Higher Fibrosis Stage Research Articles

Expression of tumour necrosis factor‐related apoptosis‐inducing ligand and caspase‐3 in relation to grade of inflammation and stage of fibrosis in chronic hepatitis C

To assess whether the distribution of the recently described proapoptotic ligand, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and the apoptosis effector, caspase-3 alters with the degree of inflammation and fibrosis present in liver biopsy specimens from patients with chronic hepatitis C virus infection. Expression of TRAIL and caspase-3 was assessed immunohistochemically in liver biopsy specimens obtained from 89 adults with chronic hepatitis C. Expression of TRAIL in hepatocytes correlated inversely with stage of fibrosis (P = 0.001), classified according to the Scheuer score; expression of caspase-3 in hepatocytes correlated with grade of inflammation (P = 0.012). Expression of TRAIL in hepatocytes was not correlated with grade of inflammation (P > 0.05); expression of caspase-3 was not correlated with stage of fibrosis (P > 0.05). Maximum expression of proapoptotic TRAIL protein was observed in cases with low grade inflammation (G0) and low stage fibrosis (S1). Maximum expression of caspase-3 in hepatocytes was observed in cases with high grade inflammation (G3-4) and high stage fibrosis (S3), but not with liver cirrhosis (S4). There is a significant decrease in TRAIL expression with increasing grade of inflammation, whereas caspase-3 expression is significantly increased with advanced fibrosis, short of cirrhosis.

Factors Associated with Low Platelet Count in Veterans with Chronic Hepatitis C

Purpose: The purpose of this study was to examine liver histology and virological characteristics as it relates to HCV-associated thrombocytopenia in a veteran population. Methods: We conducted a retrospective review of patients with chronic HCV who had undergone liver biopsy at the Atlanta Veterans Affairs Medical Center from Jan 1, 1995 to Jan 1, 2006. Data collected included: gender, age, race, laboratory results (ALT, AST, platelet count, HCV genotype, viral load), and histology based on the Scheuer histologic scoring system. We defined low platelet count as < 150 × 103/mcL. Means and categorical variables were compared using ttest and chi square respectively. We used univaraite logistic regression to explore the relationship platelet count and various variables. Forward stepwise logistic regression was used to select variables for the final model Results: Information was available for 314 patients. 97% were male and median age was 51 years (range 30–68 years). Median aspartate transaminases (AST) level was 54 IU/L and platelet count was 213 × 103/mcL. 16% of patients had platelet counts < 150 × 103/mcL. On liver biopsy, a majority of the patients had grade 1 and 2 lobular and portal inflammation (33% and 47% for lobular, 47% and 37% for portal respectively) and stage 1 and 2 fibrosis (32% and 25% respectively). A majority of patients were genotype 1 (89%) and 52% had viral loads >850,000 IU/mL. Steatosis was reported in 41% of biopsies. In univariate logistic regression, low platelet count was associated with higher grade of portal (OR 1.9; 95% CI 1.2, 2.8; P-value 0.001) and lobular (OR 1.7; 1.2,95% CI 2.6; P-value 0.004) inflammation, higher stage of fibrosis (OR 1.91; 95% CI 1.4, 2.4; P-value < 0.001) and higher odds of abnormal AST (>35 IU/L) (OR 2.5; 95% CI 1.03, 6.2; P-value 0.04). No significant relationship was found between low platelet count and viral load, genotype, or steatosis. In multivariable regression analysis, controlling for age, gender, and grade of inflammation, low platelet cont was significantly associated with higher stage of fibrosis. The odds of having low platelet count for those with advanced stage of fibrosis (Stage 3–4) were nearly 5.5 times the odds of someone with early fibrosis (stage 0–2) (OR 5.5; 95% CI 2.8, 10.1; P-value < 0.001). Conclusion: Our study did not find genotype, viral load, or steatosis to be predictive of thrombocytopenia in veterans with HCV; however, we did demonstrate a strong association between thrombocytopenia and advanced fibrosis.

