II.1). Taste threshold: Olfactometric and gustometric testing was performed in the morning at least 1 h after breakfast by a standard procedure [20]. Shortly, subjects were asked to restrain from eating, smoking and using toothpaste during that period. Prior to the gustometric measurements, anosmia was excluded by testing the smell stimuli camphor, vanillin, dichlorethane, menthol and formic acid in different concentration ranges using the sniff-bottle technique [20]. The taste threshold for sweet was quantitatively determined with 8 sucrose solutions in graded concentrations (1–256 g/l in deionized water) using the pipette method [21]. 0.5 ml of the solutions in ascending order was given drop by drop on the tip of the tongue, the

Sugar Intake in Crohn’s Disease

CD patients Monosaccharides, g/day Glucose, g/day Disaccharides, g/day Sucrose, g/day Polysaccharides, g/day Total carbohydrates, g/day

43B15 20B7 122B32*** 107B28*** 195B27* 367B64

Controls 46B14 20B5 87B16 72B74 202B21 332B70

* p ! 0.05; *** p ! 0.001.

typical site for the perception of the sweet taste, and the subjects were asked to identify the test stimulus. After each tasting the subjects expectorated the samples and rinsed their mouth with water. Taste threshold was defined as the lowest concentration which the subject correctly identified. Plasma zinc concentration: Metal-free plastic syringes and containers (Sarstedt, Nümbrecht, Germany) were used to collect blood for the zinc measurement. Zinc and other laboratory parameters (albumin, hematocrit) were determined by standard methods. Dental and oral health: The prevalence of caries was assessed by determining the percentage of decayed, missing and filled teeth (DMFT index) [22]. Low values indicate good dental health. Oral hygiene was assessed by using the API index (approximal plaque index), which is calculated as the percentage of contaminated approximal sites [23]. Analogous to the DMFT index, low values point to sufficient oral hygiene. Statistics Results are given as mean B SD. Means were compared by Mann-Whitney U-test and frequencies by the ¯2 test with p ! 0.05 as level of significance. All calculations were performed by the computer software SPSS (version 10.0, SPSS Inc., Chicago, Ill., USA).

Dig Dis 2003;21:252–257

253

60

**

200

CD

Controls

*** Number of subjects (%)

Sucrose intake (g/day)

50

100

40

30

*** ***

20

0 Controls (n = 24)

CD (n = 6) 6 years

10

0 1

Fig. 1. Sucrose intake in healthy controls and CD patients in groups

according to length of disease. Box plots with horizontal bars indicating median values, boxes indicating the 25th centiles, error bars indicating the 95% confidence interval and [ indicating values outside the 95th centile. ** p ! 0.01.

Results

Eating Habits, Sucrose and Carbohydrate Intake. Eating habits differed between patients and controls. Significantly more CD patients abstained from alcoholic beverages (wine: 50.0 vs. 12.5%; beer: 62.5 vs. 25.0%; p ! 0.01) and dried fruits (83.3 vs. 50%, p ! 0.05) compared to healthy controls. Total carbohydrate intake was not different between CD patients and healthy controls (table 2). CD patients, however, consumed 40% more disaccharides than healthy controls, which was due to a significantly higher sucrose intake (p ! 0.001) (fig. 1). This difference remained significant when sucrose intake was calculated per kilogram body weight (CD 1.72 B 0.62 vs. control 1.03 B 0.26 g/kg b.w.; p ! 0.001). Surprisingly, patients with shorter disease duration had a significantly higher sucrose intake than patients with a longer lasting disease (fig. 1). The higher sucrose intake was due to a more frequent consumption of sweet-tasting food products, such as pudding (25 vs. 0%, p ! 0.01), honey and jam (70.8 vs. 37.5%, p ! 0.05), chocolate (58.3 vs. 16.7%, p ! 0.01), and cake (50.0 vs. 12.5%, p ! 0.01). Olfactometry and Gustometry. All subjects could smell at least one concentration level of each odorant so that anosmia, which would negatively influence taste percep-

254

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2

4

8

16

32

Sucrose (g/l)

Fig. 2. Proportion of CD patients compared to healthy controls, who

detected the tested sucrose concentration. *** p ! 0.001.

tion, was excluded in the study population. Taste threshold for sweet was significantly higher in CD patients compared to healthy controls (7.31 vs. 2.91 g/l, p ! 0.001). In contrast to 58.3% of the control subjects, none of the CD patients were able to recognize the two lowest sucrose concentrations (fig. 2). There was no difference in taste detection comparing patients with active (CDAI 1150) to inactive (CDAI !150) disease. There was no correlation between the taste threshold for sweet and sucrose intake in either group. Plasma Zinc Concentration. Since plasma zinc is bound to albumin, we also measured albumin concentrations. Plasma zinc concentrations significantly correlated with albumin concentrations in both CD patients and controls (CD: r2 = 0.150, control: r2 = 0.052, both p ! 0.001). The plasma zinc values of 5 CD patients (20.8%) and 2 control subjects (8.3%) were below the normal range (10.6– 17.9 Ìmol/l). The mean value for the group of CD patients was significantly lower than that of the healthy controls (11.5 B 1.5 vs. 13.5 B 2.0 Ìmol/l; p ! 0.001) (fig. 3). Neither in CD patients nor in healthy controls were plasma zinc levels correlated with sucrose intake. Dental and Oral Health. Dental health was impaired in CD patients compared to controls. However, this became apparent only with longer lasting disease with an in-

Schütz/Drude/Paulisch/Lange/Lochs

*

18

DMFT-index (%)

Plasma zinc concentration (µmol/l)

*

30

***

20

16 14 12

20

10

10 8

0

6 Controls (n = 24)

CD (n = 24)

Controls ( = 24)

CD (n = 6) 6 years

Fig. 3. Plasma zinc concentration in healthy controls and CD patients. Box plots as explained in figure 1. *** p ! 0.001.

Fig. 4. Prevalence of caries (DMFT index) in healthy controls and in

creased DMFT index indicating higher caries prevalence (fig. 4). Oral hygiene was insufficient in CD patients with a significantly higher API index compared to controls (CD: 85.5 B 23.6% vs. control: 31.8 B 24.1%, p ! 0.001). The API index was significantly correlated to sucrose intake in both groups (CD: r2 = 0.0104; control: r2 = 0.0059; p ! 0.01). 25% of CD patients vs. 4% of controls did not regularly go to the dentist’s.

Several studies have shown a higher sugar intake in CD patients when compared to the healthy population even before the onset of the disease [4–11]. The reason for this dietary habit is unclear. However, a correlation with the decreased zinc status was suspected since zinc is an important trace element for the taste perception sweet [2, 3]. Furthermore, a higher caries prevalence would be expected in CD patients as a consequence of the higher sugar consumption. Zinc deficiency has frequently been described in CD patients [3, 24, 25], and alterations in taste acuity have been observed in these patients [13, 14, 24]. The mechanism of chemosensory dysfunction is not well understood but the key role in the influence of zinc on taste perception is attributed to the zinc-dependent parotid saliva enzyme

gustin/carbonic anhydrase IV, which is decreased in patients with hypogeusia and dysgeusia [2]. It seems to exert its action as a trophic factor on the taste bud stem cells and so promotes growth and development of taste buds. So far there have been no data on gustin/carboanhydrase IV concentrations in saliva of CD patients with impaired taste acuity. Moreover, a possible influence of medication on gustatory function must be assumed. Our data do in fact demonstrate higher sugar intake, higher caries prevalence and lower zinc plasma levels in CD patients. However, these changes appear not to be related to each other. The taste threshold for sweet was also significantly higher in CD patients than healthy controls. Only Lederer et al. [15] could also measure a significantly higher taste threshold for sweet in patients with active disease (CDAI 1200), whereas other studies only reported a significantly higher threshold for salt taste [13] and for acid taste [14]. Solomons et al. [3] found a significantly lower overall taste detection score, which comprised all four basic taste modalities, whereas Kasper et al. [12] could not detect any differences. The question has to be raised why a correlation between low plasma zinc levels and increased taste threshold for sweet could not have been found. This might be due to the fact that plasma zinc levels do not necessarily reflect the zinc status but could rather be dependent on inflammatory processes. This might, however, not ex-


Dig Dis 2003;21:252–257

Discussion

CD patients in groups according to length of disease. Box plots as explained in figure 1. * p ! 0.05.

255

plain our results since there was no difference in the taste threshold between patients with active disease versus patients with quiescent disease. It would be interesting to investigate the effect of zinc supplementation on the taste threshold in CD patients and consequently on sugar intake. To our knowledge this has not yet been adequately investigated. The higher sugar intake was not accompanied by a higher total carbohydrate intake in our study but was rather due to the consumption of sweets. This is very well in line with former studies, using different methods to evaluate dietary habits of CD patients [4–11]. This specific eating of sweets makes it unlikely that CD patients substitute carbohydrates for a possible fat intolerance since it would be expected that the intake of all carbohydrates would be increased. One consequence of high sugar intake is an increase in the incidence of caries. Dental caries is a multifactorial disease in which the effects of the two main initiating factors dental plaque and fermentable carbohydrates are modified by various endogenic and exogenic factors. CD patients are reported to have a higher incidence of dental caries than healthy controls [16, 17]. In our study the extent of caries increased with the duration of disease. This could be due to long-lasting high sugar intake but also to nutritional deficiencies like calcium and fluoride deficiency. A further explanation could be high levels of cariogenic bacteria in saliva, such as streptococci and lac-

tobacilli [26], which may result from high sucrose intake in combination with insufficient oral hygiene. Factors of the development of dental caries resulting from CD per se such as altered tooth structure [17], salivary flow rate [26] and salivary constituency in regard to antimicrobial proteins [27] have not been proven. The poor dental status was correlated to insufficient oral hygiene and the lack of regular visits to the dentist’s in CD patients. This clearly indicates that CD patients are a risk group for poor dental health, and therefore measures should be taken early in the course of the disease to avoid deterioration. Since eating habits are difficult to influence, training for dental hygiene and specific attention to regular dentist visits should be taken in CD patients.

Conclusion

The dental status in CD patients was found to be poor. The taste threshold for sweet was increased in CD patients; an association to plasma zinc concentrations and sucrose intake, however, could not be proven. Both increased sugar consumption and insufficient oral hygiene seem to cause the higher caries prevalence. Obviously, CD patients belong to a high-risk group, and preventive measures should be taken early in the course of the disease.

References 1 Geerling BJ, Badart-Smook A, Stockbrügger RW, Brummer RJ: Comprehensive nutritional status in patients with long-standing Crohn’s disease currently in remission. Am J Clin Nutr 1998;67:919–926. 2 Henkin RI, Martin BM, Agarwal RP: Efficacy of exogenous oral zinc treatment of patients with carbonic anhydrase IV deficiency. Am J Med Sci 1999;318:392–405. 3 Solomons NW, Rosenber IH, Sandstead HH Vo-Khactu KP: Zinc deficiency in Crohn’s disease. Digestion 1977;16:87–95. 4 Mayberry JF, Rhodes J, Newcombe RG: Increased sugar consumption in Crohn’s disease. Digestion 1980;20:323–326. 5 Martini GA, Brandes JW: Increased consumption of refined carbohydrates in patients with Crohn’s disease. Klin Wochenschr 1976;54: 367–371. 6 Kasper H, Sommer H: Dietary fiber and nutrient intake in Crohn’s disease. Am J Clin Nutr 1979;32:1898–1901.

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7 Silkoff K, Hallak A, Yegena L, Rozen P, Mayberry JF, Rhodes J, Newcombe RG: Consumption of refined carbohydrate by patients with Crohn’s disease in Tel-Aviv-Yafo. Postgrad Med J 1980;56:842–846. 8 Mayberry JF, Rhodes J, Allan R, Newcombe RG, Regan GM, Chamberlain LM, Wragg KG: Diet in Crohn’s disease. Two studies of current and previous habits in newly diagnosed patients. Dig Dis Sci 1981;26:444–448. 9 Järnerot G, Järnmark I, Nilsson K: Consumption of refined sugar by patients with Crohn’s disease, ulcerative colitis, or irritable bowel syndrome. Scand J Gastroenterol 1983;18: 999–1002. 10 Tragnone A, Valpiani D, Miglio F, Elmi G, Bazzocchi G, Pipitone E, Lanfranchi GA: Dietary habits as risk factors for inflammatory bowel disease. Eur J Gastroenterol Hepatol 1995;7:47–51. 11 Reif S, Klein I, Lubin F, Farbstein M, Hallak A, Gilat T: Pre-illness dietary factors in inflammatory bowel disease. Gut 1997;40:754–760.

12 Kasper H, Sommer H, Wild M: Geschmacksschwellen bei Kranken mit Enteritis regionalis (Morbus Crohn). Akt Ernähr Med 1980;5:196–198. 13 Tiomny E, Horwitz C, Graff E, Rozen P, Gilat T: Serum zinc and taste acuity in Tel-Aviv patients with inflammatory bowel disease. Am J Gastroenterol 1982;77:101–104. 14 Penny WJ, Mayberry JF, Aggett PJ, Gilbert JO, Newcombe RG, Rhodes J: Relationship between trace elements, sugar consumption and taste in Crohn’s disease. Gut 1983;24:288–292. 15 Lederer PC, Cidlinsky K, Kobal G, Lux G: Geschmacksstörungen bei M. Crohn Patienten. Elektrogustometrie und chemische Geschmacksprüfung. Z Gastroenterol 1985;23: 470. 16 Sundh B, Hultén L: Oral status in patients with Crohn’s disease. Acta Chir Scand 1982;148: 531–534.

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17 Rooney T: Dental caries prevalence in patients with Crohn’s disease. Oral Surg 1984;57:623– 624. 18 Malchow H, EWE K, Brandes JW, Goebell HM, Ehms S, Sommer H, Jesdinsky H: European Cooperative Crohn’s Disease Study (ECCDS): Results of drug treatment. Gastroenterology 1984;86:249–266. 19 Best WR, Becktel JM, Singleton W: Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–444.


20 Anonymous: Mitteilungen der Gesellschaft: Empfehlungen zur Untersuchung des Riechund Schmeckvermögens. HNO Prax 1980;5: 62–67. 21 Rollin H: Funktionsprüfung und Störungen des Geschmackssinnes. Arch Otorhinolaryngol 1975;210:165–207. 22 WHO Oral Health Survey, ed 2. Geneva, WHO, 1977. 23 Lange DE: Die gezielte Vorbehandlung vor der systemischen Paradontolbehandlung. Zahnärztl Welt/Reform 1975;8:366. 24 McClain C, Soutor C, Zieve L: Zinc deficiency: A complication of Crohn’s disease. Gastroenterology 1980;78:272–279.

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25 Ainley CC, Cason J, Carlsson LK, Slavin BM, Thompson RP: Zinc status in inflammatory bowel disease. Clin Sci 1988;75:277–283. 26 Sundh B, Emilson CG: Salivary and microbial conditions and dental health in patients with Crohn’s disease: A 3-year study. Oral Surg Oral Med Oral Pathol 1989;67:286–290. 27 Sundh B, Johansson I, Emilson CG, Nordgren S, Birkhed D: Salivary antimicrobial proteins in patients with Crohn’s disease. Oral Surg Oral Med Oral Pathol 1993;76:564–569.

