Association between IL28B polymorphism, TNFα and biomarkers of insulin resistance in chronic hepatitis C-related insulin resistance.

TNFα has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFα. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFα activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFα (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P < 0.0001) and sTNFR1 (r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA-IR (means 1.6 ± 0.9 vs 1.7 ± 1.4) and had similar circulating levels of sTNFR1 and adipokines. Independent factors associated with IR were ferritin (OR = 1.002, P = 0.02), leptin (OR = 1.06, P = 0.02) and sTNFR1 (OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA-IR or sTNFR1 level. HCV-related IR may be mediated through TNFα independent of IL28B genotype.

[Autoimmune hepatitis: diagnostic and therapeutic up-to-date]. / Hépatites auto-immunes : actualités diagnostiques et thérapeutiques.

Autoimmune hepatitis is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation). Autoimmune hepatitis is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type II (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of autoimmune hepatitis that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish autoimmune hepatitis from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. The treatment of autoimmune hepatitis has not changed for the past 30 years. It consists of corticosteroids associated with azathioprine. This treatment is rapidly effective but usually only suspensive. Relapse after treatment withdrawal is the rule (80% of cases). The main risk factor of recurrence is the degree of residual inflammation on liver biopsy. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.

Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone.

BACKGROUND/AIMS: To assess the benefit of the UDCA-budesonide combination in association with mycophenolate mofetil (MMF) in patients with primary biliary cirrhosis (PBC) at high risk of developing cirrhosis or liver failure. METHODS: Inclusion criteria for this three-year open study were: 1) suboptimal biochemical response to one-year UDCA therapy at 13-15 mg/kg/d; 2) significant interface hepatitis without cirrhosis at liver biopsy. Treatment regimen included UDCA (13-15 mg/kg/d), budesonide (6 mg/d) and MMF (1.5 g/d). All patients underwent a control biopsy at three years. RESULTS: Fifteen patients fulfilled the inclusion criteria. Six patients (41%) normalized biochemistries and seven (47%) had a partial but significant biochemical response, as defined by a serum bilirubin less than 17 micromol/L, alanine aminotransferase less than 70 UI/L and alkaline phosphatase less than 250 UI/L. Histological activity and fibrosis were markedly improved. Side effects were minimal or absent. CONCLUSIONS: Triple therapy with UDCA, budesonide and MMF may provide benefit in non-cirrhotic PBC patients with features of severe disease not responding to UDCA.

A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy.

A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.

Polyspecificity of antimicrosomal thyroid antibodies in hepatitis C virus-related infection.

OBJECTIVES: The outcome of dysthyroidism and the presence of antithyroid antibodies in patients with chronic hepatitis C virus (HCV) infection receiving interferon-alpha therapy is clearly established. However, the prevalence and the specificity of antithyroid antibodies in HCV patients before interferon-alpha therapy remain controversial. The aim of the present study is to clarify within a large population of HCV patients the prevalence of antithyroid antibodies before interferon-alpha therapy and to determine whether their immunodominant antigen is the same as described in autoimmune thyroiditis. METHODS: Sera from 99 patients with chronic hepatitis C before (n = 99) and after (n = 37) interferon-alpha treatment were investigated for the presence of antimicrosomal and antithyroperoxidase antibodies assessed by indirect immunofluorescence and ELISA, respectively. Dot blotting on human thyroid lysate was designed to further characterize these autoantibodies. Data were compared to those obtained with sera of patients with autoimmune thyroiditis (n = 75) and healthy subjects (n = 96). RESULTS: In HCV patients, antimicrosomal antibodies were found with a higher proportion before interferon-alpha therapy (12.1%) than after therapy (8%). Thyroperoxidase constitutes the main antigen in only 4% before treatment, a prevalence similar to that observed in healthy controls. CONCLUSIONS: The prevalence of antithyroid antibodies is low in patients with chronic hepatitis C before interferon-alpha therapy. Thyroperoxidase may not be their main target. Further studies are required to determine whether HCV infection leads to a breakdown of tolerance to a thyroid self-protein other than thyroperoxidase.

Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: results of a pilot study.

Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA > 100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs > 100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.

Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C.

BACKGROUND/AIMS: Steatosis could be the result of HCV (hepatitis C virus)-induced hypobetalipoproteinemia in patients with chronic hepatitis C. The aim of this study was to assess serum levels of main constituents of betalipoproteins and their relationship with steatosis in patients with chronic hepatitis C without known risk factors for steatosis. PATIENTS: One-hundred male patients with untreated biopsy proven non-cirrhotic chronic hepatitis C were included. Twenty-nine of these patients were further treated with interferon. RESULTS: Cholesterol concentration was significantly lower in patients compared to three control groups: reference male population, patients with chronic hepatitis B or with non-alcoholic fatty liver. In multivariate analysis, low apolipoprotein B concentration was an independent factor related with the degree of steatosis. Hypobetalipoproteinemia and degree of steatosis were significantly associated with infection with genotype 3. Among treated patients, only sustained virological responders had a significant increase of cholesterol (5.6 +/- 1 vs. 4.7 +/- 1.3 mmol/l; P = 0.03) and apolipoprotein B concentrations (113 +/- 19 vs. 75 +/- 14 mg/dl; P = 0.05). CONCLUSION: In chronic hepatitis C, hypobetalipoproteinemia is prevalent and associated with steatosis, especially in patients infected with genotype 3. The correction of hypobetalipoproteinemia following HCV eradication suggests that HCV itself could induce hypobetalipoproteinemia and steatosis.

Fetal microchimerism in primary biliary cirrhosis.

BACKGROUND/AIMS: Recent studies have suggested a role of fetal microchimerism in the pathogenesis of scleroderma. The present study investigated the potential role of fetal microchimerism in primary biliary cirrhosis (PBC), a closely related disease. METHODS: A quantitative nested polymerase chain reaction was used to detect Y-chromosome sequences in the peripheral blood or the liver of PBC women and controls having male children and no transfusion or miscarriage history. RESULTS: Male microchimerism was found in the peripheral blood from 45% (9 of 20) of PBC women and 25% (5 of 20) of healthy controls matched for the number of male children and age of the youngest son (p=0.28), and in the liver-biopsy specimens from 33% (5 of 15) of PBC women and 32% (8 of 25) of controls. The level of chimerism did not differ between patients and controls either in blood or in liver. Microchimerism was not related to the severity of the disease but was more frequent in PBC patients with anticentromere antibodies (p=0.049). CONCLUSIONS: Fetal microchimerism does not seem to play a major role in most cases of PBC. However, the association with anticentromere antibodies suggests a possible role in the subgroup of patients with CREST syndrome or scleroderma.

Hepatocellular carcinoma and focal hepatic glycogenosis after prolonged azathioprine therapy.

A 22-year-old woman without predisposing liver disease developed focal hepatic glycogenosis and hepatocellular carcinoma after 6 years of azathioprine therapy for Crohn's disease. Hepatocellular carcinoma without cirrhosis has previously been described during immunosuppression, but this is the first report of disseminated focal hepatic glycogenosis after long-term azathioprine therapy.

Prognostic value of serum hyaluronan in patients with compensated HCV cirrhosis.

