Liver Biopsy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

IVER IOPSY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Liver Biopsy: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00668-5 1. Liver Biopsy-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on liver biopsy. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON LIVER BIOPSY ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Liver Biopsy .................................................................................. 7 The National Library of Medicine: PubMed ................................................................................ 30 CHAPTER 2. NUTRITION AND LIVER BIOPSY .................................................................................. 75 Overview...................................................................................................................................... 75 Finding Nutrition Studies on Liver Biopsy ................................................................................. 75 Federal Resources on Nutrition ................................................................................................... 76 Additional Web Resources ........................................................................................................... 77 CHAPTER 3. PATENTS ON LIVER BIOPSY ......................................................................................... 79 Overview...................................................................................................................................... 79 Patents on Liver Biopsy ............................................................................................................... 79 Patent Applications on Liver Biopsy ........................................................................................... 81 Keeping Current .......................................................................................................................... 82 CHAPTER 4. BOOKS ON LIVER BIOPSY ............................................................................................ 83 Overview...................................................................................................................................... 83 Book Summaries: Federal Agencies.............................................................................................. 83 Book Summaries: Online Booksellers........................................................................................... 85 Chapters on Liver Biopsy ............................................................................................................. 86 CHAPTER 5. MULTIMEDIA ON LIVER BIOPSY .................................................................................. 97 Overview...................................................................................................................................... 97 Video Recordings ......................................................................................................................... 97 CHAPTER 6. PERIODICALS AND NEWS ON LIVER BIOPSY ............................................................... 99 Overview...................................................................................................................................... 99 News Services and Press Releases................................................................................................ 99 Newsletter Articles .................................................................................................................... 100 Academic Periodicals covering Liver Biopsy.............................................................................. 102 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 105 Overview.................................................................................................................................... 105 NIH Guidelines.......................................................................................................................... 105 NIH Databases........................................................................................................................... 107 Other Commercial Databases..................................................................................................... 109 APPENDIX B. PATIENT RESOURCES ............................................................................................... 111 Overview.................................................................................................................................... 111 Patient Guideline Sources.......................................................................................................... 111 Finding Associations.................................................................................................................. 114 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 117 Overview.................................................................................................................................... 117 Preparation................................................................................................................................. 117 Finding a Local Medical Library................................................................................................ 117 Medical Libraries in the U.S. and Canada ................................................................................. 117 ONLINE GLOSSARIES................................................................................................................ 123 Online Dictionary Directories ................................................................................................... 124 LIVER BIOPSY DICTIONARY ................................................................................................... 125 INDEX .............................................................................................................................................. 177

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with liver biopsy is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about liver biopsy, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to liver biopsy, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on liver biopsy. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to liver biopsy, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on liver biopsy. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON LIVER BIOPSY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on liver biopsy.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and liver biopsy, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “liver biopsy” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Survey of Current Liver Biopsy Practice Patterns Source: Journal of Clinical Gastroenterology. 35(1): 86-88. July 2002. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: Although the hepatitis C epidemic has increased the proportion of Hepatology in general gastroenterology practice, many clinicians express concern regarding the risks of percutaneous liver biopsy. This article reports on a survey of clinicians regarding their current liver biopsy practice patterns. The authors sent a questionnaire about liver biopsy practices to members of the Duke University Digestive Epidemiological Studies Consortium. The response rate was 112 of 157 physicians (71 percent). Nearly a third (29.5 percent, 33 physicians) reported that they do not perform

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liver biopsies. Reasons cited for not performing biopsies included concern about risks (72.7 percent), low reimbursement (66.7 percent), and logistical issues with space and recovery time (45.4 percent). Routine practice was biopsy without ultrasound in 53.2 percent, ultrasound marking by a radiologist or technician at the time of biopsy in 24.0 percent, previous ultrasound marking in 17.7 percent, and ultrasound marking by the gastroenterologist in 5.1 percent. For patients with hepatitis C, 76.8 percent of clinicians perform routine biopsies before treatment. The authors conclude that new approaches, especially in training programs, may be necessary to make clinicians more comfortable with this procedure. 3 tables. 19 references. •