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Serum Mineral Levels in Children with Intestinal Parasitic Infection José L. Olivares a Ramona Fernańdez a Jesu´s Fleta a Gerardo Rodrı´guez a Antonio Clavel b a Department

of Paediatrics and b Microbiology and Parasitology ‘Lozano Blesa’ Hospital, University of Zaragoza, School of Medicine, Zaragoza, Spain

Key Words Copper W Zinc W Magnesium W Enterobius vermicularis W Giardia lamblia

Abstract Parasitic infections are highly prevalent in the general population. A relation between a parasitic infection and absorption of minerals is not an easy task. Serum levels of copper, zinc and magnesium were prospectively measured in 64 children with intestinal parasitic infection. Thirty-nine children with Enterobius vermicularis were treated with pyrantel pamoate and 25 children with Giardia lamblia with tinidazole and metronidazole. Three months after treatment, significant differences in serum copper, zinc and magnesium were seen in patients with E. vermicularis infection, and in serum magnesium levels in patients with G. lamblia. Although the pathogenic mechanism is not clear, these findings could reflect a deficiency related to malabsorption due to mucous affection. Early detection and treatment of intestinal parasitosis could avoid these serum mineral deficiencies. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0213–0258$19.50/0



Introduction

Childhood is probably the most demanding period of life for meeting the body’s nutritional demands. Minerals perform important functions in children’s growth and development. The recognition that trace minerals regulate key metabolic pathways, modulate the immune response, and suppress the incidence of various disease states serves to emphasize their direct importance in health maintenance [1]. Intestinal parasitosis remains an important public health concern because of the high frequency reached in several countries as well as its nutritional consequences. Although childhood copper, zinc and magnesium deficiencies are rather unusual, recent studies suggest that several diseases (malnutrition, intestinal malabsorption syndromes and intestinal parasitosis) may produce them. Early diagnosis and treatment of these disorders are very important to obtain optimal levels of growth, development, immune response and intellectual capacity [2–4]. The aim of this study was to compare serum copper, zinc and magnesium levels in children with Enterobius vermicularis and Giardia lamblia intestinal infection, before and after treatment without infection.

Prof. José L. Olivares Lo´pez Departamento de Pediatrıá Facultad de Medicina, Universidad de Zaragoza C/. Domingo Miral s/n, ES–50009 Zaragoza (Spain) Tel. +34 976 761724/761725, Fax +34 976 761726, E-Mail [email protected]

Table 1. Anthropometric measures and serum mineral levels of

patients with E. vermicularis at diagnosis and after treatment (mean B SD)

Weight-for-age Z-score Body mass index, kg/m2 Copper, Ìg/dl Zinc, Ìg/dl Magnesium, mg/dl

Diagnosis

After treatment

– 0.65B1.37 17.28B2.31 116.34B18.62 91.32B10.90 1.65B0.11

– 0.32B1.16* 17.60B2.41** 123.08B24.29* 97.07B13.12** 1.70B0.16*

Differences between paired sets of time, diagnosis – after treatment, using Student’s test. * ! 0.05; ** ! 0.01.

Patients and Methods We studied 64 Spanish children (34 boys, 30 girls) from Aragoń, Northeast Spain, who were diagnosed as having one unique parasite infection; 39 of these 64 cases were infected by E. vermicularis and 25 by G. lamblia. Fifty-one patients came from an urban area (Zaragoza) and 13 from rural areas. Most of these children were of a medium socioeconomic status. Ages at diagnosis ranged from 10 months to 15 years (mean 9.71 B 3.63 years) for E. vermicularis and 5.82 B 3.31 years for G. lamblia. Abdominal pain, acute diarrhea, anorexia, anal itch and fever were the most frequent symptoms. Identification of E. vermicularis was carried out by the Graham technique [5]. For G. lamblia identification, concentration of fecal stool was performed by the method described by Ritchie [6], using ether instead of acetyl acetate [7, 8]. Copper, zinc and magnesium levels were assessed by atomic absorption spectrophotometer (model Video 11E, Thermo Jarrel Ash). Serum copper and zinc levels were previously diluted to a 1/5 proportion and magnesium to a 1/100. The method obtains directly measurements of mineral concentration [9]. Children were evaluated twice, first at diagnosis and on a second follow-up visit 3 months after the treatment and without active infection. Pyrantel pamoate (10 mg/kg/day, two doses separated by 2 weeks) was the treatment for E. vermicularis. Tinidazole (50 mg/kg/day, two doses, separated by 2 weeks) was used to treat G. lamblia-infected children and, when G. lamblia parasitation persisted after this treatment, metronidazole (25 mg/kg/ day, 7 days) was employed [10]. Anthropometric measures and serum copper, zinc and magnesium concentrations were determined 3 months after treatment, when patients were asymptomatic and stools were not infected. Anthropometric data were compared with international standards (Anthro database, WHO). Fecal stool samples were collected after the completion of treatment to verify that there was no intestinal parasitic infection. Kolmogorov-Smirnov (Lilliefors modification) was applied to assess normality of each variable. All variables were found to be normally distributed (Kolmogorov-Smirnov: Z 1 0.05) and then a parametric test was performed. Differences between variables at diagnosis and after treatment were examined using Student’s t test. Statistical programs SPSS for Windows 11.5 (SPSS Inc.) were employed. Statistical significance was defined as a p ! 0.05.

Serum Minerals in Intestinal Parasitic Infection

Table 2. Anthropometric measures and serum mineral levels of patients with G. lamblia at diagnosis and after treatment (mean B SD)

Weight-for-age Z-score Body mass index, kg/m2 Copper, Ìg/dl Zinc, Ìg/dl Magnesium, mg/dl

Diagnosis

After treatment

–0.11B1.25 16.88B2.50 132.17B29.23 92.03B13.42 1.64B0.12

0.34B1.38 17.42B2.62** 132.34B26.69 92.12B12.63 1.69B0.13*

Differences between paired sets of time, diagnosis – after treatment, using Student’s test. * p ! 0.05; ** p ! 0.01.

Parents were fully informed about the aims of the study and signed a consent form for participation. The study protocol was reviewed and approved by the Ethical Research Committee of the ‘Lozano Blesa’ Zaragoza University Hospital (Spain).

Results

Table 1 shows measurements of patients with E. vermicularis intestinal infection at diagnosis and 3 months after treatment, without infection. After treatment we observed a significant improvement in weight for age Zscore (p ! 0.05), body mass index (BMI) (p ! 0.01), serum copper (p ! 0.05), zinc (p ! 0.01) and magnesium (p ! 0.05) concentrations. Table 2 shows measurements of patients with G. lamblia infection at diagnosis and 3 months after treatment. We also observed a significant improvement in BMI (p ! 0.01) and serum magnesium (p ! 0.05) levels after treatment but not in weight-for-age Z-score (p = 0.083), copper (p = 0.963) and zinc (p = 0.996) levels. Differences found in patients with E. vermicularis intestinal infection compared with the G. lamblia group were only significant for copper levels at diagnosis (116.3 B 18.6 vs. 132.1 B 29.2 Ìg/dl respectively; p = 0.01) but not after treatment 3 months later (123.1 B 24.3 vs. 132.3 B 26.7 Ìg/dl respectively; p = 0.157). The rest of the variables did not show significant differences.

Discussion

The physiologic role and dietary needs for minerals in the nutrition of the children are known with varying degrees of certainty, and only limited information exists

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on the bioavailability of these elements in different foods. Copper, zinc and magnesium are components of some cellular enzymes, participate in several immune processes and they play an important role in the resistance to free radical damage by stabilizing the cellular membrane [1]. Absorption of copper in the small intestine has both active and passive components that do not appear to be dramatically influenced by the form in which the copper is presented. Inside the mucosal cells, copper can associate with metallothionein. Fructose and sucrose accentuate the deficiency signs induced by a diet low in copper, compared with the effect of starch and glucose. Although the mechanisms and control of zinc are no completely understood, intestinal absorption involves uptake by the intestinal cell, movement through the mucosal cell, transfer to the portal circulation, and secretion of endogenous zinc back into the intestinal cell. Zinc supply and tissue reserves are major factors in the homeostatic control of zinc absorption by regulation of mucosal cell absorption. Magnesium absorption occurs mainly in the ileum and colon by passive diffusion, pulling of solvent and active transport. Vitamin D increases magnesium absorption but the presence of phytates decreases it [1, 2]. The presence of gastrointestinal parasites in children is negatively associated with anthropometric characteristics, physical work capacity, blood hemoglobin levels and nutritional status [2, 11]. Pegelow et al. [4], in a study developed in 8- to 10-year-old children with E. vermicularis infection and other parasitic infestations, from ten schools of the rural districts of Sukaraja, West Java, Indonesia, concluded that their nutritional status was characterized by anemia (13%) and a stunting prevalence of 51%. In our study, after 3 months of treatment, we have observed a significant increase in weight for age Z-score and BMI in E. vermicularis group, and in BMI of children with G. lamblia infection. Koltas et al. [12], in children with enterobiosis, showed that mean levels of serum copper, zinc and magnesium were significantly lower in the infected group than in the control group. In our study we have observed a significant increase in serum concentrations of copper, magnesium and, especially of zinc, 3 months after treatment with tinidazole or metronidazole. Karakas et al. [13], in children with giardiasis or amebiasis, showed that serum zinc levels were significantly decreased when compared to controls. After metronidazole therapy, a significant increase in zinc levels was observed. There was no significant difference in serum copper levels between patients and controls before therapy. Among G. lamblia-infected children, Ertan et al. [14]

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revealed that giardiasis increased the serum copper levels and decreased the zinc and iron levels. In our study in children with parasitic G. lamblia intestinal infection, we have observed a significant increase in serum magnesium levels 3 months after treatment. There are no significant differences in serum copper or zinc levels after therapy. The pathogenic mechanism of these serum mineral changes observed in intestinal parasitic infections is not clear. Abel et al. [15] pointed out the possible roles of protein kinase A (PKA) in cell motility and excystation of the early diverging eukaryote G. lamblia. Kinetic analysis of the recombinant PKA showed that ATP and magnesium are preferred in this enzymatic process. Otherwise, Cragg et al. [16] showed that a novel zinc-regulated human zinc transporter, hZTL1 (human ZnT-like transporter 1), is located in the enterocyte apical membrane. Localization, regulatory properties and function of hZTL1 indicate a role in regulating the absorption of nutrients. In conclusion, this study shows significant differences in serum copper, zinc and magnesium levels in patients with E. vermicularis intestinal infection, and in serum magnesium concentrations in patients with G. lamblia, 3 months after treatment. Although the pathogenic mechanism is not clear, persistent small intestinal damage is a matter of importance in such children [17]. There is clear evidence that zinc and other minerals are involved in the recovery of small intestinal mucosa after injury. Early detection and treatment for each case of intestinal parasitic infection could avoid these mineral deficiencies.

Acknowledgment The authors thank Prof. Toma´s Martıńez, Department of Statistics, School of Medicine, University of Zaragoza.

Olivares/Fernańdez/Fleta/Rodrı´guez/Clavel

References 1 Milner JA: Trace minerals in the nutrition of children. J Pediatr 1990;117:147–155. 2 Stephenson LS, Lathan MC, Ottesen EA: Malnutrition and parasitic helminth infections. Parasitology 2000;121(suppl):23–38. 3 Bahader S, Ali G, Shaalan A, Khalil H, Khalil N: Effects of Enterobius vermicularis infection on intelligence quotient and anthropometric measurements of Egyptian rural children. J Egypt Soc Parasitol 1995;25:183–194. 4 Pegelow K, Gross R, Pietrzik K, Lukito W, Richards AL, Fryauff D: Parasitological and nutritional situation of school children in the Sukaraja district, West Java, Indonesia. Southeast Asian J Trop Med Public Health 1997;28: 173–190. 5 Graham CF: A device for the diagnosis of Enterobius vermicularis. Am J Trop Med 1941;21: 159–161. 6 Ritchie LS: An ether sedimentation technique for routine stool examinations. Bull US Army Med Dept 1948;8:326.

Serum Minerals in Intestinal Parasitic Infection

7 Young K, Bullock S, Melvin D: Ethyl acetate as a substitute for diethyl ether in the formalinether sedimentation techniques. J Clin Microbiol 1979;10:852–853. 8 Erdman DD: Clinical comparison of ethyl acetate and diethyl in the formalin-ether sedimentation techniques. J Clin Microbiol 1981;14: 483–485. 9 Dawson JB, Walker BE: Direct determination of zinc in wholes blood plasma and urine by atomic absorption spectrometry. Clin Chim Acta 1969;26:465–475. 10 Hill DR: Giardiasis. Issues in diagnosis and management. Infect Dis Clin North Am 1993; 7:503–525. 11 Wilson WM, Dufour DL, Staten LK, BaracNieto M, Reina JC Spurr GB: Gastrointestinal parasitic infection, anthropometrics, nutritional status and physical work capacity in Colombian boys. Am J Human Biol 1999;11:763– 771. 12 Koltas IS, Ozcan K, Tanner L, Aksungur P: Serum copper, zinc and magnesium levels in children with enterobiosis. J Trace Elem Med Biol 1997;11:49–52.

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13 Karakas Z, Demirel N, Tarakcioglu M, Mete N: Serum zinc and copper levels in southeastern Turkish children with giardiasis or amebiasis. Biol Trace Elem Res 2001;82:11–18. 14 Ertan P, Yereli K, Kurt O, Balcioglu IC, Onag A: Serological levels of zinc, copper and iron elements among Giardia lamblia-infected children in Turkey. Pediatr Int 2002;44:286–288. 15 Abel ES, Davids BJ, Robles LD, Loflin CE, Gillin FD, Chakrabarti R: Possible roles of protein kinase A in cell motility and excystation of the early diverging eukaryote Giardia lamblia. J Biol Chem 2001;276:10320–10329. 16 Cragg RA, Christie GR, Phillips SR, Russi RM, Kury S, Mathers C, Taylor PM, Ford D: A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane. J Biol Chem 2002;277:22789– 22797. 17 Walker-Smitth JA: Post-infection diarrhea. Curr Opin Infect Dis 2001:14;567–571.

