Fibrosis In Chronic Hepatitis C Research Articles

Clinical value of acoustic radiation force impulse imaging for quantitative evaluation of degree of liver fibrosis in chronic hepatitis C patients

To investigate the diagnostic value of acoustic radiation force impulse (ARFI) imaging technology for the assessment of liver fibrosis in chronic hepatitis C (CHC) patients. One-hundred-and-eight CHC patients were examined by real-time ultrasound elastography using the Acuson S2000 ARFI instrument (Siemens Healthcare) and underwent liver biopsy for pathohistological analysis. The correlation between liver fibrosis grades determined by the two approaches was analyzed. The cut-off values for diagnosis by ARFI (S more than 2, S more than 3 and S = 4) were determined by generating a receiver operating characteristic (ROC) curve. The spectrum of liver stiffness detected by ARFI sonoelastography included S1 at (1.26+/-0.27) m/s (n = 36), S2 at (1.45+/-0.51) m/s (n = 31), S3 at (2.01+/-0.54) m/s (n = 27), and S4 at (2.28+/-0.82) m/s (n = 14). The ARFI values were significantly different among the four different stages of liver fibrosis (P less than 0.001). The liver stiffness detected by ARFI sonoelastography was significantly correlated with the liver fibrosis stage determined by the gold standard pathohistological analysis (Spearman's rank coefficient: 0.61, P less than 0.001). Using the ARFI technology for assessment of liver fibrosis gave areas under the ROC curve of 0.779 for S more than 2 patients, of 0.863 for S more than 3 patients, and of 0.0880 for S = 4 patients. The real-time ultrasound elastography ARFI technology can show the elasticity modulus of liver, and its data values positively correlate with the patho-histology grade of liver fibrosis in CHC patients. ARFI technology is easy to operate, non-invasive, and quantitative, and has potential clinical value for assessing liver fibrosis in CHC.

725 The Balance Between T Helper 17 and FOXP3+ T Regulatory Cells in Patients With Chronic Hepatitis C: Relation to Disease Activity and Hepatic Fibrosis

Introduction T helper (Th)17 cells, a newly identified subset of Th cells, are major mediators of inflammation-associated disease and have a reciprocal developmental relationship with the immunosuppressive T regulatory (Treg) cells, which actively restrain the inflammatory response. The present work was designed to study the balance between Th17 cells and Treg cells in patients with chronic hepatitis C (CHC) in relation to disease activity and severity of hepatic fibrosis. Methods Twenty patients with treatment-naive CHC and 20 healthy subjects were included in the study. The Th cells, Th17 cells and Treg cell subsets in fresh whole blood samples were identified as CD3 + CD4 + , CD4 + IL17A + and CD4 + CD25 + FoxP3 + cells respectively using flow cytometry and expressed as percentages of total lymphocytic count. Serum IL17 levels were measured using solid phase sandwich enzyme linked immunosorbant assay kit. Liver biopsies from patients with CHC were examined to assess histological activity grade and fibrosis stage according to METAVIR scoring system. Liver-infiltrating CD4 + (Th cells), IL17A + cells (Th17 cells) and FoxP3 + cells (Treg cells) were detected by immunohistochemical staining and their proportions were determined as ratios of infiltrating CD4 + Th cells. Results Patients with CHC showed significant increases in the percentage of Th17 cells, Th17 cells/FoxP3 + Treg cells ratio in peripheral blood and serum IL17 levels and a significant decrease in the percentage of circulating FoxP3 + Treg cells compared with healthy subjects (p + Th cells were not statistically different between the two groups (p=0.284). The proportions of liver-infiltrating IL17A + cells and FoxP3 + cells of the total intrahepatic CD4 + cell population were inversely correlated and showed positive correlations with the percentages of circulating Th17 cells and FoxP3 + Treg cells respectively in patients with CHC (p + cells and IL17A + cells/FoxP3 + cells ratio and serum IL17 levels and were inversely correlated with the proportion of liver-infiltrating FoxP3 + cells (p Conclusion In patients with CHC, the CD4 + Th cell phenotype is skewed towards the IL17 producing-Th phenotype. The imbalance between Th17 and Foxp3 + Treg cells plays an important role in disease progression and hepatic fibrosis in CHC. Competing interests None declared.

Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy

BackgroundNoninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. MethodsSixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. ResultsFive markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. ConclusionCoopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value.

Plasma sphingolipids: potential biomarkers for severe hepatic fibrosis in chronic hepatitis C.

The plasma profile of sphingolipids in hepatic fibrosis patients with chronic hepatitis C (CHC) is rarely considered at present. The association between plasma sphingolipids and severe fibrosis in CHC remains an obscure area of research. The aim of the present study was to assess the plasma profile of sphingolipids and to examine the association between plasma sphingolipids and severe fibrosis in CHC, in order to identify potential novel markers of severe fibrosis in CHC. A cohort of 120 treatment-naïve patients with CHC were included in the present study. Liver biopsies were performed and routine serological indicators were measured. Plasma sphingolipids were detected using high performance liquid chromatography tandem mass spectrometry. A total of 44 plasma sphingolipids were detected. Plasma hexosylceramide (HexCer; d18:1/12:0), HexCer (d18:1/16:0) and HexCer (d18:1/22:0) were shown to be significantly different in patients with CHC between those with and without severe fibrosis (Metavir F ≥ 3; P < 0.05). HexCer (d18:1/12:0) was observed to be closely associated with severe fibrosis in CHC [odds ratio (OR)=1.03] following adjustment for confounding variables in a multivariate analysis. HexCer (d18:1/12:0) had diagnostic value for severe fibrosis in CHC [area under the curve (AUC)=0.69]. In patients with CHC who had developed significant fibrosis (Metavir F ≥ 2), HexCer (d18:1/12:0) remained closely associated with severe fibrosis (OR=1.08) in this subgroup. In addition, HexCer (d18:1/12:0) had sufficient diagnostic ability (AUC=0.73) to distinguish severe fibrosis in patients with CHC with significant fibrosis. In conclusion, the present study indicated that plasma HexCer (d18:1/12:0) exhibits a close correlation with severe hepatic fibrosis in CHC, particularly in patients who have significant fibrosis. Additionally, HexCer (d18:1/12:0) may be a potential marker of severe hepatic fibrosis in CHC.

Chronic hepatitis c genotype-4 infection: role of insulin resistance in hepatocellular carcinoma

BackgroundHepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma (HCC) and different HCV genotypes show characteristic variations in their pathological properties. Insulin resistance (IR) occurs early in HCV infection and may synergize with viral hepatitis in HCC development. Egypt has the highest reported rates of HCV infection (predominantly genotype 4) in the world; this study investigated effects of HCV genotype-4 (HCV-4) on prevalence of insulin resistance in chronic hepatitis C (CHC) and HCC in Egyptian patients.MethodsFifty CHC patients, 50 HCC patients and 20 normal subjects were studied. IR was estimated using HOMA-IR index and HCV-4 load determined using real-time polymerase chain reaction. Hepatitis B virus was excluded by enzyme-linked immunosorbent assay. Standard laboratory and histopathological investigations were undertaken to characterize liver function and for grading and staging of CHC; HCC staging was undertaken using intraoperative samples.ResultsHCC patients showed higher IR frequency but without significant difference from CHC (52% vs 40%, p = 0.23). Multivariate logistic regression analysis showed HOMA-IR index and International Normalization Ratio independently associated with fibrosis in CHC; in HCC, HbA1c, cholesterol and bilirubin were independently associated with fibrosis. Fasting insulin and cholesterol levels were independently associated with obesity in both CHC and HCC groups. Moderate and high viral load was associated with high HOMA-IR in CHC and HCC (p < 0.001).ConclusionsIR is induced by HCV-4 irrespective of severity of liver disease. IR starts early in infection and facilitates progression of hepatic fibrosis and HCC development.

