Case 5 -

Recurrent Disease after Liver Transplantation Arthur H. Cohen, Juan Lechago and Cynthia C. Nast

Click on the PowerPoint icon to display the lecture for this case. During the presentation, click the main presentation window once, then use the space bar to advance the slides sequentially.

The histologic parameters of this biopsy of Case #5 are entirely consistent with recurrent chronic hepatitis C. The portal infiltrate can also be found in acute cellular rejection, but it lacks the mixed character that is typical of the rejection mechanism. The lack of significant bile duct damage and endotheliitis, on the other hand, fails to support the existence of a significant rejection component. Recurrence of primary disease following liver transplantation is a growing field since, as a result of significant improvements in both surgical technology and anti-rejection regimes, patient survival has improved very significantly in the last few years. Obviously, the frequency of recurrent disease varies with the nature of the primary disease of the recipient. However, detection of such recurrent disease is often related to the presence of specific markers or histologic features and, in the absence of such specificity, complex differential diagnosis situations may arise. Hepatitis B or C? It is currently accepted that both hepatitis B and C invariably recur in the donor liver as soon as this is perfused with the recipient's blood. In the case of hepatitis B, the appearance of both core and surface antigens in hepatocytes is generally accompanied bythe development of acute hepatitis B, followed by chronic hepatitis and, ultimately, cirrhosis. This process may be slow in some cases and take an accelerated pace in others, sometimes complicated by hepatocellular carcinoma. A relatively rare and rapidly progressing form of liver dysfunction after transplantation for hepatitis B has been described. This entity, which appears 3 to 12 months after transplantation, has been termed fibrosing cholestatic hepatitis and courses with ballooning and ground glass change of the hepatocytes, marked cholestasis with canalicular and ductal bile plugs, and periportal fibrosis followed by septal fibrosis and cirrhosis. These generally unfavorable clinical courses have determined that many authors seriously question the role of liver transplantation in chronic hepatitis B. Hepatitis C, by contrast, has a much more protracted course and only about 50% of transplanted livers present histologic evidence of recurrent hepatitis C. End-stage liver disease associated with HCV infection is currently the most common indication for liver transplantation in adults. Whereas, in most instances hepatitis C and even cirrhosis develop eventually, this progression is comparatively slow, the degree of hepatitis C tends to be mild, and long survivals with good quality of life are increasingly achieved. In a recent study, it has been noted that HCV genotype 4 is associated with unfavorable outcomes more frequently whereas HCV genotype 3b portends a more favorable outcome. Whereas typical, full-blown histologic findings of acute rejection and chronic hepatitis C can be readily differentiated from each other, mild degrees of either, or coexistence of both, may present serious problems of differential diagnosis. These difficulties may be compounded by the fact that anti-rejection therapy may modify the early histopathological features of recurrent hepatitis C. Overt endotheliitis, specially of terminal hepatic veins, and widespread bile duct damage are indicative of acute rejection, as has been discussed. However, minor degrees of portal branch endotheliitis and moderate damage and distortion of bile ducts is also seen in chronic hepatitis C, whereupon the question of mild rejection may arise in some instances. Likewise, mixed portal infiltrates with eosinophils are commonly seen in allograft rejection, but can also be present in recurring hepatitis C. The main parameters of the differential diagnosis between acute rejection and recurrent hepatitis C are tabulated below: Differential Diagnosis: Acute Rejection vs. Recurrent HCV Findings Acute Rejection Recurrent Hcv Mixed portal inflammation, including eos & PMNs +/++ +/± Predominantly portal mononuclear cells + eos -/± +/++ Bile duct damage +/++ -/± Endotheliitis (pericentral) +/++ -/± Centrilobular hepatocyte necrosis & mononuclears ±/++ -/± Unusual histologic presentations in recurring hepatitis C include a rare form of fibrosing cholestatic hepatitis similar to that seen in hepatitis B, and a cholestatic variant, with hepatocellular necrosis, cholestasis, and bile ductular proliferation, but without widespread fibrosis. Both these entities also present differential diagnostic problems with bile duct obstruction, as well as chronic rejection with bile duct destruction. Autoimmune Hepatitis Liver transplantation for autoimmune hepatitis