Practice Guidelines for Liver Biopsy Source: Canadian Journal of Gastroenterology. 14(6): 481-482. June 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: Histological assessment of the liver by using biopsy remains important in the diagnosis and follow up of acute and chronic hepatic (liver) disease. This article offers practice guidelines for liver biopsy, as established by the Canadian Association of Gastroenterology (CAG). Liver biopsies may be obtained blind, i.e., by clinical estimation of organ location; by using radiological guidance with computerized tomography or ultrasound; via the transvenous (through the jugular or femoral veins) route in patients with contraindications to percutaneous (through the skin) biopsy; or via direct vision, surgically or laparoscopically in certain situations. The authors list the indications for liver biopsy and note that the prebiopsy workup of a patient should include informed consent, including an explanation of the risks of the procedure and the laboratory test results that can be obtained from the biopsy. Postbiopsy management should include a recording by the physician performing the biopsy of how many 'passes' were made, any medications administered, and any apparent complications. Contraindications to percutaneous liver biopsy include an uncooperative patient, impaired coagulation, severe uncorrected anemia, significant ascites, infection in the path of the needle, suspected extrahepatic biliary obstruction of high grade, cholangitis, echinococcal cysts, no safe unobstructed access route to biopsy, leukemia and myelofibrosis, and uremia. The authors conclude that with strict attention to the indications and contraindications, liver biopsy can be regarded as a safe and useful procedure. 2 references.

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Liver Biopsy and Nursing Intervention Source: Gastroenterology Nursing. 17(1): 17-19. August 1994. Summary: In this article, the authors present recommendations for nurses responsible for providing patient care for liver biopsy procedures. The authors stress that the nurse's role in the gastrointestinal (GI) department includes pre-and post-procedure planning, assistance during the procedure, patient and family education, and emotional support. Topics include preparation for the procedure, including a review of the equipment; the procedure itself; recovery; complications; and discharge. The authors focus on the important role of the nurse, noting that an educated, organized, and confident assistant can promote a trusting relationship between patient and physician. 3 references. (AA-M).

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Role of Liver Biopsy in Chronic Hepatitis C Source: Hepatology. 36(5 Supplemental 1): S152-S160. November 2002.

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Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: The report of the 1997 National Institutes of Health (NIH) Consensus Development Conference on hepatitis C endorse pretreatment liver biopsy. This article reviews the role of liver biopsy in chronic hepatitis C, addressing whether liver histology helps determine the urgency of, and predicts the likelihood of response to, antiviral therapy; and if surrogate markers can supplant histological assessment. Because the rate of progression of chronic hepatitis C is influenced by baseline histological grade or stage, patients can be stratified into those with moderate to severe hepatitis, who merit imminent therapy, and those with mild hepatitis, in whom therapy can be postponed until more effective or tolerable treatments become available. Less advanced baseline histology has been shown to be an independent predictor of responsiveness to antiviral therapy. Although the predictive value of biopsy is insufficient to withhold therapy from patients with advanced fibrosis, baseline biopsy helps gauge expectations for the outcome of therapy. Reports have been published recently suggesting that laboratory markers can predict distinctions between low-grade fibrosis and therapy-indicating septal fibrosis or cirrhosis (scarring). These indices, however, are insufficiently reliable to predict histological distinctions in populations with varying prevalence of fibrosis or cirrhosis or to provide anything more than broad qualitative distinctions, far short of the potential information in a liver biopsy. For most patients, the value of pretreatment liver biopsy outweighs its risks, provides information about the urgency of treatment, and should be retained. The authors call for studies to identify noninvasive laboratory markers of histological activity and stage, especially genetic predictors of accelerated disease progression. 5 tables. 59 references. •

How Long Should Patients Be Under Observation After Liver Biopsy? Source: Gastroenterology and Endoscopy News. p. 32. December 1999. Contact: Available from McMahon Publishing Group. 545 West 45th Street, 8th Floor, New York, NY 10036. (212) 957-5300. Website: www.gastroendonews.com. Summary: This brief news article reports on a recent research finding that for patients who have just undergone liver biopsy, three hours of observation is adequate, unless the patient has a low platelet count (less than 100,000). The authors also found that the length of post biopsy observation has no significant effect on the number of emergency room (ER) visits, admission rate, or incidence of complications. Patients with low platelet counts, as well as patients older than 40 years and those who have high bilirubin levels, should be observed for longer periods, as these groups are at higher risk for admission to the hospital. The study included 1,007 consecutive outpatients who underwent liver biopsy.

