Liver Transplantation National Institutes of Health Consensus Development Conference Statement June 20-23, 1983 This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/. This statement was originally published as: Liver Transplantation. NIH Consens Statement 1983 Jun 20-23;4(7):1-15. For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Liver Transplantation. NIH Consens Statement Online 1983 Jun 20-23 [cited year month day];4(7):1-15. Introduction Since performance of the first human orthotopic liver transplantation in 1963, over 540 such operations have been carried out in four medical centers in the United States and Western Europe. Additional liver transplantation procedures have been performed in other parts of the world, and more recently in several other American medical centers. Although extremely demanding and expensive, the operation has been shown to be technically feasible, and interpretable results have been reported from all four primary transplant centers. These clearly demonstrate that liver transplantation offers an alternative therapeutic approach which may prolong life in some patients suffering from severe liver disease that has progressed beyond the reach of currently available treatment and consequently carries a predictably poor prognosis. However, substantial questions remain regarding selection of patients who may benefit from liver transplantation; the stage of their liver disease at which transplantation should be performed; survival and clinical condition of patients beyond the initial year after transplantation; and overall long-range benefits and risks of transplantation in the management of specific liver diseases. In order to resolve some of these questions, the National Institutes of Health on June 20-23, 1983, convened a Consensus Development Conference on Liver Transplantation. After 2 days of expert presentation of the available data, a Consensus Panel consisting of hepatologists, surgeons, internists, pediatricians, immunologists, biostatisticians, ethicists, and public representatives considered the offered evidence to arrive at answers to the following key questions: Are there groups of patients for whom transplantation of the liver should be considered appropriate therapy? What is the outcome (current survival rates, complications) in different groups? In a potential candidate for transplantation, what are the principles guiding selection of the appropriate time for surgery? What are the skills, resources, and institutional support needed for liver transplantation? What are the directions for future research? Are There Groups of Patients for Whom Transplantation of the Liver Should Be Considered Appropriate Therapy? Liver transplantation is a promising alternative to current therapy in the management of the late phase of several forms of serious liver disease. Candidates include children and adults suffering from irreversible liver injury who have exhausted alternative medical and surgical treatments and are approaching the terminal phase of their illness. In many forms of liver disease the precise indications and timing of liver transplantation remain uncertain or controversial. Prolongation of life of good quality for patients who would otherwise have died has been reported in the following conditions: Extrahepatic biliary atresia is the most common cause of bile duct obstruction in the young infant. Patients who fail to respond to hepatoportoenterostomy (Kasai procedure) often benefit from liver transplantation. Recent data suggest that as many as two-thirds of these patients survive for 1 year or more after transplantation. Chronic active hepatitis is caused by viral infections or drug reactions, but many cases remain unexplained. Some patients with progressive liver failure are candidates for transplantation. Currently, exceptions seem to include drug-induced chronic active hepatitis, which usually responds to removal of the chemical agent, and hepatitis B-induced disease in which viremia persists. In the latter instance, rapid reappearance of infection with progressive liver failure has been reported following transplantation. Primary biliary cirrhosis is a slowly progressive cholestatic liver disease. Results of transplantation appear favorable for patients with end-stage liver injury. The procedure may improve the quality of life. Inborn errors of metabolism may cause end-stage liver damage or irreversible extrahepatic complications. Transplantation may be appropriate for such patients. Hepatic vein thrombosis (Budd-Chiari syndrome) often results in progressive liver failure, ascites, and death. Patients who have not responded to anticoagulation or appropriate surgery for portal decompression may be candidates for transplantation. Sclerosing cholangitis, a chronic non-suppurative inflammatory process of the bile ducts, may cause liver failure. Less favorable results following transplantation in this group may be due to prior multiple surgical procedures, a diseased extrahepatic bile duct, the presence of biliary infection, or other factors. Primary hepatic malignancy confined to the liver but not amenable to resection may be an indication for transplantation. Results to date indicate a strong likelihood of recurrence of the malignancy. Nonetheless, the procedure may achieve significant palliation. Alcohol-related liver cirrhosis and alcoholic hepatitis are the most common forms of fatal liver disease in America. Patients who are judged likely to abstain from alcohol and who have established clinical indicators of fatal outcome may be candidates for transplantation. Only a small proportion of alcoholic patients with liver disease would be expected to meet these rigorous criteria.   