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Predictive Value of the Fibrosis Scores in Patients with Chronic Hepatitis C Associated with Liver Fibrosis and Metabolic Syndrome

We evaluated patients with chronic hepatitis C (CHC) and compared the clinical and pathological features of steatosis and metabolic syndrome to identify the risk factors for CHC with severe fibrosis. One hundred seventy-one patients with biopsy-confirmed CHC were included in the study: 90 males and 81 females, age 56.2 ± 12.8 years; 46 with obesity (BMI≥25 kg/m(2)); 51 with hypertension; 36 with type 2 diabetes mellitus; and 20 with hypertriglyceridemia. Steatosis was detected in 79 patients (46%); 92 patients (54%) showed no steatosis. Seventy-four patients (43%) showed mild fibrosis and 97 patients (56%) showed severe fibrosis. The variables that were significantly associated with steatosis were obesity [odds ratio 2.160 (1.010-4.727), p=0.046] and type 2 diabetes [odds ratio 3.667 (1.559-8.430), p=0.027]. The variables that were significantly associated with severe fibrosis were older age [odds ratio 2.675 (1.309-5.464), p=0.007], obesity [odds ratio 2.156 (1.006-4.619), p=0.048] and type 2 diabetes [odds ratio 8.739 (2.845-26.846), p=0.0002]. Nagasaki (N) score (the total number of specific risk factors, namely an older age, obesity, and type 2 diabetes) was higher in the severe fibrosis group than in the mild fibrosis group (mild fibrosis: severe fibrosis=1.48 ± 1.14 vs.2.66 ± 94, p<0.001). Metabolic syndrome factors, including obesity and diabetes, play a critical role in the pathogenesis of fibrosis in CHC. The N score was therefore found to be a significant predictor of severe fibrosis in CHC.

Assessment of Insulin Resistance and Insulin Growth Factor-1 in Egyptian Patients with Chronic Hepatitis C

Introduction: Insulin resistance (IR) is documented in patients with chronic hepatitis C(CHC), plays an important factor in disease progression and predicting poor response to treatment. In chronic liver disease, levels of insulin-like growth factor-1 (IGF-1) were correlated with IR. Aim: To evaluate IR and serum levels of IGF-1 in Egyptian patients with CHC after anti-viral therapy. Patients and Methods: Forty biopsy-proven, non-diabetic, CHC patients, who received combined IFN/ribavirin therapy, in addition to 10 healthy controls were studied. Serum levels of IGF-1, growth hormone (GH) were measured and HOMA-IR(homeostasis model assessment of IR), body mass index (BMI) were calculated. Baseline data, retrieved from patients’ files before initiation of therapy, together with response to antiviral therapy were analyzed with respect to the measured variables. Results: All patients possessed a significant higher HOMA-IR score (p = 0.02), GH levels (p < 0.001) and blood glucose levels (p < 0.001) than controls while significantly lower levels of IGF-1 were found in patients (p = 0.008)with no significant difference between responders and non-responders as regards the previously mentioned variables. HOMA-IR score was significantly correlated with GH levels, p = 0.003 and with IGF-1 levels in both responders and non responders. Low IGF-1 levels were associated with increase in fibrosis stages and were significantly correlated with insulin(r = –0.499, p = 0.001). Conclusion: CHC patients exhibit an increased HOMA-IR score reflecting the existence of IR irrespective of treatment response. Low IGF-1 levels were associated with advanced stages of fibrosis and thus could contribute to the progression of hepatic fibrosis in CHC.

