NIH Public Access Author Manuscript Transplant Proc. Author manuscript; available in PMC 2011 December 2.
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Published in final edited form as: Transplant Proc. 1991 June ; 23(3): 1917–1921.
Liver Transplantation for Alcoholic Liver Disease, Viral Hepatitis, and Hepatic Neoplasms D.H. Van Thiel, B. Carr, S. Iwatsuki, A. Tzakis, J.J. Fung, and T.E. Starzl Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. LIVER transplantation has emerged as a result of years of surgical development and steady improvements in immunosuppression as the major therapeutic intervention for individuals with chronic, advanced liver disease, a variety of metabolic liver diseases, and fulminant hepatic failure.1–3 Despite its demonstrated success as a lifesaving procedure for individuals with advanced liver disease, liver transplantation remains a controversial issue when it is considered for individuals with certain diseases.1–5
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Three of the more controversial disease conditions for which liver transplantation has been performed are alcoholic liver disease, neoplastic disease of the liver, and the viral hepatitides.6–9 Each of these potential disease indications for liver transplantation is considered controversial by some, but not all, transplant programs for one or another of the following overt reasons: (l) there is a high rate of disease recurrence for each of these specific disease indications; (2) the use of valuable donor organs by individuals with these diseases reduces the number of donor organs available for use in individuals with other diseases who are waiting for transplants and who are thought to be more likely to experience a long-term benefit as a result of the transplant procedure; and (3) because of the high cost of liver transplantation, the benefit accrued as a result of transplantation application ought to be substantial also. There are many less overt (or possibly more appropriately identified as covert) reasons why some individuals and programs deny liver transplantation to patients with one of these diseases. Most of these reasons involve issues of societal acceptance of organ transplantation as a lifesaving therapy, the availability and successful recruitment of adequate numbers of organ donors, and the subjective “worthiness” of a given individual as opposed to another.
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It is the goal of this article to demonstrate a rationale for the utilization of liver transplantation for patients with advanced alcoholic liver disease, hepatic neoplasms, and viral hepatitis based on current experience for each of these specific disease indications.
ALCOHOLIC LIVER DISEASE Alcohol-induced cirrhosis and alcoholic hepatitis are two of the most common forms of fatal liver disease seen in the United States,10 with prevalence of 9 million and death rate of 450,000. Moreover, alcoholic liver disease is the most common form of liver disease in the United States and other Western countries and exceeds the next most prevalent liver disease in number of cases by at least a factor of 4 or 5.11 Thus, based simply on the need for the procedure, it appears obvious that liver transplantation should be available for at least some individuals with irreversible, advanced alcoholic liver disease for whom no other therapy currently exists and for whom, if liver transplantation is not made available, death in the immediate future is inevitable (Table 1). © 1991 by Appleton & Lange Address reprint requests to Dr D.H. Van Thiel, 3601 Fifth Avenue, Falk Clinic 5C, Pittsburgh, PA 15213..
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The mean age of chronic alcoholics who have been transplanted at the University of Pittsburgh has been 48.2 ± 8.7 years with a range of 21 to 70 years.12 Based on these data, it can be expected that, should the alcoholic individual survive the initial vicissitudes of the transplant experience, a long life is at least potentially possible. This potential for long-term survival appears to have been supported by the available data that show that the long-term survival of patients with alcoholic liver disease followed by liver transplantation is no different from that of individuals transplanted for various nonalcoholic chronic hepatocellular liver diseases when matched for age, gender, site, and time of transplantation, as well as estimated need for the procedure using the UNOS scoring system and Child'sPugh c1assification.12 Thus, transplantation has the potential to substantially improve the longevity of those who survive the procedure. As might be expected, the majority of alcoholics who have been transplanted have been male, with women making up only 21% of the total cases. As a result of being the principal wage earners for their families, the majority of male transplant recipients transplanted for alcoholic liver disease have returned to work, with 53% of them working full-time or parttime outside the home12 and an additional 21% working full-time at home. Thus, a total of 74% of the survivors of liver transplantation for alcoholic liver disease are able to work and contribute to society as a result of having had the transplant procedure.
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Probably the most surprising statistic concerning liver transplantation for alcoholic liver disease is the finding that 89.5% of the transplant survivors have remained alcoholabstinent.12 Of those that have resumed drinking, the majority drink only moderately (three or fewer drinks per week) as determined by self-report and corroborated by their significant other and their primary-care physicians. This alcohol abstinence following successful liver transplantation appears to be the rule rather than the exception if appropriate selection criteria are utilized for the selection of such individuals for transplantation. The factors that appear to identify those alcoholics most likely to benefit and remain abstinent after successful liver transplantation are (1) the support of a significant other, be it a spouse, friend, or relative; (2) an acceptance of alcohol as the cause for their prior liver disease; (3) active involvement in and completion of a 4- to 6-week alcohol treatment program and abstinence for 3 to 6 months prior to transplantation; and (4) an existing job or an adequate education that allows for subsequent employment and, consequently, a redirection of interests away from those associated with alcohol use toward other forms of recreation or interest.13–15
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Based on the above experience with liver transplantation for alcoholic liver disease, it would appear that the need for transplantation exists for this group. A high survival rate is possible accompanied by a high rate of subsequent employment and a surprisingly low rate of alcohol abuse recidivism. These facts would appear to justify the continued application of liver transplantation for individuals with advanced alcoholic liver disease who, without such therapy, would either die or become invalids because of their disease.
