Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation.

Treatment of recurrent hepatitis C in liver transplant is controversial. The aim of our study was to evaluate the clinical and histological efficacy of pegylated interferon alpha 2b (PEG-IFN) and ribavirin therapy of recurrent hepatitis C after liver transplantation (LT). We prospectively included 47 liver transplant patients with: 1) a positive test for hepatitis C virus (HCV)-ribonucleic acid (RNA) in serum; 2) alanine aminotransferase (ALT) >45 UI/mL; and 3) a liver biopsy showing chronic hepatitis without rejection in the previous 2 months. Patients received PEG-IFN (1.5 microg/kg/week) and ribavirin (800-1,000 mg/day) for 12 months. Follow-up was based on biochemical (ALT), virological (RNA-HCV), and histological (liver biopsy) examinations. Follow-up lasted a minimum of 6 months after the end of antiviral therapy. Sustained virological response (SVR) was achieved in 23% of the patients. A total of 33 (70%) patients had normalized ALT levels at the end of therapy. Inflammatory portal and lobular score declined significantly in patients with SVR (P < 0.05) but not in nonresponder patients. Fibrosis did not change significantly in either group. SVR was significantly associated with low gamma-glutamyltransferase GGT (P = 0.04) and HCV-RNA levels (P = 0.03), a virological response at 12 weeks (P = 0.002) and patient's compliance (P = 0.04). Ten (21%) patients were withdrawn prematurely due to adverse effects. In conclusion, Therapy with PEG-IFN and ribavirin achieved SVR and a significant histological improvement in 23% of liver transplant recipients with chronic hepatitis C. Toxicity is an important drawback of this therapy.     

Involvement of the Fas System in Hepatitis C Virus Recurrence After Liver Transplantation

To date, there have been no reports of the involvement of the Fas system in recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT). In 25 patients who underwent OLT for HCV-related liver cirrhosis, we evaluated the expression of the Fas antigen (FasAg) on hepatocytes, apoptic hepatocytes, and serum levels of soluble Fas (sFas). The level of HCV viremia and HCV genotype were determined by polymerase chain reaction. Serum sFas levels were determined by an enzyme immunoassay procedure. DNA fragmentation was determined by the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end-labeling (TUNEL) technique on deparaffinized liver samples. FasAg expression was evaluated by an immunoperoxidase method. Sixteen patients had evidence of recurrent HCV disease. The number of hepatocytes expressing FasAg and the percentage of apoptotic hepatocytes was greater among patients who developed recurrent hepatitis than among those who did not (P < .01 and P < .0001, respectively). There was a correlation between hepatic expression of FasAg, intensity of lobular inflammation (P = .007), and TUNEL index (P < .001). The levels of sFas were greater among the patients with recurrent HCV hepatitis than those without recurrent hepatitis (P < .04). We conclude that (1) Fas expression is up-regulated in recurrent HCV after OLT and is related to the grading of liver disease; likewise, levels of sFas were greater in the patients with recurrent HCV hepatitis; and (2) the demonstration of hepatocytes with FasAg expression and the labeling of the nuclei by TUNEL assay suggest that hepatic apoptosis mediated by the Fas system may have a role in the pathogenesis of recurrent HCV hepatitis after OLT. (Liver Transpl 2000;6:562-569.)     

Quantification of serum HCV core antigen by a fluorescent enzyme immunoassay in liver transplant recipients with recurrent hepatitis C--clinical and virologic implications

BACKGROUND: Monitoring hepatitis C viremia may be useful in the management of liver transplant patients with recurrent hepatitis C virus (HCV) infection. The clinical utility of a newly described fluorescent enzyme immunoassay for the detection of serum HCV core antigen was evaluated. METHODS: Serum samples prospectively collected from 57/63 consecutive patients transplanted for HCV-related end-stage liver disease were assayed for both serum HCV core antigen by fluorescent enzyme immunoassay and HCV RNA level using a branched chain DNA signal amplification assay. HCV genotype was determined by restriction fragment length polymorphism analysis based on 5' untranslated region. One- and 2-year annual protocol liver biopsies from these patients were graded for inflammation, fibrosis, and cholestasis RESULTS: Serum HCV core antigen and HCV RNA were detected in a similar proportion of samples (256/ 281 vs. 260/281, P=NS), and there was an excellent correlation between assays (r2=0.905, P<0.0001) independent of HCV genotype. A conversion equation between HCV core antigen and HCV RNA was constructed to estimate the HCV core antigen to RNA ratio to be around 231 to 1. Mean serum HCV core antigen levels peaked initially at 3 months posttransplant but there was significant interpatient variation as to when peak levels occurred. A high serum HCV core antigen level in the first 6 months was associated with histological deterioration in terms of bridging fibrosis, cirrhosis, severe cholestasis, or retransplantation by 2-year follow-up. CONCLUSION: Determination of serum HCV core antigen level reflects HCV viremia and may have clinical implications in liver transplant patients with HCV recurrence.     

