Steatosis and non-alcoholic steatohepatitis in patients with chronic hepatitis due to hepatitis C virus infection

BACKGROUND: [corrected] Hepatic steatosis is a common finding in patients with hepatitis C, mainly virus C genotype 3. Steatosis in these cases might be associated with antiviral treatment response and with prognosis of chronic hepatitis. AIMS: To determine the presence of steatosis and non-alcoholic steatohepatitis in chronic hepatitis C and its correlation with genotype and hepatic fibrosis. PATIENTS AND METHODS: One hundred and twenty patients with chronic hepatitis C were retrospectively evaluated; genotype was done in 102 patients. All specimens were stained with hematoxylin-eosin, picrosirius and perls. Staging of hepatitis C was scored by Brazilian Classification and the diagnosis of non-alcoholic steatohepatitis by the American Association for the Study of Liver Diseases criteria RESULTS: Steatosis was found in 65 of 120 cases (54.2%); it was mild in 37/65 (56.9%), moderate in 12/65 (18.5%) and severe in 10/65 (15.4%). In relation to fibrosis, 80 of 120 patients had mild fibrosis F0-F2 (66.6%) and 40 (33.3%) had more advanced fibrosis (F3 or F4). Steatosis was associated with genotype 3 (76.7%) in comparison with other genotypes (49,0%). There were no relationship between steatosis and advanced fibrosis F3/F4 (52,5%) or mild fibrosis (54,4%). Non-alcoholic steatohepatitis was diagnosed in 8/120 cases (6.7%) and was significantly associated with hepatitis C virus genotype 3 and with advanced fibrosis (F3 and F4) CONCLUSIONS: The presence of steatosis and non-alcoholic steatohepatitis in chronic hepatitis C are associated to genotype 3; moreover non-alcoholic steatohepatitis was correlated with more advanced fibrosis.     

Glucose intolerance and hypoadiponectinemia are already present in lean patients with chronic hepatitis C infected with genotype non-3 viruses

OBJECTIVES: Steatosis and metabolic abnormalities seem to be frequent and deleterious in chronic hepatitis C. Changes in glucose homeostasis and in adiponectin levels, an adipokine with anti-inflammatory and insulin-sensitive properties, were evaluated in patients with chronic hepatitis C according to steatosis, liver fibrosis and body mass index. METHODS: Seventy-three patients with chronic hepatitis C (40 men, 33 women) infected with genotypes non-3 and 22 healthy controls (11 men and 11 women) were included in the study and all had a biochemical evaluation, including metabolic parameters, adiponectin measurement, and a liver biopsy. Insulin sensitivity was assessed with the HOMA 1-IR insulin resistance model. RESULTS: Steatosis was found in 65.7% of the patients and significant fibrosis (METAVIR F2-F4) was present in 28.7%. The presence of steatosis could only be predicted by fibrosis, whereas significant fibrosis could be predicted by steatosis and age. Adiponectin levels were significantly decreased (-32%) with the severity of the steatosis. Although overweight chronic hepatitis C patients (body mass index>or=25 kg/m2) had insulin resistance and hypoadiponectinemia, lean chronic hepatitis C patients (body mass index<25 kg/m2) had already significantly higher glycemia and lower adiponectin levels than in controls. CONCLUSIONS: This study confirms the high incidence of steatosis in patients infected by hepatitis C virus genotypes non-3, well linked to the development of fibrosis and metabolic abnormalities. Importantly, the present findings put emphasis on the early development of these metabolic abnormalities as they were already found in lean patients with chronic hepatitis C. The direct implication of hepatitis C virus is thus further stressed in the development of steatosis and insulin resistance, with or without involvement of host factors.     

Factors associated with liver steatosis and fibrosis in chronic hepatitis C patients