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Impact of Body Mass Index on Fasting Blood Glucose Concentration among Helicobacter pylori Carriers Ioannis D. Kyriazanos a Ioannis Sfiniadakis b Panagiotis Dimakos c Vasilios Gizaris d Konstantinos Datsakis e Aggeliki Dafnopoulou f a 2nd

Department of Surgery and Departments of b Pathology, c Endocrinology, d Immunology and e Gastroenterology, Naval Hospital of Athens, and f Department of Radiology, P. Faliron Medical Center, Naval Hospital of Athens, Athens, Greece

Key Words Helicobacter pylori W Fasting blood glucose levels W Obesity W Body mass index

Abstract Background/Aims: Despite the fact that Helicobacter pylori (Hp) is regarded as a major gastroduodenal pathogen, it has recently been suggested to be an important factor for non-gastroenterologic conditions such as diabetes mellitus. Accordingly, it seems that Hp infection may have implications in glycemic control and in fasting plasma glucose concentrations. As overnutrition and obesity are directly related to impaired glucose tolerance, the aim of the present study was to determine whether Hp infection leads to alterations in fasting plasma glucose concentrations of Hp carriers and especially in relation to their body mass index. Methods: Serum was obtained from 224 young, male navy recruits. An enzyme-linked immunosorbent assay to detect Hp-specific IgG serum antibodies as well as gastroscopy along with biopsy was used to identify the infected individuals. Serum levels of glucose, urea, creatinine and uric acid were also determined. Non-fasting subjects and per-

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sons with abnormal oral glucose tolerance curve test were excluded. Results: Among Hp-positive individuals, obese persons presented with a significantly lower mean blood glucose level than non-obese persons. Obese Hpcontaminated participants had significantly lower mean fasting blood glucose concentrations as well as a significantly smaller percentage of participants with abnormal elevated blood glucose levels than obese participants negative to Hp infection. Conclusions: Our data suggest that obesity in combination with Hp infection may induce an enhanced response to insulin leading to reduced fasting blood glucose levels, among Hp-positive obese persons in comparison to Hp-positive lean persons. Copyright © 2003 S. Karger AG, Basel

Introduction

Despite the fact that Helicobacter pylori (Hp) is regarded as a major gastroduodenal pathogen etiologically linked with duodenal and gastric disease, it has recently been suggested to be an important factor for non-gastroenterologic conditions such as coronary heart disease and diabetes mellitus [1]. Although the relationship be-

Ioannis D. Kyriazanos, MD 22, Thetidos str. P. Faliro GR–17561 Athens (Greece) Tel. +30 2109845327, Fax +30 2107710671 E-Mail [email protected]

tween diabetes mellitus and Hp remains controversial, it seems that Hp infection may have implications in glycemic control [2]. Furthermore, Hp infection raises basal and meal-stimulated serum gastrin concentrations and lowers iron stores, which may in turn reduce fasting plasma glucose concentrations [3]. Overnutrition and obesity, due to their well-known complications including heart disease and diabetes mellitus, are directly related to impaired glucose tolerance. Although we have already reported that obesity and increased BMI cannot be considered as predisposing factors for Hp contamination [4], it could be possible that the combination of Hp infection and obesity can facilitate Hp-related alterations of plasma glucose concentrations. Accordingly, the aim of the present study was to determine whether Hp infection leads to alterations in fasting plasma glucose concentrations of Hp carriers and in relation to their body mass index (BMI).

Materials and Methods Subjects The study population consisted of 224 healthy male Hellenic navy recruits (median age 22.84 years old, range 20–30). All the subjects were Caucasians and came from different regions of the country. They were randomly selected out of 600 males inducted into the Hellenic Navy at the naval base of Salamis. A blood sample was collected in February 2000, during their induction. After centrifugation, the serum sample was split into three aliquots, which were frozen at –70 ° C and thawed once, before analysis. Determination of Biochemical Parameter Concentrations and Hp Status Titers of Hp-specific IgG antibodies, as well as serum levels of glucose, urea, creatinine and uric acid were determined in the Department of Immunology of Naval Hospital of Athens. Individuals with abnormally increased blood glucose concentrations underwent an oral glucose tolerance curve test. Persons with abnormal test results as well as non-fasting subjects were excluded from the study. For the serological determination of the specific antibody against Hp, an enzyme-linked immunosorbent assay was used (Hp IgG Elisa Kit, Hycor Biomedical GmbH, Kassel, Germany; inter-assay coefficient of variation: 7%, intra-assay coefficient of variation: 4.3%, sensitivity: 0.1 IU/ml). Levels of IgG were categorized as seropositive for Hp according to an OD titer of IgG antibodies to Hp of 1 0.5. The normal range for blood glucose was 60–110 mg/dl, for serum urea 10–40 mg/ dl, for creatinine ! 1.2 mg/dl and for uric acid up to 5.3 mg/dl. All seropositive subjects underwent endoscopy in the Department of Gastroenterology at the Naval Hospital of Athens. Along with the examination, two biopsy samples of the antrum and one of the corpus were obtained from each of the individuals, for the verification of Hp infection. Subjects with both sero-surveillance- and biopsy-positive results were finally considered as Hp-contaminated individuals.

Fasting Blood Glucose Concentrations and H. pylori Infection

Obesity Definition More specifically by calculating the BMI, we created two distinct groups: the group of overweight individuals with BMI 625 kg/m2, and the lean group with BMI ! 25 kg/m2. The cut-off point of ! 25 or 625 kg/m2 was proposed in the first federal obesity clinical guidelines released by NHLBI and NIDDK in 1998 as the most acceptable classification for obesity [5]. Statistical Analyses To examine whether the Hp-affected members differed from the non-affected members for each study variable, ¯2, Fischer’s exact and Student’s t tests were used from the SPSS statistical package version 8 (SPSS, Chicago, Ill., USA, 1997).

Results

Among several biochemical parameters, fasting blood glucose revealed interesting results. Blood glucose levels were not significantly different between either obese or non-obese participants (104.67 B 11.6 vs. 104.4 B 11.7, p = 0.86), nor between Hp-positive and Hp-negative members (103.5 B 8.3 vs. 104.9 B 12.6, p = 0.79). Abnormal elevated fasting blood glucose levels (normal range 70–110 mg/dl) were detected in 52 (23.2%) out of 224 recruits and the number of abnormal blood glucose carriers was comparable between obese and non-obese (28/137, 20.4% vs. 24/87, 27.6%, p = 0.25) as well as between Hp-positive and Hp-negative (17/61, 27.8% vs. 35/163, 21.4%, p = 0.72) groups. Subsequently and by stratifying the participants in two groups according to their Hp status (positive or negative), we further evaluated the relation between fasting blood glucose levels and BMI for each group separately. Among 163 uninfected participants (Hp-negative group) there was no significant difference between obese and nonobese persons either in the mean blood glucose levels (105.8 B 12.7 vs. 103.3 B 12.7, 95% CI = –1.5 to 6, p = 0.22) or in the number of individuals with abnormal blood glucose levels (23/102, 22.5% vs. 12/61, 19.7%, p = 0.85). On the contrary, among 61 Hp-positive individuals, obese persons presented with a significantly lower mean blood glucose level than non-obese persons (101.2 B 6.4 vs. 106.9 B 8.6, 95% CI = – 9.5 to –1.8, p = 0.005). Furthermore, a significantly higher number of non-obese individuals had blood glucose levels above the normal range (1110 mg/dl), in comparison to obese members in the Hp-positive group of participants (12/26, 46.1% vs. 5/35, 14.2%, p = 0.009). Among obese participants, Hp-positive individuals had a significantly lower mean blood glucose level (101.2 B 6.4 vs. 105.8 B 12.7, 95% CI = 1.2–7.9, p = 0.007) as

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well as a significantly smaller percentage of members with abnormal elevated fasting blood glucose concentrations (10.7% vs. 29.4%, p = 0.032) than obese Hp-negative persons. The same was not true among lean individuals.

Discussion

Hp colonization of the human stomach produces an innate host immune response, which finally stimulates G cells in production of gastrin and gastric acid [6, 7]. Hypergastrinemia becomes more enhanced by the agonistic action of the microorganism to the H3 histamine receptors and its inhibitory effect to CCK and somatostatin secretion that normally diminish gastrin release [8]. The increased levels of gastrin and the diminished somatostatin release, in combination with others hormones collectively known as the ‘enteroinsular axis’, could potentate insulin secretion, increase plasma insulin levels and as a result diminish fasting blood glucose levels [9], as somatostatin normally has an inhibitory effect on insulin release. Additionally, insulin can directly stimulate epinephrine release, which may induce hypoglycemia [10]. Accordingly, Hp infection can affect glucose metabolism and Hp-positive individuals might have higher insulin and lower glucose plasma levels in comparison to Hp-negative persons. It is already identified that the inflammatory reaction, which Hp infection produces, could be deleterious for the control of glucemia, especially for patients with diabetes, as well as that Hp gastritis may contribute to postprandial hypoglycemia due to hyperinsulinemia [11–13]. Peach and Barnett [3] reported that Hp infection may lead to a lower fasting plasma glucose concentration among women. In the present study we could not identify any significant difference in fasting blood glucose levels between Hp-positive and Hp-negative participants. Hp infection demonstrated its role in controlling fasting blood glucose concentrations only when it was combined with obesity. Among Hp-infected individuals, obese persons presented with a significantly lower mean blood glucose level than non-obese persons, further supporting the finding that obese Hp-positive individuals had a significantly lower mean blood glucose level than obese Hp-negative persons. Among Hp non-infected individuals, the mean serum glucose level was higher (even not statistically significant) for obese than lean persons as it is well known that obesity can be accompanied by alterations in glucose metabolism [14].

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The identification and sequencing of the mouse obese (ob) gene by Friedman’s group in 1994 opened important new avenues in obesity research. The ob gene encodes the protein leptin, which is produced in the adipocytes, secreted into the blood and informs the brain about the size of the fat mass. It is known that plasma leptin highly correlates to body fat content and BMI, with obese persons having increased leptin levels [15]. Accumulating evidence suggests that the role of leptin is much broader than that of an anti-obesity hormone; leptin exerts several other metabolic effects on peripheral tissue including modification of the insulin action. Supraphysiologic levels of insulin markedly increase circulating leptin levels, while administration of leptin improves insulin resistance in mice and insulin-resistance has been associated with increased leptin levels [16, 17]. Although the mechanism underlying the changes of leptin induced by insulin and vice versa remains to be studied in more detail, these data demonstrate a significant relationship between leptin and insulin. Insulin and corticosteroids are obvious candidates signaling fat cells for leptin production. Thus, the increased leptin expression observed in obesity could result from chronic hyperinsulinemia and increased cortisol turnover [18] as insulin plasma levels in obese individuals are elevated compared to those in normal subjects [19, 20]. The fact that in normoglycemic obese persons, leptin levels are higher than the leptin levels in obese persons with diabetes, can support the option that normally, leptin levels are negatively correlated with fasting glucose levels [14, 21, 22]. Taking all these points into consideration and in accordance with our results, it could be possible that in obese persons, stimulated sympathetic activity, hyperleptinemia and its related hyperinsulinemia, can be combined with the increment of gastrin, reduction of somatostatin and increased histamine resulting from Hp infection, with finally further hyperinsulinemia. This combined increment of insulin might be a reason for the lower fasting serum glucose values that we recognized in obese than in lean Hp-positive persons. Alterations of glucose metabolism in Hp colonization need further investigation.

Kyriazanos/Sfiniadakis/Dimakos/Gizaris/ Datsakis/Dafnopoulou

References 1 Senturk O, Canturk Z, Cetinarslan B, Ercin C, Hulagu S, Canturk NZ: Prevalence and comparison of five different diagnostic methods for Helicobacter pylori in diabetic patients. Endocr Res 2001;27:179–189. 2 De Luis DA, Cordero JM, Caballero C, Boixeda D, Aller C, Canton R, De la Calle H: Effect of the treatment of Helicobacter pylori infection on gastric emptying and its influence on the glycaemic control in type 1 diabetes mellitus. Diabetes Res Clin Pract 2001;52:1–9. 3 Peach HG, Barnett NE: Helicobacter pylori infection and fasting plasma glucose concentration. J Clin Pathol 2001;54:446–449. 4 Kyriazanos ID, Sfiniadakis I, Gizaris V, Hountis P, Hatziveis K, Dafnopoulou A, Datsakis K: The incidence of Helicobacter pylori infection is not increased among obese young individuals in Greece. J Clin Gastroenterol 2002;34: 541–546. 5 NIH: Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults. Bethesda, NIH, 1998. www.nhlbi.nih.gov/guidelines 6 Van Den Brink GR, ten Kate FJ, Ponsioen CY, Rive MM, Tytgat GN, van Deventer SJ, Peppelenbosch MP: Expression and activation of the NF-ÎB in the antrum of the human stomach. J Immunol 2000;164:3353–3359.

Fasting Blood Glucose Concentrations and H. pylori Infection

7 Rose S: Gastrointestinal and Hepatobilliary Pathophysiology. Philadelphia, Fence Creek Publishing, 1998, pp 161–172. 8 Calam J, Gibbons A, Haley Z, Bliss P, Arebi N: How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology 1997;113:S43–S49. 9 Acbay O, Celik AF, Gundogdu S: Does Helicobacter pylori-induced gastritis enhance foodstimulated insulin release? Dig Dis Sci 1996; 41:1327–1331. 10 Landsberg L, Krieger DR: Obesity, metabolism and the sympathetic nervous system. Am J Hypertens 1989;2:125S–132S. 11 Acbay O, Celik AF, Kadioglu P, Goksel S, Gundogdu S: Helicobacter pylori-induced gastritis may contribute to occurrence of postprandial symptomatic hypoglycemia. Dig Dis Sci 1999;44:1837–1842. 12 Perdichizzi G, Bottari M, Pallio S, Fera MT, Carbone M, Barresi G: Gastric infection by Helicobacter pylori and antral gastritis in hyperglycemic obese and in diabetic subjects. New Microbiol 1996;19:149–154. 13 Begue RE, Mirza A, Compton T, Gomez R, Vargas A: Helicobacter pylori infection and insulin requirement among children with type 1 diabetes mellitus. Pediatrics 1999;103:e83. 14 Zimmet P, Hodge A, Nicolson M, Staten M, de Courten M, Moore J, Morawiecki A, Lubina J, Collier G, Alberti G, Dowse G: Serum leptin concentration, obesity and insulin resistance in Western Samoans: Cross-sectional study. BMJ 1996;313:965–969.

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15 Janeckowa R: The role of leptin in human physiology and pathophysiology. Physiol Res 2001;50:443–459. 16 Mantzoros CS: The role of leptin in human obesity and disease: A review of current evidence. Ann Intern Med 1999;130:671–680. 17 Wolf G, Chen S, Han DC, Ziyadeh FN: Leptin and renal disease. Am J Kidney Dis 2002;39: 1–11. 18 Fried SK, Ricci MR, Russell CD, Laferrere B: Regulation of leptin production in humans. J Nutr 2000;130:3127S–3131S. 19 Rasmussen MH, Hvidberg A, Juul A, Main KM, Gotfredsen A, Skakkebaek NE, Hilsted J: Massive weight loss restores 24-hour growth hormone release profiles and serum insulinlike growth factor-I levels in obese subjects. J Clin Endocrinol Metab 1995;80:2446. 20 Larsson H, Elmstahl S, Ahren B: Plasma leptin levels correlate to islet function independently of body fat in postmenopausal women. Diabetes 1996;45:1580–1584. 21 Sorensen IT, Echwald MS, Holm JC: Leptin in obesity. BMJ 1996;313:953–954. 22 Clement K, Lahlou N, Ruiz J, Hager J, Bougneres P, Basdevant A, Guy-Grand B, Froguel P: Association of poorly controlled diabetes with low serum leptin in morbid obesity. Int J Obes Relat Metab Disord 1997;21:556–561.