慢性丙型肝炎合并脂肪肝患者Sirt1和固醇调节元件结合蛋白表达及意义

目的探讨丙型肝炎病毒（HCV）感染合并不同程度的肝脏脂肪变患者Sirt1和SREBP表达及其临床意义。 方法收集2015年7月至2017年6月于湖州市第一人民医院肝病科就诊患者共140例,其中80例丙型肝炎患者（包括20例无脂肪肝的单纯丙型肝炎患者,20例丙型肝炎合并轻度脂肪肝患者,20例丙型肝炎合并中度脂肪肝患者及20例丙型肝炎合并重度脂肪肝患者）;60例单纯脂肪肝患者（包括20例单纯轻度脂肪肝患者,20例单纯中度脂肪肝患者,20例单纯重度脂肪肝患者）。选择20例健康查体者为正常对照组。分别检测入组患者性别、年龄及HCV RNA水平（入组丙型肝炎患者抗体均为阳性）,收集患者外周血样本,通过real-time PCR及Western blot检测Sirt1和SREBP表达水平。 结果与单纯丙型肝炎患者相比,丙型肝炎合并轻度脂肪肝患者Sirt1水平差异无统计学意义（t = 0.344、P = 0.732）,丙型肝炎合并中度、重度脂肪肝患者Sirt1水平下降：mRNA水平分别下调0.724倍（t = 4.265、P < 0.001）和0.540倍（t = 2.489、P = 0.013）;蛋白水平分别下调0.69倍（t = 4.857、P < 0.001）和0.51倍（t = 10.523、P = 0.002）,差异均有统计学意义。与单纯丙型肝炎患者相比,丙型肝炎合并轻度、中度、重度脂肪肝患者SREBP-1c水平上升：mRNA水平分别上调1.132倍（t =－3.924、P < 0.001）、1.424倍（t =－4.300、P < 0.001）和1.663倍（t =－3.758、P = 0.001）;蛋白水平分别上调1.49倍（t = －9.323、P < 0.001）、1.65倍（t =－14.992、P < 0.001）和1.79倍（t =－15.847、P < 0.001）,差异均有统计学意义。单纯丙型肝炎患者、丙型肝炎合并轻度、中度、重度脂肪肝患者间SREBP-2表达差异无统计学意义（P > 0.05）。与单纯轻度脂肪肝患者比较,丙型肝炎合并轻度脂肪肝患者Sirt1表达水平差异无统计学意义（t = 0.344、P = 0.732）。与单纯中、重度脂肪肝患者相比,丙型肝炎合并中、重度脂肪肝患者Sirt1表达水平显著下降：mRNA水平分别下调0.682倍（t = 2.987、P = 0.010）和0.521倍（t = 5.366、P < 0.001）;蛋白水平分别下调0.800倍（t = 2.801、P = 0.016）和0.635倍（t = 7.891、P < 0.001）,差异均有统计学意义。与单纯轻度、中度、重度脂肪肝患者相比,丙型肝炎合并轻度、中度、重度脂肪肝患者SREBP-1c表达水平显著升高：mRNA水平分别上调1.428倍（t =－15.943、P < 0.001）、1.592倍（t =－9.135、P = 0.004）和1.521倍（t =－9.138、P < 0.001）;蛋白水平分别上调1.622倍（t = －7.960、P = 0.010）、1.749倍（t = －2.196、P = 0.012）和1.803倍（t =－8.942、P = 0.045）,差异均有统计学意义。 结论丙型肝炎病毒感染可通过抑制Sirt1及上调SREBP-1c表达而影响肝脏脂肪变。     