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Ambulatory Liver Biopsy Source: HMO Practice. 5(1): 9-10. January-February 1991. Summary: This report describes the result of ambulatory liver biopsies on 21 patients at the Rutgers Community Health Plan. All biopsies were performed in a standard treatment room in a free standing ambulatory care center. The author contends that ambulatory liver biopsy performed on an outpatient basis is a simple, safe procedure that reduces costs and saves physician time. 9 references.

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Role of Liver Biopsy in Management of Chronic Hepatitis C: A Systematic Review Source: Hepatology. 36(5 Supplemental 1): S161-S172. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: This review article considers two topics pertinent to the need for pretreatment liver biopsy in patients with chronic hepatitis C: how liver biopsy results predict treatment outcomes; and how well biochemical blood tests and serological measures of fibrosis predict biopsy findings in chronic hepatitis C. The authors searched MEDLINE and other electronic databases from January 1985 to March 2002. Additional articles were sought in references of pertinent articles and recent journals and by querying experts. Articles were eligible for review if they reported original human data from a study that used virological, histological, pathologic, or clinical outcome measures. Studies suggested that advanced fibrosis or cirrhosis (scarring) on initial liver biopsy is associated with a modestly decreased likelihood of a sustained virological response (SVR) to treatment. Also, studies relatively consistently showed that serum aminotransferases have modest value in predicting fibrosis on biopsy; that extracellular matrix tests hyaluronic acid and laminin may have value in predicting fibrosis; and that panels of tests may have the greatest value in predicting fibrosis or cirrhosis. Biochemical and serologic tests were best at predicting no or minimal fibrosis, or at predicting advanced fibrosis or cirrhosis, and were poor at predicting intermediate levels of fibrosis. Thus, evidence suggests that liver biopsy may have some usefulness in predicting efficacy of treatment in patients with chronic hepatitis C, and biochemical blood tests and serologic tests currently have only modest value in predicting fibrosis on liver biopsy. 2 tables. 81 references.

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Appropriateness of Liver Biopsy Source: Canadian Journal of Gastroenterology. 14(6): 543-548. June 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: This review article discusses the appropriateness of liver biopsy in two frequent liver diseases, hepatitis C and alcoholic liver disease. The authors reviewed the medical literature, published between 1965 and 1999, by using MEDLINE. Only 0.1 percent of the publications were devoted specifically to the appropriateness of liver biopsy. Not all studies observed a significant agreement among doctors on the decision to use liver biopsy. Therefore, there is a possibility that hepatologists have significant, heterogeneous opinions concerning the appropriateness of liver biopsy. Appropriateness should be evaluated for different techniques such as percutaneous liver biopsy, guided or not by ultrasonography, and the types of needles, automatic or not. The article reviews the evaluation of liver biopsy appropriateness in the real world, the adverse events and mortality of liver biopsy, and the appropriateness of liver biopsy in alcoholic liver disease and chronic hepatitis C. The authors conclude that liver biopsy is appropriate for a few diagnoses, and for the staging of chronic liver diseases such as alcoholic liver disease and chronic hepatitis C. However, excess use of liver biopsy, because of its cost and risk, may be a barrier to treatment. Underused liver biopsy may lead to inappropriate treatment of hepatitis. 3 figures. 1 table. 44 references.

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Federally Funded Research on Liver Biopsy The U.S. Government supports a variety of research studies relating to liver biopsy. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to liver biopsy. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore liver biopsy. The following is typical of the type of information found when searching the CRISP database for liver biopsy: •

