Rapidly Progressive Recurrent Hepatitis C Virus Infection Starting 9 Days After Liver Transplantation

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1 LIVER TRANSPLANTATION 13: , 2007 SHORT REPORT Rapidly Progressive Recurrent Hepatitis C Virus Infection Starting 9 Days After Liver Transplantation Neeraj Saraf, 1 M. Isabel Fiel, 2 Graciela DeBoccardo, 3 Sukru Emre, 3 and Thomas D. Schiano 1,3 1 Mount Sinai Medical Center Division of Liver Diseases, 2 Lillian and Henry M. Stratton-Hans Popper Department of Pathology, and 3 Recanati-Miller Transplantation Institute, New York, NY Early histological recurrence of hepatitis C after liver transplantation (LT) has a negative impact on patient and graft survival. We report a case of histological recurrence of HCV occurring in the second week after LT. A 75-year-old woman with chronic HCV and hepatocellular carcinoma underwent LT with an organ from a 75-year-old HCV-negative deceased donor. After an uneventful early postoperative period, an increase in the transaminases was observed, and on postoperative day 9 day, the alanine aminotransferase (ALT) was 673 IU/mL and aspartate aminotransferase (AST) 300 IU/mL, with normal alkaline phosphatase and bilirubin. Analysis of liver biopsy samples showed diffuse necroinflammatory changes with acidophilic bodies and concomitant mild acute cellular rejection. Subsequently there was a further increase in the transaminases, and on postoperative day 13, the AST rose to 445 IU/mL and ALT to 992 IU/mL. Repeat biopsy was performed, and analysis of the samples revealed lymphocytic portal inflammation with lymphoid aggregates and mild interface hepatitis, parenchymal necrosis, activation of sinusoidal lining cells, and mild steatosis. The biopsy sample was characteristic for HCV recurrence. The HCV RNA level was 84,000,000 copies/ml, and markers for other viral causes were not present. The patient became jaundiced and her course progressively worsened. She died on day 87 after transplantation. To our knowledge, this is the earliest reported case of histological recurrence of HCV after LT. It illustrates the importance of older donor and recipient age in the same patient as cofactors for early HCV recurrence and poor outcome. Liver Transpl 13: , AASLD. Received September 1, 2006; accepted March 16, Chronic hepatitis C virus (HCV) is the most common indication for liver transplantation (LT) in western countries; recurrence of infection is universal. 1,2 Recurrent HCV may follow an aggressive course, leading to cirrhosis and graft failure in a high proportion of patients as early as a few months after LT. 1-3 Many factors related to the host, donor, virus, and immunosuppression used influence the natural history of recurrent HCV. 4-7 Among them, donor age strongly affects post-lt HCV disease progression. 8 Earlier histological recurrence appears to portend decreased patient and graft survival due to recurrent HCV. 9,10 Although HCV virus levels may be extremely high just after the anhepatic phase, early histological recurrence does not typically occur during the first several months after surgery, even when protocol liver biopsies are performed to survey this Guerrero et al. 14 were able to detect HCV RNA by reverse transcriptase polymerase chain reaction as early as 5 days after LT, although they found no relation to histologic recurrence. Herein, we describe a case of rapid histological recurrence of HCV occurring at week 2 after LT, possibly related to the advanced age of both the donor and recipient. CASE REPORT A 75-year-old African-American woman with cirrhosis and hepatocellular carcinoma related to chronic HCV infection underwent LT on November 19, Before LT, the patient had a viral load of 257,000 copies/ml Abbreviations: HCV, hepatitis C virus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LT, liver transplantation; ACR, acute cellular rejection; ALP, alkaline phosphatase. Address reprint requests to Thomas D. Schiano, MD, Mount Sinai Medical Center, Division of Liver Diseases, Box 1104, One Gustave L. Levy Place, New York, NY Telephone: ; FAX: ; Thomas.Schiano@mountsinai.org DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 914 SARAF ET AL. Figure 1. Liver needle biopsy showing a portal tract containing mild inflammatory infiltration of mixed type including eosinophils, as well as mild bile duct damage (arrow). The surrounding parenchyma shows foci