Advances in the management of both chronic and acute hepatic disease have been made possible and even mandated by the development of liver transplantation. The clinical use of transplantation has proceeded at a rapid pace since a Consensus Development Conference of the National Institutes of Health concluded in June 1983 that liver transplantation had become a service and not simply an experimental procedure.1 The liver can be transplanted as an extra (auxiliary) organ at an ectopic site, or in the orthotopic location after the removal of the host liver (Fig. 1). This article will focus primarily on the orthotopic procedure. However, there has been renewed interest in the auxiliary operation, which will be discussed separately. Figure 1 Orthotopic Liver Transplantation Candidacy for Transplantation The conceptual appeal of liver transplantation is so great that the procedure may come to mind as a last resort for virtually every patient with lethal hepatic disease. The selection of appropriate recipients from such a large pool requires strict individual assessment. A 1982 estimate of the annual need for liver transplantation was 15 per million population,2 but the current need is undoubtedly higher because there are now fewer restrictions on candidacy. Between 4000 and 50,000 liver transplantations a year may be needed in the United States. The supply of organs will increasingly influence the criteria for candidacy and limit the use of the procedure. Discussions about rationing transplantation services for this reason are nonetheless premature, because the balance between need and supply has not been determined. In the United States, the yearly rate of liver transplantation has reached approximately 1600; it averaged 147 a month between July and December 1988 (Vaughn W, United Network of Organ Sharing: personal communication). The annual rate in Europe approaches this figure. Policies on organ donation will have to be reexamined if substantial growth is to occur. Many potential liver donors are probably rejected unjustifiably. The arbitrary upper age limit observed by most programs3 cannot be justified, because senescence largely spares the liver.4 Atherosclerosis of the hepatic arteries is not usually found beyond the origin of the celiac axis.4 Our own limited experience with livers from donors over 50 years old has been encouraging. Potential donors of all ages are often excluded because of poor arterial-blood gas levels, their need for inotropic or vasopressor drugs, minor abnormalities of liver function, or diseases such as diabetes mellitus.3 The results with livers from such donors in both the United States5 and Europe6 have been as good as those with healthier donors. The use of better techniques of preservation,7-9 which allow the safe storage of liver grafts for a day instead of the previous six or eight hours, should reduce organ wastage, since with this extra time, countrywide and worldwide networks of organ sharing can be created. If there is an adequate organ supply and a way to finance transplantation, the medical issues of candidacy are relatively clear. In a patient with nonmalignant end-stage liver disease that will not recur in the hepatic graft, there is little debate about the rationale for transplantation. Transplantation is more debatable if the recurrence of a non-neoplastic disease is predictable. The most controversial indication for liver transplantation is for the treatment of hepatic cancers. However, none of these applications should be arbitrarily excluded from future trials. Non-neoplastic Liver Diseases By 1982 liver transplantation had been used to treat more than 20 benign diseases.2 Since then, the list has become so long10-15 that it is increasingly reported in broad categories, such as cholestatic or parenchymal disease16 (Table 1). It is therefore easy to lose sight of the fact that more than 60 distinct diseases have been treated with liver transplantation, including 16 in the broad category of inborn errors of metabolism and 14 in the category of cholestatic disease. Table 1 Native Liver Disease in 400 Pediatric and 858 Adult Recipients of Liver Transplants at the University of Pittsburgh, 1981–1988 In adults, the most common diagnoses have been chronic active hepatitis, cryptogenic cirrhosis, primary biliary cirrhosis, alcoholic cirrhosis, and inborn errors of metabolism. Half or more of the pediatric recipients have had biliary atresia, with inborn metabolic errors a distant second.10-13 A number of diseases in which transplantation might have been precluded or strongly discouraged 5 or 10 years ago are no longer absolute contraindications for the procedure, and some are not even questionable. A prime example is alcoholic cirrhosis. With multidisciplinary care for substance abuse in properly selected cases, the results of transplantation for Laennac's cirrhosis are as good as those for other diseases.17 Somewhat