Project Title: ADULT LIVE DONOR LIVER TRANSPLANT-A COMPARATIVE ANALYSIS Principal Investigator & Institution: Abecassis, Michael; Associate Professor of Surgery; Surgery; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant):The shortage of available cadaver organs has prompted the transplant community to consider living donor liver transplantation (LDLT) as an effective alternative to cadaveric liver transplantation (CLT). The potential limitations of LDLT consist primarily of 1) the potential risk to an otherwise healthy donor, and 2) the uncertainty regarding graft and patient outcomes for LDLT as compared to CLT. The core project of this proposal will compare outcomes for recipients of LDLT to those of CLT, while addressing the potential complications to living donors. In addition, we propose to analyze two separate issues. First, we will evaluate donor hepatic steatosis in both LDLT and CLT. We will compare novel non-invasive measurements of steatosis in living donors with the current gold standard, a liver biopsy. We will compare the results of transplanting steatotic livers from living and cadaveric donors, assessing graft and patient outcomes in both groups. We will also evaluate the role of hepatic steatosis on liver regeneration in both the living donor and recipient. We hypothesize that outcome of transplantation in steatotic livers of LDLT is superior to results obtained in steatotic CLT recipients. This first aim will help design a decision algorithm for the use of steatotic livers in both CLT and LDLT while validating non-invasive measurements of hepatic steatosis. Second, we propose to address the potential role for LDLT in the multimodal management of hepatocellular carcinoma (HCC). Given the lack of randomized trials and large case series, this issue has been recently addressed in studies utilizing decision-modeling analysis. This second aim will provide clinical data to validate these studies, and will compare CLT, with its inherent waiting times, to LDLT, a strategy that theoretically eliminates waiting times. We hypothesize that the outcome of transplantation of HCC in LDLT is superior to results obtained with CLT. In the aggregate, these studies will define the efficacy of LDLT in

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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the US, while a focus on both a donor issue (hepatic steatosis) and a recipient issue (the special problem of HCC) will help delineate the potential advantages of LDLT over CLT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BARIATRIC SURGERY RESEARCH CONSORTIUM Principal Investigator & Institution: Flum, David R.; Professor; Surgery; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Bariatric procedures offer sustained and significant weight reduction with the potential to effect general patient health, comorbid conditions, quality of life and the healthcare system. A Bariatric Surgery Clinical Research Consortium (BSCRC) wilt provide important prospective information about the true impact of the procedure on patients and opportunities to better explore the physiologic mechanisms that result in post-surgical weight loss. The BSCRC will prospectively collect clinical, demographic, epidemiological, laboratory and histological information. In addition to this database the BSCRC will complete the following studies: 1. A cross-sectional examination of the epidemiology of non-alcoholic steatohepatitis (NASH) in patients undergoing bariatric surgery and a prospective evaluation of the effect of surgically induced weight loss on the severity NASH and cellular markers of cytotoxic activity. There is a need for epidemiologic information about the prevalence, risk factors for, and impact of fatty liver disease in patients undergoing bariatric surgery. We propose a study to evaluate liver histology in a large group of patients undergoing bariatric procedures. Patients with evidence of NASH by biopsy will undergo subsequent liver biopsy at one year to determine if NASH improves with rapid weight loss. Patients with NASH who improve after weight loss represent an important model for evaluating the cellular mechanisms that are involved in the development of NASH. This study will evaluate markers of oxidative stress and hepatic mitochondrial structure to determine their relationship to NASH during and after rapid, surgical weight loss. 2. A prospective evaluation of the relationship between ghrelin, PYY3-36, appetite and weight loss outcomes after gastric bypass. Ghrelin and PYY3-36 are gut-derived peptides that are involved in energy homeostasis principally through their effect on appetite. We propose a prospective study to determine the relationship of ghrelin and weight loss after gastric bypass and to determine if the degree of ghrelin suppression is correlated to hunger suppression and/or the amount of weight lost. This study will determine if inclusion of ghrelin producing cells in the gastric pouch is correlated to worsened weight loss outcomes. Lastly the study will begin to evaluate the relationship of PYY3-36 and ghrelin and determine if it is altered by or in response to the physiologic changes associated with gastric bypass. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC HEPATITIS C: MOLECULAR & CELLULAR MARKERS Principal Investigator & Institution: Farrell, Geoffrey C.; University of Sydney Main Quadrangle, Bld A14 Sydney, 2006 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Only a minority of HCV-infected individuals have progressive forms of chronic hepatitis that will result in cirrhosis in 20 to 30 years. This project is concerned with the biological basis of disease progression in chronic hepatitis C. We have noted that, to date, viral factors and the systemic immune response to HCV are poorly