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Selenium Is Depleted in Crohn’s Disease on Enteral Nutrition Fumitoshi Kuroki Takayuki Matsumoto Mitsuo Iida Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan

Key Words Selenium W Crohn’s disease W Enteral nutrition

Abstract Backgroud/Aims: Selenium is an important trace element and its deficiency has been reported to be associated with cardiomyopathy or gastrointestinal cancer. The aim of this study is to clarify the selenium status in Crohn’s disease (CD) on enteral nutrition. Methods: We measured serum selenium concentrations in 53 patients with CD and compared them with those in 21 healthy controls. Twenty-nine patients were under the treatment by enteral nutrition (EN group), and the remaining 24 patients were free from formulated enteral nutrition (non-EN group). Results: While the serum selenium concentration in the non-EN group was not decreased when compared to controls, the value in the EN group was significantly lower than those in the non-EN group and in controls. Clinical manifestations of selenium deficiency were found in a patient on exclusive enteral nutrition. In the EN group, the serum selenium concentration showed an inverse correlation with the duration and the daily dose of enteral nutrition. In the non-EN group, the serum selenium concentrations were inversely corre-

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lated with the Crohn’s disease activity index. Conclusion: These findings suggest that patients with CD on enteral nutrition are at risk for selenium deficiency and that even patients without enteral nutrition may develop selenium deficiency at the active phase of the disease. Copyright © 2003 S. Karger AG, Basel

Introduction

Selenium is an essential trace element which is a component of enzyme glutathione peroxidase. The enzyme protects membrane structures by detoxifying oxygen species. Because selenium is contained in various foods, deficiency of the trace mineral rarely occurs, except in subjects who reside in areas where the soil contains a low amount of selenium and for patients on long-term parenteral nutrition [1, 2]. Because patients with Crohn’s disease (CD) usually have various nutritional disturbances, parenteral nutrition or enteral nutrition (EN) are applied for the management of malnutrition. In addition, EN has been reported to be one of the primary therapies for active CD [3, 4] and widely accepted for prolongation of remission in children and adolescents [5]. On such occasions, subnormal seleni-

Fumitoshi Kuroki Department of Medicine and Clinical Science Graduate School of Medical Sciences, Kyushu University 3-1-1 Maidashi, Higashiku, Fukuoka City 812-8582 (Japan) Tel. +81 982 550505, Fax +81 982 550500, E-Mail [email protected]

Table 1. Details of the patients’ clinical characteristics at the time of investigation

Controls (n = 21)

Patients EN group (n = 29)

non-EN group (n = 24)

16–77 (29.8B11.7) 25/4 14.8–24.2 (19.2B2.2) 0.2–18 (7.1B5.6) 13–377 (127B98)

16–53 (30.6B10.4) 18/6 15.1–24.3 (19.2B2.5) 0.1–28 (6.6B7.1) 15–414 (129B106)

Bowel involvement Small bowel only Large bowel only Small and large bowel History of intestinal resection

10 2 17 9

11 5 8 5

Current medical treatments Salazosulfapyridine Prednisolone None

10 1 18

2 2 22

Age, years Sex, m/f Body mass index Time intervalc CD activity index

a b c

22–46 (30.0B6.3) 14/7 15.8–22.7 (20.0B2.0)

NSa NSa NSa NSa NSa

NSb NSb

Values are expressed as the range (mean B SD). Comparison among the EN group, non-EN group, and controls. Comparison between the EN group and non-EN group. Time interval from onset of symptoms to diagnosis, in years.

um status in CD patients on total parenteral nutrition has already been reported [6, 7]. However, there have been a few reports concerning the selenium status in CD patients on EN [8, 9]. The aim of this study is to investigate the selenium status in CD patients with a reference to EN.

Subjects and Methods Subjects Fifty-three patients with an established diagnosis of CD and 21 healthy control subjects were enrolled for the present study. The diagnosis of CD was based on confirmation of clinical, radiographic, or endoscopic findings and histologic features characteristic of this disease. None of the patients had steatorrhea, which is a major clinical manifestation of malabsorption. CD patients were divided into two groups – EN and non-EN. EN was used for primary therapy for active disease and for prolongation of remission. The EN group was composed of 29 patients who had been treated by EN. The non-EN group consisted of 24 patients who had been ingesting ordinary Japanese foods without any formulated diet. Ten of them had not been treated by any medical and nutritional treatments, and the others had rejected EN. Details of the patients’ clinical characteristics at the time of investigation are shown in table 1. In the EN group, 7 patients had been ingesting elemental diet (Elental, Roussel Morishita, Osaka, Japan), 7 had been ingesting polymeric diet (Ensure Liquid, Dainabot, Osaka, Japan), and 15 had

Selenium and Crohn’s Disease

been ingesting both. Among the EN group, 22 had been ingesting ordinary foods, but 3 had been on exclusive EN without any food intake. The duration of EN ranged from 0.1 to 5.3 years (1.5 B 1.3 years, mean B SD), and the daily dose of EN ranged from 500 to 2,300 kcal (1,384 B 483 kcal). Twenty-one normal healthy volunteers participated in this study. They were randomly selected from our laboratory staff, according to the following criteria: (1) completely free from previous or present illness, (2) normal physical examination and blood chemistry, and (3) consumption of ordinary Japanese food. Neither the CD patients nor controls had been supplied with trace minerals at the time of selenium measurement. Informed consent was obtained from each patient and control prior to blood sampling. Disease Activity Activity of CD at the time of investigation was calculated, according to the formula described as Crohn’s disease activity index (CDAI) [10]. A cut-off value of CDAI 150 was used to divide each patient into active (CDAI 1 150) or inactive (CDAI ^ 150) disease. Measurement of Serum Selenium Concentration After an overnight fast, blood samples were obtained from each patient and control. Blood was centrifuged for separation of serum. After the initial reduction of the serum sample and treatment with the palladium modifier, the concentrations of selenium were determined by graphite-furnace atomic absorption spectrometry using Model AA-40G atomic absorption spectrophotometer (Varian Canada Inc., Georgetown, Ont., Canada) [11]. In addition, hematocrit value, erythrocyte sedimentation rate, serum albumin and C-reactive

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Fig. 2. a Thumbnails of the patient prior to selenite supplementation. The nails are rough and wavy. b The rough and wavy changes of

the nails have improved after selenite supplementation.

Fig. 1. Comparison of serum selenium concentrations among the EN group, non-EN group, and controls.

protein were measured and body mass index (BMI) was calculated as follows: weight (kg)/height (m)2. Statistical Analysis Results are expressed as mean B SD. Comparisons among the EN group, non-EN group and the controls were performed by oneway analysis of variance with ‘a posterior’ Scheffé test. Correlation coefficients (r) between serum selenium concentrations and various parameters in each CD group were calculated by regression analysis. Probabilities ! 0.05 were considered significant.

Results

Age, gender and BMI values were not different among the two CD groups and the controls (table 1). Serum albumin concentration in the CD groups showed lower values than the controls (p ! 0.0001), but the value was not different between the two CD groups (EN group, 3.9 B 0.6 mg/dl; non-EN group, 3.8 B 0.6 mg/dl; controls, 4.8 B 0.2 mg/dl). Comparison of Selenium Status The selenium status of the CD patients and controls are shown in figure 1. The serum selenium concentration in the EN group (7.1 B 3.5 Ìg/dl) was significantly lower than in the non-EN group (10.2 B 2.0 Ìg/dl, p ! 0.0001) and in controls (11.8 B 1.4 Ìg/dl, p ! 0.0001). In particu-

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lar, the serum selenium concentration in 3 patients with exclusive EN showed extremely low values (0.6, 0.7 and 2.9 Ìg/dl, respectively). One of them had been clinically diagnosed as having selenium deficiency because of impaired serum glutathione peroxidase activity, cardiac dysfunction, fingernail deformities, and subsequent improvement of clinical symptoms by selenite supplement (fig. 2). In each CD group, the serum selenium concentration was not different according to the site of the disease and to prior history of the intestinal resection. The CDAI ranged from 13 to 414 (128 B 101). As indicated in table 1, the CDAI was not different between the EN and non-EN group. The serum selenium concentration was not different between active CD and inactive CD in each group. When possible, the correlation between serum selenium concentration and CDAI was further investigated, the selenium concentration was inversely correlated with CDAI in the non-EN group (r = –0.513, p ! 0.01) (fig. 3), but such a significant correlation was not found in the EN group. In contrast, the serum selenium concentration in the EN group correlated with daily dose (r = –0.374, p ! 0.05) and duration of EN (r = –0.433, p ! 0.05) with statistical significance (fig. 4). In both EN and non-EN groups, the serum selenium concentration did not show any significant correlation with serum albumin levels, BMI, C-reactive protein or erythrocyte sedimentation rate values.

Kuroki/Matsumoto/Iida

Fig. 3. Correlation between serum selenium concentration and

CDAI in the non-EN group (r = –0.513, p ! 0.01).

Discussion

Cardiomyopathy, weakness in proximal muscle, elevation of liver transaminase and creatine kinase activities, and nail changes are the major clinical manifestations of selenium deficiency [12]. In addition, selenium depletion has been known to be associated with an increased risk for gastrointestinal and prostatic cancer [13]. Because cardiomyopathy in selenium deficiency is irreversible and fatal [2], early recognition of the condition seems to be inevitable. In clinical situations, selenium status has generally been assessed by serum or erythrocyte glutathione peroxidase activities. Because a significant correlation between serum selenium concentration and glutathione peroxidase activity has been established, the former applied for the present investigation has been regarded to be appropriate for the assessment of selenium status [14]. CD has been known to be accompanied by various nutritional disturbances. Low selenium concentrations in active CD have been shown in previous investigations [14–19], and insufficient oral intake and/or malabsorption have been considered to be the main cause of low selenium levels. In this study, the selenium concentration in the non-EN group was not different from controls. The insignificant difference in selenium concentration can be explained by the inclusion of inactive or mild disease. However, since the selenium concentration showed inverse correlation with CDAI in the non-EN group, CD

patients with severe disease may develop profound selenium deficiency. Parenteral nutrition and EN are established strategies for the management of CD [1–9, 14]. These nutritional therapies contribute to the improvement of nutritional status, intestinal lesions and disease activity [3, 4]. In particular, EN has been accepted to prolong the remission of CD in children and in adolescents [5]. Because most of the enteral formulas prevailing in Japan or in the USA do not contain sufficient selenium [20–22], patients on EN are at high risk of selenium deficiency. In this study, the serum

Selenium and Crohn’s Disease

Dig Dis 2003;21:266–270

Fig. 4. Correlation between serum selenium concentration and daily dose of EN (a) (r = –0.374, p ! 0.05) or duration of EN (b) (r = –0.433, p ! 0.05) in the EN group.

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selenium concentration in the EN group was significantly lower than in the non-EN group and controls. Because there were no differences in clinical or nutritional parameters other than the diet between the two CD groups, insufficient selenium content in the enteral formulas seems to be the major cause for decreased selenium concentration in the EN group. It has been reported that Elental and Ensure Liquid used as the formula of EN for our patients contain 1.6 and 7.3 Ìg/1,000 kcal of selenium respectively [22]. Because the recommended dietary allowance of selenium has been established to be 0.87 Ìg/kg/day by the US Research Council [23], selenium intake with the formula of EN alone would be much lower than the recommended value. In fact, selenium concentrations in 3 cases on exclusive

EN showed an extraordinarily low value, and a patient had actually developed clinical manifestations of selenium deficiency. In addition, the selenium concentration was even low in patients who ingested both EN and ordinary food. Because the selenium levels were inversely correlated with the dose and the duration of EN, it would be necessary to take account of selenium deficiency in CD patients under a prolonged period of EN even if ordinary food is not prohibited. In conclusion, this study indicated that selenium deficiency possibly occurs in patients with CD, especially in those on EN. While selenium supplement seems to be necessary for a certain proportion of CD patients, the optimal dose in consideration of possible toxic effects should further be elucidated.

References 1 Van Riji AM, Thomson CD, Mckenzie JM, Robinson MF: Selenium deficiency in total parenteral nutrition. Am J Clin Nutr 1979;32: 2076–2085. 2 Fleming CR, Lie JT, McCall JT, OBrien JF, Baillie EE, Thistle JL: Selenium deficiency and fatal cardiomyopathy in a patients on home parenteral nutrition. Gastroenterology 1982; 83:689–693. 3 Gonza´lez-Huix F, de Leoń R, Fernańdez-Bañares F, Esteve M, Cabré E, Acero D, AbadLacruz A, Figa M, Guilera M, Planas R, Gassull MA: Polymeric enteral diet as primary treatment of active Crohn’s disease: A prospective steroid controlled trial. Gut 1993;34:778– 782. 4 Hiwatashi N: Enteral nutrition for Crohn’s disease in Japan. Dis Colon Rectum 1997;40: S48–S53. 5 Wilschanski M, Sherman P, Pencharz P, Davis L, Corey M, Griffiths A: Supplementary enteral nutrition maintains remission in paediatric Crohn’s disease. Gut 1996;38:543–548. 6 Fleming CR, McCall JT, O’Brien JF, Forsman RW, Ilstrup DM, Petz J: Selenium status in patients receiving home parenteral nutrition. J Parenter Enteral Nutr 1984;8:258–262. 7 Jacobson S, Plantin LO: Concentration of selenium in plasma and erythrocytes during parenteral nutrition in Crohn’s disease. Gut 1985;26: 50–54.

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8 Fernańdez-Bañares F, Mingorance MD, Esteve M, Cabré E, Lachica M, Abad-Lacrus A, Gil A, Humbert P, Boix J, Gassull MA: Serum zinc, copper, and selenium levels in inflammatory bowel disease: Effect of total enteral nutrition on trace element status. Am J Gastroenterol 1990;85:1584–1589. 9 Thomas AG, Miller V, Shenkin A, Fell GS, Taylor F: Selenium and glutathione peroxidase status in paediatric health and gastrointestinal disease. J Pediatr Gastroenterol Nutr 1994;19: 213–219. 10 Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s disease activity index. Gastroenterology 1976;70:439–444. 11 Jacobson BE, Lockitch G: Direct determination of selenium in serum by graphite-furnace atomic absorption spectrometry with deuterium background correction and a reduced palladium modifier: Age-specific reference ranges. Clin Chem 1988;34:709–714. 12 Lockitch G: Selenium: Clinical significance and analytical concepts. Crit Rev Clin Lab Sci 1989;27:483–541. 13 Willett WC, Morris JS, Pressel S: Prediagnostic serum selenium and risk of cancer. Lancet 1983;ii:130–134. 14 Rannem T, Ladefoged K, Hylander E, Hegnhøj J, Staun M: Selenium depletion in patients with gastrointestinal disease: Are there any predictive factors? Scand J Gastroenterol 1998;33: 1057–1061. 15 Penny WJ, Mayberry JF, Aggett PJ, Gilbert JO, Newcombe RG, Rhodes J: Relationship between trace elements, sugar, consumption and taste in Crohn’s disease. Gut 1983;24:288– 292.