Prevalence of hepatitis C virus genotypes in a Spanish liver transplant unit

INTRODUCTION: Among the at least six major identified genotypes of HCV, genotype 1b, the one associated with a poorer prognosis, is the most prevalent in Spain. We aimed to compare the distribution of hepatitis C virus genotypes in our liver transplant unit with that of the other HCV patients at our institution (n = 413) in order to assess whether genotype 1b is more prevalent among patients with more severe liver disease. PATIENTS AND METHODS: One hundred eight patients of mean age 56 years included 81 (75%) OLT recipients and 27 (25%) with HCV cirrhosis. Determination of HCV genotypes was made with the Inno-LiPA HCV III. RESULTS: The overall distribution of genotypes was: 1b, 93 patients (86.1%); 1a; eight patients (7.4%); 3, four patients (3.7%); 4; two patients (1.9%), and 2; one patient (0.9%). The distribution was similar among patients with cirrhosis and OLT. Genotype 1b patients were older. Eleven (78.6%) of 14 patients with hepatocellular carcinoma had genotype 1b. In the control group the distribution was: 1b, 287 patients (69.5%); 1a, 54 patients (12.1%); 3, 41 patients (9.9%); 4, 20 patients (4.8%), and genotype 2, 11 patients (2.7%). This differences in the distribution of genotypes between our population and the control group was statistically significant (P < .001). CONCLUSIONS: Genotype 1b, the most prevalent genotype in our liver transplant unit, included older patients in whom hepatocellular carcinoma was common, perhaps due to their higher prevalence of cirrhosis.     

肝移植后丙型病毒性肝炎复发治疗时获得持续病毒应答的影响因素

目的 探讨聚二乙醇干扰素治疗肝移植后丙型病毒性肝炎复发的效果,分析影响产生持续病毒应答率(SVR)的因素.方法 将肝移植后丙型病毒性肝炎复发并使用聚乙二醇干扰素α-2a进行抗丙型肝炎病毒(HCV)治疗的39例患者纳入研究,其中有21例因为抗HCV治疗无效或发生不良反应而中途停药,其余18例接受了全疗程规范治疗.18例患者中,男性13例,女性5例,平均年龄54岁(27～67岁),疗程25～105周.治疗后4、12、24周,病毒转阴后24周及停药后24周,检测HCV RNA的复制水平.停药后24周HCV RNA复制持续阴性为产生SVR.对患者年龄,性别,治疗前HCV RNA水平,HCV基因型,是否获得早期病毒应答(EVR),治疗前血清AST水平等因素与获得SVR的相关性进行分析.结果 有4例(22.2%)患者获得了SVR,其平均治疗周期为57周.经统计分析显示,HCV基因型为非1B型(P=0.023),治疗前HCV RNA载量＜106拷贝/ml(P=0.044),以及获得EVR(P=0.019)等3个参数与获得SVR密切相关.结论 HCV基因型为非1B型、治疗前低水平HCV RNA复制和获得EVR可作为肝移植后丙型病毒性肝炎复发抗HCV治疗疗效的有效预测因子.

Abstract：

Objective To investigate the efficacy of pegylated interferon (Peg-IFN) plus ribavirin to treat hepatitis C virus (HCV) recurrence, and analyze possible factors associated with sustained viral responses (SVR). Methods The enrolled 39 patients, who had recurrence of hepatitis C after liver transplantation and received antiretroviral therapy, were analyzed. Treatment was discontinued in 21 patients due to side effects, and the remaining 18 patients [13 males, 5 female,median age of 54 (27-67) years, treatment duration of 25-105 weeks)] were subjected to whole standard treatment. During the treatment, HCV RNA was measured at 4, 12, 24, and 24 weeks after HCV negative change as well as drug withdrawal. SVR was defined as HCV RNA negativity within 24 weeks after the drug withdrawal. The following variables were analyzed: ages, gender,pretreatment viral load, genotype, early viral response (EVR), levels of alanine aminotransferase before treatment and their association with SVR. Results The mean treatment duration was 57weeks with an SVR achieved in 4/18 (22. 2 %). Statistical analysis revealed that the genotype of non1B (P=0.023), RNA ＜106 copy/ml (P= 0. 044) before treatment and EVR (P=0.019) were the variables associated with SVR. Conclusion Genotype of nor-1B, low level RNA before treatment and EVR were the effective predictors of interferon antiviral therapy for recurrent hepatitis C after liver transplantation.     