of lobular inflammation with rare acidophilic bodies (arrowheads). These findings are consistent with mild acute cellular rejection and concomitant mild hepatitis (H&E, original magnification 200 ). and was genotype 2a/2c; she had refused treatment with interferon. The hepatic synthetic function was well preserved, other hematological and renal parameters were in the normal range, and human immunodeficiency virus serology was negative. There was no other comorbid illness. The donor was a 75-year-old woman who had died from a stroke. All donor viral serologies, including HCV antibody, were negative. The warm ischemic time was 30 minutes; the cold ischemic time was 10 hours. The intraoperative transfusion requirement was 3 U of packed red blood cells and 3 U of fresh frozen plasma. The duration of surgery was 5 hours. The preperfusion liver biopsy findings were remarkable only for mild lipofuscinosis and pleomorphism of hepatocyte nuclei, with no evidence of steatosis, iron deposition, or any other form of liver injury. The postperfusion liver biopsy samples showed no evidence of ischemia-reperfusion injury. The surgery and the immediate postoperative period were uneventful. The patient received a standard immunosuppression protocol with daclizumab on days 1 and 4, along with a corticosteroid taper and tacrolimus (initiated on post-lt day 4). An abrupt increase in the aminotransferases was observed on day 9 after surgery, with ALT 673 U/L and AST 300 U/L; alkaline phosphatase (ALP) and bilirubin were normal. Doppler ultrasound revealed normal bile ducts and hepatic artery blood flow. A liver biopsy was performed to rule out acute cellular rejection (ACR), and analysis of biopsy samples showed mild mixed portal inflammation with eosinophils, foci of necroinflammation including acidophilic bodies, and patchy endotheliitis (Fig. 1). The changes were consistent with mild acute hepatitis and concomitant mild ACR. The patient did not receive parenteral corticosteroids but only had her tacrolimus dose increased from 2 mg twice a day to 2.5 mg twice a day to maintain a therapeutic trough level of 15.0 ng/ml. Subsequently, there was a further increase in the transaminases to AST 445 U/L and ALT 992 U/L. A repeat liver biopsy was performed on postoperative day 13, and analysis of samples revealed lymphocytic portal inflammation with prominent large lymphoid aggregates with marked interface hepatitis. Many foci of parenchymal necrosis with acidophilic bodies, activation of sinusoidal lining cells, and mild steatosis were seen (Fig. 2). No portal vein endotheliitis or central venulitis was present that indicated concomitant ACR; therefore, the histology strongly indicated recurrent HCV. 15 In view of the striking histological findings, 2 experienced liver pathologists reviewed the biopsy findings independently and agreed on the histological diagnosis. The HCV RNA level was 84,000,000 copies/ml, and serologies for other viral etiologies, including cytomegalovirus, Epstein-Barr virus, and acute hepatitis A and hepatitis B, were negative. Anti-HCV therapy was planned once the patient became clinically stable. However, after LT, her liver function continued to worsen (ALT 772 U/L, AST 732 U/L, ALP 235 U/L, bilirubin 16.5 mg/ dl). White blood cell counts and blood cultures were normal, with no evidence of sepsis. HCV RNA was 41,000,000 copies/ml. The patient s laboratory profile is summarized in Table 1. Liver biopsy was repeated on day 36 after LT and revealed marginal proliferation of bile ductules accompanied by neutrophils. The lobules showed marked cholestasis with feathery degeneration of hepatocytes, numerous acidophilic bodies, and fibrosis of portal tracts with fibrous septa. Portal lymphocytic infiltration with dense lymphoid aggregates was present. The biopsy was consistent with the cholestatic variant of recurrent HCV with fibrosis progression that demonstrated portal fibrosis with fibrous septa extensions (consistent with stage 2 out of 4 fibrosis of the Ludwig and Batts staging system) 16 (Fig. 3). Endoscopic retrograde cholangiopancreatography revealed a redundant Figure 2. Liver needle biopsy showing representative portal tract with dense lymphoid aggregate (long arrow) and marked interface hepatitis (short arrows), findings highly suggestive of hepatitis C infection. There is no evidence of acute cellular rejection (H&E, original magnification 400 ).