Although fulminant hepatic failure with massive hepatocellular necrosis induced by hepatitis viruses, hepatotoxins, or certain drugs may warrant liver transplantation, rapid progression of the disease and multi-organ system failure frequently preclude this option.   What Is the Outcome (Current Survival Rates, Complications) in Different Groups? The survival and complication rates of patients who have undergone liver transplantation are the major criteria for judging efficacy. Data are available from four locations (Pittsburgh; Cambridge, England; Hannover, Germany; and Groningen, The Netherlands). The interpretation of the existing data on survival is extremely difficult because no control data are given for comparison, surgical techniques and drug therapies varied over time, and patient selection criteria and management differed across centers. While sufficient data for thorough assessment of liver transplantation are not available to date, today certain trends appear to emerge: Patients currently being accepted for transplantation have a high probability of imminent death and a low quality of life in the absence of transplantation. Patients undergoing transplantation have an operative mortality (within 1 month) of 20 to 40 percent. One-year survival among transplant recipients since 1980 is favorable when compared with their expected course in the absence of transplantation. Since 1980, 1-year survival appears improved over the earlier transplant experience. Individual patients have survived for many years with good quality of life after transplantation. Data are insufficient to evaluate survival rates beyond 1 year following transplantation with current technologies. Short-term quality of life is probably enhanced in many transplant survivors. We lack systematically gathered information on quality of life among long-term survivors.   Severe non-lethal complications of transplantation frequently occur and must be taken into account in judging efficacy of this procedure. Massive hemorrhage is the most serious intraoperative and early postoperative problem. Other postoperative complications include renal dysfunction, rejection, biliary tract complications, graft vascular obstruction, and infection. With accumulating expertise in medical and surgical management and with new developments in technology (e.g., intraoperative veno-venous bypass and cyclosporine), these complications can be expected to diminish.   In a Potential Candidate for Transplantation, What Are the Principles Guiding Selection of the Appropriate Time for Surgery? Selecting an appropriate stage for a given illness for liver transplantation is a complex issue: transplantation just prior to death may significantly diminish the life-saving potential of the procedure since hepatic decompensation in its latest stages poses a formidable surgical risk. Transplantation early in the course of hepatic decompensation may deprive a patient of an additional period of useful life. An ideally timed liver transplantation procedure would be in a late enough phase of disease to offer the patient all opportunity for spontaneous stabilization or recovery, but in an early enough phase to give the surgical procedure a fair chance of success. For most patients, these phases are difficult to define prospectively. While no single best time for surgery can be specified, transplantation should be reserved for patients in any of the following phases of disease: When death is imminent. When irreversible damage to the central nervous system is inevitable. When quality of life has deteriorated to unacceptable levels.   The exact choice of the time for liver transplantation in an individual requires the judgment of a qualified medical team and a well-informed patient. The following are offered as guidelines for individual liver diseases. Extrahepatic Biliary Atresia Biliary enteric anastomosis (hepatoportoenterostomy of Kasai) performed in the first 2 months of life provides significant improvement for at least 5 years in one-third of the patients, although cirrhosis and disappearance of the intrahepatic bile ducts occur with increasing age. While success of this procedure cannot be predicted for the individual patient, it should be used as initial therapy for extrahepatic biliary atresia. In the absence of severe hepatic decompensation in these children, liver transplantation should be delayed as long as possible to permit the child to achieve maximum growth. In children with successful hepatoportoenterostomy, liver transplantation should be deferred until progressive cholestasis, hepatocellular decompensation, or severe portal hypertension supervene. Multiple attempts at hepatoportoenterostomy or surgical porto-systemic shunting render eventual transplant surgery technically more difficult and operationally more dangerous and therefore should be avoided in favor of liver transplantation. Chronic Active Hepatitis The potential for spontaneous