Intrahepatic cytokine profiles associated with posttransplantation hepatitis C virus[ndash ]related liver injury

Recurrent chronic hepatitis, cholestatic hepatitis, and acute rejection in conjunction with hepatitis C virus (HCV) recurrence are well-recognized clinical sequelae of reinfection of the hepatic allograft with HCV. The aim of this study is to characterize intrahepatic cytokine responses associated with reinfection of the allograft with HCV in these settings. Intrahepatic messenger RNA expression of T helper cell subtype 1 (TH1) cytokines interleukin-2 (IL-2), interferon-[gamma ], and tumor necrosis factor-[alpha ] and TH2 cytokines IL-4 and IL-10 was measured by real-time polymerase chain reaction system using TaqMan probes in 53 liver specimens from six groups of patients. These were: (1) recurrent chronic hepatitis C (CH-I; n = 15), (2) cholestatic hepatitis (n = 6), (3) acute rejection associated with HCV recurrence (AR-HCV; n = 12), (4) acute rejection in non[ndash ]HCV-infected allografts (AR non-HCV; n = 5), (5) patients with chronic hepatitis C who did not undergo transplantation (CH-C; n = 10), and (6) nondiseased liver tissue (n = 6). Intrahepatic viral loads were measured using an Amplicor monitor assay (Roche Diagnostic Systems, Branchburg, NJ). The CH-I and CH-C groups had similar TH1 intrahepatic cytokine profiles. Compared with the CH-I group, the cholestatic group expressed increased levels of the TH2 cytokines IL-10 (P = .024) and IL-4 (P = .0024). The AR-HCV group also expressed more TH2 cytokines IL-10 (P = .014) and IL-4 (P = .034) compared with the CH-I group. Both the AR-HCV and AR non-HCV groups showed similar intrahepatic cytokine profiles. Intrahepatic viral loads were highest in the cholestatic group compared with the AR-HCV, CH-I, and CH-C groups (P = .0007). In conclusion, a novel observation is that the cholestatic group showed upregulation of the TH2 cytokines IL-10 and IL-4, in addition to high viral loads. In this setting, the TH2 immune response may favor viral replication and graft damage. (Liver Transpl 2002;8:292-301.)     

Hepatitis C virus genotypes and quantitation of serum hepatitis C virus RNA in liver transplant recipients: Relationship with severity of histological recurrence and implications in the pathogenesis of HCV infection

The reasons for the wide variation of incidence and severity of recurrent hepatitis C after liver transplantation are not clear. We have studied liver transplant recipients to assess the impact of hepatitis C virus (HCV) genotype and HCV RNA quantification on HCV recurrence after transplantation. Twenty-two patients received transplants for HCV cirrhosis and were followed up with virological and histological assessments. Mean follow-up was 39 months. HCV genotype was determined with line probe assay (Inno-Lipa). HCV RNA quantity was determined in serum samples by use of polymerase chain reaction nested assay. HCV genotype 1 was detected in 13 patients and other genotypes in 9. Histological recurrence rates were 69% in patients with genotype 1 and 66% in patients with other genotypes. All cases of severe histological injury (chronic active hepatitis or cirrhosis) were observed in patients with genotype 1. HCV RNA quantity was significantly higher in patients with genotype 1 (mean, 2.023 x 10³ copies/mL) than in patients with other genotypes (mean, 27,403 copies/mL). In conclusion, the severity of histological recurrence after liver transplantation for HCV disease was higher in patients infected by HCV genotype 1 than in those infected with other genotypes. The levels of viral replication were higher in patients with HCV genotype 1 than in those with other genotypes. (Liver Transpl Surg 1997 Sep;3(5):501-5)     

Progression of liver fibrosis in patients with chronic hepatitis C after orthotopic liver transplantation