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correlated with disease progression. The key pathobiological process that determines progression of liver disease in chronic hepatitis C is fibrogenesis, with hepatocyte cell death and proliferation playing lesser roles. In the present proposal, these processes are conceptualized as responses to hepatic inflammation and oxidative stress causing activation of hepatic stellate cells and liver cell injury. Thus our overall objective is to characterize how interactions between HCV, the hepatic inflammatory response and liver cells promote fibrogenesis and disease progression in chronic hepatitis C. In particular, we will test the hypothesis that, in the early stages of chronic HCV infection, an intrahepatic "molecular map" can be created to identify subsets of individuals who will develop progression of liver disease. We will then seek to identify patterns of hepatic gene expression that correlate with the pathogenesis of fibrosis, hepatocyte death and proliferation. A particular focus will be on the identification of genes not previously known to be associated with individual susceptibility to HCV. A unique feature of these studies is that they will be performed on serial liver biopsy samples obtained at 3 to 5 year intervals from 200 patients with mild to moderate chronic hepatitis C who will be followed prospectively and monitored by quantitative liver functional assessments. The Specific Aims are: 1) To establish the relationship between cytokine mediators of the hepatic inflammatory response, macrophage activation and the presence of oxidative stress in the liver, and to compare these with characteristics of the HCV infection in hepatocytes and other cell types; 2) To determine whether expression of these cytokines and/or oxidative stress correlate with the activity of hepatic fibrogenesis, using both cross-sectional and prospective longitudinal approaches. 3) To identify hepatic genes previously not known to be associated with a progressive course for hepatitis C. The findings may allow those individuals most at risk of progressive liver disease from HCV to be identified at a time when they are most likely to respond to antiviral therapy. It will also allow the design of adjunctive treatments more appropriately targeted towards the key pathogenic processes that determine disease progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLASS I RESTRICTED T CELL RESPONSE DURING HCV INFECTION Principal Investigator & Institution: Greenberg, Harry B.; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002 Summary: We propose to study the class I restricted cellular immune response to hepatitis C virus (HCV) using new techniques, including peptide-MHC tetramers and intracellular cytokine staining. We are focusing on the class I cellular response because it is likely that the magnitude and/or the specificity of the response plays an important role in the control and possibly pathogenesis of HCV infection. The individual specific aims are: A1. To examine the role of HCV-specific CD8+ T lymphocytes in the control of HCV by quantitation and characterization if such peripheral blood. It is our hypothesis that: (i) the outcome (clearance or persistence) of HCV infection is correlated with characteristics and quantity of circulating CD8+ T cell populations specific for HCV; (ii) the HCV viral load is inversely related to HCV-specific CD8+ T cells; and (iii) the quality and quantify of HCV-specific T cells can be modulated by antiviral treatment. To test these hypotheses we will conduct we will conduct prospective studies on patients of interest, including patients with acute HCV infection, patients with chronic HCV infection, patients with chronic HCV infection receiving or not receiving antiviral therapy (IFN/ribavirin combination), and patients undergoing orthotopic liver