Serum α-Foetoprotein Level Predicts Treatment Outcome in Chronic Hepatitis C

Objectives To analyse the association between serum α-foetoprotein (AFP) levels and sustained virological response (SVR) in treated patients. Methods One-hundred patients with chronic hepatitis C were treated with pegylated interferon α-2a plus ribavirin for 48 weeks. The primary endpoint was SVR. Linear regression analysis was performed to identify clinical, biological, and histological factors affecting baseline AFP levels. The association between pretreatment serum AFP and SVR was assessed by multivariate logistic regression analysis. Results Of 100 patients, 95 were infected with genotype 4, one with genotype 1, and four with undetermined genotype. The median serum AFP level was 4.5 ng/ml and AFP values ranged from 1.2 to 49.8 ng/ml. In multivariate analysis, higher fibrosis stage and higher steatosis score were independently associated with higher serum AFP levels. SVR rate was 61.0% (61/100), and was lower for patients with AFP levels above rather than below the median value (40.8% versus 80.4%, respectively, P&lt;0.001). In multivariate analysis, including adjustment for age, gender, body mass index, steatosis score, fibrosis stage, ALT level, haemoglobin level, clotting time, HCV RNA viral load, and treatment dose received, a baseline serum AFP level above the median value was associated with a lower SVR rate (OR [95% CI]=0.10 [0.03–0.42], P&lt;0.001). None of the seven patients with increased (above 15 ng/ml) pretreatment AFP achieved SVR. Conclusions In this study, higher baseline serum AFP levels independently predicted a lower SVR rate among patients with chronic hepatitis C. If confirmed with genotypes other than 4, these findings would suggest adding serum AFP to the list of factors predictive of treatment response.

Pathological analysis of oxyphilic granular hepatocytes and hepatocellular mitochondria in chronic hepatitis C

Oxyphilic granular hepatocyte (OGH) results from hepatocellular changes associated with chronic hepatitis. The histopathological significance of OGH has not been clarified. The subjects consisted of two groups of patients with hepatitis C: one group of patients who had undergone liver biopsy 3.8 times on average, and were followed for 8 years on average, and one group of hepatocellular carcinoma (HCC) patients who had undergone hepatectomy. The following items were examined: frequency of OGH, relationship between OGH and the degree of fibrosis and inflammation; amount of mitochondria in resected tissues; activity of mitochondrial enzymes; relationship between the development of HCC and OGH; and relationship between the duration of infection and OGH in the post-transfusion patients. The incidence of OGH was 35.3% in liver biopsy patients and 46.9% in resected patients. A higher stage of fibrosis was associated with a higher frequency of OGH. Not only OGH but also hepatocyte mitochondria in the peripheral zone increased with the progression of fibrosis. Hepatocytes with or without increased mitochondria were randomly distributed. The mitochondrial enzyme activity was increased in hepatocytes with increased mitochondria. In the post-transfusion patients, a longer duration of infection and a higher stage of fibrosis were associated with a higher frequency of OGH. A high percentage of patients with OGH developed HCC. Mitochondrial changes are important histological findings related to the progression of liver lesions and the possible development of HCC.

Early Histologic Changes in Fibrosing Cholestatic Hepatitis C

Recurrent hepatitis C (RHCV) after liver transplantation is almost universal, and occasional patients will have an aggressive course characterized histologically by pericellular/sinusoidal fibrosis and cholestasis, known as fibrosing cholestatic hepatitis (FCH). The early stages and evolution of this disease have not been well characterized. A total of 77 liver biopsies performed for indication (nonprotocol) were evaluated for necroinflammation, rejection, cholestasis, and fibrosis. Control groups were composed of protocol biopsies from HCV transplant patients (10 biopsies) as well as non-HCV transplant patients (6 biopsies). Scoring for necroinflammation, rejection, and fibrosis were compiled using standard criteria (hepatic activity index, Banff, Ishak, METAVIR). Pericellular fibrosis was staged with a novel "sinusoidal" system. A cholestasis scoring system was developed to quantitate parenchymal and portal features of cholestasis. Biopsies were categorized as rejection, RHCV, FCH, and stable based on histology and clinical information. FCH was found to have a higher fibrosis stage overall when compared to most diagnostic groups, regardless of the staging system used. Additionally, sinusoidal fibrosis was significantly higher in the FCH diagnosis group. Cholestasis was more prominent in biopsies of FCH in all comparisons. In conclusion, the presence of cholestasis and fibrosis with mild to moderate RHCV should raise the suspicion of FCH. When studying the evolution of these cases, the first abnormality to appear is RHCV and cholestasis, fibrosis develops soon after, and both continue to worsen until the point of allograft failure or patient death.