3 RAPID HCV RECURRENCE AFTER LT 915 TABLE 1. Laboratory Profile Detailing Recurrence of the Patient s HCV Days after LT ALT (IU/mL) AST (IU/mL) ALP (U/L) Total bilirubin (mg/dl) HCV viral load (million copies/ml) Not determined Abbreviations: LT, liver transplantation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase. biliary tree with a common bile duct of 10 mm and mild intrahepatic ductal dilatation. A precautionary biliary stent was placed. However, it did not result in improvement of liver function. The dose of prednisone was decreased by 5 mg a month. The patient continued to deteriorate clinically, and her liver function continued to worsen. She died on day 87 after LT, unable to receive anti-hcv therapy because of her debilitated condition. DISCUSSION Three patterns of HCV recurrence after LT have been described with different clinical presentations, pathogeneses, and prognoses. 1-8 Acute hepatitis is characterized by lobular infiltrates, varying degrees of hepatocyte necrosis, and fatty infiltration similar to the nontransplanted HCV patient. The aminotransferases are mildly to moderately increased with some degree of hyperbilirubinemia. The most common form of recurrence evolves over time to a chronic hepatitis with many portal and lobular infiltrates, hepatocyte necrosis, and portal bridging fibrosis. Disease progression in this setting is accelerated compared with the nontransplant chronic HCV. 1-8 Accelerated fibrosis in the HCV allograft leads to the development of graft cirrhosis in 25% of recipients (range, 8-44%) within 5 years. 1-8,10 Cholestatic hepatitis is an infrequent form of HCV recurrence that leads to graft failure in up to 50% of patients within a few months to years of onset. 1-4 It is characterized by hyperbilirubinemia in the absence of bile duct or vascular complications, very high serum and intrahepatic HCV RNA levels, and high ALP and gamma glutamyl transferase. Histologically, there is presence of severe hepatocyte ballooning, intrahepatic cholestasis, pericellular and portal fibrosis, ductular proliferation, and minimal inflammation. 4 This injury often occurs with high levels of immunosuppression and is believed to represent an alternative response to the usual acute hepatitis. A cytopathic mechanism of allograft damage is thought to be involved given the concurrence of high viral loads, lack of specific HCV immune response, and increased Th2 cytokine expression rather than Th1 response. 4 The case we describe herein represents an unusual and rapid form of recurrent HCV, given the high transaminases, minimally increased ALP and gamma glutamyl transferase levels, and classical portal lymphoid aggregates found on analysis of liver biopsy samples. The patient did not receive long-term, aggressive immunosuppression, and she did not have any prior episodes of ACR that required therapy with corticosteroids. Various studies have evaluated the median time to histological recurrence. Ghobrial et al., 9 in a 10-year experience calculated the median time to histological recurrence as 34 months, and in another study, chronic hepatitis with portal lymphoid aggregates was observed an average of 356 days after LT (range, 89-1,365 days). 10 One of the most rapid onsets of histological recurrence of HCV was described by Takeishi et al., 17 in which a patient developed histological recurrence 69 days after a living related LT. Time to histological recurrence may predict long-term progression of allograft hepatitis, and early recurrence is associated with poor patient and graft survival rates. The use of older donors is clearly associated with more severe HCV recurrence This is difficult to avoid, however, because of the shortage of organ donors. Typically, HCV recurrence is not considered in the differential diagnosis of graft dysfunction in the first month after LT, but this may not always hold true, as this report implies. Many factors may potentially contribute to disease progression in HCV-infected patients after LT. Viral factors like high pre-lt HCV RNA levels and genotype 1b may affect the post-lt progression of HCV, 1-4 but none of these factors was present in the current case. Early post-lt viral load has been shown to influence late post-lt outcome. This patient had a more favorable genotype, so it is unlikely that either pre-lt virus load or the genotype contributed to the rapid recurrence, and there was no evidence that the donor had HCV. Corticosteroid treatment for ACR is associated with marked increases in viremia. 