The importance of steatosis in chronic hepatitis C infection and its management: A review

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with approximately 180 million people infected worldwide. Hepatic steatosis is a frequent histological finding in chronic hepatitis C (CHC) infection and is 2- to 3-fold more common than would be expected by chance alone. A high body mass index with excess visceral fat distribution is associated with steatosis in patients infected with HCV genotype 1 but not genotype 3, re-enforcing the concept that in patients with CHC, some have "metabolic steatosis", predominantly HCV genotype 1, and others "viral steatosis", mainly HCV genotype 3. Accumulating evidence suggests that steatosis may contribute to progression of fibrosis in CHC. Hepatic insulin resistance appears to play a role through the pro-fibrogenic effects of compensatory hyperinsulinemia. The aim of this review was to assess the effect host and viral factors play in steatosis development in patients with CHC infection and its possible relationship with hepatocellular carcinoma. The review examines the mechanisms by which CHC infection causes hepatic steatosis, the impact hepatic steatosis has on the natural history of the disease and finally, explores if treatments leading to a reduction in the amount of steatosis might lead to improved treatment outcomes. The basic medical science of steatosis in CHC will be discussed including proposed models of steatogenesis and the influence of viral and metabolic factors at the molecular level and how these might impact on current and future therapies.

Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: Differences and similarities

To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD). Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (>30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis >30% in CHC, whereas only age and BMI were related to steatosis in CHB. These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.

Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B

Objective. The results of retrospective studies suggest an association between smoking, insulin resistance, steatosis and fibrosis in patients with chronic hepatitis C (CHC); no data are available for chronic hepatitis B (CHB). The purpose of this study was to evaluate the relationship, if any, of such factors on liver fibrosis in a cohort of patients with CHB and CHC. Material and methods. The study prospectively included 271 consecutive patients with CHB (n=95) or CHC (n=176) who had undergone liver biopsies. Each patient completed a questionnaire on smoking habits; anthropometric measurements and laboratory examinations were carried out and histological lesions were recorded. Results. In CHC patients, severe fibrosis was independently associated with a higher body mass index (BMI) (OR: 1.180, 95% CI: 1.028–1.354; p=0.019), heavy smoking (OR: 3.923, 95% CI: 1.356–11.348; p=0.012), higher alanine aminotransferase (ALAT) levels (OR: 1.010, 95% CI: 1.003–1.017; p=0.005) and alkaline phosphatase (ALP) levels (OR: 1.016, 95% CI: 1.001–1.030; p=0.03) and presence of necroinflammation (OR: 11.165, 95% CI: 1.286–96.970; p=0.029). Moreover, steatosis was independently associated with high gamma-glutamyl transpeptidase (GGT) values, heavy smoking and presence of necroinflammation. In CHB patients, no association between smoking habits and fibrosis or steatosis was noted. Conclusions. Heavy smoking is associated with severe fibrosis in CHC but not CHB. Heavy smoking is also significantly associated with steatosis in CHC and this could be the link between smoking and fibrosis progression.

Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors

Hepatic steatosis is commonly seen in chronic hepatitis C (CHC) patients. It has been reported to be associated with both metabolic factors and viral factors, and affects the severity of fibrosis in CHC. However, the relationship between hepatic steatosis and chronic hepatitis B (CHB) is unclear. The aims of this study were to investigate the frequency of hepatic steatosis in CHB patients, to identify the factors associated with its presence, and assess the relationship between the stage of steatosis and the severity of fibrosis. Medical records of 153 adult patients with CHB who had undergone a liver biopsy within the past 4 years were included in the study. Body mass index (BMI) and age of CHB patients with steatosis was significantly higher than the patients without steatosis (P < 0.05), as determined by the univariate analysis. Steatosis was found to correlate with the BMI values and alanine aminotransferase (ALT) levels, and ALT levels were associated with hepatitis B virus (HBV)-DNA levels and histology activity index (HAI) scores, stages of fibrosis were associated with the HAI score and HBV-DNA, as determined by the multivariate analysis. In contrast, there was no significant association between advanced stages of fibrosis and steatosis. Our data indicate that hepatic steatosis is more frequently present in CHB patients than in the general population. We hypothesize that steatosis in CHB patients may be due to metabolic factors and the ability of HBV to indirectly facilitate the development of steatosis. In the present study, steatosis in CHB patients was not found to be associated with the severity of fibrosis.

Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C

The contribution of oxidative stress to the pathogenesis of chronic hepatitis C (CHC) is still poorly elucidated. This study investigated the relationship between oxidative stress, insulin resistance, steatosis and fibrosis in CHC. IgG against malondialdehyde-albumin adducts and HOMA-IR were measured as markers of oxidative stress and insulin resistance, respectively, in 107 consecutive CHC patients. Oxidative stress was present in 61% of the patients, irrespective of age, gender, viral load, BMI, aminotransferase level, histology activity index (HAI) and HCV genotype. Insulin resistance and steatosis were evident in 80% and 70% of the patients, respectively. In the patients infected by HCV genotype non-3, but not in those with genotype 3 infection HOMA-IR (p<0.03), steatosis (p=0.02) and fibrosis (p<0.05) were higher in the subjects with oxidative stress than in those without. Multiple regression analysis revealed that, HOMA-IR (p<0.01), fibrosis (p<0.01) and oxidative stress (p<0.05) were independently associated with steatosis, whereas steatosis was independently associated with oxidative stress (p<0.03) and HOMA-IR (p<0.02). Steatosis (p<0.02) and HAI (p=0.007) were also independent predictors of fibrosis. In patients infected by HCV genotype non-3, oxidative stress and insulin resistance contribute to steatosis, which in turn exacerbates both insulin resistance and oxidative stress and accelerates the progression of fibrosis.

Noninvasive serum markers in the diagnosis of structural liver damage in chronic hepatitis C virus infection

Several noninvasive markers are being used to assess the structural liver damage in patients with chronic hepatitis C (CHC). We evaluated the capacity of serum hyaluronic acid (HA), aspartate aminotransferase (AST)/ALT ratio, the AST to platelet ratio index (APRI) and gamma-glutamyltransferase (GGT) levels to predict the intensity of hepatic fibrosis in patients with CHC. In a total of 206 hepatitis C virus RNA-positive biopsied patients, AST, ALT, GGT levels, platelet count and serum HA concentration were determined. The APRI was calculated as the ratio of AST to platelets. HA levels were best correlated with disease stage (r=-0.694; P<0.001). In the diagnosis of significant fibrosis (F2-F4), HA levels [AUC=0.879, 95% CI (0.832-0.927)] and APRI [AUC=0.824 (0.772-0.903)] were the markers with the best diagnostic accuracy. These parameters also best identified the presence of cirrhosis (F4), with an AUC of 0.908 (0.868-0.949) for HA and of 0.837 (0.772-0.903) for APRI. Serum HA was the parameter that alone presented the best diagnostic accuracy in the assessment of hepatic fibrosis in CHC. The APRI showed a better diagnostic sensitivity than GGT levels or the AST/ALT ratio. Its simple determination and low cost make this index a valid alternative for the noninvasive staging of CHC.

Relationship Between Steatosis, Inflammation, and Fibrosis in Chronic Hepatitis C: A Meta-Analysis of Individual Patient Data

Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Effect of interferon alpha and ribavirin treatment on serum levels of transforming growth factor-β1, vascular endothelial growth factor, and basic fibroblast growth factor in patients with chronic hepatitis C