VIRAL LIVER DISEASE Liver transplantation is a therapeutic option for patients with either fulminant hepatic failure or end-stage liver disease (cirrhosis) occurring with or without hepatocellular cancer due to viral hepatitis (Tables 2 and 3). As was the case for alcoholic liver disease, the prevalence of viral liver disease is substantial, and the need for some type of therapy, be it medical or surgical, is obvious (Table 1). To date, with the exception of the controversial use of prostaglandins in patients with fulminant hepatic failure, no specific medical therapy exists, and liver transplantation is the Transplant Proc. Author manuscript; available in PMC 2011 December 2.
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only realistic therapeutic option currently available.16 Compared with historical controls, liver transplantation for individuals with fulminant hepatic failure increases the survival rate 11-fold. When compared to individuals given maximal medical therapy with intent to transplant, liver transplantation increases the chance for survival threefold.17 Fulminant hepatitis attributable to type A or B hepatitis typically occurs at the two extremes of life. Specifically, in children it occurs in those under 10 years of age, and in adults it typically occurs in those older than 50. As a result, the potential for a long life following recovery from these two types of fulminant hepatitis is only limited by the older age of about half the total cases (the adults older than 50 years of age). Moreover, recurrent disease can occur following liver transplantation for fulminant hepatitis due to the A, B, or C viruses.18–20 The data currently available relative to the issue of disease recurrence following fulminant type C hepatitis as opposed to types A and B have only been clinical, but they are nonetheless widely accepted.1–3 A unique complication of both types B and C fulminant hepatitis that can occur with either spontaneous recovery from the hepatitis or transplantation and that limits long-term survival is marrow aplasia involving one or more of the stem-cell lines present within the marrow.21
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Worldwide, chronic viral hepatitis leading to decompensated cirrhosis is due either to type B or C hepatitis and is the single most frequent indication for liver transplantation. As was the case with alcoholic liver disease, most of the patients with chronic type B hepatitis who are considered for liver transplantation are in their mid-40s and should therefore have the potential for a long life following successful liver transplantation.20–22 The major impediment to achieving this goal of a long life following successful transplantation for type B hepatitis (and probably also for type C hepatitis) has been the high rate of disease recurrence, reported to be almost 100% for those with type B hepatitis and as high as 10% to 25% for those with type C hepatitis. Preliminary data suggest that the long-term survival of transplant recipients with chronic viral hepatitis may approach that in patients with other chronic hepatocellular diseases with the use of alpha-interferon23 and possibly with repeated administrations of either hepatitis B immune globulin (HBIG) or one or another of the monoclonal antibodies raised against the HBsAg. These agents have an activity many orders of magnitude greater than that present in commercial lots of HBIG.20,24–26 Even without such therapies, a 50% to 60% survival rate to 5 years can be expected, despite disease recurrence with liver transplantation for chronic viral hepatitis. Thus, it would appear that sufficient numbers of patients survive and return to a normal, active life to justify the continued performance of the procedure.27,28 With an additional 5 or more years of life, those who become reinfected may live until an effective antiviral agent can be discovered and therefore be made available to treat them without the need for retransplantation. The results with such retransplantations, however, have been less satisfactory than those obtained with first grafts for chronic hepatitis.20 Based upon the above data, it would appear that substantial numbers of patients could benefit from liver transplantation for either acute or chronic liver disease. The survival rate of such patients may be lower than that achieved for other diseases but is sufficiently great to justify transplantation. Moreover, the quality of life of transplant survivors who were transplanted for viral hepatitis is dramatically improved and appears not to be significantly different from that of the normal population.
HEPATIC MALIGNANCY Hepatocellular carcinoma (Table 4) is an uncommon, but not rare, form of cancer with an annual estimated incidence of 13,600 cases within the United States.29 When considering this figure, one has to recognize that the United States is a low-incidence area, and more Transplant Proc. Author manuscript; available in PMC 2011 December 2.
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populous countries such as China, South Africa, and others have an incidence that exceeds 20 cases per 100,000 population, making it one of the more frequent types of cancer worldwide. The major etiologic factor for hepatic cancer is HBV infection, especially early onset or infant/childhood disease that occurs as a consequence of vertical transmission from mother to child. Hepatoma is also a rather common, untoward consequence of chronic liver disease, particularly cirrhosis and a number of heritable metabolic liver diseases.