remission and the complex course of chronic active hepatitis make valid predictions of the subsequent course difficult except in the latest stages of the disease. Using strict criteria, patients can be identified who have almost no chance of survival beyond 6 months. Such patients may be suitable candidates for transplantation. Primary Biliary Cirrhosis The indolent course of primary biliary cirrhosis and the potential for spontaneous improvement even in patients with advanced disease make transplantation potentially suitable only in the final stages of liver failure or when the quality of life has deteriorated to an unacceptable level. Alpha-1-Antitrypsin Deficiency Of the some 20 phenotypes in this genetic disorder, only Pi ZZ is associated with significant hepatic disease in children. Of infants with this phenotype, neonatal cholestasis occurs in 5.5 percent. Jaundice usually is transient, clearing before 6 months of age although biochemical evidence of activity may persist. Liver transplantation is indicated in children with Pi ZZ phenotype only when cirrhosis has developed and when evidence of hepatic failure is present. Adults with alpha-1-antitrypsin deficiency may have liver disease associated with phenotype Pi ZZ, MZ, or SZ. If hepatic failure occurs, liver transplantation may be indicated. Wilson's Disease Patients with Wilson's disease usually are responsive to chelation therapy with penicillamine. However, some patients present with fulminant hepatic failure and/or progressive disease unresponsive to adequate chelation therapy. Liver transplantation may be indicated in these instances. Crigler-Najjar Syndrome Of the two types of this genetic disorder associated with severe unconjugated hyperbilirubinemia, patients with Type I invariably develop bilirubin encephalopathy usually before 15 months of age. Because of the inevitability of central nervous system damage and the limitations of phototherapy, liver transplantation is indicated in such patients at an early age. Miscellaneous Metabolic Diseases A number of rare genetic diseases may involve the liver and cause cirrhosis and eventual hepatic failure. Patients with tyrosinemia, Byler's disease, Wolman's disease, and glycogen storage diseases Types O and IV may be candidates for hepatic transplantation. Liver transplantation may also be indicated for patients with certain genetic diseases associated with severe neurological complications, such as hereditary deficiency of urea cycle enzymes and disorders of lactate/pyruvate or amino acid metabolism. Hepatic Vein Thrombosis The course of hepatic vein thrombosis is variable, and therefore transplantation should be reserved for patients with severe hepatic decompensation. The possibility of later transplant surgery should not discourage the use of portal venous decompression when otherwise indicated. Primary Sclerosing Cholangitis No clinical, biochemical, serologic, or histologic factors have proved to be of value in predicting outcome. When appropriate attempts at biliary tract diversion and dilatation have failed, and death from liver failure is imminent, liver transplantation should be considered. Alcoholic Liver Disease At least 50 percent of the cases of cirrhosis in the United States are attributable to the abuse of alcohol, and alcohol abuse is the leading cause of hepatic morbidity and mortality. Alcoholic liver disease is most favorably affected by abstinence. The natural history of untreated alcoholic hepatitis and/or cirrhosis is extremely variable, and there are few precise prognostic indicators in any but the terminal phase of the disease. Liver transplantation may be considered for the patients who develop evidence of progressive liver failure despite medical treatment and abstinence from alcohol.   What Are the Skills, Resources, and Institutional Support Needed for Liver Transplantation? The requirements for conducting a liver transplantation program by a sponsoring institution are formidable. Accordingly, any institution embarking on this program must make a major commitment to its support. In addition to the full array of services required of a tertiary care facility and a program in graduate medical education, an active organ transplantation program should exist. Few hospitals are likely to meet these prerequisites. Liver transplant recipients are seriously ill before surgery. The transplant effort is prodigious, and the postoperative intensive care interval, averaging 2 weeks, is punctuated by complications and frequent need for reoperation. In this context, experts in hepatology, pediatrics, infectious disease, nephrology with dialysis capability, pulmonary medicine with respiratory therapy support, pathology, immunology, and anesthesiology are needed to complement a qualified transplantation team. Extensive blood bank support to provide the needed copious quantities of blood components is mandatory. Similarly, sophisticated microbiology, clinical chemistry, and radiology assistance are required. Emotional support for patient and family warrants psychiatric participation. Availability of effective social services to assist patients and families is indispensable. The transplantation surgeon must be trained specifically for liver grafting and must assemble and train a team to function whenever a donor organ is available. Institutional