The role of steatosis in the progression of liver damage in chronic hepatitis C (CHC) was studied. Enrolled were 180 consecutive liver biopsy-proven CHC patients and 41 additional subjects with a known duration of infection. We evaluated the histological activity index (HAI), grade of fibrosis and steatosis, body mass index (BMI; kg/m 2 ), distribution of body fat, HCV genotype, and levels of HCV RNA. Eighty six (48%) patients showed steatosis, and a higher prevalence was observed in genotype 3a infection (P < .01). A correlation between the grade of steatosis and fibrosis was observed (P < .001). Fibrosis was also associated with age (P < .001). After adjusting for age, the association between steatosis and fibrosis remained significant. The grade of steatosis also correlated with the HAI (P < .007) with a significant increase in periportal necrosis. No relation was found between steatosis and age, gender, iron storage, or levels of HCV RNA. Patients with a high grade of steatosis (>30%) showed higher serum levels of ␥-GT and ALT (P < .001). Overall, steatosis was not significantly associated to BMI. Analysis by single genotype showed a significant association between the grade of steatosis and BMI in type 1 infection r ‫؍‬ .689; P < .001) and with levels of HCV RNA in type 3a infection r ‫؍‬ .786; P < .001). Visceral fat distribution rather than BMI proved to be associated with steatosis (P < .001). Data obtained from patients with a known date of infection confirmed that steatosis grades 3-4 were associated with a higher annual rate of fibrosis progression, and showed that alcohol and steatosis act together in increasing fibrosis (P < .05). Our data indicate that steatosis is an important cofactor in increasing liver necroinflammatory activity and in accelerating fibrosis in CHC. Visceral obesity and genotype 3a play a role in the development of steatosis. (HEPATOLOGY 2001;33: 1358-1364

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The clinical outcome of cirrhotic patients with hepatocellular carcinoma (HCC) depends both on the residual liver function and tumor characteristics. However, the relative prognostic weight of these variables is not well defined. The aims of this study were to verify the value of known prognostic factors and to devise a prognostic index more sensitive than the commonly used Okuda stage. A retrospective analysis of the cases of HCC diagnosed at 16 Italian institutions from 1990 to 1992 was performed. Overall survival was the only end point used in the analysis. The Cox model, stratified by locoregional treatment, was used for multivariate analyses. The final model was derived from 10 randomly chosen training samples, and the prognostic validity of the Cancer of the Liver Italian Program (CLIP) score was assessed on the corresponding testing samples. Four hundred thirty-five cases of HCC were collected. As of January 1997, 313 patients (72%) were deceased. Overall median survival was 20 months. At multivariate analysis, independent predictive factors of survival were Child-Pugh stage, tumor morphology, alpha-fetoprotein (AFP), and portal vein thrombosis. A simple scoring system (CLIP score) was thus produced, assigning linear scores (0/1/2) to the covariates. Compared with Okuda stage, the CLIP score, structured as a six-category tool, has a greater discriminant ability, revealing a class of patients with an impressively more favorable prognosis and another class with a relatively shorter life expectancy. The CLIP score is a new prognostic system that accounts for both liver function and tumor characteristics. It is easy to calculate and appears to give more precise information than the Okuda stage.