Liver steatosis is a common finding in patients infected with hepatitis C virus (HCV). Host and viral factors have been associated with steatosis, but their relative contributions have not been clearly addressed. It has been suggested that steatosis plays a role in the progression of liver fibrosis. AIMS: To assess: a) factors associated with steatosis in patients infected with hepatitis C virus; b) their impact on liver fibrosis. PATIENTS AND METHODS: Three hundred and fourteen untreated patients were included. Lifetime alcohol consumption was estimated. Liver fibrosis, inflammation and necrosis were assessed using the METAVIR score. Body mass index (BMI) was determined. The scoring system for steatosis was as follows: 0, no steatosis; 1, less than 10%; 2, 10% to 30%; 3, 30% to 70%; 4, more than 70% of hepatocytes affected. RESULTS: In univariate analysis, steatosis was associated with elevated BMI (P=0.001), excessive alcohol intake (P=0.005), genotype 3 (P<0.001) and moderate to severe histological activity (P=0.01). Multivariate analysis showed that steatosis correlated with two independent factors: genotype 3a (OR=60.7; 95% CI: 7.6-483.4) (P<0.001) and BMI (OR=4.86; 95% CI: 1.8-13.15) (P=0.002). In univariate analysis, severe fibrosis (F2-F3-F4) was associated with older age (P<10(-5)), male gender (P=0.001), disease duration (P<0.006), BMI (P<10(-4)), alcohol intake (P<10(-6)), severity of histological activity (P<10(-5)) and steatosis (P<10(-6)). In multivariate analysis, three independent factors were associated with severe fibrosis: disease duration > 10 years (OR=3.17; 95% CI: 0.65-15.4) (P=0.015), presence of steatosis (OR=3.17; 95% CI: 1-9.99) (P<0.049) and genotype 3a (OR=5.56; 95% CI: 1.4-22.1) (P=0.015). CONCLUSION: In patients with chronic hepatitis C, steatosis is significantly associated with genotype 3 infection and high BMI. Steatosis is an independent risk factor associated with severe fibrosis. These results have major implications for the management of patients with chronic hepatitis C.     

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C

The relationship between cryoglobulin and severity of liver lesions is debated. No study has focused on the relationship between cryoglobulin, liver steatosis, and fibrosis. The aim of this study was to determine the relationship between cryoglobulins and liver lesions (necroinflammation, fibrosis, and steatosis) in patients with hepatitis C virus (HCV) infection. Four hundred and thirty-seven consecutive patients with untreated chronic hepatitis C who had been admitted for liver biopsy were included in the study. Risk factors for fibrosis and steatosis were assessed. The mean age was 50.9 +/- 13.8 years, and 49% were male. Cryoglobulin was present in 286 patients, 103 of whom had vasculitis. One hundred and eighty-six patients (43%) had steatosis greater than 10%, and 110 (25%) had advanced fibrosis (Metavir score F3-F4). On multivariate analysis, cryoglobulin increased by nearly threefold the risk of having advanced fibrosis and steatosis greater than 10%. Steatosis greater than 10% was associated with a higher body mass index (P < .001), HCV genotype 3 (P < .001), cryoglobulin (P = .002), and advanced liver fibrosis (P = .009). Advanced fibrosis (F3-F4) was associated with a higher level of gamma-glutamyltransferase (P = .04), cryoglobulin (P < .001), a high grade of necroinflammation (Metavir score A2-A3) (P < .001), and steatosis higher than 10% (P = .04). In conclusion, our study shows an independent association between cryoglobulin and steatosis as well as advanced fibrosis.     

Impact of human immunodeficiency virus infection on the prevalence and severity of steatosis in patients with chronic hepatitis C virus infection

BACKGROUND/AIMS: Although steatosis is strongly associated with hepatitis C virus (HCV) infection, little is known about this finding in patients coinfected with human immunodeficiency virus (HIV) and HCV. The aims of the present study were to determine the prevalence and severity of steatosis in HIV/HCV coinfected patients. METHODS: Consecutive patients undergoing liver biopsy were prospectively identified and were interviewed to obtain detailed demographic and clinical data. Steatosis was scored according to the percentage of hepatocytes involved: 0 (none), 1 (<33%), 2 (33-66%), or 3 (>66%); fibrosis was scored on a scale from 0 to 4. RESULTS: A total of 708 patients were enrolled, including 154 with HIV/HCV coinfection and 554 with HCV monoinfection. Steatosis of any grade (72.1 vs. 52.0%, P<0.001), grade 2/3 steatosis (48.1 vs. 20.2%, P<0.001), and stage 3/4 fibrosis (43.5 vs. 30.0%, P=0.002) were significantly more common in coinfected patients. Compared to HCV monoinfected subjects, HIV/HCV coinfection was associated with a significantly increased odds of steatosis of any grade (OR=3.21; 95% CI, 1.84-5.60) and grade 2/3 steatosis (OR=5.63; 95% CI, 3.05-10.36) after adjusting for potential confounding variables. Among coinfected patients, the fibrosis progression rate increased in a linear fashion with the grade of steatosis. CONCLUSIONS: Steatosis is more common and more severe in HIV/HCV coinfected patients than in those with HCV monoinfection.     

Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies

BACKGROUND AND AIMS: Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies. METHODS: Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load. RESULTS: The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p<0.03) steatosis at diagnosis. Overall, fibrosis progression was observed in 31% of patients and stability in 69%. In a univariate analysis, fibrosis progression was associated with male sex (p=0.05), worsening of histological activity (p=0.04), and worsening of steatosis (p=0.0003). In a multivariate analysis, the only factor independently associated with fibrosis progression was worsening of steatosis (worsening v improvement/stability: odds ratio 4.7 (95% confidence interval 1.3-10.8); p=0.0001). CONCLUSIONS: Our results suggest that in untreated patients with CHC and serial liver biopsies, fibrosis progression is strongly associated with worsening of steatosis.     

A diagnostic algorithm for assessment of liver fibrosis by liver stiffness measurement in patients with chronic hepatitis B

Steatosis could affect liver stiffness measurement in patients with nonalcoholic fatty liver disease and chronic hepatitis C. In this study, we aimed to investigate the impact of steatosis on liver stiffness in hepatitis B virus (HBV)‐infected patients and develop a diagnostic algorithm for prediction of liver fibrosis by liver stiffness based on the controlled attenuation parameter. A total of 488 HBV‐infected patients who underwent clinical examination, Fibroscan and liver biopsy were prospectively enrolled. The best liver stiffness measurement (kPa) cut‐offs for significant fibrosis (S≥3) and advanced fibrosis (S≥4) were 8.1 and 10.9, respectively. The best controlled attenuation parameter cut‐off for severe steatosis (≥30%) was 287 dB/m. Among patients with low‐grade fibrosis (S0‐S2/S0‐S3), mean liver stiffness values were significantly higher in subjects with severe steatosis or controlled attenuation parameter ≥287 dB/m compared with those without. Moreover, in subjects with low‐grade fibrosis, a higher rate of false‐positive rate was observed in patients with severe steatosis than those in patients without (F0‐F2: 28.2% vs 9.7%; F0‐F3: 17.0% vs 5.3%), and in patients with CAP≥287 dB/m compared with their counterpart (F0‐F2: 23.7% vs 9.2%; F0‐F3: 14.1% vs 4.8%). Low‐grade fibrosis was accurately identified by γ‐glutamyl transpeptidase‐to‐platelet ratio (GPR) with a cut‐off value of 0.17. In patients with GPR<0.17, similar results were observed. The presence of steatosis may lead to overestimation of fibrosis assessed by liver stiffness measurement in patient with chronic hepatitis B. A diagnostic algorithm for assessing fibrosis using liver stiffness was developed by combining both controlled attenuation parameter and GPR values.     

Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C

Conflicting data exist regarding the relationship between hepatitis C virus genotype 1 and hepatic steatosis as well as the latter's role in the progression of fibrosis and treatment response. We assessed factors associated with hepatic steatosis in genotype 1 chronic hepatitis C and the impact of hepatic fat on fibrosis development and interferon responsiveness. Two hundred ninety-one non-diabetic patients with genotype 1 chronic hepatitis C were examined for the presence of steatosis and its correlation with clinical, virological, and biochemical data, including insulin resistance (IR), evaluated by the homeostasis model assessment (HOMA) score. Steatosis was graded as mild (1%-20% of hepatocytes involved), moderate (21%-40% of hepatocytes involved), and severe (>40% of hepatocytes involved). Steatosis was mild in 110 of 291 (37.8%) and moderate/severe in 55 of 291 (18.9%) subjects. By logistic regression, moderate/severe steatosis was independently associated with the female sex (odds ratio [OR] 2.74; 95% CI 1.40-5.35), high gamma-glutamyltransferase levels (OR 1.52; 95% CI 1.22-1.91), and HOMA-score (OR 1.076; 95% CI 1.001-1.26). By logistic regression, moderate/severe steatosis (OR 2.78; 95% CI 1.21-6.4), and platelet counts (OR 0.97; 95% CI 0.96-0.98) were independent predictors of advanced fibrosis. Patients with moderate/severe steatosis had an OR of 0.52 (95% CI 0.30-0.90) for sustained virological response compared with patients with mild/absent steatosis. In conclusion, in nondiabetic European patients with genotype 1 hepatitis C at low risk for the metabolic syndrome, the prevalence of steatosis was nearly 60%. IR is a risk factor for moderate/severe steatosis, especially in men. Moderate/severe steatosis has clinical relevance, being associated with advanced fibrosis and hyporesponsiveness to antiviral therapy.     