1-4,22,23 The role of most other immunosuppressive agents is controversial at present, although basiliximab and muromonab (OKT3) and alemtuzumab have been shown to increase HCV viremia and to be associated with worse HCV recurrence. 24,25 Although there have been reports of anti interleukin-2 receptor therapy being associated with more severe HCV recurrence after LT, it is unlikely the 2 doses this patient received in the absence of other immunosuppression would trigger such a rapid HCV recurrence. 26 Our patient had a high post-lt viral load but did not receive any of these immunosuppressive agents. It is difficult to argue that the short course of standard immunosuppression this patient received

4 916 SARAF ET AL. could have played a major role in inducing this severe HCV recurrence. Host-related factors such as underlying immunosuppression, nonwhite race, and female gender have been shown in small studies to be related to more severe recurrence of HCV. 1-7 In general, older recipients may have more complications after LT, but there is little evidence to suggest that the age of the host is a predictor of more rapid and severe HCV recurrence. 27 The age of the donor ( 50 years) has been found to be independently associated with disease severity, progression, and graft and patient survival. 1-3,18-21,28 Other donor factors such as steatosis, increased hepatic iron content, and positive anti-hcv status also affect HCV recurrence and disease progression after LT The advanced age of the donor in our case probably played an important role in the rapid progression of recurrent HCV. This might be related to a decreased replicative reserve in the older donor liver. As seen in the preperfusion and initial allograft biopsy samples, there was increased lipofuscin deposition as well as pleomorphism of hepatocyte nuclei consistent with a liver from an older donor. 33 In conclusion, our patient experienced an extremely rapid histological recurrence of HCV starting the second week after LT, followed by rapid progression to graft failure and death. To our knowledge, this is among the earliest histological recurrences of HCV described to date. It is unlikely that immunosuppression, pre-lt viral load, or HCV genotype played a role in this rapid cholestatic HCV recurrence. Donor age was probably a key factor in the rapid recurrence and disease progression, but recipient age may have been an additional negative factor. The patient did not have any other negative prognostic features, such as a high pretransplantation viral load, genotype 1, human immunodeficiency virus coinfection, or long-standing immunosuppression. Transplanting an organ from an older donor into this older recipient may have contributed to the extremely early and rapidly progressive recurrence of HCV. Recurrent HCV may need to be considered in the differential diagnosis of increased liver chemistry tests soon after LT when organs from older donors are transplanted into older recipients. REFERENCES Figure 3. Liver needle biopsy showing cholestatic variant of recurrent hepatitis C. (a) Low-power view showing severe cholestasis with feathery degeneration of hepatocytes (arrowheads) and foci of lobular inflammation including acidophilic bodies (small arrows) (H&E, original magnification 400 ). (b) Same biopsy sample with a representative portal tract showing prominent ductular reaction (arrows) (H&E, original magnification 600 ). (c) Same biopsy sample showing portal fibrosis and fibrous septum formation consistent with rapid progression of recurrent hepatitis C (trichrome stain, original magnification 400 ). 1. Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001;35: Wiesner RH, Sorrell M, Villamil F; International Liver Transplantation Society Expert Panel. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003;9:S1-S9. 3. Gane E. The natural history and outcome of liver transplantation in hepatitis C virus infected recipients. Liver Transpl 2003;9:S28-S McCaughan GW, Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation. J Hepatol 2004;40: Brown RS. Hepatitis C and liver transplantation. Nature 2005;436: Berenguer M, Aguilera V, Prieto M, Carrasco D, Rayon M, San Juan F, et al. Delayed onset of severe hepatitis C re-

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