16 Loeschke K, König A, Haeberlin SH, Lux F: Low blood selenium concentration in Crohn disease. Ann Intern Med 1987;106:908. 17 Hinks LJ, Inwards KD, Lloyd B, Clayton B: Reduced concentrations of selenium in mild Crohn’s disease. J Clin Pathol 1988;41:198– 201. 18 Rannen T, Ladefoged K, Hylender E, Hegnhøt J, Jarnum S: Selenium status in patients with Crohn’s disease. Am J Clin Nutr 1992;56:933– 937. 19 Geerling BJ, Badart-Smook A, Stockbrügger RW, Brummer RJM: Comprehensive nutritional status in patients with long-standing Crohn disease currently in remission. Am J Clin Nutr 1998;67:919–926. 20 Zabel NL, Harland J, Gormican A, Ganther HE: Selenium content of commercial formula diets. Am J Clin Nutr 1978;31:850–858. 21 Martin RF, Young VR, Janghorbani M: Selenium content of enteral formulas. J Parenter Enteral Nutr 1986;10:213–215. 22 Tanaka T, Higashi A, Matsuda I, Suzuki I, Asakawa M: Selenium content of Japanese enteral formulas (Engl abstract). J Jpn Soc Nutr Food Sci 1995;48:147–50. 23 Food and Nutritional Board, National Research Council: Trace Elements. Recommended Dietary Allowances, ed 10. Washington, National Academy Press, 1989, pp 217– 224.

Kuroki/Matsumoto/Iida


L-Carnitine in the Treatment of Mild or Moderate Hepatic Encephalopathy Mariano Malaguarnera a Giovanni Pistone a Marinella Astuto c Simona Dell’Arte a Giovanna Finocchiaro a Emilia Lo Giudice a Giovanni Pennisi b a Dipartimento b Dipartimenti

di Scienze della Senescenza, Urologiche e Neurologiche, Università degli Studi di Catania, e di Neuroscienze e c Specialità Medico-chirurgiche Sez. Anestesiologia, Università di Catania, Italia

Key Words Hepatic encephalopathy W L-Carnitine treatment

Abstract Hepatic encephalopathy (HE) is one of the major complications of cirrhosis. Experimental and clinical findings observed in liver, muscle and brain have provided new insights into the ammonia mechanism of action. L-Carnitine (LC), inducing ureagenesis, may decrease blood and brain ammonia levels. 120 patients meeting inclusion criteria were randomized either to a treatment for 60 days with LC or placebo (2 g twice a day). Previous studies have reported a significant protective effect of LC in mice and rats, which is associated with a significant reduction of blood and brain ammonia concentration, suggesting an action of LC either at peripheral or central sites. Results of our study show a protective effect of LC in ammonia-precipitated encephalopathy in cirrhotic patients. Either in subjects with HE 1 or 2 we observed a significant reduction at day 30 and more markedly at day 60 of treatment. A significant therapeutic effect of LC was also observed in the NCT-A, which is an accepted and reliable psychometric test for the assessment of mental function in cirrhotic patients with HE. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0213–0271$19.50/0



Introduction

Hepatic encephalopathy (HE) is one of the major complications of cirrhosis. Clinical grading is based on impaired mental function, neurological disorders and altered states of consciousness, to stupor and coma. Pathogenesis of this common syndrome remains partially unknown. Hyperammoniemia, due to the several mechanisms proposed, is one of the main pathogenetic factors in the development of HE, as shown by the association of increased serum ammonia levels with impairment of mental function in patients with liver failure. Experimental and clinical findings observed in liver, muscle and brain have provided new insights into the ammonia mechanism of action. In fact, these organs play a fundamental role in the removal of ammonia in cases of hyperammoniemia [1, 2]. A decrease in the muscle mass is a jeopardizing factor for the development of encephalopathy [3]. Muscle mass loss is also associated with a decreased ability to change ammonia in glutamine. All morphological and functional characteristics of the brain in experimental models and humans rule out an initial involvement of neurons in HE, the astrocytes being the first target of the disease [4]. As showed by Ullian et al. [5], these cells play a key role in the correct development and function of neurons. In HE, no

Mariano Malaguarnera, AP Viale Andrea Doria, 69 IT–95126 Catania (Italy) Tel. +39 095 7262008, Fax +39 095 7262011 E-Mail [email protected]

morphological neuronal alterations are detected, changes in astrocyte characteristics being present (Alzheimer type II cells) [6]. The majority of therapeutic measures currently in use are therefore aimed at reduction of serum ammonia levels, by decreasing enteric ammonia production [7]. Carnitine is a natural substance involved in regulating substrate flux and energy balance across cell membranes. It is a cofactor for the shuttle mechanism whereby longchain fatty acids are transformed into L-acetylcarnitine metabolites and may be carried out into mitochondria in order to be part of ß-oxidation [8]. Furthermore, carnitine and the carnitine acetyltransferase are involved in the following reaction: acetyl-coenzyme A + carnitine = acetylcarnitine + coenzyme A. This reaction modulates the intracellular concentration of coenzyme A and acetylCoA. By this reaction, carnitine produces free CoA for other metabolic reactions and reduces the ratio of acetylCoA to CoA. This reduction stimulates the activity of pyruvate dehydrogenase and, thus, enhances the oxidative use of glucose. O’Connor et al. [9] showed a protective effect of Lcarnitine (LC) administration to mice 1 h before a lethal injection of ammonium acetate. Therrien et al. [10] reported that LC in the portocaval shunted rat prevented not only the development of severe encephalopathy, but also reduced mortality. It was suggested that LC, inducing ureagenesis, may decrease blood and brain ammonia levels. In order to assess the clinical efficacy of LC in the treatment of HE, a randomized, double-blind, placebocontrolled study with oral administration in cirrhotic patients with hyperammoniemia and chronic symptoms has been carried out. The aim of our study was to evaluate in a practiceadapted design the influence of LC using the number connection test A (NCT-A), mental conditions and ammonia effects.

Patients and Methods 120 randomly selected patients (9 alcoholics, 33 hepatitis B virus infected, 63 hepatitis C virus infected, 15 cryptogenetic cirrhosis) met the following inclusion criteria and were enrolled in the study: (1) chronic hepatitis with spontaneous manifest HE (mental state grade 1 or 2 according to the West Haven criteria) and an NCT-A performance time 1 30 s; (2) hyperammoniemia (venous ammonia concentration 1 50 mmol/l), and (3) cooperative, hospitalized adult patients with liver cirrhosis diagnosed by clinical, histological and ultrasonographic findings. Exclusion criteria were the following: (1) major complications of portal hypertension, such as gastrointestinal blood loss, hepatorenal syndrome or bacterial peritonitis; (2) acute superimposed liver inju-

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ry; (3) patient with other neurological disease and metabolic disorders such as alcoholism, diabetes mellitus, unbalanced heart failure and/or respiratory failure or end-stage renal disease; (4) severe HE (mental state grade 3–4); (5) administration of anti-HE medications such as neomycin, lactulose, lactitol, branched-chain amino acids; (6) any additional precipitating factors such as high protein intake (additional high-protein meals), constipation or intake of psychostimulants, sedatives, antidepressants, benzodiazepines, or benzodiazepine antagonists (flumazenil), and (7) patients with fever, sepsis or shock were also excluded to avoid variations caused by body temperature.

Study Design Patients meeting inclusion criteria were randomized in a doubleblind fashion to either a treatment for 60 days with LC (2 g twice a day) (group A) or placebo (which were identical in appearance and packaging) (group B). Randomization was based on a computer-generated list. The consumption of oral LC at a dose of 4 g/day divided into two doses (2 g in the morning and 2 g in the evening) for 60 days met the 100% of compliance. A minimum of 210 pills (each pill 1 g) was considered as good compliance. Concomitant medications (whose administration continued throughout the study) included diuretics (36 of group A and 30 of group B) and ß-blockers (27 of group A and 25 of group B). All study series were subdivided into groups belonging to HE 1 or HE 2 according to the initial HE grade (West Haven criteria). Group A was composed of patients with initial HE 1 (LC 35 patients, placebo 33 patients); group B with initial HE 2 (LC 25 patients, placebo 27 patients). The effectiveness of therapy was compared and evaluated separately in the different subgroups. The groups were homogeneous with regard to anamnestic and diagnostic criteria. Differences in the composition of the two groups with respect to precipitant factors may be minimized, because the patient population was well defined by inclusion and exclusion criteria. Any pathological, clinical or laboratory findings observed during the study were monitored and documented until their normalization. NCT-A The NCT-A measures cognitive and motor ability, and consists of a combination of number series on a sheet with best celerity possible. A decrease in the time employed to complete the NCT-A reflects an improvement of the neurological function. Venous Ammonia Concentration The blood ammonia levels were evaluated by the enzymatic determination using glutamate dehydrogenase in a rapid and interference-free photometric determination (340 nm) of NH +4 in native blood plasma according to the De Fonseca-Wollheim method [12]. The blood sample was immediately taken after withdrawal to the laboratory for immediate (within 15 min) determination of NH4 +4. Hepatic Encephalopathy Encephalopathy grade was diagnosed on the basis of the evaluation of consciousness, intellectual functions, behavior and neuromuscular functions according to the West Haven criteria introduced by Conn and Liebenthal [13, 14].

Malaguarnera/Pistone/Astuto/Dell’Arte/ Finocchiaro/Lo Giudice/Pennisi

Table 1. Baseline characteristics of patients

Parameter

Carnitine group (A)

Placebo group (B)

Male/female Age Cirrhosis etiology Alcohol Post-hepatitis B Post-hepatitis C Cryptogenetic Child-Pugh class A B C Prothrombin time, % Serum albumin level, g/dl Serum bilirubin level, mg/dl Serum alanine aminotransferase level, IU/l Blood urea nitrogen, mg/dl Serum creatinine level, mg/dl Natriemia, mEq/l

40/20 51.7B11.8

38/22 52.4B10.4

4 16 32 8

5 17 31 7

29 32 9 60.4B6.7 2.7B0.6 3.8B1.4 128B61 44B10 1B0.15 133B3.4

30 31 9 61.2B6.9 2.8B0.5 3.6B1.5 120B63 43B12 0.98B0.14 132B4.7

Safety Parameters Safety parameters included blood tests (hemoglobin, hematocrit, white and red blood cell count, platelet count) and liver function tests (alanine aminotransferase, aspartate aminotransferase, Á-glutamyltranspeptidase, cholinesterase activity, serum bilirubin, serum albumin concentrations, prothrombin time and partial thromboplastin time) on days 0, 30 and 60. Statistical Analysis Descriptive statistics were prepared from the study sample and results were expressed as means B SD. Statistical significance in contingency tables was evaluated using ¯2 test and Fisher’s exact test. Student’s test for unpaired data, one-way ANOVA and Mann-Whitney rank sum test were used for comparisons of continuous variables. Statistical analyses were performed using appropriate tests for repeated measures as well as by controlling for multiple comparisons with correction of the Duncan procedure. The study protocol was received and approved by the Institutional Review Board of the Hospital following the guidelines of the 1975 Declaration of Helsinki.

Results

Baseline Values The two groups were homogeneous for demographic characteristic, etiology, casting of disease and Child-Pugh grade. Serum NH +4 fasting concentrations were not significantly different before the treatment. NCT-A did not show significant differences at baseline. L-Carnitine Treatment The patients treated with carnitine either in group HE 1 or in group HE 2 showed fasting statistical significant

L-Carnitine in the Treatment of Mild or Moderate HE

differences in serum NH +4 levels. In group HE 1, after 30 days of treatment, p was 0.003 (CI 6.37–30.43), being 0.000 (CI 27.82–48.98) after 60 days compared to baseline values and 0.000 (CI 11.14–28.86) compared to day 30. In group HE 2, p was 0.000 (CI 15.76–40.04) after 30 days, being 0.000 (CI 32.96–53.24) after 60 days compared to baseline values and 0.001 (CI 6.01–24.39) compared to day 30 of treatment respectively. With reference to NCT-A, in group HE 1 we observed a p of 0.000 (CI 6.23–19.17) after 30 days and 0.000 (CI 17.78–30.62) after 60 days compared to baseline values as well as 0.000 (CI 5.15–17.85) with respect to day 30 of treatment respectively. In group HE 2 we found a p of 0.000 (CI 7.91–21.89) after 30 days and 0.000 (CI 20.20–34.20) after 60 days compared to baseline values and 0.000 (CI 5.63–18.97) with respect to day 30 of treatment. Placebo Treatment No statistical difference was found in these patients at days 30 and 60 with respect to baseline and day 30 values respectively in both groups. In fact, for fasting serum NH +4 levels, in group HE 1 we found a p of 0.477 after 30 days (CI –7.63 to 16.23), after 60 days a p of 0.419 (CI –7.21 to 17.21) with respect to baseline values and 0.905 compared to values of day 30 of treatment (CI –10.87 to 12.27). In group HE 2 we found a p of 0.396 (CI –7.01 to 17.61) after 30 days and of 0.303 (CI –5.95 to 18.95) after 60 days with respect to baseline and 0.832 (CI –10.01 to 12.41) with respect to values of day 30 respectively. For

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Table 2. Comparison between evaluated parameters of the two groups (days of treatment)

Carnitine group

NH +4 fasting NCT-A

HE 1 HE 2 HE 1 HE 2

Placebo group

0 days

30 days

60 days

0 days

30 days

60 days

80.2B36.9 88.7B35.6 62.8B18.1 66.4B20.2

61.8B29.2 60.8B31.4 50.1B17.7 51.5B18.4

41.8B18.7 45.6B17.5 38.6B17.4 39.2B18.5

80.7B34.7 86.7B37.2 60.7B20.3 65.8B21.4

76.4B31.2 81.4B30.6 58.7B19.4 65.1B19.7

75.7B32.8 80.2B31.4 56.7B20.7 63.2B23.1

NCT-A, in group HE 1 we found a p of 0.582 after 30 days (CI –5.18 to 9.18) and of 0.287 (CI –3.41 to 11.41) after 60 days compared to baseline values and 0.586 (CI –5.25 to 9.25) with respect to values of day 30. Following the same sequence of the previously listed parameters, in group HE 2 we found a p of 0.852 (CI –6.74 to 8.14) after 30 days, 0.524 (CI –5.45 to 10.65) after 60 days with respect to basal conditions and 0.629 (CI –5.86 to 9.66) compared to day 30 of administration. Comparison between Treatments In group HE 1 for NH +4 at day 30 of administration, the patients treated with carnitine showed a response statistically significant with respect to placebo (p = 0.009 CI –25.252 to –3.68); in group HE 2, at day 30 of administration p was 0.000 (CI –31.81 to –9.39). For NCT-A, in group HE 1 at day 30 of administration a statistical difference was found with p 0.012 (CI –15.31 to –1.89), while in group HE 2 at day 30 of administration p was 0.000 (CI –20.49 to –6.71) in favor of carnitine patients. At day 60 for NH +4 in group HE 1, carnitine-treated patients showed a better significant response than placebo patients, p was 0.000 (CI –43.55 to –24.25); in group HE 2, p was 0.000 (CI –43.73 to –25.41) in favor of carnitine. About NCTA, at day 60 the response was strikingly in favor of carnitine-treated patients: in group HE 1, p was 0.000 (CI –25.01 to –11.19), while in group HE 2, p was 0.000 (CI –31.57 to –16.43). Adverse Events Both LC and placebo were well tolerated in 100% of patients. In the group treated with LC, 1 patient complained of nausea, 2 of slight headache and 2 of abdominal pain. In placebo group, 2 patients complained of diarrhea and 1 of moderate headache. Nobody withdrew from the planned treatment.