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transplantation. A2. To characterize the nature, functional activity and localization of HCV-specific CD8+ T lymphocytes in HCV-infected liver. We hypothesize that intrahepatic T cell response against HCV-specific CD8+ T lymphocytes in HCV-infected liver. We hypothesize that intrahepatic T cell responses against HCV are important determinants of outcomes and severity of liver infection. In order to test these hypotheses, we first plan to better characterize these cells. We will isolate and quantify intrahepatic lymphocytes from liver specificity and cytokine profile of such cells, and compare them to HCV-specific CD8+ T cells in the peripheral blood. We will also develop assays to identify and localize HCV specific CD8+ T cells directly in liver biopsy material. A3. To investigate mechanisms of HCV persistence. We intend to test the hypothesis that HCV may persists by one or more of the following mechanisms following viral mutation of epitope peptides: the target peptide of the virus (i) can no longer be recognized by circulating HCV- specific CD8+ T cells; or (ii) can be recognized as an altered peptide ligand but fails to induce adequate effector functions in the specific D8+ T cells, or (iii) acts as a T cell agonist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL Principal Investigator & Institution: Wallace, Jeanne M.; Associate Professor; Wake Forest University 1834 Wake Forest Road Winston-Salem, Nc 27106 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: The primary objectives of the Animal Core are as follows: 1. Provide veterinary care for the monkeys and mice of the Program Project. 2. Provide veterinary and technical support for liver biopsy surgeries and for associated postoperative care. 3. Provide technical support for collection of blood samples, blood pressures, body weights, administering isotopes and performing urine sample collection, and preparing data sheets. 4. Coordinate and supervise the diet laboratory and animal care staffs to assure that diets are prepared and fed according to protocol. 5. Insure that liver perfusion studies and necropsies are performed according to protocol. 6. Evaluate atherosclerosis extent and severity in the aorta, coronary, carotid and iliac arteries. 7. Provide technical support for the transgenic mouse breeding colony. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--MICROARRAY & VIROLOGY Principal Investigator & Institution: Katze, Michael G.; Professor; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: In the Microarray & Virology Core, we have brought together a diverse group of NIH-funded investigators from basic science and clinical medicine. These investigators have a common interest in using state-of-the-art technologies to better understand the molecular mechanisms underlying the progression from HCV infection to end-stage liver disease. Our goal is to use DNA microarrays to provide a molecular blueprint of the changes in cellular gene expression that occur at multiple points along the continuum from virus infection to liver disease, including cirrhosis and hepatocellular carcinoma. Our Specific Aims are the following: Aim 1: Supply biological samples for microarray and proteomic analyses and provide molecular biology and virology support. Investigators associated with this core will provide the biological samples used for microarray and proteomic analyses. These samples will come from a variety of in vitro and in vivo systems, including HCV replicon cell lines, cultured

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primary human hepatocytes, liver biopsy material from patients with recurrent HCV after liver transplantation, and liver biopsy material from patients co-infected with HCV and human immunodeficiency virus (HIV). Aim 2: Use DNA microarrays to profile changes in cellular gene expression that occur during HCV infection and HCVassociated liver disease. This core will leverage the capabilities of a pre-existing microarray facility, the Center for Expression Arrays, to apply the technologies of global gene expression analysis to the study of HCV infection and liver disease. This technology infrastructure will be coupled with expertise in hepatitis C virology, virushost interactions (including extensive experience in the use of global gene expression profiling), and liver disease and transplantation. Data obtained from these analyses will be provided to the Bioinformatics & Biostatistics core for analysis and integration with data generated by the Proteomics & Modeling core. The information is likely to yield improved diagnostic methods, markers of disease progression, and novel approaches for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG METABOLISM AND CHRONIC LIVER DISEASE Principal Investigator & Institution: Branch, Robert A.; Professor and Director; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): This is a resubmission of a proposal whose goal is to use pharmacogenetic principles to better understand the influence of liver disease associated with hepatitis C on drug disposition and develop new tools to evaluate hepatic function. We propose to address the following specific hypotheses: In Specific Aim 1: Hepatitis C influences the clearance of drugs that undergo metabolism in comparison to matched controls. Furthermore, the extent of change in clearance is different for drugs that are metabolized by different drug metabolizing enzymes and is associated with the severity of the liver disease. Specific Aim 2: Selective decreases in drug metabolism in patients with hepatitis C without hepatic decompensation is associated with enzyme specific down-regulation of hepatic expression of mRNA for that enzyme and increased circulating levels of the cytokines, Interleukin-6 and Tumor Necrosis Factor- ?. Specific Aim 3: The measurement of activity of multiple drug metabolizing enzymes can be interpreted in the context of a sequential, progressive model of hepatic dysfunction to provide an integrated assessment of hepatic function and prognosis in patients with hepatitis C. We propose to study patients with hepatitis C (n= 112) associated with chronic persistent hepatitis, chronic active hepatitis and cirrhosis with or without hepatic decompensation and age, sex matched controls (n=48) on two occasions. Each study subject will participate in three pharmacokinetic (PK) studies that uses drugs selected as probes of substrates metabolized predominantly or exclusively by an individual drug metabolizing enzyme. Part 1: A cocktail to include: caffeine (CYP1A2), flurbiprofen (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and dapsone (acetylation). Part 2: Semisimultaneous oral:intravenous administration with midazolam to measure intestinal and hepatic contributions to CYP3A metabolism and Part 3: oral administration of acetaminophen (UGT1A6) simultaneously with intravenous morphine (UGT2B7). When feasible, liver tissue obtained at the time of diagnostic liver biopsy as part of routine patient care will have concentrations of mRNA for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A6 and UGT2B7 measured. Patients with hepatitis C-associated liver disease will be followed at 6 monthly intervals until liver