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The optimal therapy for hepatocellular carcinoma is partial or subtotal hepatectomy. Unfortunately, these procedures can only be accomplished in individuals with normal residual livers and typically those with single tumors involving a single hepatic lobe.30,31 Even in the best of hands, such surgery carries an operative mortality that ranges from 5% to 30%.32 These figures have to be counterbalanced by the fact that fewer than 50% of the cases explored without intent to transplant are resectable, and that fewer than 20% of the cases explored have their tumors fully resected.33 Obviously the only hope for those with large tumors involving more than one lobe of the liver, those that are located centrally near the porta, those that occur in cirrhosis, and those that, until recently, have been treated with incomplete tumor removal, is a total hepatectomy with liver transplantation. Figure 1 shows the actuarial survival after liver transplantation for hepatitis B carriers with and without liver cell cancer compared to that of over 1000 individuals transplanted for other causes. It is true, as noted earlier, that patients who are HBsAg-positive at the time of transplantation have a survival rate that is reduced by approximately 20% from 2 to 5 years after transplantation as compared with all other recipients. It can also be seen from this figure that those who have a hepatoma and are HBsAg-positive at the time of transplantation have a 20% reduction in long-term survival from 3 to 5 years following transplantation. Thus, the presence of a hepatoma clearly reduces the long-term prognosis. This is not to say that the situation is hopeless. When looked at another way, these same data are quite hopeful. After 3 years, it seems that 30% of the patients transplanted for hepatocellular carcinoma are cured of their disease. These cases represent cures in individuals who could not be treated with a smaller resection, who are HBsAg-positive, and who had no hope of survival with current modes of chemotherapy, with or without adjuvant chemotherapy.34
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It should be noted further that transplant recipients who have an incidental tumor, that is, one whose largest diameter is less than 5 cm and typically is encapsulated and shows no evidence for vascular invasion upon histologic examination of the resected specimen, can be cured with a 90% survival rate at 3 years or more after transplantation. As expected, the removal of such cases from the larger group of all cases transplanted for hepatocellular carcinoma reduces the rate of success achieved in the remaining cases. The data available from Europe appear to corroborate the data available from Pittsburgh concerning these issues.8,35 The reported experience with fibrolamellar carcinoma36–38 and epithelial hemangioendothelioma39–41 is somewhat better than that observed with other types of hepatic cancer. Conversely, the prognosis with cholangiolar carcinoma has been considerably worse.5,9,42 The improvements that may occur with the addition of adjuvant chemotherapy, immunotherapy, and an aggressive attack upon micrometastasis identified during the anhepatic phase of the procedure using radiolabelled monoclonal antibodies directed at oncofetal hepatocyte surface antigens remain to be determined, but they are expected to improve current results.
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Thus, the fact that (1) transplantation can cure as many as 25% to 30% of patients that would otherwise die without transplantation; that (2) disease-free intervals of 2 to 3 years can be achieved, providing those destined to experience disease recurrence an extension of high-quality life; and that (3) no competitive medical or radiotherapy options currently exist, suggest rather strongly that liver transplantation ought to be and will continue to be offered to individuals with hepatocellular carcinoma. The data also suggest that as techniques for cancer surveillance such as quarterly alpha-fetoprotein and descarboxyprothrombin and semiannual ultrasound examinations become routine, more hepatic cancers will be identified while they are “incidental” lesions, when the prognosis with liver transplantation is markedly improved. As a result, the overall prognosis of individuals transplanted for hepatic cancer should improve remarkably.
SUMMARY
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In closing, it is important to note that the indications for liver transplantation are not static but rather are remarkably dynamic and capable of change over time. Thus yesterday's major indications can become relative contraindications, while yesterday's absolute contraindications have become today's nuisances. The goal for physicians who care for individuals with problems such as alcoholic liver disease, viral hepatitis, and hepatic cancer should be to develop new strategies of care that will ultimately eliminate these diseases as problems, rather than eliminating individuals with such health problems from currently available health options. In other words, physicians who accept the responsibility for a patient's life should be searching for the best form of therapy available for their patient rather than examining the reasons that exist for limiting one's choice in health care.
Acknowledgments This work was supported in part by grants from NIDDKD 32556 and NIAAA AA06601.
REFERENCES