BACKGROUND: Hepatitis C virus (HCV)-related cirrhosis is the leading indication for orthotopic liver transplantation (OLTx). HCV recurrence is universal after OLTx, with a highly variable course. This study aimed to find factors that affect progression of fibrosis in recurrent HCV. METHODS: Fifty-eight HCV patients underwent OLTx at our center who were selected on the basis of available preOLTx serum or explanted liver sample and liver biopsy obtained at least 6 months postOLTx. All liver biopsies were performed when clinically indicated and were scored using the modified Hepatitis Activity Index (HAI). Primary immunosuppression consisted of tacrolimus and prednisone. RESULTS: The group included 41 males (mean age 49.6 years). HCV genotype distribution was 1a, 31 (53%); 1b, 16 (28%), and others 11 (19%). The mean follow-up was 53.1 months. Patients with genotype 1a (n=31; mean 46.3 months) had significantly lower fibrosis-free survival analyzed by the presence of fibrosis stages 5 and 6 when compared with other genotypes (n=27; mean 60.1 months; P=0.0088, log rank test). Mean HAI scores were significantly higher in HCV genotype 1a, although there were no differences in survival between genotypes. Similarly, patients with cytomegalovirus (CMV) infection postOLTx (n=4) had a higher fibrosis progression rate compared with those without CMV (n=54) (mean fibrosis-free survival 29.0 vs. 53.0 months P=0.0004, log-rank test). Human leukocyte antigen matching and rate of acute rejection did not influence progression of fibrosis. CONCLUSION: Patients with HCV genotype 1a and those developing CMV postOLTx have a higher rate of hepatic fibrosis progression after OLTx for HCV-related chronic liver disease.     

Platelet-derived growth factor gene polymorphism in recurrent hepatitis C infection after liver transplantation

BACKGROUND: Recurrent hepatitis C virus (HCV) infection is particularly aggressive in the post liver transplantation setting, with rapid progression of liver fibrosis. Platelet-derived growth factor (PDGF) is reportedly involved in the pathogenesis of liver fibrosis. The aim of this study was to evaluate the possible contribution of molecular variants of the PDGF-B gene to recurrent HCV infection after liver transplantation. METHODS: DNA was extracted from peripheral blood mononuclear cells of 40 patients who underwent liver transplantation for chronic HCV infection and genotyped for polymorphisms in PDGF-B at positions +1135 (A to C) and +286 (A to G). Intrahepatic PDGF-B expression was detected by immunohistochemistry and assessed semiquantitatively. Forty-seven healthy individuals served as controls. RESULTS: Recurrent HCV infection occurred in 34 patients (85%) after a median interval of 10.5 months (range 1.5-60.0). A statistically significant difference was observed in the distribution of the PDGF-B gene polymorphism at position +1135, but not +286 between patients and controls (P=0.05). The A/A genotype occurred at a highly significantly increased rate in patients with recurrent HCV infection than in those without (64.7% vs. 16.67%, P=0.0001), and in patients with severe than in those with nonsevere recurrence (100% vs. 53.85%, P=0.05). The expression level of intrahepatic PDGF-B was found to be highly correlated with the fibrosis stage (P<0.0001). Further analysis yielded a highly statistically significant relationship between the PDGF-B gene polymorphism at position +1135 and clinical parameters of disease severity. CONCLUSIONS: PDGF-B gene polymorphism appears to be associated with severe recurrent HCV infection after liver transplantation. PDGF-B may play an essential role in the development and progression of hepatic fibrosis. These findings, if confirmed, may have important therapeutic implications.     

Allograft transmission of hepatitis C virus infection from infected donors in cardiac transplantation

BACKGROUND: The frequency and outcome of hepatitis C virus (HCV) infection in recipients of hearts from HCV-infected donors remains poorly characterized. METHODS: Between 1991 and 1999, 10 anti-HCV-negative patients received hearts from donors who were anti-HCV and HCV RNA-positive. Each recipient was tested for anti-HCV and HCV RNA and serially evaluated for liver dysfunction. Recipient records were reviewed for cumulative steroid boluses in the first posttransplant year and other components of the immune suppression regimen. We analyzed recipient outcome in relation to the virologic status of the donor, including the level of HCV RNA and genotype and the type of antirejection therapy. RESULTS: All 10 recipients became HCV RNA positive. Donor-recipient pairs expressed identical genotypes in each instance. Six of nine evaluable recipients developed biochemical evidence of hepatitis. Recipients with genotype 1 (1a, 1b) accounted for five of the six cases, and all patients with genotype 1 developed hepatitis. Severe liver injury occurred in two patients. Two deaths occurred, both of which were genotype 1 patients who had been given multiple boluses of corticosteroids in the first posttransplant year. No definite relationship between viral load in the donor and recipient outcome was found. CONCLUSION: Transmission of HCV infection from cardiac donors who are viremic at the time of organ donation occurs with high frequency and can cause severe hepatitis. Hearts from infected patients should probably be restricted to those recipients who already have evidence for hepatitis C or are in need of emergent transplantation.     