commitment to the program mandates that operating room, recovery room, laboratory, and blood bank support exist at all times. Allocation of intensive care and general surgical beds is important. Recruitment of a cohort of specialized nurses and technicians to staff these areas is necessary. Access to tissue typing capability; ongoing research programs in liver disease, organ preservation, and transplantation immunology; and available hemoperfusion and microsurgical techniques are desirable attributes of a transplantation effort. Participation in a donor procurement program and network is essential, and an interdisciplinary deliberative body should exist to determine on an equitable basis the suitability of candidates for transplantation. Institutions conducting liver transplantation are obligated to prospectively collect and share data in a coordinated, systematic, and comprehensive manner in all patients selected as transplantation candidates, so that the role of liver transplantation in the management of patients with liver disease can be assessed properly. Additional information permitting cost-benefit analysis should be secured. Finally, the panel feels that adherence to these guidelines detailing the essentials to conduct a transplantation program offers the best assurance of high quality in performing this very difficult operation.   What Are the Directions for Future Research? The Consensus Panel identified several broad areas related to liver transplantation in which critically important information is either unavailable or so incomplete as to defy meaningful interpretation. It is recommended that a registry or clearinghouse be established for collection and evaluation of all available data on liver transplantation. Such a center would develop unified criteria for selection of patients for transplantation and for reporting and evaluating all data related to the outcome of the operation and the patients' postoperative and long-term condition. As methods of immunosuppression improve and the logistic obstacles are resolved, the feasibility and desirability of randomized clinical trials of liver transplantation should be explored for suitable subgroups of patients with specific liver diseases. High priority also should be given to research projects related to several aspects of the transplant procedure itself. Means should be developed to improve preservation of human liver ex vivo and criteria should be established to evaluate its viability. Improved control of organ rejection requires urgent attention; this includes thorough evaluation of the benefits and risks of cyclosporine as an immunosuppressive agent in liver transplantation. The design of the hemodynamic support system during transplantation needs evaluation and potential improvement. Research should be encouraged for developing better supportive measures for patients in liver failure, including maintenance of proper renal and cerebral function. In the broad areas of the cause, pathogenesis, and natural course of chronic liver disease, present knowledge is fragmentary and incomplete, and research in these areas should be fostered and supported by all available means. Particular attempts should be made to determine the possible role of liver transplantation in the management of hepatocellular carcinoma at a stage when metastatic spread appears remote. Similarly, approaches should be sought to limit infection of the transplanted liver by hepatotropic viruses. Finally, liver transplantation should be explored as a modality of replacement therapy in genetically determined multi-organ enzyme deficiencies.   Conclusion After extensive review and consideration of all available data, this panel concludes that liver transplantation is a therapeutic modality for end-stage liver disease that deserves broader application. However, in order for liver transplantation to gain its full therapeutic potential, the indications for and results of the procedure must be the object of comprehensive, coordinated, and ongoing evaluation in the years ahead. This can best be achieved by expansion of this technology to a limited number of centers where performance of liver transplantation can be carried out under optimal conditions.   Consensus Development Panel Rudi Schmid, M.D. (Panel Chairman) Professor of Medicine and Dean University of California, San Francisco School of Medicine San Francisco Medical Center San Francisco, California Donald M. Berwick, M.D. Assistant Professor of Pediatrics Harvard Medical School Acting Director of Research Harvard Community Health Plan Boston, Massachusetts Burton Combes, M.D. Professor of Internal Medicine The University of Texas Health Science Center at Dallas Dallas, Texas Ralph B. D'Agostino, Ph.D. Professor of Mathematics and Statistics Boston University Boston, Massachusetts Stuart H. Danovitch, M.D. Private Practice of Gastroenterology Washington, D.C. Harold J. Fallon, M.D. Professor and Chairman Department of Medicine Medical College of Virginia Richmond, Virginia Olga Jonasson, M.D. Professor of Surgery University of Illinois Chief of Surgery Cook County Hospital Chicago, Illinois Charles E. Millard, M.D., A.B.F.P. Family Practitioner Medical Associates of Bristol County Vice Chairman Biomedical Ethics Commission Roman Catholic Diocese of Providence Bristol, Rhode