Delayed onset of severe hepatitis C-related liver damage following liver transplantation: A matter of concern?

Abstract

Although histological hepatitis occurs in the majority of hepatitis C virus (HCV)-infected liver transplant recipients, the natural history is highly variable. Whereas progression to cirrhosis occurs in up to 30% after 3 to 7 years, the disease remains stable in another third of patients, in whom protocol liver biopsies might be avoided. However, there is recent concern that with prolonged follow-up, some patients with initial benign recurrence may develop a late-onset aggressive course. Aims of the study are to determine the incidence and factors associated with this event. Based on yearly protocol biopsies (median, five biopsies; range, three to seven biopsies), we evaluated the histological outcome of 57 HCV type 1b-infected transplant recipients with initial benign recurrence, defined as stable histological state (fibrosis stage F0 or F1) during the first 3 years posttransplantation. Severe late-onset liver damage is defined as progression to F3 or F4 in patients with previous benign recurrence. Potential predictors of this event include demographics, donor-related factors, liver enzyme levels at 1 and 3 (or baseline) years posttransplantation, activity grade and fibrosis stage at 1 and 3 years posttransplantation, nonalcoholic steatohepatitisrelated variables occurring within the first 3 years posttransplantation (diabetes, hyperlipidemia, obesity), use of some drugs (renin-angiotensin inhibitors, ursodeoxycholic acid), and the advent of any unusual event. The incidence of severe late-onset liver damage was 35% (n ‫؍‬ 20). Twelve transplant recipients progressed to F3, whereas 8 transplant recipients progressed to F4. Sudden histological deterioration was observed on postoperative biopsy 5 in 12 patients; biopsy 6 or 7, in 7 patients; and biopsy 4, in 1 patient. Variables associated with this event in univariate analysis were fibrosis stage and activity grade (and its components) at baseline (P < .0001), recipient female gender (P ‫؍‬ .04), alanine aminotransferase (ALT) level at 1 year posttransplantation (P ‫؍‬ .02), and aspartate aminotransferase (AST) and ALT levels at baseline (P ‫؍‬ .008 and P ‫؍‬ .005, respectively). By multivariate analysis, only one variable was retained in the model: fibrosis stage at baseline (relative risk, 11; 95% confidence interval, 3 to 41; P ‫؍‬ .0007), whereas AST level almost reached statistical significance (P ‫؍‬ .07). In conclusion, delayed HCVrelated severe liver damage is not infrequent in transplant recipients with initial benign recurrence, occurring in approximately one third of them. The presence of some degree of fibrosis at baseline appears to predict this sudden change in the natural history of recurrent hepatitis C. Based on these findings, we recommend continuing protocol biopsies and evaluating potential antiviral therapy in transplant recipients with evidence of some fibrosis (even if it is only portal). (Liver Transpl 2003;9: 1152-1158.)

Hepatic venous pressure gradient to assess fibrosis and its progression after liver transplantation for HCV cirrhosis

“…There were 25 pressure evaluations (18 patients) that fulfilled our definition of potentially discrepant results with respect to the expected fibrosis stage or HVPG. The median biopsy length of the entire "discrepant" group was 22 mm (range, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and the number of fragments was 3.5 (range, 2-8) similar to the population as a whole. In the discrepant group, 56% of biopsies did not show severe nodularity/cirrhosis with 4 (range, 1-9) complete portal tracts and 8 (range, 2-13) partial portal tracts.…”

“…17 Fibrosis associated with recurrent HCV infection after liver transplantation (LT). [18][19][20] progresses faster to cirrhosis and decompensation compared to the pretransplantation HCV setting. 21 Transjugular liver biopsy (TJB) 22 enables multiple cores of tissue to be obtained 23 and is easily combined with hemodynamic evaluations.…”

Liver biopsy interpretation for causes of late liver allograft dysfunction

“…Considerations such as potential morbidity and mortality, cost, inconvenience, use of resources, and potential impact of unexplained histopathological findings should be weighed against potential individual and/or societal benefits. 4,[19][20][21][22][23][24] These include (1) early detection of clinically inapparent disease, 19,24 (2) recognition of nonalcoholic steatohepatitis as a significant cause of cryptogenic cirrhosis in the United States 25 but not in England, 26 (3) identification of recipients that might be successfully weaned from immunosuppression, 27 (4) recognition of late-onset rapid hepatitis C virus (HCV) progression, 21 and (5) impact of alcohol use. 20 Approximately 75% of biopsies from long-surviving recipients with abnormal liver tests or symptoms show significant histopathological abnormalities.…”

“…20 Approximately 75% of biopsies from long-surviving recipients with abnormal liver tests or symptoms show significant histopathological abnormalities. 4,[19][20][21][22][23] These abnormalities are usually attributable to recurrent disease or biliary tract strictures, some of which occur as a late complication of preservation injury. 4,[19][20][21][22][23] The incidence and significance of histopathological abnormalities in long-surviving recipients without abnormal liver tests or symptoms is dependent on the original disease: up to 25% show significant abnormalities when obtained from recipients with original diseases that commonly recur (e.g., HCV, PBC, AIH).…”

“…4,[19][20][21][22][23] These abnormalities are usually attributable to recurrent disease or biliary tract strictures, some of which occur as a late complication of preservation injury. 4,[19][20][21][22][23] The incidence and significance of histopathological abnormalities in long-surviving recipients without abnormal liver tests or symptoms is dependent on the original disease: up to 25% show significant abnormalities when obtained from recipients with original diseases that commonly recur (e.g., HCV, PBC, AIH). 4,[19][20][21][22][23] Even in the absence of recurrent disease, minor histopathological abnormalities appear in approximately two thirds of biopsies obtained from long-surviving asymptomatic recipients with normal liver tests.…”