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1. Starzl TE, Demetris AJ, Van Thiel DH. N Engl J Med. 1989; 321:1014. [PubMed: 2674716] 2. Starzl TE, Demetris AJ, Van Thiel DH. N Engl J Med. 1989; 321:1092. [PubMed: 2677722] 3. Starzl TE, Iwatsuki S, Van Thiel DH, et al. Hepatology. 1982; 2:614. [PubMed: 6749635] 4. Markus BH, Dickson ER, Grambsch PM, et al. N Engl J Med. 1989; 320:1709. [PubMed: 2659986] 5. Marsh JW, Iwatsuki S, Makowka L, et al. Ann Surg. 1988; 207:21. [PubMed: 2827593] 6. Van Thiel DH, Gavaler JS, Tarter RE, et al. C1in Exp Res. 1989; 13:181. 7. Carithers, RL.; Yee, YS.; Mills, AS., et al. Current Hepatology. Gitnik, G., editor. Yearbook Medical Publishers; Chicago: 1990. p. 226 8. Pichlmayr R. Transplant Proc. 1988; 20:478. [PubMed: 2450417] 9. O'Grady JG, Polson RJ, Rolles K. Ann Surg. 1988; 207:373. [PubMed: 2451484] 10. Consensus Panel of the Consensus Development Conference on Liver Transplantation. NIH Consensus Development Statement—Liver Transplantation: Hepatology. 1984; 4(suppl 1):1075. 11. Maddrey, WC.; Friedman, LS.; Munoz, SJ.; Hahn, EG. Transplantation of the Liver. Maddrey, WC., editor. Elsevier Science Publishing; New York: 1988. p. 40 12. Kumar S, Stauber R, Basista M, et al. Hepatology. 1990; 11:159. [PubMed: 2307394] 13. Beresford TP, Turcotte JG, Merion R, et al. Psychosomatics. 1990; 31:241. [PubMed: 2095755] 14. Lucey, M.; Campbell, D.; Meriam, R., et al. Liver Transplantation for Alcoholic Patients. submitted for publication 15. Beresford TP, Blow FC, Wilson D, et al. Alcoholism Clin Exp Res. 1990; 14:271. 16. Sinclair SB, Greig PD, Bloundis LM, et al. J Clin Invest. 1989; 84:1063. [PubMed: 2794044] 17. Peleman RR, Gavaler JS, Van Thiel DH, et al. Hepatology. 1987; 7:484. [PubMed: 3552924]
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18. Fagan EA, Yousef G, Brahm J, et al. J Med Virol. 1990; 30:131. [PubMed: 2156006] 19. Demetris AJ, Jaffe R, Sheahan DG, et al. Am J Pathol. 1986; 125:161. [PubMed: 3535528] 20. Todo S, Demetris AJ, Van Thiel DH, et al. Hepatology. in press. 21. Tzakis AG, Arditi M, Whitington PF, et al. N Engl J Med. 1988; 319:393. [PubMed: 3135496] 22. O'Grady JG, Williams R. Br Med Bull. 1990; 46:481. [PubMed: 2116215] 23. Block GD, Hill P, Van Thiel DH. Gastroenterology. 1990; 98:A570. 24. Lauchart W, Muller R, Pichlmayr R. Transplant Proc. 1987; 19:2387. [PubMed: 2978894] 25. McMahon, G.; McCarthy, LA.; Dottabio, D.; Ostberg, I. Abstract presented at 1990 International Symposium on Viral Hepatitis and Liver Disease.; Houston, Texas. April 4–10, 1990; 26. Raimondo, G.; Stauber, M.; Will, H. Abstract presented at International Symposium on Viral Hepatitis and Liver Disease.; Houston, Texas. April 4–10, 1990; 27. Tarter, RE.; Erb, S.; Biller, PA., et al. Gastroenterology Clinics of North America. Makowka, L.; Van Thiel, DH., editors. WB Saunders; Philadelphia: 1988. p. 207 28. Tarter RE, Switala J, Arria A, et al. Transplantation. 1990; 50:632. [PubMed: 2219286] 29. Silverberg E. CA. 1986; 36:9. [PubMed: 3113694] 30. Iwatsuki S, Shaw BW Jr, Starzl TE. Ann Surg. 1982; 197:247. [PubMed: 6830332] 31. Iwatsuki, S.; Starzl, TE. Hepatobiliary and Pancreatic Malignancies: Diagnosis, Medical, and Surgical Management. Lygidakis, NJ.; Tytgat, GNJ., editors. Thieme Medical Publishers; New York: 1989. p. 191 32. Foster, JH.; Berman, MM. Solid Liver Tumors. WB Saunders; Philadelphia: 1977. p. 36 33. Van Thiel, DH.; Dindzans, V.; Gavaler, JS.; et al. Keppler, D.; Weber, G. Liver Cell Carcinoma. Bannasch, P., editor. Kluwer Academic Publishers; Boston: 1989. p. 499 34. Bassendine, MF. Clinical Gastroenterology. Williams, R.; Johnson, PF., editors. Blaidleve-Tindall; Philadelphia: 1989. p. 1 35. Bismuth H, Castains D, Ericzon BG, et al. Lancet. 1987; ii:674. [PubMed: 2887952] 36. Craig JR, Peters RC, Edmondson HA, Omata M. Cancer. 1980; 46:372. [PubMed: 6248194] 37. Berman MM, Libbey P, Foster JH. Cancer. 1980; 46:1148. 38. Starzl TE, Iwatsuki S, Shaw BW Jr, et al. Surg Gynecol Obstet. 1986; 162:145. [PubMed: 3003942] 39. Weiss JW, Enzinger FM. Cancer. 1982; 50:970. [PubMed: 7093931] 40. Weldon-Linne CM, Victor T, Christ MC, Fry WA. Arch Pathol Lab Med. 1981; 105:174. [PubMed: 6260056] 41. Ishak KG, Sesterleen IA, Goodman MZD, et al. Human Pathol. 1984; 15:839. [PubMed: 6088383] 42. Rolles K, Williams R, Newburger J, Calne R. Hepatology. 1984; 4(suppl):50S. [PubMed: 6363259]
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Fig 1.
Actuarial survival after liver transplantation for hepatitis B carriers and liver cancer compared to other indications.
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Table 1
Rationale for Transplantation for Alcoholic Liver Disease
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Need for the procedure
Disease prevalence
Age at time of transplantation
Potential for long-term survival
Survival
Equal to that of other types of chronic hepatocellular disease
Rehabilitation
Equal rate of return to work
Prognosis
Low rate of recidivism
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Table 2
Annual Incidence of Viral Hepatitis and Purported Need for Transplantation
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Disease Type
Cases per Year
Type A hepatitis Annual incidence
1,200,000
Fulminant cases
1,200
Type B hepatitis Annual incidence
300,000
Fulminant cases (0.1%) Chronic cases (5%)
300 15,000
Type C hepatitis Annual incidence
175,000
Fulminant cases (0.1%) Chronic cases (25–50%)
175 43,750
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Table 3
Indications for Liver Transplantation in Cases of Viral Hepatitis
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Type A hepatitis
Rare cases of fulminant hepatitis
Type B hepatitis
Fulminant and chronic liver disease Hepatoma
Type B+D hepatitis
Same as for type B Fulminant hepatitis is more likely
Type C hepatitis
Same as for types A and B
Other NANB hepatitis
Similar to type C
Unusual types (Herpes, CMV, EBV, adenovirus, and others)
Usually fulminant hepatitis in an immunocompromised host
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Table 4
Hepatobiliary Cancer
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Annual incidence: 13,600 cases (US) HBV is responsible for 80% of cases worldwide HBsAg-positive individuals have a 200- to 300-fold increased risk Age at time of infection determines carrier risk ≥85% if ≤10 years ≤10% if ≥20 years
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Published in final edited form as: Transplant Proc. 1991 June ; 23(3): 1917–1921.