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transplantation, death or duration of funding. The study will be repeated either after a change in clinical status or at 2 years in patients with liver disease and after one or 12 months in control subjects. Collectively, these studies will provide a consolidated base of information within the same cohort of patients with hepatitis C and normal subjects to better understand the influence of hepatitis C-associated live disease on drug metabolizing enzymes. This information has potential to create new integrated indices to evaluate hepatic function and prognosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF POLYUNSATURATED LECITHIN ON LIVER FIBROSIS Principal Investigator & Institution: Schenker, Steven; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002 Summary: This is a multicenter, placebo-controlled, parallel study of polyunsaturated lecithin on the progression of fibrosis to cirrhosis in patients with alcoholic liver damage. Its objective is to evaluate the preventive effect of polyunsaturated lecithin and to assess the corresponding changes in hepatic collagen measured directly (by liver biopsy) and indirectly (by propeptide changes in the blood). The effect of lecithin on histologic parameters of steatosis, inflammation, and necrosis will also be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EMORY MEDICINE LASER CAPTURE MICRODISSECTION FACILITY Principal Investigator & Institution: Hagedorn, Curt H.; Professor; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2003 Summary: The information in the human genome database promises to provide a new means to investigate human diseases. However, a limiting factor in using this database in identifying new diagnostic/prognostic markers and defining the molecular mechanisms of disease is the challenge of isolating specific cell populations and their mRNA from clinical tissue biopsies Investigators have isolated specific cell types from small samples of tissue using micropipette dissection methods. However, they require a high degree of manual skill and are time-consuming. A Laser Capture Microdissection (LCM) system was developed at NIH to meet this challenge and more rapidly isolate specific cells from clinical biopsy samples. By combining LCM with non-thermophilic RNA amplification methods it is now possible to produce aRNA from 100-1,000 cells and probe high-density arrays for in vivo functional genomic studies of specific cells in clinical biopsies. The Emory Medicine LCM facility will be incorporated into the Vascular Medical Center at Emory University. It will be used to investigate gene expression of specific cell types in a variety of chronic inflammatory diseases such as atherosclerosis, hepatitis C, graft vs. host disease following stem cell transplantation, and studies regarding the in vivo source of actor VIII during chronic liver disease. Specific programs that will utilize the LCM facility include: 1) Comparing gene expression within Kupffer, endothelial stellate, and T cells in liver biopsy samples of control patients and those with chronic hepatitis C (acute vs. chronic; siblings with nonprogressive vs. severe progressive inflammation/fibrosis; responders vs. nonresponders to treatment); 2) Studying the modulation of gene expression in individual endothelial cells in humans and experimental animals exposed to different hemodynamic milieus and treatments; 3) Studying the in vivo gene expression of