has been followed by recurrent disease in 30% to 40% of the cases 35 to 280 days after the transplant. High-grade inflammation in the native liver appears to be a strong predictor of recurrence. An interesting problem of differential diagnosis has been brought to light in the last few years, namely the appearance of de novo autoimmune hepatitis in the liver of patients transplanted for other etiologies. The first report of such occurrence deals with two adults transplanted because of primary biliary cirrhosis. However, further data have accrued on the appearance of autoimmune hepatitis in pediatric patients who were given orthotopic liver transplants for a variety of conditions and who did not have a previous history of autoimmune hepatitis. It is important to keep this possibility in mind and to look for the parameters of autoimmune hepatitis because, in pediatric patients, the hepatitis does not respond to the more commonly used tracrolimus or even cyclosporin and requires treatment with steroids and azathioprine. Cryptogenic Cirrhosis and NASH The so-called cryptogenic cirrhosis behaves variously after liver transplantation, probably reflecting a variety of etiologies. Approximately 20% of such cases of cryptogenic cirrhosis have been associated with autoimmune hepatitis. Interestingly, another 33% of such cryptogenic cirrhosis cases have been associated with non-alcoholic steatohepatitis (NASH) and have shown a 22% recurrence rate. Risk factors for recurrence are obesity, type2 diabetes mellitus and hyperlipidemia. Hepatocellular Carcinoma A subject of considerable controversy is the use of liver transplantation in cases of malignancy of the liver. The most common malignancy present at the time of transplantation tends to be hepatocellular carcinoma (HCC). In most cases, the existence of the neoplasm is known at the time of the operation, but in a few instances, a small HCC is found, somewhat "incidentally," in the explanted liver that had cirrhosis for another reason. With the exception of the fibrolamellar variant, which has a relatively favorable evolution, most HCCs that are large and known to be present recur soon after transplantation and cause the death of the patient between 3 and 36 months from the operation. A study carried out at the Mayo Clinic several years ago found that the best prognosis in terms of survival applies to patients with elevated alpha-fetoprotein (AFP) in circulation, but with no visible mass: 80% 2-year disease-free survival. By contrast, patients with incidental HCC at the time of operation presented 68% 2-year disease-free survival, and those with a visible mass lesion, the 2-year disease-free survival was only 50%. In patients with known HCC, it has been recently determined that non-resective ablation therapies are safe and effective means of reducing the progression of the neoplasm while awaiting transplantation. Other Examples of Primary Disease Recurrence Other examples of primary disease recurrence are primary biliary cirrhosis and primary sclerosing cholangitis. Because of their histopathological and temporal presentation, these entities will be discussed in Case #6. Recipient and Donor Factors in Graft Survival A number of parameters have been identified in an effort to predict the outcome of a liver transplantation which relate to both, recipient and donor. For example, a recipient who has end stage liver disease because of alcoholic liver disease poses an interesting ethical problem inasmuch as persistence of alcohol abuse will surely doom the precious transplanted organ. Whereas alcoholic liver disease is by itself an excellent indication for liver transplantation, recent studies reveal that the period of documented alcohol abstinence prior to the operation is very significant. Patients who were abstinent for less than 6 months had a recurrence rate of 65% accompanied by significant mortality. By contrast, when abstinence was for 6-12 months the recurrence rate was 11.8% and 2 year-plus abstinence resulted in a recurrence rate of 5.5%. Other factors related to the recipient that portend unfavorable outcomes, particularly when more than two such factors are present in the same patient, include Child classification of liver insufficiency, preoperative gastrointestinal bleeding, mechanical ventilation, hemodialysis, and requirement for catecholamines. All of these have been found to be significant in the rate of development of the so called multiple organ dysfunction syndrome (MODS), a quantitable parameter with prognostic value. The Model of End-Stage Liver Disease (MELD) score, an accurate predictor of survival in patients awaiting liver transplantation, has also been applied to the assessment of progression after transplantation. It has been found that the survival without bridging fibrosis in the allograft at one year post transplantation is significantly lower in patients with higher MELD