To assess the role of transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the pathogenesis of fibrosis associated with chronic hepatitis C (CHC) and to evaluate the influence of the antiviral therapy on above parameter levels depending on the treatment results (complete response or no response). Study group included 100 patients with CHC, in whom fibrosis in liver specimens was assessed (Scheuer fibrosis score: 1-4 points). Control group included 30 subjects with antibodies anti-HCV present and persistently normal ALT level, without fibrosis (Scheuer fibrosis score: 0 points). Concentration of studied parameters was assayed in the serum by immunoenzymatic method before and after the therapy with interferon alpha-2b and ribavirin. TGF-beta1 levels were significantly higher in the study group compared to the control group (35.89 vs 32.37 ng/mL; P=0.023). Such differences were not found in VEGF and bFGF levels. In patients showing complete response (negative HCV RNA and normal ALT level), significant increase in VEGF (112.8 vs 315.03 pg/mL; P<0.05) and bFGF (2.51 vs 15.79 pg/mL; P=0.04) levels were found. Significant decrease in TGF-beta1 level was observed both in responders (37.44 vs 30.02 ng/mL; P=0.05), and in non-responders (38.22 vs 30.43 ng/mL; P=0.043). bFGF levels before the treatment were significantly lower (2.51 vs 5.94 pg/mL; P=0.04), and after the treatment significantly higher (15.79 vs 4.35 pg/mL; P=0.01) in patients with complete response than in those with no response. Among the analyzed parameters TGF-beta1 seems to play the most important role in the pathogenesis of fibrosis in CHC. Levels of this factor are significantly lower in subjects who do not have fibrosis developed in them. Good therapeutic effect in CHC patients is associated with significant changes in TGF-beta1, VEGF, and bFGF levels. bFGF seems to have the highest usefulness in the prognosis of treatment efficacy.

HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C

Patients infected with HIV-1 who are heterozygous at HLA class I loci present greater variety of antigenic peptides to CD8+ cytotoxic T lymphocytes, slowing progression to AIDS. A similar broad immune response in chronic hepatitis C (CHC) infection could result in greater hepatic injury. Although specific HLA class II alleles may influence outcome in CHC patients, the role of HLA class I heterogeneity is generally less clearly defined. Our aims were to determine whether HLA class I allelic diversity is associated with disease severity and progression of fibrosis in CHC. The study population consisted of 670 adults with CHC, including 155 with advanced cirrhosis, and 237 non-HCV-infected controls. Serological testing for HLA class I antigens was performed via microlymphocytotoxicity assay. Peptide expression was defined as heterozygous (i.e., a different allele at each locus) or homozygous. Fibrosis staging was determined using METAVIR classification. Heterozygosity at the B locus (fibrosis progression rate [FPR] 0.08 vs. 0.06 units/yr; P = .04) and homozygosity at the A locus (FPR 0.10 vs. 0.08 units/yr; P = .04) predicted a higher median FPR. Age at infection, genotype, and duration of infection were also predictors of FPR. A higher proportion of patients with stage F2-F4 expressed HLA-B18 compared with controls (OR 2.2, 95% CI 1.17-4.23; P = .02). These differences were not observed in patients with advanced cirrhosis. HLA zygosity at 1, 2, or 3 alleles was not associated with fibrosis stage, liver inflammation, or treatment outcome. In conclusion, HLA class I allelic diversity has a minor influence on FPRs and disease severity in CHC.

Performance of serum marker panels for liver fibrosis in chronic hepatitis C

Chronic hepatitis C (CHC) is characterised by hepatic fibrosis, used as a proxy measure of prognosis. Liver biopsy is a flawed reference standard and serum markers of fibrosis offer an attractive alternative. A systematic review was conducted to assess the performance of panels of serum markers of hepatic fibrosis in CHC, incorporating analyses placing markers in a clinical context. 14 studies were included with 10 different panels. Median AUC in validation populations was 0.77 and training populations 0.81. Likelihood ratios (LR) ranged from -LR 0.1 to 0.9, + LR 1.2 to 33.1, diagnostic odds ratios (DOR) were 9.0 (median) with a range of 5 to 27- mostly below values of robust tests. Tests perform with either high sensitivity with low specificity or vice versa. Cut-off levels that gave clinically relevant predictive values for the presence/absence of significant fibrosis were applicable to 35% of the population. Serum markers can rule-in or rule-out fibrosis in up to 35% of patients, but cannot differentiate stages of fibrosis reliably. Improvement of index and reference test in needed including evaluation of clinical outcomes as reference. Improved test reporting is needed to derive LR and DOR as performance indicators.

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 accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity

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/m2), 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 γ-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.)