Aspartate aminotransferase (AST) more than alanine aminotransferase (ALT) levels predict the progression of liver fibrosis in chronic HCV infection

The development and severity of liver fibrosis in patients with chronic HCV infection can be evaluated best according to the staging of fibrosis in blind liver biopsy. So far there is however no biochemical indicator suggesting advanced fibrosis or progression of fibrosis in chronic HCV infection. In 1997 - 1999 60 adult out-patients (32 women) with chronic HCV infection were examined by blind liver biopsy. The grading of hepatitis was scored according to Knodell and staging of fibrosis according to Desmet. All patients were anti-HCV positive, assessed by the ELISA-3 method and 48/60 had positive HCV RNA in serum. The main risk factor of HCV infection was blood transfusion (67%). Of 27 examined patients 20 (74%) had serotype HCV 1. Staging of fibrosis: histologically confirmed fibrosis was not recorded in 11 patients (18.3%), mild and medium fibrosis was recorded in 25 (42%), severe fibrosis in 14 (23%) and cirrhosis in 10 (17%). With confirmed fibrosis correlated more closely AST serum activity (p < 0.002) than ALT activity (p < 0.03). Steatosis of the liver was found in 25 (42%) patients. The mean age of patients with steatosis was significantly higher than that of patients without steatosis (p < 0.0008). Steatosis was more frequent in patients with fibrosis (p < 0.04), in particularin the age group above 60 years. The development of fibrosis in patients with chronic HCV infection is suggested by permanently elevated activity of both transaminases whereby AST has a higher predictive value than ALT activity. A total of 40% histologically tested patients had the highest staging of fibrosis (3 - 4). Steatosis is in chronic HCV infection a very frequent finding (42%), in particular in patients above 60 years and those with serious fibrosis. The finding of fibrosis should stimulate the initiation of antiviral treatment which can lead to regression of fibrosis and improvement of the histological finding.     

Hepatitis C and diabetes mellitus: effect of diabetes on the course of the liver disease

The prevalence of diabetes mellitus is higher in chronic hepatitis C than in hepatitis B, even without cirrhosis. OBJECTIVE: To study the host, specific viral factors associated with diabetes mellitus and the influence of diabetes mellitus on the intensity of steatosis and the severity of fibrosis. MATERIAL AND METHODS: The following data were collected in a cohort of 1249 patients with chronic hepatitis C established between December 1991 and June 2004: age, gender, body mass index (BMI). None of the patients were under treatment for their liver disease. Serum transaminase level and hepatitis C serology with search for viral RNA, viral load and genotype were obtained. The Metavir score, iron overload using the Perls score (0-4) and steatosis class (0-3) were determined on liver biopsies. RESULTS: Mean patient age was 52.5+/-10 years (56% male). Mean BMI was 24.6+/-24 kg/m2. Forty-three patients (17.2%) presented diabetes mellitus. The mean duration of their diabetes was 8.9 years. Genotype 1 predominated (60.4%) and mean viral load was 7.7x10(6) eq.v/ml. Steatosis was present in 69.7% of the diabetic patients versus 17% of the non-diabetic patients. Grade 2 fibrosis (F2) was observed in 32.5% of diabetic patients versus 29% in non-diabetic patients and F3, F4 in 73% of the diabetic patients versus 57% of the non-diabetic patients. Comparison between diabetic and non-diabetic patients demonstrated an absence of statistically significant difference (at 5%) between the groups for gender, viral load and genotype. Diabetic persons were older (58.7 years against 51 years) and liver biopsy revealed steatosis and fibrosis (F3, F4) more often in diabetic patients (69.7% versus 49.5%). CONCLUSION: These findings suggest that steatosis could favor progression of fibrosis in diabetics with chronic hepatitis C.     

Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis

OBJECTIVES: The clinical significance of hepatic steatosis in chronic hepatitis B virus patients is poorly understood. The purpose of this study was to determine risk factors for liver steatosis in chronic hepatitis B patients and its relationship with fibrosis. METHODS: We retrospectively evaluated liver biopsies from patients with chronic hepatitis B treated in our department. Patients co-infected with other viruses (hepatitis C virus, HIV) or suffering from liver disease of any other cause were excluded from the study, as well as patients consuming alcohol above 30 g/day for males or 20 g/day for females. Liver steatosis, necroinflammation and fibrosis were assessed. RESULTS: A total of 233 patients with chronic hepatitis B were included in the study. The mean age was 44.7+/-16.2 years. There were 164 men (70.4%) and 69 women (29.6%). The majority of patients were HbeAg-negative, 196/233 (84.1%). Thirty-seven patients had cirrhosis (15.9%). Steatosis was present in 42 patients (18%). Steatosis was independently associated with fasting glucose level (P=0.019) and being overweight (body mass index >or=25; P=0.021). No correlation was found with stage of fibrosis, grade of inflammation, alcohol use or other parameters. Ninety-four out of 233 patients (40.3%) had advanced fibrosis. Patients with advanced fibrosis were older than those with minimal or no fibrosis (47.6+/-17 versus 42.3+/-15.2 years, P=0.024) and more frequently had a higher grade of necroinflammation activity (57/94 (60.6%) versus 26/139 (18.7%), P<0.0001). There was no significant association between advanced fibrosis and the presence of steatosis or mild alcohol consumption. CONCLUSION: Hepatic steatosis is present in 18% of our patients with biopsy-proven chronic hepatitis B. Steatosis is independently associated only with body mass index and fasting glucose level, risk factors for metabolic steatohepatitis, and was not correlated with the degree of fibrosis.     

Liver steatosis in children with chronic hepatitis C

OBJECTIVES: Steatosis is common in adults with chronic hepatitis C, and is involved in the progression of fibrosis. Because little is known about steatosis in pediatric hepatitis C, the aims of this study were to determine the prevalence and severity of steatosis in a pediatric population with chronic hepatitis C, and to evaluate its correlation with clinical parameters. METHODS: Liver biopsies were obtained from 66 consecutive Italian and Spanish children with chronic hepatitis C (87.6% genotype 1). Grade and stage were assessed according to Ishak's system. Steatosis was scored as absent, minimal (less than 5% of steatosic hepatocytes), mild (>5%, 33%, 66%); moderate and severe scores were combined for statistical purposes. The BMI-for-age percentile (BMI%) was calculated in all cases at the time of liver biopsy. Cholesterol and triglyceride serum levels were available in 55 cases. RESULTS: The prevalence of steatosis was 27% (18/66 cases, 16/18 with genotype 1), and it was higher in Italian than in Spanish patients (10/21 vs.7/45, P= 0.01). BMI% correlated significantly with both the presence of steatosis (P= 0.002) and its severity (P= 0.000). Steatosis also correlated with serum triglyceride levels (P= 0.04). CONCLUSION: Steatosis is associated with BMI in children with chronic hepatitis C due mainly to genotype 1, and with no confounding hepatotoxic factors (alcohol or drugs). This may reflect its metabolic rather than viral origin and raise new issues in the management of children with hepatitis C.     

The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C

Summary.  Recent attention has focused on the liver profibrogenic role of leptin in animal models. The purpose of this study was to evaluate the role of leptin and TNF- α in the severity of liver fibrosis in patients with chronic hepatitis C (CHC). We used a radioimmunoassay to determine serum leptin concentrations in 77 consecutive patients with CHC and 22 healthy controls. Leptin was correlated with liver histological (METAVIR) and metabolic indices. Sixty five patients had none to moderate liver fibrosis (F0-F2) and twelve severe fibrosis (F3-F4). Steatosis was observed in all but 27 patients. Leptin was significantly increased in patients compared with controls and was significantly more elevated in females both in patients and controls. The age, age at infection, prothrombin index, body mass index (BMI), triglycerides, glycaemia, ferritin, leptin and TNF- α , were associated with severe fibrosis. Steatosis was significantly more pronounced in patients with severe than those without or moderate fibrosis ( P  = 0.04). Only leptin was significantly and independently associated with severe fibrosis (OR = 1.2, CI 95%: 1.1–1.4, P  = 0.03). Leptin was significantly associated with BMI ( r  = 0.64, P  < 0.001) and glycaemia ( r  = 0.43, P  < 0.001). Significant correlations were found between steatosis and BMI ( r  = 0.30, P  < 0.01) and glycaemia ( r  = 0.30, P  < 0.01). In patients with CHC and higher BMI and glycaemia levels, the severity of liver fibrosis is associated with serum leptin. TNF- α is a putative candidate involved in the mechanism.     

Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure

Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women. Four hundred seventy-two HCV-infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (+/-SE) was lower in women who received HRT compared with untreated patients (0.099 +/- 0.016 vs. 0.133 +/- 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 +/- 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV-infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long-term progression of liver fibrosis.     