scores. Regarding the donor, the status of the transplanted liver has proven to be significant in the development of the so-called primary non-function (PNF). After some debate, it seems reasonably established that, in the absence of active hepatitis or other obvious disqualifiers, the degree and type of steatosis is a highly reliable predictor for the occurrence of PNF. Interestingly, it has been determined that microvesicular steatosis by itself is of little significance, a fortunate fact since this is sometimes a feature very difficult to demonstrate using routine stains during an intraoperative consultation. Macrovesicular steatosis has proven to be a defining parameter: whereas low degrees of macrovesicular steatosis in the donor liver (up to an estimated 30% of hepatocytes involved) did not result in the development of PNF to a significant degree, moderate (30-60% involvement) and severe (over 60%) macrovesicular steatosis resulted in poor outcomes. Other factors, such as advanced age of the donor, length of time in intensive care prior to death, and others appear to have some influence, but have not been accurately assessed as independent predictors. References Ayata G, Gordon FD, Lewis WD, et al. Liver transplantation for autoimmune hepatitis: a long-term pathologic study. Hepatology 2000;32:185-192. Ayata G, Gordon FD, Lewis WD, et al. Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation. Hum Pathol 2002;33:1098-1104. Bellamy CO, DiMartini AM, Ruppert K, et al. Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence. Transplantation 2001;72:619-626. Czaja AG. Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance. Liver Transpl 2002;8:505-513. Demetris AJ, Jaffe R, Sheahan DG, et al. Recurrent hepatitis B in liver allograft recipients. Differentiation between viral hepatitis B and rejection. Am J Pathol 1986;125:161-172. Garcia RF, Morales E, Garcia CE, Saksena S, Hubscher SG, Elias E. Recurrent and de novo non-alcoholic steatohepatitis following orthoptic liver transplantation. Arq Gastroenterologia 2001;38:247-253. Gugenheim J, Baldini E, Mazza D, et al. Recurrence of hepatitis C virus after liver transplantation. Transplant Internat 1994;7(suppl 1):S224-226. Hernandez HM, Kovarik P, Whitington PF, Alonso EM. Autoimmune hepatitis as a late complication of liver transplantation. J Ped Gastroent Nutr 2001;32:131-136 Jones KD, Ferrell LD. Interpretation of biopsy findings in the transplant liver. Seminars in Diagnostic Pathology 1998;15:306-317. Maluf D, Fisher RA, Maroney T, et al. Non-resective ablation and liver transplantation in patients with cirrhosis and hepatocellular carcinoma (HCC): safety and efficacy. Am J Transplant 2003;3:312-317. Maor-Kendler Y, Batts KP, Burgart LJ, et al. Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alochol, hepatitis C, and cholestatic liver disease. Transplantation 2000;70:292-297. Negro F, Giostra E, Krawczynski K, et al. Detection of intrahepatic hepatitis C virus replication by strand-specific semi-quantitative RT-PCR: preliminary application to the liver transplantation model. J Hepatol 1998;29:1-11. O'Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease: results in 93 consecutive patients. Ann Surg 1988;207:373-379. Onaca NN, Levy MF, Netto GJ, et al. Pretransplant MELD score as a predictor of outcome after liver transplantation for chronic hepatitis C. Am J Transplant 2003;3:626-630. Ong J, Younossi ZM, Reddy V, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transplant 2001;7:797-801. Pelletier SJ, Iezzoni JC, Crabtree TD, Hahn YS, Sawyer RG, Pruett TL. Prediction of liver allograft fibrosis after transplantation for hepatitis C virus: persistent elevation of serum transaminase levels versus necroinflammatory activity. Liver Transplant 2000;6:44-53. Petrovic LM, Villamil FG, Vierling JM, Makowka L, Geller SA. Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation. Liver Transpl Surg 1997;3:398-406. Starzl TE, Demetris AJ, Van Thiel, D. Liver transplantation (part two). N Engl J Med 1989;321:1092-1099. Tan CK, Gores GJ, Steers JL, et al. Orthotopic liver transplantation for preoperative early-stage hepatocellular carcinoma. Mayo Clinic Proc 1994;69:509-514. Van Thiel DH, Gavaler JS. Recurrent disease in patients with liver transplantation: when does it occur and how can we be sure? Hepatology 1987;7:181-183. Vargas V, Comas P, Castells L, et al. Incidence and outcome of hepatitis C virus infection after liver transplantation. Transplant Internat 1994;7(suppl1):S216-220. Wong LL, Tanaka K, Lau K, Komura S. Pre-transplant treatment of hepatocellular carcinoma: assessment of tumor necrosis in explanted livers. Clin. Transplant. 2004;18:227-234. Zekry A, Whiting P, Crawford DH, et al. Liver transplantation of HCV-associated liver cirrhosis: predictors of outcomes in a population with significant genotype 3 and 4 distribution. Liver Transplantation 2003;9:339-347.