Liver Transplantation for Alcoholic Liver Disease, Viral Hepatitis, and Hepatic Neoplasms D.H. Van Thiel, B. Carr, S. Iwatsuki, A. Tzakis, J.J. Fung, and T.E. Starzl Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. LIVER transplantation has emerged as a result of years of surgical development and steady improvements in immunosuppression as the major therapeutic intervention for individuals with chronic, advanced liver disease, a variety of metabolic liver diseases, and fulminant hepatic failure.1–3 Despite its demonstrated success as a lifesaving procedure for individuals with advanced liver disease, liver transplantation remains a controversial issue when it is considered for individuals with certain diseases.1–5
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Three of the more controversial disease conditions for which liver transplantation has been performed are alcoholic liver disease, neoplastic disease of the liver, and the viral hepatitides.6–9 Each of these potential disease indications for liver transplantation is considered controversial by some, but not all, transplant programs for one or another of the following overt reasons: (l) there is a high rate of disease recurrence for each of these specific disease indications; (2) the use of valuable donor organs by individuals with these diseases reduces the number of donor organs available for use in individuals with other diseases who are waiting for transplants and who are thought to be more likely to experience a long-term benefit as a result of the transplant procedure; and (3) because of the high cost of liver transplantation, the benefit accrued as a result of transplantation application ought to be substantial also. There are many less overt (or possibly more appropriately identified as covert) reasons why some individuals and programs deny liver transplantation to patients with one of these diseases. Most of these reasons involve issues of societal acceptance of organ transplantation as a lifesaving therapy, the availability and successful recruitment of adequate numbers of organ donors, and the subjective “worthiness” of a given individual as opposed to another.
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It is the goal of this article to demonstrate a rationale for the utilization of liver transplantation for patients with advanced alcoholic liver disease, hepatic neoplasms, and viral hepatitis based on current experience for each of these specific disease indications.
ALCOHOLIC LIVER DISEASE Alcohol-induced cirrhosis and alcoholic hepatitis are two of the most common forms of fatal liver disease seen in the United States,10 with prevalence of 9 million and death rate of 450,000. Moreover, alcoholic liver disease is the most common form of liver disease in the United States and other Western countries and exceeds the next most prevalent liver disease in number of cases by at least a factor of 4 or 5.11 Thus, based simply on the need for the procedure, it appears obvious that liver transplantation should be available for at least some individuals with irreversible, advanced alcoholic liver disease for whom no other therapy currently exists and for whom, if liver transplantation is not made available, death in the immediate future is inevitable (Table 1). © 1991 by Appleton & Lange Address reprint requests to Dr D.H. Van Thiel, 3601 Fifth Avenue, Falk Clinic 5C, Pittsburgh, PA 15213..
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The mean age of chronic alcoholics who have been transplanted at the University of Pittsburgh has been 48.2 ± 8.7 years with a range of 21 to 70 years.12 Based on these data, it can be expected that, should the alcoholic individual survive the initial vicissitudes of the transplant experience, a long life is at least potentially possible. This potential for long-term survival appears to have been supported by the available data that show that the long-term survival of patients with alcoholic liver disease followed by liver transplantation is no different from that of individuals transplanted for various nonalcoholic chronic hepatocellular liver diseases when matched for age, gender, site, and time of transplantation, as well as estimated need for the procedure using the UNOS scoring system and Child'sPugh c1assification.12 Thus, transplantation has the potential to substantially improve the longevity of those who survive the procedure. As might be expected, the majority of alcoholics who have been transplanted have been male, with women making up only 21% of the total cases. As a result of being the principal wage earners for their families, the majority of male transplant recipients transplanted for alcoholic liver disease have returned to work, with 53% of them working full-time or parttime outside the home12 and an additional 21% working full-time at home. Thus, a total of 74% of the survivors of liver transplantation for alcoholic liver disease are able to work and contribute to society as a result of having had the transplant procedure.
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Probably the most surprising statistic concerning liver transplantation for alcoholic liver disease is the finding that 89.5% of the transplant survivors have remained alcoholabstinent.12 Of those that have resumed drinking, the majority drink only moderately (three or fewer drinks per week) as determined by self-report and corroborated by their significant other and their primary-care physicians. This alcohol abstinence following successful liver transplantation appears to be the rule rather than the exception if appropriate selection criteria are utilized for the selection of such individuals for transplantation. The factors that appear to identify those alcoholics most likely to benefit and remain abstinent after successful liver transplantation are (1) the support of a significant other, be it a spouse, friend, or relative; (2) an acceptance of alcohol as the cause for their prior liver disease; (3) active involvement in and completion of a 4- to 6-week alcohol treatment program and abstinence for 3 to 6 months prior to transplantation; and (4) an existing job or an adequate education that allows for subsequent employment and, consequently, a redirection of interests away from those associated with alcohol use toward other forms of recreation or interest.13–15
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Based on the above experience with liver transplantation for alcoholic liver disease, it would appear that the need for transplantation exists for this group. A high survival rate is possible accompanied by a high rate of subsequent employment and a surprisingly low rate of alcohol abuse recidivism. These facts would appear to justify the continued application of liver transplantation for individuals with advanced alcoholic liver disease who, without such therapy, would either die or become invalids because of their disease.