More Advanced Hepatic Fibrosis in Hispanics with Chronic Hepatitis C Infection: Role of Patient Demographics, Hepatic Necroinflammation, and Steatosis

We sought to assess whether Hispanics have more advanced hepatitis C virus (HCV)-related liver disease than non-Hispanic whites (NHW) and to identify contributory factors. Patients were recruited from the Los Angeles county hepatitis clinic. Liver fibrosis and necroinflammation (NI) were assessed by the Ishak scoring system. Hepatic steatosis was graded as 0-4. A total of 232 patients were evaluated, 63 NHW and 169 Hispanic. Hispanics were older and had a higher prevalence of blood transfusion (40%vs 21%), obesity (body mass index > 30) (47%vs 21%), diabetes mellitus (DM) (16%vs 5%), and hepatic steatosis (79%vs 47%), p < 0.02. Independent predictors of hepatic steatosis were Hispanic ethnicity (odds ratio [OR] 3.8, 95% CI 1.7-8.7, p= 0.001) and obesity (OR 5.7, 95% CI 2.3-14.1, p= 0.0002). Compared with NHW, Hispanics also had higher fibrosis stage (3.3 +/- 2 vs 2.3 +/- 6.9, p= 0.001), NI grade (6.4 +/- 1.8 vs 5.6 +/- 1.6, p= 0.002), and faster fibrosis progression/yr (0.14 +/- 0.09 vs 0.09 +/- 0.07, p= 0.0002). Presence of DM (OR 2.9, p= 0.02), grade 1-2 hepatic steatosis (OR 2.3, p= 0.03), AST/ALT > 1 (OR 4.3, p= 0.01), NI grade (OR 1.7, p < 0.0001), age at biopsy (OR 1.1, p < 0.0001), and serum bilirubin (OR 5.4, p < 0.0001) were independent predictors of fibrosis stage > or =4. This study confirms that Hispanics have more advanced hepatic fibrosis than NHW. This is related to older age, higher NI grade, and greater prevalence of hepatic steatosis and DM.

Long-term clinical outcome and effect of glycyrrhizin in 1093 chronic hepatitis C patients with non-response or relapse to interferon

Objective. Patients with chronic hepatitis C who do not respond to interferon can be treated with glycyrrhizin to reduce disease activity. The objective of this study was to evaluate the effect of glycyrrhizin on the incidence of hepatocellular carcinoma (HCC) during long-term follow-up after non-response to interferon. Material and methods. We analyzed individual patient data of all consecutive patients treated with interferon in 12 major Japanese hospitals between 1990 and 1995 who showed no sustained response. Results. The study comprised 1093 patients. During a mean follow-up of 6.1±1.8 years, 107 patients developed HCC. The Cox regression analysis with time-dependent variables showed that older age, male gender, higher alanine aminotransferase (ALAT) and higher fibrosis stage were significantly associated with a higher risk of developing HCC. Response to glycyrrhizin, defined as ALAT < 1.5×upper limit of normal, was significantly associated with a decreased incidence of HCC: hazard ratio 0.39 (95% CI 0.21–0.72; p<0.01). G-estimation, used to correct for ALAT as the confounder, showed no significant benefit of glycyrrhizin in the overall study population. Conclusions. This study provides some evidence to show that interferon non-responder patients with chronic hepatitis C and fibrosis stage 3 or 4 may have a reduced incidence of HCC if glycyrrhizin therapy leads to normalization of ALAT levels.

Impact of Steatosis on Long-Term Histological Outcome in Chronic Hepatitis C after Antiviral Therapy

Steatosis is recognized as a cofactor influencing the presence and progression of fibrosis in chronic hepatitis C. It has been reported that antiviral therapy may reduce the progression of fibrosis and leads to regression in chronic hepatitis C patients achieving a sustained virological response (SVR). Whether steatosis might affect the long-term histological outcome of antiviral therapy remains unclear. One-hundred and sixty-one consecutive patients (genotype 1, n=76; genotype 2, n=73) receiving interferon-alpha2b and ribavirin were analysed. Ninety patients had paired biopsies with a mean interval of 29.1 +/- 7.1 months. Variables associated with baseline steatosis were higher body mass index (> or = 25, P=0.002) and higher fibrosis stage (> or = 2, P=0.019). Neither the presence nor the severity of steatosis was associated with SVR. Evaluation of paired biopsies showed no different distribution of steatosis evolution between patients with and without SVR (P=0.374). Among patients achieving a SVR, there was a significant difference in fibrosis changes between those with grade 0 or 1 steatosis and with grade 2 or 3 steatosis at post-treatment biopsy (-0.6 +/- 1.2 vs 0.3 +/- 1.3, P=0.041), whereas changes in histological activity index did not differ (-3.7 +/- 2.6 vs -4.0 +/- 2.9, P=0.740). Stepwise logistic regression analysis showed that SVR (odds ratio [OR]: 16.33, P=0.004) and grade 0 or 1 post-treatment steatosis (OR: 12.82, P=0.018) were independently associated with fibrosis regression. In patients with chronic hepatitis C, steatosis not only correlates with advanced fibrosis at baseline but also affects fibrosis regression after antiviral therapy.