Timing of reinfection and mechanisms of hepatocellular damage in transplanted hepatitis C virus[ndash ]reinfected liver

Pathogenic mechanisms and dynamics of hepatitis C virus (HCV) reinfection in orthotopic liver transplantation (OLT) are poorly defined. This study focuses on these aspects by studying 55 frozen biopsy specimens from transplant recipients with various histological diagnoses obtained from 4 days to 4 years post-OLT and 10 patients with HCV-related chronic hepatitis. The percentage of HCV-infected hepatocytes, number and distribution of CD8 and natural killer cells, and rates of hepatocellular apoptosis and proliferation were quantified by immunohistochemistry. HCV antigens were detected in 37% of biopsy specimens obtained within 20 days and 90% of biopsy specimens obtained from 21 days to 6 months after OLT. The number of HCV-infected hepatocytes was never less than 40% in acute hepatitis specimens and never greater than 30% in the other cases. Hepatocellular apoptosis was high in biopsy specimens of acute hepatitis and moderate in those from transplant recipients with normal histological characteristics, but still greater than in specimens of chronic active hepatitis. Proliferation correlated significantly with apoptosis. Lymphocyte infiltration was high and similar among cases of acute hepatitis, chronic hepatitis, and rejection. These data: (1) show that the detection of liver HCV antigens is sensitive enough to be used in clinical practice as a diagnostic tool to detect infection of the transplanted liver and might be useful, combined with conventional histological evaluation to detect hepatitic damage, for therapeutic decision making; (2) suggest direct cytotoxicity of HCV, as well as immunologic mechanisms possibly prevalent in chronic hepatitis and rejection, at least in the phase of acute massive liver infection; and (3) show that hepatocellular apoptosis and regeneration might be active enough to lead to replacement of the entire transplanted liver in 2 weeks. (Liver Transpl 2002;8:10-20.)     

Histopathological features of hepatitis C in renal transplant candidates [see comment

BACKGROUND: Although hepatitis C virus (HCV) infection is common in renal transplant candidates, its clinical significance remains unclear in this population. Little detailed information is available about the histological severity of HCV infection in these patients. We evaluated the liver biopsy features of chronic HCV in a large population of renal transplant candidates and investigated associations between histopathological changes and host- and virus-related factors. METHODS: Thirty-seven patients seropositive for anti-HCV with chronic renal failure (CRF) referred to UCLA Medical Center for kidney or kidney/liver transplantation during the period 1992-1997 were included. HCV genotype and viral load were measured. A multivariate analysis by logistic regression model was performed: age, gender, race, HCV load and genotype, CRF level, aspartate and alanine aminotransferase activity, duration of HCV infection, underlying nephropathy, and alcohol abuse were independent variables; liver histology score was assumed a dependent variable. RESULTS: Liver disease was present in all HCV-infected patients. Logistic regression analysis revealed that histological damage was (P = 0.0017) independently associated with the CRF level; the severity of liver disease, as shown by univariate analysis, being significantly higher in CRF patients not requiring dialysis than among dialysis population. All patients on dialysis showed mild or moderate necroinflammatory activity; the majority (22/28 = 79%) of these individuals had fibrosis, three (3/28 = 11%) dialysis patients had established cirrhosis. Thirty-one (84%) of 37 patients were tested by polymerase chain reaction, 25 (81%) patients had detectable HCV RNA in serum, the mean HCV load among viremic patients was 10.9x10(5) copies/ ml. The most frequent HCV genotypes were la (8/24 = 33%) and 1b (7/24 = 29%), followed by genotype 2b (3/24 = 12%). CONCLUSIONS: Pathological changes on liver biopsy were observed in all HCV-infected patients awaiting renal transplantation. The severity of histologic damage observed on liver biopsy was less in dialysis than predialysis CRF patients. All dialysis patients had mild or moderate necroinflammatory activity; fibrosis was frequent with 11% of them having cirrhosis. The HCV viral load was rather low; no relationship between liver histology changes and virological features of HCV or aminotransferase activity was apparent. Further studies with repeat liver biopsies after kidney transplantation to observe the evolution of HCV-related liver disease after immunosuppressive therapy are indicated. We suggest including liver biopsy in the evaluation of the HCV-infected renal transplant candidate.     

Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation

Recurrent hepatitis C infection after orthotopic liver transplantation (OLT) is frequent and may occur as early as a few weeks postoperatively. Early histopathological features of recurrent hepatitis C virus (HCV) infection may be modified by immunosuppressive therapy and can be difficult to differentiate from acute allograft rejection (AAR). Thus, we retrospectively compared histopathological features of liver biopsy specimens from two carefully selected patient groups: one with unequivocal recurrent hepatitis C, the other with unequivocal AAR. Index biopsy specimens obtained at the time of the appearance of liver test abnormalities after OLT and all serial liver biopsy specimens (2 to 13 per patient) were assessed under code and scored semiquantitatively for 44 histopathological variables. The index biopsy specimens from patients with recurrent HCV infection and AAR index biopsies (AAR-Ib) differed significantly (P < .05) for 11 features (10 features were statistically associated with AAR and 1 with early recurrence of HCV infection). Statistically significant features associated with AAR included bile duct injury with overlapping nuclei, lymphocytic infiltrates and necrosis, endothelialitis, portal inflammatory infiltrates containing eosinophils and polymorphonuclear leukocytes, hepatocyte mitoses, and zone 3 canalicular cholestasis. In contrast, the only statistically significant feature associated with early recurrent HCV was sinusoidal dilatation. Stepwise discriminant analysis showed that the presence of eosinophils in the portal inflammatory infiltrate, bile duct necrosis, and bile duct lymphocytic infiltrates were independently associated with AAR. However, serial biopsy specimens from patients with recurrent HCV infection showed statistically significant progression in scores for portal inflammation, portal lymphoid aggregates, and lobular inflammation. We conclude that (1) multiple histopathological features are associated with AAR; (2) early recurrent HCV infection is characterized by elevated alanine aminotransferase levels, positive HCV RNA by polymerase chain reaction (PCR), and absence of diagnostic histopathological features; and (3) serial biopsies are needed to demonstrate progression of histopathological features of recurrent hepatitis C. (Liver Transpl Surg 1997 Jul;3(4):398-406)     

Anonymous pilot study of hepatitis C virus prevalence in liver transplant surgeons.

The risk of hepatitis C virus (HCV) transmission to surgeons is related to the HCV prevalence in the surgical patient population. As HCV-related cirrhosis is the commonest indication for liver transplantation in Europe and North America, liver transplant surgeons are at particular risk. The prevalence of HCV infection in liver transplant surgeons is unknown. The aim of this study was to estimate the prevalence of HCV infection in liver transplant surgeons attending the 9th Congress of the International Liver Transplantation Society using unlinked anonymous testing for HCV. Surgeons attending the conference were invited to complete an anonymised questionnaire regarding their surgical and transplant practice and provide an unlinked anonymised blood spot sample by finger prick. Samples were screened for antibodies to HCV (enzyme-linked immunosorbent assay III, Ortho Diagnostics, Raritan, NJ). Polymerase chain reaction testing for HCV RNA was performed on reactive samples.A total of 117 liver transplant surgeons (79 European, 16 North American, 10 Asian, 9 South American, 3 Australasian) provided a blood spot sample. Two (1.7%) surgeons had antibodies to HCV, 1 (0.8%) had detectable HCV RNA (genotype 1a). Assuming that both infections were acquired during surgery, the estimated maximum rate of HCV transmission is 1 per 743 to 1,045 years of surgical (0.96 to 1.35 HCV transmissions per 1,000 years of general surgical practice) and 449 to 683 years of liver transplant practice (1.46 to 2.23 HCV transmissions per 1,000 years of liver transplantation practice). In conclusion, risk of HCV transmission to liver transplant surgeons appears to be low despite the particular risks associated with frequently operating on HCV infected patients.     