VIRAL LIVER DISEASE Liver transplantation is a therapeutic option for patients with either fulminant hepatic failure or end-stage liver disease (cirrhosis) occurring with or without hepatocellular cancer due to viral hepatitis (Tables 2 and 3). As was the case for alcoholic liver disease, the prevalence of viral liver disease is substantial, and the need for some type of therapy, be it medical or surgical, is obvious (Table 1). To date, with the exception of the controversial use of prostaglandins in patients with fulminant hepatic failure, no specific medical therapy exists, and liver transplantation is the Transplant Proc. Author manuscript; available in PMC 2011 December 2.
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only realistic therapeutic option currently available.16 Compared with historical controls, liver transplantation for individuals with fulminant hepatic failure increases the survival rate 11-fold. When compared to individuals given maximal medical therapy with intent to transplant, liver transplantation increases the chance for survival threefold.17 Fulminant hepatitis attributable to type A or B hepatitis typically occurs at the two extremes of life. Specifically, in children it occurs in those under 10 years of age, and in adults it typically occurs in those older than 50. As a result, the potential for a long life following recovery from these two types of fulminant hepatitis is only limited by the older age of about half the total cases (the adults older than 50 years of age). Moreover, recurrent disease can occur following liver transplantation for fulminant hepatitis due to the A, B, or C viruses.18–20 The data currently available relative to the issue of disease recurrence following fulminant type C hepatitis as opposed to types A and B have only been clinical, but they are nonetheless widely accepted.1–3 A unique complication of both types B and C fulminant hepatitis that can occur with either spontaneous recovery from the hepatitis or transplantation and that limits long-term survival is marrow aplasia involving one or more of the stem-cell lines present within the marrow.21
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Worldwide, chronic viral hepatitis leading to decompensated cirrhosis is due either to type B or C hepatitis and is the single most frequent indication for liver transplantation. As was the case with alcoholic liver disease, most of the patients with chronic type B hepatitis who are considered for liver transplantation are in their mid-40s and should therefore have the potential for a long life following successful liver transplantation.20–22 The major impediment to achieving this goal of a long life following successful transplantation for type B hepatitis (and probably also for type C hepatitis) has been the high rate of disease recurrence, reported to be almost 100% for those with type B hepatitis and as high as 10% to 25% for those with type C hepatitis. Preliminary data suggest that the long-term survival of transplant recipients with chronic viral hepatitis may approach that in patients with other chronic hepatocellular diseases with the use of alpha-interferon23 and possibly with repeated administrations of either hepatitis B immune globulin (HBIG) or one or another of the monoclonal antibodies raised against the HBsAg. These agents have an activity many orders of magnitude greater than that present in commercial lots of HBIG.20,24–26 Even without such therapies, a 50% to 60% survival rate to 5 years can be expected, despite disease recurrence with liver transplantation for chronic viral hepatitis. Thus, it would appear that sufficient numbers of patients survive and return to a normal, active life to justify the continued performance of the procedure.27,28 With an additional 5 or more years of life, those who become reinfected may live until an effective antiviral agent can be discovered and therefore be made available to treat them without the need for retransplantation. The results with such retransplantations, however, have been less satisfactory than those obtained with first grafts for chronic hepatitis.20 Based upon the above data, it would appear that substantial numbers of patients could benefit from liver transplantation for either acute or chronic liver disease. The survival rate of such patients may be lower than that achieved for other diseases but is sufficiently great to justify transplantation. Moreover, the quality of life of transplant survivors who were transplanted for viral hepatitis is dramatically improved and appears not to be significantly different from that of the normal population.
HEPATIC MALIGNANCY Hepatocellular carcinoma (Table 4) is an uncommon, but not rare, form of cancer with an annual estimated incidence of 13,600 cases within the United States.29 When considering this figure, one has to recognize that the United States is a low-incidence area, and more Transplant Proc. Author manuscript; available in PMC 2011 December 2.
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populous countries such as China, South Africa, and others have an incidence that exceeds 20 cases per 100,000 population, making it one of the more frequent types of cancer worldwide. The major etiologic factor for hepatic cancer is HBV infection, especially early onset or infant/childhood disease that occurs as a consequence of vertical transmission from mother to child. Hepatoma is also a rather common, untoward consequence of chronic liver disease, particularly cirrhosis and a number of heritable metabolic liver diseases.