Risk factors of accelerated liver fibrosis in HIV-HCV coinfection: a matched analysis: original

Introduction: Chronic liver diseases have become a significant cause of mortality in HIV patients. Few reports have assessed risk factors for HCV disease progression in HIV infected patients. Objectives: The aim of our study was to compare the progression rate of liver fibrosis in HIV-HCV coinfected patients with that of HCV-only infected patients. We sought to identify the risk factors associated with accelerated progression rates and higher fibrosis stage. Methods: Eighteen HCV/HIV coinfected patients were matched to fifty-four HCV patients in a 1 to 3 ratio. The matching variables included duration of HCV, alcohol use, age, gender and race. Both unmatched and matched analyses were performed on estimated fibrosis progression rate and fibrosis stage separately. An ordinal logistic regression analysis was used to identify risk factors. Results: Using Metavir unit system, the mean (+ standard deviation [SD]) estimated fibrosis rates were 0.26 (+ 0.17) and 0.11 (+ 0.09) for HIV-HCV coinfected and HCV-only patients respectively (unmatched analysis p=0.001). The mean (+ SD) duration of HCV infection was 22.05 (+ 1.10) and 15.50 (+ 2.20) for coinfected and HCV-only patients, respectively. There was a statistically significant difference in the proportion of patients with stage 4 liver fibrosis between both groups (HIV-HCV 33 %, HCV 9%, P =0.004). Ordinal Logistic Regression model (unmatched analysis) suggested that duration of HCV (Odds Ratio [OR]= 1.11, 95 % confidence interval [CI] 1.03 to 1.20, P = 0.01), HIV status (OR =9.49, CI 2.39 to 37.75, P = 0.001) (overall model R2= 0.16, F = 0.0002) and age (OR=1.14, CI 1.01 to 1.28, P = 0.03) are statistically significant independent predictors of accelerated progression rate and higher fibrosis stage. Conclusions: Duration of HCV infection, age, and HIV status are significant independent predictors of accelerated fibrosis in HIV-HCV coinfected patient population. HIV-HCV coinfected patients should be counseled and their providers informed regarding the risk factors for accelerated progression of liver fibrosis. Further studies are needed to investigate the underlying biological and immunological mechanisms of accelerated liver fibrosis in HCV patients coinfected with HIV. South African Gastroenterology Review Vol.2(3) 2004: 14-17

The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic Fatty liver disease.

Autoantibodies may exist in serum of patients with nonalcoholic fatty liver disease (NAFLD) although their prevalence and clinical significance is uncertain. We aimed at examining the prevalence of autoantibodies and autoimmune hepatitis among patients with NAFLD. Prevalence of antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), and autoimmune hepatitis (AIH) based on the International AIH Group were determined in 225 patients with liver biopsy-proven NAFLD. Fifty-one patients [23% (95% CI 17.3-28.2%)] had autoantibodies in serum which is significantly higher than the prevalence in the general population. ANA were present in 46 patients (20%), SMA in 6 (3%), and both antibodies in one patient. Positive autoantibodies were associated with higher fibrosis stage (p= 0.03), higher inflammatory grade (p= 0.02), and higher levels of gammaglobulin (p= 0.01). Prior to liver biopsy, 45 of the 51 (88%) patients with positive autoantibodies fulfilled diagnostic criteria for 'probable' or 'definite' AIH. After liver biopsy, however, only four patients fulfilled diagnostic criteria. Routinely measured autoantibodies are present in one quarter of patients with NAFLD and are associated with more severe histological damage. Liver biopsy is required to rule out AIH in most NAFLD patients with positive autoantibodies.

The pathogenesis of hepatitis C virus is influenced by cytomegalovirus.

We investigated the effect of beta-herpesviruses on allograft failure and mortality, hepatitis C virus (HCV) replication, and liver histologic characteristics among 92 HCV-infected liver transplant recipients. Reactivation of cytomegalovirus (CMV) but not of human herpesvirus 6 (HHV-6) was independently associated with allograft failure and mortality (risk ratio, 3.71; 95% confidence interval, 1.64-8.39); allograft failure and mortality was observed in 48% of patients with CMV disease, 35% of patients with subclinical CMV infection, and 17% of patients without CMV infection (P=.0275). CMV reactivation was highly predictive of mortality (P<.001), regardless of whether it remained subclinical or evolved into CMV disease. Patients with CMV disease had a higher fibrosis stage (P=.05) and had a trend toward a higher hepatitis activity index (P=.10) and HCV load (P=.10) at 16 weeks after liver transplantation. The pathogenesis of HCV is influenced by its interaction with CMV but not with HHV-6.