BACKGROUND/AIM: Serum hyaluronan (HA) levels increase according to the degree of liver fibrosis in patients with chronic viral hepatitis C. Patients with liver disease and markedly high serum HA levels have cirrhosis with typical signs of hepatic sinusoidal capillarization, a factor of aggravation of cirrhosis The aim of this study was to evaluate the prognostic value of serum HA for severe complications in asymptomatic patients with HCV cirrhosis. METHODS: Six hundred and sixty-eight patients with anti-HCV antibodies and increased serum alanine aminotransferase were referred to our hospital for evaluation, including liver biopsy. At entry, serum HA levels were measured in 91 patients (64 men, 27 women, 56 +/-11 years old) out of 103 who had asymptomatic, biopsy-proven cirrhosis According to the criteria of Child-Pugh, 82 were classified A and 9 B. The follow-up period was 6 to 82 months (median: 38 months), and 51 of these patients received alpha-interferon therapy during the first year. Severe complications were defined as death or liver transplantation, ascites, bleeding from esophageal varices, encephalopathy, or hepatocellular carcinoma. RESULTS: Serum HA levels at entry were higher in the cirrhotic patients in whom severe complications occurred during the follow-up period (520+/-426 microg/l vs 197+/-146 microg/l, p<0.0001). The patients with serum hyaluronan levels >350 microg/l displayed higher probabilities of occurrence of severe complications (p<0.0001). Other factors associated with the occurrence of complications or death were: serum bilirubin >18mol/l (p = 0.03), platelet count <112x10(9)/l (p= 0.02), prothrombin time <63% (p<0.0001), serum albumin <36 g/l (p=0.002), alkaline phosphatase >81 IU/l (p=0.01), and no interferon treatment (p= 0.0003). Multivariate analysis identified five independent factors predictive of severe clinical complications, namely: hyaluronan (p=0.006), prothrombin time (p=0.04), bilirubin (p=0.04), albumin (p=0.04), and no therapy (p=0.03). CONCLUSION: Serum HA level is predictive for occurrence of severe complications in HCV cirrhosis, and can be used as a prognostic marker, in addition to the parameters of the Child-Pugh score, particularly in patients with compensated cirrhosis.

Chronic cholestatic diseases.

Chronic cholestatic diseases, whether occurring in infancy, childhood or adulthood, are characterized by defective bile acid transport from the liver to the intestine, which is caused by primary damage to the biliary epithelium in most cases. In this article, approaches to diagnosis and management of the main specific disorders are provided and some of the recent developments in this field are discussed. Major advances in the understanding of the cellular and molecular physiology of bile secretion have led to identification of genetic defects responsible for the different types of progressive familial intrahepatic cholestasis (PFIC). The potential role of the genes involved in PFIC in some adult cholestatic disorders remains to be determined. The majority of adult patients with chronic cholestasis have primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Recently, variant forms of PBC have been described. The term autoimmune cholangitis is used to describe patients having chronic non-suppurative cholangitis with negative antimitochondrial antibodies (AMA) but positive antinuclear and/or antismooth muscle antibodies. Autoimmune cholangitis and AMA-positive PBC are quite similar in terms of clinical presentation, survival and response to ursodeoxycholic acid (UDCA) therapy. In contrast, autoimmune cholangitis must be distinguished from PBC-autoimmune hepatitis (AIH) overlap syndrome in which biochemical and histological characteristics of both PBC and AIH coexist. Combination of UDCA and corticosteroids is required in most patients with overlap syndrome to obtain a complete clinical and biochemical response. Long-term UDCA treatment improves survival without liver transplantation in PBC patients. Among the putative mechanisms of the beneficial effects of UDCA, description of anti-apoptotic properties and effect on endotoxin disposal in biliary cells have provided new insights. In patients with incomplete response to UDCA, combination of UDCA with antiinflammatory or immunosuppressive drugs is under evaluation. Variant forms of PSC have also been described, including PSC-AIH overlap syndrome, especially in children or young adults, and small-duct PSC, which is characterized by normal cholangiogram in patients having chronic cholestasis, histologic features compatible with PSC and inflammatory bowel disease. Development of cholangiocarcinoma (CC) is a major feature of PSC, occurring in 10-15% of patients. Early diagnosis of CC is a difficult challenge, although positron emission tomography seems a promising tool. Unlike PBC, effective medical therapy is not yet available in PSC, reflecting the lack of knowledge about the exact pathogenesis of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease, although recurrence of PSC in the graft may occur.