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vascular adventitial myofibroblasts during post- angioplasty restenosis; 4) Studying the in vivo expression of vascular adventitial myofibroblasts during post-angioplasty restenosis; 4) Studying gene expression of Factor VIII in liver endothelial and parenchyma cells during chronic liver diseases; 5) studying the in vivo gene expression of endothelial cells of proliferating vs. regressing hemangiomas; and 6) studying the in vivo gene expression of human dermal endothelial cells during cutaneous inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GALACTOSEMIA: IDENTIFICATION BY METABOLIC LIVER BIOPSY Principal Investigator & Institution: Segal, Stanton; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 31-JAN-2006 Summary: (provided by applicant): Galactosemia, the inherited inability to metabolize galactose, a major nutrient in milk, due to deficient galactose-1-phosphate uridyltransferase (GALT), is an enigmatic disorder. The therapeutic use of galactoserestricted diets has failed to prevent long-term complications of cognitive impairment, speech disorders, neurologic ataxias and ovarian failure. The development of new therapeutic strategies is an imperative. Most patients, even those considered to have a severe mutation, have an ability to slowly oxidize galactose to CO2 which accounts in large part for disposition of their endogenous galactose production. Augmenting that ability may be a new therpeutic approach if the mechanism(s) involved can be delineated. The aim of this proposal is to determine, by a new technique of "metabolic biopsy" of liver uridinedisphospho glucose (UDPglu) pool, if galactosemic patients have residual GALT activity to explain their limited ability to metabolize the sugar and how much is accounted for by other known alternate pathways. The method involves the powerful tool of 13C NMR and 1H NMR to measure the 13C enrichment and total quantity of urinary acetaminophen (Tylenol) glucuronide over 24 hr following oral bolus administration of 2-13C galactose with concomittant administration of acetaminophen. Acetaminophen is largely excreted (65%) in subjects over age 9 yr as the glucuronide, which is derived from UDPglu, the key intermediate in the normal pathway of galactose metabolism. The extent to which this happens will indicate how much of the normal pathway remains. The study will be performed in normal subjects and galactosemics homozygous for the Q188R mutation which accounts for 50% of Caucasian patients, Q188R compound heterozygotes, S135L in African Americans who we know to have residual activity and Ashkenazi with homozygous gene deletions who cannot have any residual activity. An analysis will be made of residual GALT function in relation to various genetic types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HCV COINFECTION

REPLICATION

AND

IMMUNE

RESPONSE

IN

HIV

Principal Investigator & Institution: Gretch, David R.; Associate Professor, Director Viral He; Laboratory Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: Coinfection with hepatitis C virus and HIV is not uncommon. Approximately 10 percent to 30 percent of HIV-infected individuals are also infected with HCV. Many

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natural history studies have found that those with coinfection have more significant, and more rapidly progressive, liver disease than HCV-infected individuals who are HIV-negative. While the pathogenesis of HCV liver disease is not well understood, many believe that the more advanced liver disease seen in those with coinfection is due to HIV-related immune deficiency. The specific aims of this proposals are as follows: Aim 1: To determine serum HCV RNA levels and quasispecies complexity and diversity in HCV-infected patients with and without HCV coinfection. This study will test the hypothesis that those with coinfection have higher HCV viremia and lower quasispecies complexity and diversity than those who are HIV-negative. Aim 2: To determine intrahepatic HCV RNA by in situ assay in HCV-infected patients with and without HIV coinfection. This study will utilize an in situ assay for genomic and replicative HCV RNA to test the hypotheses that intrahepatic HCV replication is increased in those with HIV and correlates with liver disease severity. It will also test the hypothesis that both HCV replication and liver disease are increased in those with more advanced HIVrelated immune suppression. Aim 3: To determine the effect of HAART on HCV viremia, quasispecies complexity and diversity, intrahepatic HCV replication, and the immune response to HCV. HIV infected patients who are to be treated with HAART will undergo liver biopsy for measurement of intrahepatic HCV replication both before and 12 months after initiating HAART. Other pre- and post-HAART measurements will include HCV viremia, HCV quasispecies complexity and diversity, an increase in intrahepatic staining for CD4 and CD8 cells, and an increase in peripheral lymphoproliferative responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HCV TREATMENT IN AFRICAN AMERICANS VS NON HISPANIC WHIT* Principal Investigator & Institution: Jeffers, Lennox J.; Professor; Medicine; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 21-AUG-2001; Project End 30-JUN-2006 Summary: The proposed project is a 5-year multicenter open-label trial designed to evaluate the efficacy of 40 kDa Pegylated interferon alfa-2a (Peginterferon alfa-2a) in combination with Ribavirin in the treatment of genotype-1 chronic hepatitis C (HCV, genotype-1) in African American men and women as compared to non-Hispanic whites. The Primary Aim of this proposal is to establish rates of sustained virologic response to a 48-week course of Peginterferon alfa-2a in combination with ribavirin in African Americans as compared to non-Hispanic whites with chronic HCV genotype 1 as assessed at the end of 48-week post-treatment follow-up by HCV RNA (