Fat,diabetes, and liver injury in chronic hepatitis C

It is increasingly recognized that host factors can modulate the fibrogenic response in patients with chronic hepatitis C. Obesity, because of its prevalence, and diabetes, which seems to occur more frequently in patients infected by the hepatitis C virus (HCV), are often present in patients with chronic hepatitis C. Both conditions result in fatty liver, which in turn is associated with more severe liver damage, especially fibrosis or inflammation. Steatosis can either originate from associated metabolic alterations (insulin resistance resulting in metabolic steatosis) or from a direct cytopathic effect of the virus (genotype 3, resulting in viral steatosis). Metabolic steatosis seems to be a factor in resistance to antiviral therapy, whereas viral steatosis is reduced in sustained responders. Whether metabolic steatosis has a direct role in liver fibrosis progression or is only a surrogate marker of an underlying defect triggering fibrogenesis, such as insulin resistance, is a subject of debate. High serum glucose levels and diabetes have a strong and independent profibrogenic impact. Exciting new data are expanding our understanding of the mechanisms of steatogenesis in HCV infection and providing potential links between insulin resistance or hyperglycemic states and liver fibrogenesis.     

Fibrosis progression in initially mild chronic hepatitis C

The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 +/- 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 +/- 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow-up parameters. Sixty-four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (DeltaF/year) was associated with age (P < 0.0001), baseline and follow-up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years and advanced fibrosis/cirrhosis develops in one-third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C.     

Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients

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 micromol/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.     

Steatosis, insulin resistance and fibrosis progression in chronic hepatitis C

Steatosis is a common histological feature of chronic hepatitis C. Two distinct mechanisms seem to be involved in the pathogenesis of hepatic steatosis in chronic hepatitis C virus (HCV) infection. In HCV genotype 3-infected patients, steatosis is likely viral-induced, and represents a direct cytopathic effect of HCV, whereas in patients infected with other genotypes, host metabolic risk factors for insulin resistance such as obesity, type 2 diabetes and hyperlipidemia play a major role in intracellular lipids accumulation. Interestingly, the outcome of steatosis matches the virological response to treatment in HCV genotype 3-infected patients who have purely virus-induced steatosis but not in patients with metabolic causes of steatosis. Suspected molecular underlying mechanisms include interactions between the HCV core protein and intracellular lipid metabolism pathways as well as induction of insulin resistance. Steatosis is of clinical importance as it appears to be associated with more rapid liver fibrosis progression and impaired response to antiviral therapy. However, whether metabolic and host factors associated with steatosis, steatosis per se or both, may be responsible for this association remains to be clarified. This review is aimed at describing the current knowledge of steatosis, insulin resistance and fibrosis progression in chronic hepatitis C.     

Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial

There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds-C Trial, designed to test the efficacy and safety of peginterferon alfa-2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment-na?ve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non-overweight. In conclusion, in this cohort of HCV-infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment-na?ve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.     

Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis

Steatosis is a frequent histological finding in chronic hepatitis C infection; however, the pathophysiology of steatosis and its role in disease progression have not been established. We studied 148 consecutive patients with untreated chronic hepatitis C to assess the effect of body mass index, diabetes mellitus, alcohol consumption, hepatic iron content, and viral load on steatosis and hepatic fibrosis. Ninety-one patients (61%) had steatosis: grade 1 (<30% hepatocytes involved) in 61 (41%), grade 2 (30%-70% hepatocytes involved) in 17 (11%), and grade 3 (>70% hepatocytes involved) in 13 (9%). After adjusting for potential confounding variables, a highly significant relationship was found primarily between steatosis and body mass index (P <.0001). The mean (+/-SD) body mass index of patients with no steatosis was 23.9 +/- 4.3 kg/m2, whereas for grade 1 steatosis it was 26.5 +/- 5.1 kg/m2, and for grade 2 and 3 steatosis combined the body mass index was 28.4 +/- 4. 9 kg/m2. Hepatic fibrosis was significantly associated with age (P =. 002). After adjusting for potential confounding variables, including age, hepatic fibrosis was also significantly associated with steatosis (P <.03). There was no significant association between hepatic iron content, alcohol intake, gender, and viral load and steatosis or fibrosis. These findings suggest that increasing body mass index has a role in the pathogenesis of steatosis in chronic hepatitis C and that steatosis may contribute to fibrosis. The association between body mass index and steatosis and fibrosis has important prognostic and therapeutic implications in the management of patients with chronic hepatitis C virus.