Effect of pretransplantation ursodeoxycholic acid therapy on the outcome of liver transplantation in patients with primary biliary cirrhosis.

As ursodeoxycholic acid (UDCA) delays the need for transplantation, this could result in patients with more comorbid disease, therefore more likely to have a worse outcome posttransplantation. The aim of this study is to compare posttransplantation outcome in patients who received UDCA versus placebo who subsequently required a liver transplant. Data on all trial patients referred for transplantation were retrospectively collected from three randomized controlled trials of UDCA in patients with primary biliary cirrhosis (PBC). An intent-to-treat analysis was conducted with patients assigned to their original treatment allocation. UDCA and placebo groups were compared at trial entry, transplant referral, just before transplantation, and 1 month and 1 year posttransplantation. From 1987 to 1996, 37 UDCA-treated and 53 placebo patients were referred for transplantation; their age, sex, and serum bilirubin levels were similar at study entry. Immediately before transplantation, these two groups were again similar with respect to age, bilirubin level, Mayo risk score, and serum creatinine level. Posttransplantation survival rates at 1 month were 93.9% in the UDCA group and 88.4% in the placebo group, and 1 year survival rates were 90.3% and 78.4%, respectively (not significant). Posttransplantation, the two groups had similar rates of infection (53.9% v 58%); however, rejection occurred significantly less often in the UDCA group; 42.9% versus 68. 8% in the placebo group (P =.04). The posttransplantation outcome of UDCA-treated patients with PBC is no different from those who were administered placebo. There is no evidence to suggest the beneficial effect of UDCA in delaying the need for transplantation is associated with a worse outcome once liver transplantation becomes necessary.

Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group.

BACKGROUND/AIMS: This study aimed to assess the relationships which may link elementary histological lesions with symptoms and biochemistries in primary biliary cirrhosis. METHODS: We studied 103 patients with primary biliary cirrhosis who participated in a double-blind, placebo-controlled trial of UDCA treatment and in whom liver biopsy specimens obtained at entry were reassessed. Relationships between histological features, fatigue, pruritus and biochemistries were calculated by using exact tests for 2 ordinal variables. RESULTS: The degrees of severity of fatigue and pruritus were significantly and exclusively related to the presence of florid interlobular bile duct lesions (p<0.01 and p<0.02, respectively). The only laboratory parameter associated with the presence of interlobular bile duct florid lesion was IgM level. The most discriminant biochemical test for interlobular bile duct paucity was gamma glutamyltranspeptidase activity. The degree of severity of both lymphocytic hepatocellular piecemeal necrosis and lobular inflammation and necrosis was mainly associated with increased gammaglobulin and IgG levels and to a lesser extent with increased IgM and aspartate aminotransferase levels. The extent of fibrosis was mainly associated with gammaglobulin levels and to a lesser degree with serum albumin, bilirubin and IgG levels. CONCLUSIONS: Symptoms and biochemistries classically used to assess primary biliary cirrhosis reflect in part the degree of severity of the main elementary histological lesions. We propose that the picture of primary biliary cirrhosis results from the clinical and biochemical expression of three distinct processes, e.g., bile duct inflammation and destruction, parenchymal inflammation and necrosis, and fibrosis. The various combinations of these processes may explain why the spectrum of primary biliary cirrhosis varies from typical primary biliary cirrhosis to mixed type of primary biliary cirrhosis and autoimmune hepatitis and suggests that the response to therapies may depend on the predominance of each process in a given patient.

Determinants of outcome of compensated hepatitis C virus-related cirrhosis.