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Discussion

Several pathogenetic mechanisms have been suggested to explain the onset and progression of HE. The most ancient hypothesis is linked to the neurotoxicity of ammonia. The majority of blood NH +4 amount results from muscle protein catabolism at intestinal level; the remnant is produced by the action of colic bacteria on the natrium present in digested foods. Ammonia is vehicled to the liver throughout the portal flux and is normally eliminated as urea. The liver damage or the presence of portosystemic shunts increase its serum levels [15, 16]. The exceeding ammonia is eliminated from the blood by transforming of glutamate into glutamine in skeletal muscle as well as central nervous system. Neurotoxicity of ammonia is probably due to a direct action on neurons, because the reduction of glutamate and the increase of glutamine may induce a swelling of the astrocytes [16]. Previous studies have reported a significant protective effect of LC in mice and rats, which is associated with a significant reduction of blood and brain ammonia concentration [9, 17], suggesting an action of LC either at peripheral or central sites. In the study by O’Connor et al. [9], blood urea concentrations were significantly increased and inversely related to the lowering of blood ammonia after one carnitine administration to normal mice to whom toxic doses of ammonia were administered. This fact suggests that LC’s effect in these animals was caused, at least partially, by an action on hepatic urea synthesis. Results of our study show a protective effect of LC in ammonia-precipitated encephalopathy in cirrhotic patients. Either in subjects with HE 1 or HE 2, we observed a significant reduction at day 30 and more markedly at day 60 of treatment. A significant therapeutic effect of carnitine was also observed in the NCT-A, which is an accepted and reliable psychometric test for the assessment of mental function in cirrhotic patients with HE [13, 18]. LC crosses the hematoencephalic barrier

Malaguarnera/Pistone/Astuto/Dell’Arte/ Finocchiaro/Lo Giudice/Pennisi

slowly (brain uptake index 5.5%) but in spite of this fact, its amount in the brain is relatively large [19]. In the study of Therrien et al. [20], the protective effect of LC was accompanied by a significant attenuation of the increased cerebrospinal fluid and brain alanine as well as cerebrospinal fluid lactate content, caused by ammonium acetate administration. This fact suggests that mitochondria respiration is at least partially restored in LC-treated ani-

mals. The possible beneficial effect of carnitine may be related to an improved pyruvate oxidation, Krebs cycle and flux through glutamate dehydrogenase. The latter could then explain the lowering of blood ammonia levels that follows LC administration. In conclusion, this study demonstrates a clinically significant effect of LC on mental conditions and ammonia levels in patients with mild or moderate HE.

References 1 Basile AS, Jones EA: Ammonia and GABAergic neurotransmission: Interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology 1997;25:103–105. 2 Lockwood AH, Yap EWH, Wong WH: Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab 1991;11: 337–341. 3 Tarter RE, Panzak G, Switala J, Lu S, Simkevitz H, Van Thiel D: Isokinetic muscle strength and its association with neuropsychological capacity in cirrhotic alcoholics. Alcohol Clin Exp Res 1997;21:191–196. 4 Haussinger D, Kircheis G, Fischer R, Schiess F, Von Dahl S: Hepatic encephalopathy in chronic liver disease: A clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 2000;32:1035–1038. 5 Ullian EM, Sepperstein SK, Christopherson KS, Barres BA: Control of synapse number by glia. Science 2001;291:657–661. 6 Noremberg MD: Astrocyte-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996;16:245–253. 7 Conn HO, Leevy CM, Vlahovic ZR, et al: Comparison of lactulose and neomycin in the treatment of chronic portal systemic encephalopathy. Gastroenterology 1997;72:573–583.

L-Carnitine in the Treatment of Mild or Moderate HE

8 Bremer J: The role of carnitine in cell metabolism; in De Simone C, Famularo G (eds): Carnitine Today. Heidelberg, Springer, 1997, pp 1–37. 9 O’Connor JE, Costell M, Grisolia S: Prevention of ammonia toxicity by L-carnitine: Metabolic changes in brain. Neurochem Res 1984;9:563–570. 10 Therrien G, Rose C, Butterworth J, Butterworth RF: Protective effect of L-carnitine in ammonia-precipitated encephalopathy in the portocaval shunted rat. Hepatology 1997;25: 551–556. 11 Reitan RM, Woegson D: The Halstead-Reitan. Neuropsycological test battery: theory and clinical interpretation. Tucson, Neuropsychology Press, 1993. 12 De Fonseca-Wollheim F: Direkte Plasmaammoniakbestimmung ohne Enteiweissung. J Clin Chem Clin Biochem 1973;11:421–431. 13 Conn HO, Liebertahl MM: The Hepatic Coma Syndrome and Lactulose. Baltimore, Williams & Wilkins, 1979, pp 1–121. 14 Conn HO: Trail-making and number connection tests in the assessment of mental state in portal systemic encephalopathy. Am J Dig Dis 1977;22:541–550.

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15 Rikkers L, Jenko P, Rudman D, Freides D: Subclinical hepatic encephalopathy: Detection prevalence and relationship to nitrogen metabolism. Gastroenterology 1978;75:462–469. 16 Gilberstadt SJ, Gilberstadt H, Zieve L, Buegel B, Collier RO, McClain CJ: Psychomotor performance defects in cirrhotic patients without overt encephalopathy. Arch Intern Med 1980; 140:519–521. 17 Matsouka M, Igsu H, Kohriyama K, Inoue N: Suppression of neurotoxicity of ammonia by Lcarnitine. Brain Res 1991;567:328–331. 18 Atterbury CE, Maddrey WC, Conn HO: Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. Dig Dis 1978;23:398–408. 19 Hearn TJ, Coleman AE, Lai JCK, Griffith OW, Cooper AJL: Effect of orally administered Lcarnitine on blood ammonia and L-carnitine concentrations in portocaval-shunted rats. Hepatology 1989;10:822–828. 20 Therrien G, Giguere JF, Butterworth RF: Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy. Metab Brain Dis 1991;6:231–238.

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Fructose Breath Hydrogen Test – Is It Really a Harmless Diagnostic Procedure? P. Müller a, b C. Meier b H.J. Böhme c T. Richter b, d a HELIOS

Hospital, Leisnig; b Children’s Hospital, University of Leipzig; c Institute of Biochemistry, University of Leipzig, and d St. Georg Hospital, Leipzig, Germany

Key Words Fructose malabsorption W Hereditary fructose intolerance W Fructose breath hydrogen test

Abstract Usage of hydrogen breath tests has become one of the standard procedures in diagnosing chronic unspecific abdominal pain. These tests are said to be of sufficient specificity and sensitivity, are easily done, non-invasive and are more often practiced in outpatients. A 13-yearold boy is reported with chronic unspecific abdominal pain and growth retardation and so far misdiagnosed hereditary fructose intolerance (HFI), who developed lifethreatening adverse effects during the fructose breath hydrogen test. It is concluded that the possibility of HFI should be excluded first by a carefully explored dietary history before the fructose breath test is performed under medical supervision. If there is any suspicion of HFI, a molecular genetic analysis should be preferred. Copyright © 2003 S. Karger AG, Basel

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Introduction

Patients with chronic abdominal pain, enteritis and meteorism are frequent clients in clinical and ambulatory practice. One possible cause of these complaints are individual distinctions of the intestinal capacity of absorption for fructose, which is estimated in adults between 0.07 and 0.7 g/kg body weight (b.w.) [1]. If this individual intestinal maximum of absorption for fructose is exceeded, fructose will be metabolized by bacterial fermentation and typical signs and symptoms of an isolated fructose malabsorption develop [2]. The prevalence of this clinical entity increases with increasing use of high fructose corn syrup as sweetener in processed food. The current view in the literature is that fructose is transported across the brush-border membrane by GLUT-5, a member of the facilitative fructose transporter family [3]. However, screening for mutations in the coding region of the GLUT-5 gene was without success and the conclusion of the study was that isolated fructose malabsorption does not result from the expression of mutant GLUT-5 protein [4]. Moreover, it has recently been shown that in addition to GLUT-5, GLUT-2 also contributes to the fructose transport across the brush-border membrane – at least in rats [5]. Thus, isolated fructose malabsorption still awaits

Peter Müller, MD Department of Pediatrics, HELIOS Hospital Leisnig Colditzer Strasse 48 DE–04703 Leisnig (Germany) Tel. +49 34321 8310, Fax +49 34321 8111, E-Mail [email protected]

an explanation. Hydrogen breath tests are known as sufficient methods to detect intestinal carbohydrate malabsorptions. An increase of exhaled hydrogen of 120 ppm after oral application of fructose (1 g/kg b.w., maximum 25 g) points to fructose malabsorption [6, 7]. Although this test seems to be simple and safe, evaluations in infants and children showed problems when measurement results had to be interpreted and when the predictive value and consecutive indications of this breath test were proven [8–10]. We report on an adverse effect during a hydrogen breath test with fructose in a schoolboy who suffered from unknown inherited fructose intolerance. Such a case has not been described so far and therefore, it is not advisable to perform a hydrogen-exhaled breath test after oral fructose loading without relevant indications.

Case Report A growth-retarded 13-year-old boy who had suffered from abdominal pain for several years visited for gastroenterological consultation. At the time, a partial growth hormone deficiency was treated with growth hormone. The family history was unremarkable regarding gastrointestinal diseases. Parents were of normal heights, but a sister who was 2 years older was also growth-retarded. The patient’s dietary history was suspicious with aversion to fruits, small amounts of sugar, but a considerable amount of milk products. In contrast, his sister tolerated fructose-containing foods very well. The boy’s appetite was good, stool was normal and reduction of weight or efficiency was not observed. Clinical investigation, especially of the abdomen, showed normal findings. The liver was palpable 1 cm below the ribs. A fructose breath hydrogen test was performed to confirm the suspected fructose malabsorption. 60 min after oral fructose load with 1.5 g/kg b.w., the patient became indisposed with tachycardia (110/ min), hypotonia (105/70 mm Hg), cold-sweaty skin, disturbed consciousness and vomiting. Measurement of blood glucose revealed a hypoglycemia with 2.2 mmol/l and a metabolic acidosis (pH 7.32, base excess –7.5 mmol/l). Signs and symptoms immediately normalized after intravenous injection of 10 g glucose. Further investigations revealed elevated liver enzyme activities of GPT (1.10 Ìmol/ s-l) and GOT (1.68 Ìmol/s-l) and an increased lactate concentration (3.3 mmol/l), while anorganic phosphate was slightly reduced to 1.41 mmol/l. Uric acid in serum was found to be in the normal range. These findings pointed to hereditary fructose intolerance. Mutational analysis revealed compound heterozygosity of the patient for the two common mutations A149P in exon 5 and the mutation N334K in exon 9 of the aldolase B gene and therefore, no liver biopsy for the determination of the enzyme activity of aldolase B was needed. The patient was treated with a diet low in fructose and sucrose (maximum 15 g fructose/day) with the results of physical wellness and catch-up growth without hormone therapy.

Fructose Breath Hydrogen Test – Really a Harmless Diagnostic Procedure?

Discussion

At present, the content of fructose as the naturally sweetest occurring sugar in foodstuffs is enormous in developed industrial countries. The estimated daily consumption of sugar was 4.5 g per capita in England in 1700, in 1800 already 37 g was consumed and in 1968 this had risen to 140 g per capita daily [11]. These remarkable changes in nutritional habits are one of the common causes of chronic unspecific abdominal pain in children (toddler’s diarrhea) due to fructose malabsorption. Beside other influences of environment and stress, this dysfunction is also a frequent cause of chronic enteritis, meteorism and irritable bowel syndrome in adults, especially in cases where sorbitol-containing food for diabetics is consumed [12]. If the fructose malabsorption is recognized as the cause of complaints, the dietary management with supplementation of equimolar amounts of glucose will immediately lead to recovery [13]. Affected children have no growth retardation. In contrast, poor growth and failure to thrive are typical signs of patients with autosomal recessively inherited fructose intolerance (HFI) after chronic fructose intoxication, which is pathogenetically distinguished from intestinal absorption disturbances [14]. HFI was first described as a clinical entity in 1956 [15]. The molecular basis of this disease is a deficiency of the enzyme aldolase B (EC 4.1.2.13) in liver, intestine and kidney [16]. After exposition to fructose, dose-dependent cytosolic accumulations of fructose-1-phosphate occur which inhibit liver phosphorylase A. Glycogenolysis and glycolysis are interrupted and the resulting hypoglycemia is resistant to glucagon. Hypophosphatemia, which intensifies the inhibition of liver phosphorylase A, is another consequence of sequestration of phosphate as fructose-1phosphate. Intracellular deficiency of ATP and phosphate lead to hyperuricemia and hypermagnesemia, respectively [14]. At present, 21 mutations within the human aldolase B gene have been published, of these, 15 are singlebase substitutions. In Germany, 93% of HFI alleles are one of three common mutations: A149P, A174D and N334K [17, 18]. Hypoglycemia, metabolic acidosis, hypophosphatemia, hyperuricemia and hypermagnesemia are the laboratory hallmarks. Several of these findings pointed to the diagnosis in our case. To the best of our knowledge, this is the first report with casual diagnosis of HFI by means of the fructose breath hydrogen test. This possibility has to be taken into account when a hydrogen breath test is intended to be performed because an oral fructose load with 1 up to 2 g/kg b.w. (we give a maximum of 25 g) is considerably high. This amount of fructose is

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even higher than the dose used for an oral fructose loading test, which is meanwhile considered as an obsolete procedure to diagnose HFI [19]. Patients with HFI who are not recognized within the first year of life very often develop aversions against all sweet foods. This habit becomes gradually accepted by the parents, and the diet will be adapted by preparations that avoid symptoms like vomiting and/or abdominal pain. For these reasons, it was reported several times that patients with unrecognized HFI were diagnosed during childhood or even during adulthood [12, 20]. Moreover, tragedies of iatrogenic deaths related to medicinal use of fructose-based intravenous solutions are known [21]. As a consequence, before an oral fructose load test is performed, it is necessary to get exact information about the subject’s nutritional habits. HFI is probable when an avoidance to fruits or sweets is reported. The mutational analysis is then a feasible first-line investigation because in 93% of the German HFI patients there is a prevalence of three mutations, which can easily be detected [18]. Considering the propagandized practicability of the fructose hydrogen breath test, especially in outpatients, we think that the fructose load

under domestic conditions is risky and therefore, we recommend to perform this procedure under medical supervision and blood glucose monitoring (0, 30 and 60 min), for instance at a pediatric day-ward. In order to prevent such incidents as in our case, we recommend the following diagnostic work-up: If there are any doubts regarding fructose tolerance after exploring the dietary history, a PCR-based mutational analysis of the aldolase B gene should be performed because the prevalence of HFI carriers in Caucasians is about 1:50 [17]. If no relevant mutation can be detected, the fructose breath hydrogen test is indicated to exclude fructose malabsorption. But it should be pointed out that the absence of hydrogen-producing bacteria in intestine can lead to false-negative results. Therefore, it is advisable to perform a following breath test with lactulose which is not absorbed by the small bowel. In dependence of hydrogen production, we investigate an intestine biopsy and measure the enzyme activity of sucrase. In cases with normal enzyme activities, other causes of chronic abdominal pain than fructose-induced disturbances have to be examined.