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The optimal therapy for hepatocellular carcinoma is partial or subtotal hepatectomy. Unfortunately, these procedures can only be accomplished in individuals with normal residual livers and typically those with single tumors involving a single hepatic lobe.30,31 Even in the best of hands, such surgery carries an operative mortality that ranges from 5% to 30%.32 These figures have to be counterbalanced by the fact that fewer than 50% of the cases explored without intent to transplant are resectable, and that fewer than 20% of the cases explored have their tumors fully resected.33 Obviously the only hope for those with large tumors involving more than one lobe of the liver, those that are located centrally near the porta, those that occur in cirrhosis, and those that, until recently, have been treated with incomplete tumor removal, is a total hepatectomy with liver transplantation. Figure 1 shows the actuarial survival after liver transplantation for hepatitis B carriers with and without liver cell cancer compared to that of over 1000 individuals transplanted for other causes. It is true, as noted earlier, that patients who are HBsAg-positive at the time of transplantation have a survival rate that is reduced by approximately 20% from 2 to 5 years after transplantation as compared with all other recipients. It can also be seen from this figure that those who have a hepatoma and are HBsAg-positive at the time of transplantation have a 20% reduction in long-term survival from 3 to 5 years following transplantation. Thus, the presence of a hepatoma clearly reduces the long-term prognosis. This is not to say that the situation is hopeless. When looked at another way, these same data are quite hopeful. After 3 years, it seems that 30% of the patients transplanted for hepatocellular carcinoma are cured of their disease. These cases represent cures in individuals who could not be treated with a smaller resection, who are HBsAg-positive, and who had no hope of survival with current modes of chemotherapy, with or without adjuvant chemotherapy.34
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It should be noted further that transplant recipients who have an incidental tumor, that is, one whose largest diameter is less than 5 cm and typically is encapsulated and shows no evidence for vascular invasion upon histologic examination of the resected specimen, can be cured with a 90% survival rate at 3 years or more after transplantation. As expected, the removal of such cases from the larger group of all cases transplanted for hepatocellular carcinoma reduces the rate of success achieved in the remaining cases. The data available from Europe appear to corroborate the data available from Pittsburgh concerning these issues.8,35 The reported experience with fibrolamellar carcinoma36–38 and epithelial hemangioendothelioma39–41 is somewhat better than that observed with other types of hepatic cancer. Conversely, the prognosis with cholangiolar carcinoma has been considerably worse.5,9,42 The improvements that may occur with the addition of adjuvant chemotherapy, immunotherapy, and an aggressive attack upon micrometastasis identified during the anhepatic phase of the procedure using radiolabelled monoclonal antibodies directed at oncofetal hepatocyte surface antigens remain to be determined, but they are expected to improve current results.
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Thus, the fact that (1) transplantation can cure as many as 25% to 30% of patients that would otherwise die without transplantation; that (2) disease-free intervals of 2 to 3 years can be achieved, providing those destined to experience disease recurrence an extension of high-quality life; and that (3) no competitive medical or radiotherapy options currently exist, suggest rather strongly that liver transplantation ought to be and will continue to be offered to individuals with hepatocellular carcinoma. The data also suggest that as techniques for cancer surveillance such as quarterly alpha-fetoprotein and descarboxyprothrombin and semiannual ultrasound examinations become routine, more hepatic cancers will be identified while they are “incidental” lesions, when the prognosis with liver transplantation is markedly improved. As a result, the overall prognosis of individuals transplanted for hepatic cancer should improve remarkably.
SUMMARY
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In closing, it is important to note that the indications for liver transplantation are not static but rather are remarkably dynamic and capable of change over time. Thus yesterday's major indications can become relative contraindications, while yesterday's absolute contraindications have become today's nuisances. The goal for physicians who care for individuals with problems such as alcoholic liver disease, viral hepatitis, and hepatic cancer should be to develop new strategies of care that will ultimately eliminate these diseases as problems, rather than eliminating individuals with such health problems from currently available health options. In other words, physicians who accept the responsibility for a patient's life should be searching for the best form of therapy available for their patient rather than examining the reasons that exist for limiting one's choice in health care.
Acknowledgments This work was supported in part by grants from NIDDKD 32556 and NIAAA AA06601.
REFERENCES
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1. Starzl TE, Demetris AJ, Van Thiel DH. N Engl J Med. 1989; 321:1014. [PubMed: 2674716] 2. Starzl TE, Demetris AJ, Van Thiel DH. N Engl J Med. 1989; 321:1092. [PubMed: 2677722] 3. Starzl TE, Iwatsuki S, Van Thiel DH, et al. Hepatology. 1982; 2:614. [PubMed: 6749635] 4. Markus BH, Dickson ER, Grambsch PM, et al. N Engl J Med. 1989; 320:1709. [PubMed: 2659986] 5. Marsh JW, Iwatsuki S, Makowka L, et al. Ann Surg. 1988; 207:21. [PubMed: 2827593] 6. Van Thiel DH, Gavaler JS, Tarter RE, et al. C1in Exp Res. 1989; 13:181. 7. Carithers, RL.; Yee, YS.; Mills, AS., et al. Current Hepatology. Gitnik, G., editor. Yearbook Medical Publishers; Chicago: 1990. p. 226 8. Pichlmayr R. Transplant Proc. 1988; 20:478. [PubMed: 2450417] 9. O'Grady JG, Polson RJ, Rolles K. Ann Surg. 1988; 207:373. [PubMed: 2451484] 10. Consensus Panel of the Consensus Development Conference on Liver Transplantation. NIH Consensus Development Statement—Liver Transplantation: Hepatology. 1984; 4(suppl 1):1075. 11. Maddrey, WC.; Friedman, LS.; Munoz, SJ.; Hahn, EG. Transplantation of the Liver. Maddrey, WC., editor. Elsevier Science Publishing; New York: 1988. p. 40 12. Kumar S, Stauber R, Basista M, et al. Hepatology. 1990; 11:159. [PubMed: 2307394] 13. Beresford TP, Turcotte JG, Merion R, et al. Psychosomatics. 1990; 31:241. [PubMed: 2095755] 14. Lucey, M.; Campbell, D.; Meriam, R., et al. Liver Transplantation for Alcoholic Patients. submitted for publication 15. Beresford TP, Blow FC, Wilson D, et al. Alcoholism Clin Exp Res. 1990; 14:271. 16. Sinclair SB, Greig PD, Bloundis LM, et al. J Clin Invest. 1989; 84:1063. [PubMed: 2794044] 17. Peleman RR, Gavaler JS, Van Thiel DH, et al. Hepatology. 1987; 7:484. [PubMed: 3552924]
Transplant Proc. Author manuscript; available in PMC 2011 December 2.
Van Thiel et al.