Island Linda Miller, M.S. Executive Director Volunteer Trustees of Not for Profit Hospitals Washington, D.C. Frank G. Moody, M.D. Professor and Chairman Department of Surgery University of Texas Medical School at Houston Surgeon-in-Chief Hermann Hospital Houston, Texas William K. Schubert, M.D. Professor and Chairman Department of Pediatrics University of Cincinnati College of Medicine Physician Executive Director Children's Hospital Medical Center Cincinnati, Ohio Laurence Shandler, M.D. Private Practice of Pediatrics Santa Fe, New Mexico Henry J. Winn, Ph.D. Senior Associate in Surgery Harvard Medical School Immunologist General Surgical Services Massachusetts General Hospital Boston, Massachusetts Speakers Daniel Alagille, M.D. "Alpha-1-Antitrypsin Deficiency" "Extrahepatic Biliary Atresia" Professor of Pediatrics Universite Paris Sud Hopital de Bicetre FRANCE Joseph R. Bloomer, M.D. "The Liver in Crigler-Najjar Syndrome, Protoporphyria, and Other Metabolic Disorders" Professor of Medicine Section of Gastroenterology University of Minnesota Minneapolis, Minnesota James L. Boyer, M.D. "Primary Biliary Cirrhosis" Professor of Medicine Director of Liver Study Unit Chief, Division of Digestive Diseases Yale School of Medicine New Haven, Connecticut E. Rolland Dickson, M.D. "Primary Sclerosing Cholangitis" Professor of Medicine Mayo Clinic Mayo Medical School Rochester, Minnesota Roger W. Evans, Ph.D. "Perspective Gained from Kidney and Heart Transplantation" Research Scientist Battelle Human Affairs Research Centers Seattle, Washington Harvey V. Fineberg, M.D., Ph.D. "Principles of Technology Assessment Applied to Liver Transplantation" Professor of Health Policy and Management Harvard School of Public Health Boston, Massachusetts Ruud A.F. Krom, M.D. "Orthotopic Liver Transplantation in Groningen (The Netherlands) 1979-1983" Staff Surgeon Department of Surgery State University of Groningen University Hospital Groningen Groningen THE NETHERLANDS Willis C. Maddrey, M.D. "Hepatic Vein Thrombosis (Budd-Chiari Syndrome)" Magee Professor of Medicine and Chairman of the Department Jefferson Medical College Philadelphia, Pennsylvania Kunio Okuda, M.D., Ph.D. "Primary Hepatocellular Carcinoma--Prognosis in 600 Patients" Chairman and Professor First Department of Medicine Chiba University School of Medicine Inohana, Chiba JAPAN Rudolf Pichlmayr, Professor Dr. med. "Consensus Development Conference on Liver Transplantation--Experience with Liver Transplantation" Zentrum Chirurgie der Medizinischen Hochschule Hannover Hannover WEST GERMANY Keith Rolles, B.Sc., F.R.C.S. "Orthotopic Liver Transplantation 1968-1983--The Cambridge Experience" Lecturer in Surgery Department of Surgery Addenbrooke's Hospital Cambridge ENGLAND Paul S. Russell, M.D. "Some Immunological Considerations in Liver Transplantation" John Homans Professor of Surgery Harvard Medical School Visiting Surgeon-in-Chief, Transplantation Unit Massachusetts General Hospital Boston, Massachusetts Bruce F. Scharschmidt, M.D. "Experience with Liver Transplantation" Associate Professor of Medicine University of California, San Francisco San Francisco, California Steven Schenker, M.D. "Alcoholic Liver Disease" Professor of Medicine and Pharmacology Chief, Division of Gastroenterology and Nutrition Department of Medicine University of Texas Health Science Center San Antonio, Texas Sheila Sherlock, M.D. "Chronic Hepatitis/Cirrhosis" Professor of Medicine University of London Royal Free Hospital School of Medicine Hampstead, London ENGLAND Thomas Starzl, M.D. "Surgical Results and Followup" Professor of Surgery School of Medicine University of Pittsburgh Pittsburgh, Pennsylvania Irmin Sternlieb, M.D. "Wilson's Disease--Indications for Liver Transplants" Professor of Medicine Albert Einstein College of Medicine Bronx, New York David H. Van Thiel, M.D. "Medical Aspects of Liver Transplantation" Professor of Medicine University of Pittsburgh Pittsburgh, Pennsylvania Dr. John M. Vierling "Epidemiology and Clinical Course of Liver Disease" Denver Veterans Administration Medical Center Denver, Colorado Roger Williams, M.D., F.R.C.P. "Acute Liver Failure" Director of the Liver Unit and Consultant Physician Kings College Hospital Denmark Hill London ENGLAND Planning Committee Steven Schenker, M.D. (Chairman) Professor of Medicine and Pharmacology Chief, Division of Gastroenterology and Nutrition Department of Medicine University of Texas Health Science Center San Antonio, Texas Itzhak Jacoby, Ph.D. Deputy Director Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Sarah C. Kalser, Ph.D. Program Director for Liver and Biliary Diseases National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland Curtis Meinert, Ph.D. Professor of Epidemiology and Biostatistics School of Hygiene and Public Health Johns Hopkins University Baltimore, Maryland Harold P. Roth, M.D. Director Division of Digestive Diseases and Nutrition National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland Paul S. Russell, M.D. John Homans Professor of Surgery Harvard Medical School Boston, Massachusetts Conference Sponsors National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases Lester B. Salans, M.D. Director Office of Medical Applications of Research J. Richard Crout, M.D. Director

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