References 1 Ramussen JJ, Gudmand-Hoyer E: Absorption capacity of fructose in healthy adults. Comparison with sucrose and its constituent monosaccharides. Gut 1986;27:1161–1168. 2 Ledochowski M, Widner B, Bair H, Probst T, Fuchs D: Fructose- and sorbitol-reduced diet improves mood and gastrointestinal disturbances in fructose malabsorbers. Scand J Gastroenterol 2002;35:1113–1126. 3 Burant CF, Takeda J, Brot-Laroche E, Bell GI, Davidson NO: Fructose transporter in human spermatozoa and small intestine is GLUT-5. J Biol Chem 1992;267:14523–14526. 4 Wassermann D, Hoekstra JH, Tolia V, Taylor CJ, Kirschner S, Takeda J, Bell GI, Taub R, Rand EB: Molecular analysis of the fructose transporter gene (GLUT-5) in isolated fructose malabsorption. J Clin Invest 1996;98:2398– 2402. 5 Helliwell, PA, Richardson M, Affleck J, Kellett, GL: Regulation of GLUT-5, GLUT-2 and intestinal brush-border fructose absorption by the extracellular signal-regulated kinase, p38 mitogen-activated kinase and phosphatidylinositol 3-kinase intracellular signalling pathways: Implications for adaptation to diabetes. Biochem J 2000;50:163–169. 6 Barnes G, McKellan W, Lawrence S: Detection of fructose malabsorption by breath hydrogen test in a child with diarrhea. J Pediatr 1983; 103:575–577.

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7 Bond, JH, Levitt MD: Investigation of small bowel transit time in man utilizing pulmonary hydrogen (H2) measurements. J Lab Clin Med 1975;85:546–555. 8 Romagnuolu J, Schiller D, Bailey RJ: Using breath tests wisely in a gastroenterology practice: An evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol 2002;97:1113–1126. 9 Hoekstra JH: Fructose breath hydrogen test in infants with chronic non-specific diarrhoea. Eur J Pediatr 1995;154:362–364. 10 Götze H, Mahdi A: Role of fructose malabsorption in dysfunctional bowel disorders. Monatsschr Kinderheilkd 1992;140:814–817. 11 Cox TM: Fructose intolerance: Diet and inheritance. Proc Nutr Soc 1991;50:305–309. 12 Wössmann W, Wiemann J, Körber F, Görtner L: Hereditäre Fruktoseintoleranz (HFI) als Ursache einer isolierten Á-GT-Erhöhung bei einem 5-jährigen Jungen mit Hepatomegalie. Klin Pädiatr 2000;212:108–109. 13 Kneepkens CMF, Vonk RJ, Fernandes J: Incomplete intestinal absorption of fructose. Arch Dis Child 1984;59:735–738.

14 Steinmann B, Gitzelmann R, van den Berghe G: Disorders of fructose metabolism; in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York, McGraw-Hill, 2001, pp 1489–1520. 15 Chambers RA, Pratt RTC: Idiosyncrasy to fructose. Lancet 1956;271:340. 16 Hers HG, Joassin G: An anomaly in hepatic aldolase during fructose intolerance. Enzymol Biol Clin 1961;1:4–14. 17 Tolan DR: Molecular basis of hereditary fructose intolerance: Mutations and polymorphisms in the human aldolase B gene. Hum Mutat 1995;6:210–218. 18 Müller P, Koppelt B, Böhme HJ, Bührdel P: Detection of DNA mutations in German patients with hereditary fructose intolerance. Amino Acids 1997;12:389. 19 Koppelt B, Pöge AP, Müller P, Bührdel P, Böhme HJ: Molecular biological investigation in a family with hereditary fructose intolerance and diagnostic consequences. Monatsschr Kinderheilkd 1996;144:383–386. 20 Burmeister LA, Valdivia T, Nuttall FQ: Adult hereditary fructose intolerance. Arch Intern Med 1991;151:773–776. 21 Cox TM: Iatrogenic deaths in hereditary fructose intolerance. Arch Dis Child 1993;69:413– 415.

Müller/Meier/Böhme/Richter

Dig Dis 2003;21:279–285 DOI: 10.1159/000073985

Screening for Iron Overload in the Turkish Population Gultekin Barut a Huriye Balci b Mithat Bozdayi d Ibrahim Hatemi a Dervis Ozcelik c Hakan Senturk a a Department

of Internal Medicine, b Central Research Laboratory, c Department of Biophysics, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, and d Institute of Hepatology, Ankara Medical Faculty, University of Ankara, Ankara, Turkey

Key Words Hereditary hemochromatosis W HFE gene mutation W Epidemiology W Iron overload, prevalence

Abstract Background/Aims: Hereditary hemochromatosis (HH), the most common autosomal recessive disease in the white population, is characterized by excessive gastrointestinal absorption of iron and loading of parenchymal organs. HFE mutations of C282Y and H63D are largely responsible for HH in populations of Celtic ancestry. Although many screening studies related to HH have been done in Northern Europe, the USA and Australia, as yet, no such study has been published on Turkey. In this study we aimed to screen the Turkish population for iron overload. Methods: Random samples were obtained from 4,633 healthy adults (3,827 male, 806 female, mean age B SD 35 B 8 years, range 14–76) for the measurement of transferrin saturation (TS). Measurements were repeated after an overnight fast in the subjects whose initial TS was 650%. Serum ferritin levels and C282Y and H63D gene mutations were studied in cases when fasting TS was 650%. In cases where the serum ferritin level was 1 200 ng/ml with or without HFE mutations, liver biopsy was performed for histological evaluation and determination of iron content. Results: In 158 subjects, TS was 650% in the non-fasting state. A second deter-

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mination of TS after an overnight fast was performed in 135 subjects. In 26 subjects, the TS was 650% in the fasting state. HFE mutation and serum ferritin levels were measured in these 26 subjects. Eleven subject (10 male, 1 female) were heterozygote and 1 male subject was homozygote in reference to H63D. C282Y mutation was not found. Four of these 26 subjects (all males, aged 23, 24, 40, 49) had increased serum ferritin levels and liver biopsy was performed. In 1 male (aged 49) who was heterozygote for H63D genotype with a serum ferritin level of 645 ng/ml, iron overload in liver tissue was shown by histology as well as atomic absorption spectrophotometry. Conclusion: The prevalence of hemochromatosis in the Turkish population is much lower in comparison to populations of Celtic ancestry and C282Y mutation is non-existent. Copyright © 2003 S. Karger AG, Basel

Introduction

Hereditary hemochromatosis (HH) is the most common autosomal recessive disease in the white population [1–3]. Typical clinical symptoms do not develop until very late stages of the disease at which time treatment is not rewarding. The value of screening studies largely by means of measurement of transferrin saturation (TS) was evaluated in several populations [1–10]. Mutation of HFE

Hakan Senturk, MD, Professor in Medicine Cihangir, Akyol cad. No:18-5 Makbul apt TR–80060 Istanbul (Turkey) Tel./Fax +90 212 5299565 E-Mail [email protected]

Fig. 1. Frequency distribution of transferrin saturation in 4,633 participants.

gene, is largely responsible for this disease in populations of Celtic origin [6, 11]. To date, 37 allelic variants of the HFE gene have been reported – C282Y and H63D are the most common. The gene frequency is 5% in the AngloSaxon population. Homozygote HH prevalence is between 0.3 and 0.5%, and the heterozygote carrier rate is approximately 10% in European populations [1–5, 12, 13]. As yet, no such screening study has been published on Turkey. HH is known as an inherently rare disease in this country. In this study we aimed to screen the Turkish population for iron overload.

of Feder et al. Serum ferritin levels were measured by an immunoassay system by chemiluminescent immunoassay method in 26 subjects who had 650% fasting TS and were analyzed for HFE gene mutations. Percutaneous needle biopsy of the liver were performed in 4 subjects who had a fasting TS of 650% with a serum ferritin level 1 200 ng/ml. The tissue specimens were sent for routine histological examination with Prussian blue staining. Liver iron content was measured by atomic absorption spectrophotometry and hepatic iron index (HII) was calculated by dividing liver iron concentration in Ìmol Fe/g dry liver weight with subject’s age in years.

Results Methods We included 4,633 healthy subjects (3,827 men, 806 women; mean age B SD 35 B 8, range 14–76) who were employees of Istanbul’s gas distribution, and water and sewage companies. Ten milliliters of venous blood was obtained from non-fasting volunteers. Serum was separated by centrifugation and frozen at –70 ° C until analysis. Serum iron levels and total iron binding capacity (TIBC) were measured by a standard colorimetric method on an automated analyzer (model Au-800, Olympus). Serum TS was calculated as serum iron/TIBC ! 100. In cases where the TS value was 650%, the participant was re-contacted to obtain a second sample in the fasting state and measurement of TS was repeated. Fifteen-milliliter whole-blood samples were obtained from 26 subjects whose fasting TS was 650%. These blood samples were immediately transported to the laboratory within 24 h at +4 ° C for analysis of HFE gene mutations. DNA was prepared from these whole-blood samples by a method reported elsewhere [14]. The two HFE mutations were screened with PCR assay followed by restriction-enzyme digestion with Rsa1 for the C282Y mutation and Bcl1 for H63D mutation. PCR amplification of the regions containing these two HFE mutations was performed with the primer sequences

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The mean TS was 29% for males and 25% for females (fig. 1). In 158 subjects (142 men and 16 women; mean age B SD 36 B 8 years, range 17–52) who constituted 3.4% of total screened population, TS was 650% in the non-fasting state. A second determination of TS after an overnight fast was performed in 135 of 158 subjects. Twenty-three subjects either could not be re-contacted or denied further examination. In 26 subjects (24 men and 2 women; mean age B SD 34 B 8 years, range 22–52), who constituted 0.6% of total screened population and 19% of re-evaluated population, the TS was 650% in the fasting state. Analysis of HFE mutations was done in these 26 subjects (fig. 2). C282Y mutation was not detected. Homozygote H63D mutation was found in only 1 male subject who had a normal serum ferritin level. Heterozygote H63D mutation was found in 10 males and 1 female. Serum ferritin levels were also measured in 26 subjects. In 4, the serum ferritin level was 1200 ng/ml, while in 1 of

Barut/Balci/Bozdayi/Hatemi/Ozcelik/ Senturk

Fig. 2. The algorithm of screening.

these 4 subjects, the serum ferritin level was 645 ng/ml; in 3 other subjects, it was !300 ng/ml (table 1) – all 4 were males. In the subject with a serum ferritin level of 645 ng/ml, an increased liver iron content (133.05 Ìmol/g and HII = 2.71) and intensive iron staining were found.

This subject had heterozygote H63D genotype. Remaining three subjects did not have either increased liver iron content or staining. The HII of these 3 subjects was !1.9 (table 1). Only 1 of these 3 subjects had heterozygote H63D genotype (HII = 0.67) (table 1).

Hereditary Hemochromatosis in Turkey

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Table 1. Laboratory features of participants whose phenotypes and genotypes were analyzed Hepatic iron Hepatic concentration iron Ìmol/g index

37.27

1.55

25.20

1.09

26.81

0.67

133.05

2.71

Serum ferritin ng/ml

Transferrin Mutation Mutation Age saturation C282Y H63D years %

85.0 37.4 238.5 57.2 39.9 100.2 36.3 33.6 67.2 47.8 200.8 116.6 53.1 42.9 27.8 17.1 69.6 190.0 161.3 86.6 285.4 70.9 146.3 645.2 68.7 103.0

51.2 51.4 90.6 66.8 52.0 65.3 59.8 55.8 64.9 51.2 52.3 51.0 65.2 51.4 52.4 52.9 60.1 55.1 71.9 67.9 58.8 63.8 55.5 52.5 56.5 64.8

–/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/– –/–

–/– –/– –/– –/+ –/+ –/– –/– –/+ –/+ –/+ –/– –/– –/+ +/+ –/– –/– –/– –/+ –/– –/+ –/+ –/+ –/– –/+ –/+ –/–

34 28 24 39 27 40 34 37 29 29 23 27 31 25 29 42 28 52 42 40 40 36 29 49 34 30

Discussion

Turkey bridges the Middle East, Middle Asia and Europe and has a population of over 60 million. The current Turkish population is a mixture of people who migrated from Middle Asia (now Mongolia) around 1071 AD and the indigenous population of Anatolia. Over 95% of the population is Muslim and the rate of alcohol consumption is much lower in comparison to European countries and the USA. This study was performed in Istanbul and consisted of 4,633 workers from sewage and gas distribution companies. Istanbul is Turkey’s melting pot and most of the workers have come from different parts of Anatolia in the last decade. Therefore, this population represents not only Istanbul but Turkey in general. HH is the most common autosomal recessively inherited disease in the white population [1–3]. The prevalence of HH is supposed to be equal in both males and females,

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since it is inherited autosomal recessively. However, the prevalence of HH and iron overload was higher in males than females in previous screening studies which had been based on the phenotyping expression of the disease [4, 6]. This can be explained by decreased clinical expression resulting from menstrual blood loss and pregnancy in women. Many epidemiologic studies about HH and iron overload have been reported from different countries and populations in the last 15 years. The prevalence of iron overload resulting from HH was found to be 0.36% in Australia where the population is predominantly composed of whites of European descent [2]. The prevalence of iron overload attributable to HH was reported as 0.40, 0.42 and 0.45% from different ethnic populations of the USA [6–8]. The prevalence was lower in blacks [3, 6, 15]. Different approaches have been proposed for screening HH and iron overload. The choice of screening method depends on whether one is seeking to detect all homozygotes or only those with iron overload [13]. As screening tests, TS, unsaturated iron binding capacity, serum ferritin level and HFE gene analysis were used in combination or alone. Because of its ease of application, low cost, high sensitivity and acceptable specificity, TS was the initial screening test in most of the previous studies [1–10]. The problems with TS are related to its ill-defined threshold value as well as low positive predictivity. The threshold value in previous studies has ranged from 45 to 70% [1, 5–8, 13, 15–17]. The rate of false positivity was intended to be reduced with repeated measurements of TS after an overnight fast in the subjects who had higher initial non-fasting TS. Lower threshold TS values have been used for females compared to males in previous studies. It has been reported that a TS of 60% or more, identifies nearly all homozygotes with iron loading, whereas a TS of 50% identifies nearly all homozygotes regardless of sex or iron loading [13]. We set the threshold value to 50% to detect all homozygotes regardless of sex. A combination of determination of iron status with phenotyping methods associated with DNA testing have the best sensitivity and specificity to detect risk from iron overload [7]. We used a strategy which was reported as worthy of consideration in a previous study and started with determination of TS followed by an HFE gene analysis in subjects with elevated fasting TS [7]. In the four screening programs which were performed in the USA, the TS was elevated on initial testing in 2.5– 5.8% of the several screened populations [8]. The ratio was 6.2% in the Edwards’ study [4]. The prevalence of an elevated initial TS rate of 3.4% in our screened population was similar to these studies.