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NIH-PA Author Manuscript NIH-PA Author Manuscript
18. Fagan EA, Yousef G, Brahm J, et al. J Med Virol. 1990; 30:131. [PubMed: 2156006] 19. Demetris AJ, Jaffe R, Sheahan DG, et al. Am J Pathol. 1986; 125:161. [PubMed: 3535528] 20. Todo S, Demetris AJ, Van Thiel DH, et al. Hepatology. in press. 21. Tzakis AG, Arditi M, Whitington PF, et al. N Engl J Med. 1988; 319:393. [PubMed: 3135496] 22. O'Grady JG, Williams R. Br Med Bull. 1990; 46:481. [PubMed: 2116215] 23. Block GD, Hill P, Van Thiel DH. Gastroenterology. 1990; 98:A570. 24. Lauchart W, Muller R, Pichlmayr R. Transplant Proc. 1987; 19:2387. [PubMed: 2978894] 25. McMahon, G.; McCarthy, LA.; Dottabio, D.; Ostberg, I. Abstract presented at 1990 International Symposium on Viral Hepatitis and Liver Disease.; Houston, Texas. April 4–10, 1990; 26. Raimondo, G.; Stauber, M.; Will, H. Abstract presented at International Symposium on Viral Hepatitis and Liver Disease.; Houston, Texas. April 4–10, 1990; 27. Tarter, RE.; Erb, S.; Biller, PA., et al. Gastroenterology Clinics of North America. Makowka, L.; Van Thiel, DH., editors. WB Saunders; Philadelphia: 1988. p. 207 28. Tarter RE, Switala J, Arria A, et al. Transplantation. 1990; 50:632. [PubMed: 2219286] 29. Silverberg E. CA. 1986; 36:9. [PubMed: 3113694] 30. Iwatsuki S, Shaw BW Jr, Starzl TE. Ann Surg. 1982; 197:247. [PubMed: 6830332] 31. Iwatsuki, S.; Starzl, TE. Hepatobiliary and Pancreatic Malignancies: Diagnosis, Medical, and Surgical Management. Lygidakis, NJ.; Tytgat, GNJ., editors. Thieme Medical Publishers; New York: 1989. p. 191 32. Foster, JH.; Berman, MM. Solid Liver Tumors. WB Saunders; Philadelphia: 1977. p. 36 33. Van Thiel, DH.; Dindzans, V.; Gavaler, JS.; et al. Keppler, D.; Weber, G. Liver Cell Carcinoma. Bannasch, P., editor. Kluwer Academic Publishers; Boston: 1989. p. 499 34. Bassendine, MF. Clinical Gastroenterology. Williams, R.; Johnson, PF., editors. Blaidleve-Tindall; Philadelphia: 1989. p. 1 35. Bismuth H, Castains D, Ericzon BG, et al. Lancet. 1987; ii:674. [PubMed: 2887952] 36. Craig JR, Peters RC, Edmondson HA, Omata M. Cancer. 1980; 46:372. [PubMed: 6248194] 37. Berman MM, Libbey P, Foster JH. Cancer. 1980; 46:1148. 38. Starzl TE, Iwatsuki S, Shaw BW Jr, et al. Surg Gynecol Obstet. 1986; 162:145. [PubMed: 3003942] 39. Weiss JW, Enzinger FM. Cancer. 1982; 50:970. [PubMed: 7093931] 40. Weldon-Linne CM, Victor T, Christ MC, Fry WA. Arch Pathol Lab Med. 1981; 105:174. [PubMed: 6260056] 41. Ishak KG, Sesterleen IA, Goodman MZD, et al. Human Pathol. 1984; 15:839. [PubMed: 6088383] 42. Rolles K, Williams R, Newburger J, Calne R. Hepatology. 1984; 4(suppl):50S. [PubMed: 6363259]
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Fig 1.
Actuarial survival after liver transplantation for hepatitis B carriers and liver cancer compared to other indications.
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Table 1
Rationale for Transplantation for Alcoholic Liver Disease
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Need for the procedure
Disease prevalence
Age at time of transplantation
Potential for long-term survival
Survival
Equal to that of other types of chronic hepatocellular disease
Rehabilitation
Equal rate of return to work
Prognosis
Low rate of recidivism
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Table 2
Annual Incidence of Viral Hepatitis and Purported Need for Transplantation
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Disease Type
Cases per Year
Type A hepatitis Annual incidence
1,200,000
Fulminant cases
1,200
Type B hepatitis Annual incidence
300,000
Fulminant cases (0.1%) Chronic cases (5%)
300 15,000
Type C hepatitis Annual incidence
175,000
Fulminant cases (0.1%) Chronic cases (25–50%)
175 43,750
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Table 3
Indications for Liver Transplantation in Cases of Viral Hepatitis
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Type A hepatitis
Rare cases of fulminant hepatitis
Type B hepatitis
Fulminant and chronic liver disease Hepatoma
Type B+D hepatitis
Same as for type B Fulminant hepatitis is more likely
Type C hepatitis
Same as for types A and B
Other NANB hepatitis
Similar to type C
Unusual types (Herpes, CMV, EBV, adenovirus, and others)
Usually fulminant hepatitis in an immunocompromised host
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Table 4
Hepatobiliary Cancer
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Annual incidence: 13,600 cases (US) HBV is responsible for 80% of cases worldwide HBsAg-positive individuals have a 200- to 300-fold increased risk Age at time of infection determines carrier risk ≥85% if ≤10 years ≤10% if ≥20 years
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