The aim of this study was to assess the incidence of decompensation (ascites, jaundice, variceal bleeding, and encephalopathy), hepatocellular carcinoma (HCC) and death or liver transplantation in patients with compensated hepatitis C virus (HCV)-related cirrhosis, taking into account the viral genotype and interferon (IFN) therapy. Between 1989 and 1994, 668 patients with no clinical evidence of decompensation were referred to our department for liver biopsy because of positivity for anti-HCV antibodies and elevated aminotransferase activity; 103 of these patients had cirrhosis. The median follow-up was 40 months. Fifty-nine patients were treated with IFN for a mean duration of 11+/-6 months; 3 (5%) had a prolonged biochemical and virological response. Baseline characteristics of IFN-treated and untreated patients were not significantly different. HCV genotypes (InnoLiPa) were predominantly 1b (48%) and 3a (20%). During follow-up, complications of cirrhosis occurred in 26 patients, HCC in 11 patients, and decompensation not related to HCC in 19 patients. Sixteen patients died, 94% of liver disease. Three patients were transplanted for liver failure. The 4-year risk of HCC was 11.5% (annual incidence 3.3%) and that of decompensation was 20%. Survival probability was 96% and 84% at 2 and 4 years, respectively. In multivariate analysis, the absence of IFN therapy was the only independent factor predictive both for HCC and decompensation. A low albumin level at entry and the absence of IFN therapy were the two independent factors predictive of death or liver transplantation. Probability of survival at 2 and 4 years was significantly different between IFN-treated and untreated patients (respectively 97% and 92% vs 95% and 63%, P < .0001). In conclusion, in patients with compensated HCV-related cirrhosis: 1) complications of cirrhosis are frequent, whatever the viral genotype; and 2) the severity of cirrhosis and the absence of IFN therapy are independently predictive of bad outcome.

Circulating albumin messenger RNA in hepatocellular carcinoma: results of a multicenter prospective study.

The presence of circulating tumor cells might be an indicator of hematogenous spread of tumor cells leading to extrahepatic metastasis. Messenger RNA (mRNA) expression of human albumin, as a liver specific cell marker, has been proposed for this purpose in hepatocellular carcinoma. We conducted a multicenter prospective study in 101 patients with biopsy-proven hepatocellular carcinoma followed-up every 3 months for 1 year or until death. At entry into the study, albumin mRNA was detected in the blood by reverse transcription-polymerase chain reaction (RT-PCR). At entry into the study, 45% of the patients had a positive albumin mRNA test, 53% a single tumor, 16% a portal or venous hepatic thrombosis, and 16% had proven metastasis. After 1 year, there was no significant difference in survival of patients with positive or negative albumin mRNA at entry (P = .16, log-rank test). When patients with metastasis at entry were excluded, again survival did not differ between the two groups (P = .20). Independent prognostic factors of survival were radical therapeutic procedures, metastasis, number of tumors, Child-Pugh score, and thrombosis, but not the albumin mRNA test. Taking the presence of metastasis as a reference, the specificity of the test was 56%, its sensitivity 50%, and its negative predictive value 85%. The present study shows that circulating albumin mRNA detected by means of RT-PCR fails to provide significant information in the diagnosis and prognosis of hepatocellular carcinoma. Further studies are needed to determine whether the use of specific tumor markers could have clinical relevance in this setting.

Interferon alfa therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity.

BACKGROUND & AIMS: Chronic hepatitis C virus carriers may have repeatedly normal aminotransferase activity despite detectable viremia and histological hepatitis. The aim of this study was to determine the effect of interferon in this population. METHODS: Three million units of interferon alfa was administered 3 times weekly for 6 months in 10 patients with chronic hepatitis C virus infection, repeatedly normal alanine aminotransferase activity, and chronic hepatitis on liver biopsy. Serum hepatitis C virus RNA was detected by polymerase chain reaction and quantified by branched DNA before, at the end, and 1 year after treatment. A liver biopsy was performed 1 year after treatment withdrawal. RESULTS: At treatment withdrawal, hepatitis C virus RNA levels had significantly decreased, but RNA was still detectable by polymerase chain reaction in 8 of 10 patients. During the 1-year follow-up period, 6 of 9 patients had elevated aminotransferase activity on at least one occasion. One year after treatment withdrawal, RNA levels had returned to pretreatment values and no significant histological improvement was observed in the 7 patients who underwent liver biopsy. CONCLUSIONS: In patients with chronic hepatitis C and repeatedly normal aminotransferase activity, standard interferon therapy does not lead to sustained virological or histological responses despite a transient effect on hepatitis C virus replication.