A second determination of TS after an overnight fast was performed in 135 of 158 subjects with elevated initial TS. All drop-outs appeared at this stage of screening. The compliance rate for a second determination of TS after an overnight fast was calculated as 85.4% (135/158). The same rate in Phatak’s study, Edwards’ study and in the other two United States’ studies were 80.2% (747/932), 67.6% (465/688), 85.0% (1,147/1,349) and 87% (47/53) respectively [4, 6, 8]. In 26 subjects (24 men and 2 women), who constitute 19.2% (26/135) of our re-evaluated population, the TS was 650% in the fasting state in our study. The rates of elevated fasting TS in Edwards’ study, in Kaiser Permanente Medical Group’s study and in Phatak’s study were 24.5% (114/465), 23% (73/318) and 10.9% (82/747) (the threshold value for TS was 55% in this study), respectively [4, 6, 8]. These rates are also similar to rates of the present study. In our study, 15.4% (4/26) of the subjects with elevated fasting TS had 6200 ng/ml serum ferritin levels. The value was 50.2% (128/255) in Phatak’s study [6]. In our population, most of the subjects with elevated fasting TS did not have increased serum ferritin levels which is an important marker for liver iron content [6]. Liver biopsy was performed in 4 subjects who had increased serum ferritin. Iron overload was detected in only 1 subject in our study. In conclusion, the prevalence of iron overload was 0.021% in our population. The prevalence of iron overload was reported as 0.36% from Australia and 0.4, 0.42 and 0.45% from different ethnic populations of the USA [2, 6–8]. The candidate gene leading to hemochromatosis was first discovered in 1996 by Feder et al. on the short arm of chromosome 6, and was termed the ‘HFE gene’ [18]. This HFE gene mutation is largely responsible for HH and related iron overload in populations of Celtic origin [6, 11]. The interest was focused on C282Y and H63D mutations. The C282Y mutation results from G to A transition at nucleotide 845 of the HFE gene (845G→A) that produces a substitution of cysteine for a tyrosine at amino acid position 282 in the protein product [16]. In the H63D mutation, a G replaces C at nucleotide 187 of the gene (187C→G), causing aspartate to substitute for histidine at amino acid position 63 in the HFE protein [16]. In the last 10 years, studies performed in populations of largely Celtic descent showed that 60–100% of patients with typical HH were homozygotes for C282Y mutation [3, 7, 9, 12, 15–17, 19]. In the general population, compound heterozygote (C282Y/H63D) and homozygote H63D genotypes occur more frequently than homozygote C282Y, but these genotypes are responsible for only a

small proportion of patients with iron loading [16]. The average prevalences of homozygote and heterozygote C282Y mutations were reported to be 0.4 and 9.2% respectively from different European countries [16]. Although C282Y homozygosity has not been reported, C282Y heterozygosity has been found to be 1–3% in Southern or Eastern Europe populations [16]. The highest prevalence of heterozygote C282Y mutation has been reported as 24.8% from Ireland [16]. The prevalence of homozygosity for C282Y mutation is 0.5% and the prevalence of heterozygosity is 9% in North America [16]. C282Y homozygosity was not found in the Asian-Indian subcontinent, African/Middle Eastern and Australasian populations, and the frequency of C282Y heterozygosity was very low (0–5%) [16]. The prevalences of compound heterozygote (C282Y/H63D) and homozygote H63D have been found to be approximately 2% in European populations [16]. The prevalences of compound heterozygotes (C282Y/H63D), homozygote H63D and heterozygote H63D were reported 2.5, 2.1 and 23% respectively in North American populations [16]. The prevalence of heterozygote H63D was 15–22% in European populations [9, 16]. Another study showed that only 64% of patients with hemochromatosis in Italy were homozygotes for the C282Y mutation [19]. The study performed in Hong Kong showed that the C282Y mutation was not found in Chinese patients with hepatic iron overload disease [20]. In a review by Lucotte [11] concerning 20 European populations, the highest C282Y allele frequency (6.88%) was observed in residual Celtic populations in the UK and France. This study showed that C282Y allele frequencies were distributed among a decreasing line from north to south of Europe [11]. The lowest C282Y allele frequencies were observed in Italians (1.00%), Ashkenazi Jews (1.31%) and French Basques (1.63%) [11]. These data suggest that HFE gene mutation is probably of Celtic origin. In our study, analysis of HFE mutations was done in 26 subjects whose fasting TS values were 650%. C282Y mutation was not detected. Homozygote H63D mutation was found in only 1 subject, and heterozygote H63D mutation was found in 11 subjects. The subject who had homozygote H63D mutation did not have any clinical symptom for hemochromatosis. In this subject, there was no clinical expression of HH except fasting TS (fasting TS: 51.3%) and the serum ferritin level was within normal ranges (serum ferritin: 42.9 ng/ml). Our data are insufficient to comment on the prevalence of HFE mutations in the general population of this country.


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In previous studies, different populations were chosen for screening hemochromatosis – blood donors [1, 4, 17], hospital inpatients [3, 5], primary care patients [6], bank and insurance company employees [2], employees of health maintenance organizations [7]. The advantages of using blood donors for screening were expounded in the screening study of Adams’ group [1, 17]: (1) exclusion of persons with conditions such as hepatitis B and C and sometimes elevated liver enzyme values reduce the number of false-positive screening tests; (2) blood has already been obtained for other reasons; (3) systems are well established for collection and distribution of samples, and (4) donors represent a young asymptomatic population that would benefit from the early detection of hemochromatosis. In spite of all these advantages, there are some disadvantages of using blood donors, for example; the false negative results for measurement of TS and serum ferritin may occur because regular donation may cause false low iron stores [6], subjects with elevated liver enzyme concentrations and sideroblastic anemia who may have HFE gene mutation are excluded from the blood donor pool. Hospital inpatients are, by nature, selected groups, therefore they do not represent the general population. The other screening populations are less selective, but the actual prevalence of disease in the general population cannot be detected with these groups because they may not contain a sufficient enough number of subjects. Increasing the number of screened subjects makes the investigation difficult due of logistic and economical reasons. However, we believe that our screened population was sufficiently large enough to represent a general population. The serologic tests of hepatitis B and C were done, and none of the HFE-gene-analyzed subjects with 650% fasting TS had HBsAg or anti-HCV. Most of the subjects in our study are teetotalers and none consumed 180 g/day alcohol. The age range in this study was 14–76 years. The minimum age in Edwards’, Phatak’s and Olynyk’s studies were 17, 18 and 20 years, respectively [4, 6, 9]. The maximum age in this study was similar to the maximum age of previous ones. The mean age was 35.7 in males and 32.2 in females in our study. It was 37.5 in males and 34.7 in females in Edwards’ study [4]. The major limitation of our study was that males predominated (83%). Life-threatening clinical manifestations, such as liver failure, heart failure and diabetes mellitus, usually occur after a latent period of 40–60 years in subjects with iron overload [1]. The risk of death as a direct consequence of liver cirrhosis is significantly increased in patients with

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hemochromatosis as compared to a matched normal population [12]. The risk of death from liver cancer in a patient with hemochromatosis is more than 100 times that of the matched healthy subjects [4]. There is a long asymptomatic phase in HH. The fact that hemochromatosis has a high prevalence, a potential to cause substantial morbidity and mortality, a long asymptomatic phase and prevention of disease-associated complications by means of early diagnosis and treatment such as phlebotomy, make screening studies a cost-effective strategy [1, 13]. Recent studies have reported that hemochromatosis screening based on TS testing is cost-effective [7]. The cost analysis study of Adams and Valberg [17], which was one of the largest comparing genotyping and phenotyping models, showed that an optimal strategy for screening includes initial testing for iron overload (phenotyping) with confirmatory genetic testing, or initial genetic testing if the test is less than USD 28 for each person screened. In this study, it was reported that the cost of detecting one homozygote with potential life-threatening illness by initial testing for iron overload (phenotyping) with confirmatory genetic testing was USD 2,711 [17]. For cost analysis, 10,000 blood donors were used and the prevalence of HH was 0.3% [17]. Adams and Valberg [17] concluded that the cost of detection of one homozygote with HH by initial testing for iron overload (phenotyping) with confirmatory genetic testing can be higher in a population with a lower prevalence of the disease. The prevalence of iron overload in our study was 0.021%. Homozygote C282Y mutation was not found and the prevalence of homozygote H63D mutation was 0.021%. The cost of HFE gene mutation analysis for each person was USD 75 in our study. The total cost of the study was calculated approximately USD 50,000 by using cost analysis. This total cost was equal to the cost of detection in the only subject with iron overload. However, it seems that such a screening is not cost-effective in the Turkish population; the rationality of prevention of one case of cirrhosis with eventual decompensation necessitating liver transplantation or death at a cost of USD 50,000 should be further scrutinized. In conclusion, the prevalence of HH and iron overload in the Turkish population is much lower in comparison to North European populations of Celtic ancestry and C282Y mutation as a cause of HH is non-existent. Acknowledgement This work was supported by the Research Fund of The University of Istanbul, Project No. T-825/07032000.


References 1 Adams PC, Gregor JC, Kertesz AE, Valberg LS: Screening blood donors for hereditary hemochromatosis: Decision analysis model based on a 30-year database. Gastroenterology 1995; 109:177–188. 2 McLaren CE, McLachlan GJ, Halliday JW, Webb SI, Leggett BA, Jazwinska EC, Crawford DHG, Gordeug VR, McLaren GD, Powell LW: Distribution of transferrin saturation in an Australian population: Relevance to the early diagnosis of hemochromatosis. Gastroenterology 1998;114:543–549. 3 Beutler E, Felitti V, Gelbart T, Ho N: The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000;133: 329–337. 4 Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP: Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988;21:1355–1362. 5 Balan V, Baldus W, Fairbanks V, Michels V, Burrit M, Klee G: Screening for hemochromatosis: A cost-effectiveness study based on 12,258 patients. Gastroenterology 1994;107: 453–459. 6 Phatak PD, Sham RL, Raubertas RF, Dunnigan K, O’Leary MT, Braggins C, Cappuccio JD: Prevalence of hereditary hemochromatosis in 16,031 primary care patients. Ann Intern Med 1998;129:954–961.


7 McDonnell SM, Hover A, Gloe D, Ou CY, Cougswell ME, Grummer L: Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri. Am J Med 1999;107:30–37. 8 McDonnell SM, Phatak PD, Felitti V, Hover A, McLaren GD: Screening for hemochromatosis in primary care settings. Ann Intern Med1998;129:962–970. 9 Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW: A populationbased study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999; 341:718–724. 10 McLaren CE, Gordeug VR, Looker AC, Hasselblad V, Edwards CQ, Griffen LM, Kushner JP, Brittenham GM: Prevalence of heterozygotes for hemochromatosis in the white population of the United States. Blood 1995;86:2021– 2027. 11 Lucotte G: Celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Mol Dis 1998;24:433–438. 12 Niederau C, Erhard A, Haussinger D, Strohmeyer G: Haemochromatosis and liver. J Hepatol 1999;30:6–11. 13 Edwards CQ, Kushner JP: Screening for hemochromatosis. N Engl J Med 1993;328:1616– 1620.

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14 Boretto J, Jouanolle AM, Yaouaq J, et al: Anonymous markers located on chromosome 6 in the HLA-A class I region: Allelic distribution in genetic haemochromatosis. Hum Genet 1992; 89:33–36. 15 Cogswell ME, McDonnell SM, Khoury MJ, Franks AL, Burke W, Brittenham G: Iron overload, public health and genetics: Evaluating the evidence for hemochromatosis screening. Ann Intern Med 1998;129:971–979. 16 Hanson HE, Imperatore G, Burke W: HFE gene and hereditary hemochromatosis. HuGE Rev IPDAS #549 (March 12, 2001). 17 Adams PC, Valberg LS: Screening blood donors for hereditary hemochromatosis: Decision analysis model comparing genotyping to phenotyping. Am J Gastroenterol 1999;94:1593– 1600. 18 Feder JN, Gnirke A, Thomas W, et al: A novel MHC class-I like gene is mutated in patients with hereditary hemochromatosis. Nat Genet 1996;13:399–408. 19 Pietrangelo A, Montosi G, Totaro A, Garuti C, Conte D, Cassanelli S, Fraquelli M, Sardini C, Vasta F, Gasparini P: Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 1999;341:725–732. 20 Tsui WM, Lam PW, Lee KC, Ma KF, Chan YK, Wong MW, Yip SP, Wong CS, Chow AS, Lo ST: The C282Y mutation of the HFE gene is not found in Chinese haemochromatotic patients: Multicentre retrospective study. Hong Kong Med J 2000;6:153–158.

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Author Index Vol. 21, No. 3, 2003

Astuto, M. 271 Avgerinos, C. 214 Balci, H. 279 Barut, G. 279 Baumann, G. 245 Böhme, H.J. 276 Bozdayi, M. 279 Botsios, D.S. 228 Burmester, G.-R. 245 Clavel, A. 258 Dafnopoulou, A. 262 Datsakis, K. 262 Delis, S. 214 Dell’Arte, S. 271 Dervenis, C. 196, 214 Dierkes, J. 237 Dimakos, P. 262 Drude, C. 252 Dudrick, S.J. 198

Ebert, M. 237 Fernańdez, R. 258 Finocchiaro, G. 271 Fleta, J. 258 Gassull, M.A. 220 Gizaris, V. 262 Hatemi, I. 279 Iida, M. 266 Kemps, M. 245 Kuroki, F. 266 Kyriazanos, I.D. 262 Lange, K.-P. 252 Lo Giudice, E. 271 Lochs, H. 196, 245, 252 Lübke, H.J. 245 Luhman, N. 245 Luley, C. 237 Malaguarnera, M. 271 Malfertheiner, P. 237

Matsumoto, T. 266 Meier, C. 276 Müller, P. 276 Olivares, J.L. 258 Ozcelik, D. 279 Palesty, J.A. 198 Paulisch, E. 252 Pennisi, G. 271 Pirlich, M. 245 Pistone, G. 271 Plauth, M. 245 Richter, T. 276 Rizos, S. 214 Rodrı´guez, G. 258 Schütz, T. 245, 252 Senturk, H. 279 Sfiniadakis, I. 262 Vasiliadis, K.D. 228

Subject Index Vol. 21, No. 3, 2003

Acute pancreatitis 214 Anorexia 198 Body mass index 262 Cachexia 198 Cancer 198 – cachexia syndrome 198 L-Carnitine treatment 271 Copper 258 Crohn’s disease 252, 266 Dental caries 252 Enteral nutrition 214, 266 Enterobius vermicularis 258 Epidemiology 279 Fasting blood glucose levels 262 Fructose breath hydrogen test 276 – malabsorption 276

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© 2003 S. Karger AG, Basel


Gastrointestinal cancer 198 – diseases 245 Giardia lamblia 258 Growth factors 228 Gut adaptation 228 – barrier 214 Helicobacter pylori 262 – infection 237 Hepatic encephalopathy 271 Hereditary fructose intolerance 276 – hemochromatosis 279 HFE gene mutation 279 Homocysteine 237 Intestinal failure 228 Iron overload, prevalence 279 Magnesium 258

Malnourished hospitalized patients 245 Malnutrition 198 –, diagnoses 245 –, prevalence 245 Obesity 262 Pernicious anemia 237 Selenium 266 Subjective global assessment 245 Sugar intake 252 Taste changes 252 Total parenteral nutrition 214 Vitamin B12 deficiency 237 Zinc 252, 258

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