Quality of life in long-term survivors after liver transplantation: impact of recurrent viral hepatitis C virus hepatitis

Post liver transplant recurrence of infection with hepatitis C virus (HCV) occurs in approximately 50% of patients transplanted because of HCV-related liver disease. The aim of this study was to assess long-term quality of life, psychologic distress, and coping in patients with recurrent HCV after liver transplantation in comparison to patients transplanted for other etiologies of underlying liver disease. All liver transplant recipients transplanted at a University affiliated Veterans Affairs Medical Center who had greater than 6 months follow-up were sent a questionnaire investigating quality of life (assessed by Medical Outcomes study health survey SF-36), depression (assessed by Beck Depression Inventory), total mood disturbance (assessed by Profile of Mood States scale), coping (assessed by Billing and Moos Inventory of coping with illnesses), and employment status. Lower Beck Depression Inventory score (p = 0.001), lower mood disturbance score (p = 0.0001), overall satisfaction with present work (p = 0.0001), and lesser use of avoidant coping (p = 0.06) were predictors of better quality of life in long-term survivors of liver transplantation. At a mean follow-up of 4 yr after liver transplantation, patients with histopathologically diagnosed recurrent viral HCV hepatitis had significantly lower global quality of life score (mean score of 76.4 versus 86.2, p = 0.011) and physical functioning score (mean score 20 versus 25, p = 0.015), as compared to all other patients. In summary, quality of life and physical functioning were significantly impaired in liver transplant recipients with histopathologically diagnosed recurrent HCV hepatitis, as compared to those whose HCV hepatitis had not recurred or those transplanted for other reasons.     

Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft.

BACKGROUND: The impact of hepatitis C virus (HCV) infection recurrence after orthotopic liver transplantation (OLT) on graft viability is still not accurately defined. Our study aims to evaluate the magnitude and rate of progression of HCV-induced liver damage after OLT in a single institution cohort of 122 HCV-infected recipients. METHODS: All patients transplanted at our institution between 1988 and 1996 with positive serum HCV antibodies before OLT, minimum postoperative survival of 6 months, and without hepatitis B virus coinfection or severe non-HCV-related graft complications were retrospectively included in the study. RESULTS: HCV infection recurrence was almost universal, and genotype 1b was observed in 87% of the cases. After a median histological follow-up of 43 months (range: 7-96), evidences of HCV-induced histological damage were found in 94% of the cases. The actuarial rates of severe graft damage (including cirrhosis, fibrosing cholestatic hepatitis, and submassive liver necrosis) were 15%, 33%, and 44% at 3, 5, and 7 years, respectively, and among these patients, 52% developed decompensated liver disease during the follow-up and 36% lost their grafts. The biochemical severity at the onset of the recurrent hepatitis and the development of cholestasis or cytomegalovirus disease were independent predictors of severe HCV-related graft damage. No differences were found in graft and patient survival when positive-HCV OLT recipients were compared with a coetaneous cohort of 215 non-HCV OLT recipients. CONCLUSIONS: HCV infection recurrence leads to severe liver damage and subsequently to clinical decompensation in a significant proportion of OLT recipients. Some clinical and biochemical characteristics can predict the severity of HCV-induced graft damage.     

Role of replicative senescence in the progression of fibrosis in hepatitis C virus (HCV) recurrence after liver transplantation

BACKGROUND: Although hepatitis C virus (HCV) recurrence is almost universal after orthotopic liver transplantation (OLT), the impact of viral infection on liver graft is highly variable and difficult to predict. Because of the possible relationship between replicative senescence (RS) and the accelerated development of liver fibrosis, we aimed to assess the potential role of RS in the severity of HCV-related chronic hepatitis recurrence after OLT. METHODS: One hundred three liver biopsies from 56 patients receiving transplants for HCV-related cirrhosis were studied, including 30 revascularization biopsies and 52 and 21 biopsies performed during and beyond the first year of OLT, respectively. The presence of senescent cells in liver grafts was assessed by the senescence-associated beta-galactosidase (SA-beta-Gal) staining method. Chronic hepatitis was defined by fibrosis stage and necrotico-inflammatory activity grade using the METAVIR score. RESULTS: A total of 34 of the 103 (33%) frozen liver biopsies displayed SA-beta-Gal-positive cells, including 6 (20%) of the revascularization biopsies, 14 (34%) of the biopsies performed within the first year, and 10 (46%) of the biopsies performed beyond 1 year of follow-up. The presence of senescent cells in revascularization biopsies was significantly associated with the degree of ischemic necrosis at time of OLT (P = 0.01) and hepatitis C recurrence in the first year after OLT (P = 0.05). Furthermore, the presence of RS in the biopsy performed within the first year was associated with further development of fibrosis (P = 0.05). CONCLUSIONS: These data show that RS has a significant impact upon the course of liver transplantation, especially in the long-term progression of fibrosis observed in HCV-infected patients.