Plasma alpha-glutathione S-transferase assessed as a marker of liver damage in patients with chronic hepatitis C.

alpha-Glutathione S-transferase (alpha-GST; EC 2.5.1.18) has been advocated as a better marker of hepatocellular damage than the transaminases in toxic and autoimmune hepatitis. We have assessed the potential interest of plasma alpha-GST determination in 94 anti-hepatitis C virus-positive patients with histologically proven chronic hepatitis C (34 women, 60 men, ages 40.0 +/- 11.9 years). Blood samples were assayed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase, alkaline phosphatase, and alpha-GST on the same day a liver biopsy was performed. alpha-GST concentrations were significantly above reference values in 64% of patients (compared with 58% for AST, 68% for ALT), and this increase was seen in 52% of patients with normal values for transaminases and a Knodell score > 3. Furthermore, there was a significant correlation between alpha-GST and lobular necrosis score (r = 0.31; P < 0.01). Our findings suggest that association of plasma alpha-GST with ALT may improve the biochemical assessment of liver damage in patients with chronic hepatitis C.

Quantitation of hepatitis C virus RNA in liver transplant recipients.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is common in liver transplant recipients, yet the effects of immunosuppression on HCV RNA levels and the relationship of HCV RNA levels to hepatic damage have not been studied. METHODS: To explore these issues, we measured HCV RNA in serum by polymerase chain reaction amplification and branched DNA assay from 100 HCV-infected patients undergoing liver transplantation. RESULTS: Mean posttransplant levels were 16-fold higher than pretransplant values (7,935,000 and 496,000 Eq/mL, respectively; n = 65; P < 0.0001). Patients with high pretransplant levels had higher mean posttransplant levels than those with low pretransplant levels (17,119,000 and 6,504,000 Eq/mL, respectively; P = 0.064). Posttransplant levels were similar in patients with recurrent and acquired infection and were independent of time of sampling. Fifty percent of patients with HCV infection had normal liver biopsy specimens, and there was no strong relationship between level of viremia and degree of hepatic damage. CONCLUSIONS: HCV RNA levels increase markedly following liver transplantation. The frequent finding of viremia in the absence of histological hepatitis suggests that a "carrier state" is common. Absence of allograft damage in some (despite high levels of viral RNA) suggests that in immunosuppressed patients, HCV infection may be tolerated without direct hepatic damage.

Effect of liver transplantation on sex-hormone disorders in male patients with alcohol-induced or post-viral hepatitis advanced liver disease.

The effects of liver transplantation on the pituitary-gonadal axis and sex-hormone metabolism were evaluated by studying hormonal status (androgens, oestrogens, and gonadotropins) and sex-hormone-binding globulin levels in men with advanced liver disease of both alcoholic and viral origins. Comparison of the results prior to and 6 months after liver transplantation showed that successful liver transplantation in men induced significant differences in sex-hormone levels and in pituitary-gonadal function in both alcoholic and post-hepatitis patients. Plasma testosterone and dihydrotestosterone levels increased, oestrogen (oestrone and oestradiol) and androstenedione levels fell while gonadotropin (FSH and LH) levels increased. There was also a fall in plasma prolactin levels. Sex-hormone binding globulin plasma levels were elevated prior to transplantation and decreased thereafter. These data show that male patients with advanced liver disease have biological hypogonadism and feminization, irrespective of the aetiology, and that these abnormalities rapidly improve after successful liver transplantation. Therefore in men with advanced liver disease the biochemical signs of sex hormone disturbance are reversible and may be largely related to the liver disease.