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Summary. The pathogenesis of thrombocytopenia in chronic hepatitis is not well known. This study evaluated the relationship between liver injury, serum thrombopoietin, splenomegaly and thrombocytopenia in chronic viral hepatitis. Two hundred and nine patients were enrolled, 85 with splenomegaly and 124 without. Thrombocytopenia was present in 71% and 23% of patients with or without splenomegaly respectively. In subjects with low platelet count, those with splenomegaly showed significantly lower platelet numbers than those without splenomegaly. The spleen size correlated with portal hypertension. An inverse correlation between spleen size and platelet count was observed (r 20´54; P , 0´0001). In patients without splenomegaly, thrombocytopenia was associated with the grade of fibrosis; platelet counts were the highest in patients with fibrosis 0±2, lower in those with grade 3 (P , 0´008) and lowest in those with grade 4 (P , 0´05). These findings were independent of demographic and biochemical characteristics, hepatic necroinflammatory activity, portal hypertension and splenomegaly. Patients with normal platelet counts showed higher thrombopoietin levels than those with low platelet counts (P , 0´0001). An inverse correlation between thrombopoietin levels and fibrosis grade was observed (r 2 0´50; P , 0´0001). Median thrombopoietin levels were 58 and 27 pg/ml for fibrosis grade 0±1 and grade 4 respectively (P , 0´001). These data indicate that advanced hepatic fibrosis, causing an altered production of thrombopoietin and portal hypertension, plays the central role in the pathogenesis of thrombocytopenia in chronic viral hepatitis.

The overall prevalence of steatosis in patients with Hepatitis C virus (HCV) chronic infection is 55.5% (range 34.8-81.2%). This is a two to threefold increase compared with the prevalence of steatosis in chronic hepatitides because of other aetiologies and of the figures expected on the grounds of a steatosis-HCV chance association. HCV genotype 3 (HCV-3) has specific epidemiological features; furthermore, as compared with HCV-non-3 genotypes, it is associated with a higher prevalence (74.1%vs 47.9%, P < 0.01) and with more severe grades of steatosis (prevalence of grade 3 steatosis 29.6 vs 5.5 P < 0.01). Host and viral factors play a role, although to a variable extent, in the pathogenesis of HCV-3 and non-3 steatosis. HCV load and body mass index are associated with steatosis in HCV-3 and in HCV-non-3 patients respectively. Serum cholesterol levels and liver steatosis at baseline follow an inverse relationship in HCV infection. As hypocholesterolaemia corrects only in those sustained responders to antiviral treatment both in genotype 3 and in non-3 genotypes, the occurrence of a virally induced, acquired and reversible hypobetalipoproteinaemia seems plausible. Steatosis affects the natural course of HCV infection: it is associated with fibrosis, a possible mediator of increased risk to develop type 2 diabetes, it impairs the response to antiviral treatment in HCV-3 patients and might constitute a risk factor for the development of hepatocellular carcinoma. These observations indicate the need to evaluate the efficacy of combined antiviral and 'metabolic' approaches vs standard antiviral regimes in patients with steatosis and HCV chronic infection.

The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r ‫؍‬ 0.367; P ‫؍‬ .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 mol/L, respectively (P ‫؍‬ .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P ‫؍‬ .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR ‫؍‬ 7.1), HAI (OR ‫؍‬ 3.8), liver fibrosis (OR ‫؍‬ 4.0), and HCV genotype 3 (OR ‫؍‬ 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P ‫؍‬ .03), HAI (P ‫؍‬ .0001), and steatosis (P ‫؍‬ .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC. ( H epatic steatosis frequently occurs in hepatitis C virus (HCV) infection, more so than in subjects with hepatitis B virus. 1 The prevalence of fatty infiltration in the livers of chronic hepatitis C (CHC) has been reported to average around 50%, with a range of 30% to 70%. 2-4 For HCV genotype 3 infection, it has been suggested that the virus exerts a direct steatogenic effect, supported by correlation of steatosis with the levels of HCV RNA, and by the reversal of steatosis as the result of antiviral therapy. [5][6][7][8] Moreover, the degree of steatosis has been related to the extent of hepatic fibrosis in CHC. 5,[9][10][11][12] The mechanisms involved in HCV-associated steatosis are unknown. Several host (body mass index [BMI], insulin resistance, hypertrigliceridemia) and viral factors may be implicated. Among viral factors, at least two HCV proteins-core and NS5A-have been credited with the ability to alter lipid metabolism in infected cells, thus causing hepatic steatosis in the absence of immune response. 13,14 In the transgenic mouse model, it has also been shown that the HCV core protein induces steatosis. 15 Transgenic mice expressing HCV co...