more controversial is transplantation in patients with cirrhosis due to hepatitis B virus, because the recurrence of viral infection cannot be reliably prevented. However, many such patients have benefited from transplantation, and it is therefore difficult to make the carrier state an absolute contraindication. An even more difficult issue is whether patients with antibodies to the human immunodeficiency virus (HIV) should be excluded from candidacy. Shortly after screening tests for this disease became widely available in the spring of 1985, HIV infections were reported in kidney, heart, and liver recipients. At our institution, HIV antibodies were found in the stored serum of 18 of 1043 kidney, heart, or liver recipients (1.7 percent) treated between 1981 and 1986.18 The incidence of HIV in the liver recipients was 2.6 percent, and in one third the antibodies predated transplantation. Seroconversion after transplantation — through infection from blood-component therapy or (uncommonly) from the donor's liver — made up the other two thirds.18 The rate of seroconversion at our institution and others has remained unchanged, despite the use of screening assays for HIV antibodies beginning in March 1985.18,19 The patients infected with HIV have been available for study since their transplantation. We have followed 10 children who were six months to 16 years old at the time of transplantation for 1½ to 6 years, with only one late death from a complication related to the acquired immunodeficiency syndrome (AIDS). Among 16 adults, the AIDS-related mortality has been 37 percent. Many patients can thus have prolonged benefit from liver transplantation in spite of positive tests for HIV. How this fact has been used in decision making varies with the transplantation center. The most commonly accepted policy in the United States is to screen all recipients for HIV, but not to exclude transplantation solely because of a positive test. The screening of potential donors is obligatory at all centers. Tests that identify both HIV antigens and antibodies may make the screening of recipients as well as donors more foolproof than it is now. In addition to disease states that at one time would have ruled out liver transplantation, inflexible age proscriptions have been dropped. An upper age limit was eliminated when it was demonstrated that recipients over 50 have a 5-year survival after transplantation, similar to that of younger adults.20 At the other extreme, liver transplantation in very small infants and even newborns has become common, although the results are better with older children.21 Extensive thromboses of the portal, mesenteric, or splenic veins, which previously made transplantation difficult or impossible, have been eliminated in many cases through the use of vein grafts. The vein grafts are connected to the superior mesenteric vein and brought through the transverse mesocolon anterior to the pancreas into the liver hilum for anastomosis to the portal vein of the new liver.22,23 The routine use of imaging techniques to measure the size of the liver and determine the state of the host vessels helps to identify these cases in advance, and appropriate plans can be made. Scarring from multiple upper-abdominal operations, once considered a contraindication by many transplantation teams, is no longer an overriding deterrent in major centers. Earlier splenectomy or portal–systemic shunts cause the greatest concern. Since any of these operations can alter the portal vein, it is no surprise that the majority of complications of portal-vein reconstruction during transplantation have been in patients with earlier shunt operations.24 Mesocaval and distal splenorenal shunts have been least harmful, since they do not involve dissection of the portal hilum. The shunt must be closed at the time of transplantation for optimal vascularization of the graft. Should shunting operations ever be recommended to treat variceal hemorrhage, given that these procedures can jeopardize the success of the ultimate step, liver transplantation? Probably only rarely, since endoscopic sclerosis of the varices is an effective alternative. In some patients with grade A (good-risk) cirrhosis according to Child's system, a distal splenorenal anastomosis may be the best way to relieve portal hypertension. However, it is important to emphasize that a liver transplantation itself decompresses portal hypertension throughout the capillary bed of the healthy new liver. Among patients with variceal bleeding who were too sick to be considered for any operation other than transplantation, the five-year survival after their livers were replaced was far superior to that reported in series of patients at generally better risk who underwent shunting operations.25 The obvious limitations of the shunt in treating variceal bleeding have greatly reduced the frequency of portal diversions in Western countries.