Mechanisms and significance of liver steatosis in hepatitis C virus infection

INTRODUCTION The hepatitis C virus (HCV) is a major cause of chronic liver disease with an estimated 170 million people infected worldwide. The spectrum of severity of the liver disease associated with HCV varies widely from non- specific, minimal inflamm…     

Noninvasive assessment of liver steatosis, fibrosis and inflammation in chronic hepatitis C virus infection.

BACKGROUND: Duplex-Doppler ultrasound is a noninvasive method for the assessment of hepatic hemodynamics beyond conventional gray-scale imaging. The clinical value of the method for the grading and staging of chronic hepatitis C virus (HCV) infection and the prediction of hepatic steatosis still has to be determined. This study aimed to compare Duplex-Doppler and ultrasound with the histologic staging and the estimation of hepatic steatosis in chronic HCV infection. PATIENTS AND METHODS: One hundred and nineteen consecutive patients with chronic HCV infection underwent both liver biopsy and ultrasound with Duplex-Doppler. Maximum portal venous blood flow velocity, portal venous flow undulation, hepatic venous flow pattern and spleen size were assessed and compared with histologic findings. Histologic grading and staging was performed according to the modified HAI and hepatic steatosis was estimated. RESULTS: Doppler ultrasound was unable to discriminate between different degrees of fibrosis. Sensitivity/specificity of portal venous flow and undulations for the diagnosis of hepatic cirrhosis was 74.5%/53% and 76.5%/100%. The PPV and NPV of reduced undulations was 100% and 96.2%. Mono- or biphasic hepatic venous flow indicated advanced hepatic steatosis (sensitivity 88.2%, specificity 74.5%, PPV 36.6%, NPV 97.5%). Spleen size was significantly enlarged both in patients with cirrhosis and steatosis. CONCLUSIONS: Although Duplex-Doppler of the portal and hepatic veins is not a substitute for histologic grading and staging, portal vein undulations can predict liver cirrhosis with considerable accuracy. Moreover, triphasic patterns of hepatic venous flow virtually exclude significant fatty liver disease. Additional studies should perform intraindividual follow-up investigations to further define the role of Duplex-Doppler ultrasound in chronic HCV infection.     

The predictive value of steatosis in hepatitis C virus infection

Steatosis is a complication of hepatitis C virus (HCV) infection and the mechanisms of its development are complex, involving viral and host factors. Steatosis that is prevalently viral is associated with HCV genotype 3, and steatosis that is prevalently metabolic is associated with non-3 genotypes. Viral steatosis is correlated with the level of HCV replication, whereas metabolic steatosis is related to insulin resistance. The two types of steatosis have a different impact on HCV disease and may have an additive effect. HCV infection is a multifaceted disease with hepatic and extrahepatic manifestations. There is a body of evidence indicating that HCV-related steatosis plays a role in many HCV manifestations and, thus, the presence of steatosis is a predictive factor for the development of such events. The current data show that HCV-related steatosis predicts an advanced liver disease and a more rapid progression of fibrosis, as well as an increased risk of development of hepatocellular carcinoma. Moreover, the presence of steatosis in a HCV patient has a high predictive value that the subject may have or may develop insulin resistance, diabetes and metabolic syndrome. Recently, a strict association between HCV-related steatosis and development of atherosclerosis has been demonstrated. In addition, steatosis negatively impacts response rate to interferon-based treatment, even in HCV genotype-3 infection. Therapeutic strategies to improve steatosis and, consequently, response to standard antiviral therapy and outcome of disease are wanted. The authors summarize current knowledge of impact of steatosis on the above reported clinical conditions associated with HCV infection.     

Insulin resistance and liver steatosis in chronic hepatitis C infection genotype 3

Hepatitis C virus (HCV) infection is a common chronic liver disease worldwide. Non-alcoholic fatty liver disease and insulin resistance (IR) are the major determinants of fibrosis progression and response to antiviral therapy. The pathogenetic link between IR and chronic HCV infection is complex, and is associated with HCV genotype. Liver steatosis is the most common in the patients infected with genotype 3 virus, possibly due to direct effects of genotype 3 viral proteins. To the contrary, hepatic steatosis in the patients infected with other genotypes is thought to be mostly due to the changes in host metabolism, involving IR. In HCV genotype 3, liver steatosis correlates with viral load, reverts after reaching the sustained virologic response and reoccurs in the relapsers. A therapeutic strategy to improve IR and liver steatosis and subsequently the response to antiviral treatment in these patients is warranted.     

Evaluation of hepatic steatosis by ultrasound in patients with chronic hepatitis C virus infection.

OBJECTIVE: To compare two alternative ultrasound parameters, hepatic vein flow (HVF) pattern and presence of focal hypoechoic areas (FHA) within the liver hilus, as non-invasive predictors of liver steatosis in patients with chronic hepatitis C virus (HCV) infection. DESIGN: In 122 consecutive patients with chronic HCV infection, the HVF pattern and presence of FHA within the liver hilus were assessed by Duplex-Doppler and B-mode sonography. All patients underwent liver biopsy and the sonographic results were compared with a histological score of steatosis used as the gold standard for this purpose. Association of fatty infiltrations with clinical and sonographic features were evaluated by a stepwise logistic regression analysis. RESULTS: Reduced HVF and FHA, but not standard clinical and laboratory parameters, strongly correlated with steatosis on histology (P<0.001). Both sonographic parameters made excellent predictions for the subgroup of patients with severe steatosis, particularly when both tests were combined [sensitivity (SE) 95%, specificity (SP) 96%, positive predictive value (pPV) 93%, negative predictive value (nPV) 97%, and accuracy 96%]. However, the sensitivity and accuracy of HVF pattern analysis were markedly reduced when all degrees of steatosis were defined as positive (SE 71%, SP 76%, pPV 81%, nPV 64%, and accuracy 73%). In contrast, the dichotomous parameter FHA remained a powerful indicator even under the latter conditions (SE 74%, SP 100%, pPV 100%, nPV 72%, and accuracy 84%). The combination of both sonographic tests resulted in improved sensitivity (82%), but significant loss of specificity (76%) and accuracy (80%) for prediction of liver steatosis. CONCLUSION: Sonographic evaluation of reduced HVF and FHA within the liver hilum is easy to perform, non-invasive, and, when present, gives a high degree of confidence in the diagnosis of liver steatosis. However, the lack of sonographic evidence of steatosis cannot definitively exclude the presence of mild steatosis, as shown on biopsy.     

Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation

BACKGROUND AND AIMS: Hepatic steatosis is a histological characteristic in patients with chronic hepatitis C virus (HCV) infection. The aim of this study was to evaluate the prevalence of hepatic steatosis in Chinese patients with chronic hepatitis C, and to look for possible correlation with various histopathological changes and to look for possible correlation with various clinical and pathologic variables. METHODS: One hundred and six patients were enrolled, and patients with alcoholism or diabetes mellitus were excluded. Clinical, biochemical and virologic data, including HCV genotype and serum HCV-RNA titer and histological findings, were compared between patients with and without hepatic steatosis. RESULTS: Fifty-five (52%) of the 106 patients with chronic hepatitis C had hepatic steatosis. Patients with hepatic steatosis had significantly higher mean serum levels of triglyceride and gamma-glutamyl transpeptidase, higher body mass index, and a higher incidence of obesity compared with patients without hepatic steatosis. No significant differences in serum HCV-RNA titer and HCV genotype or the response to interferon therapy were noted between the two groups. Histological analysis showed patients with hepatic steatosis had a significantly higher mean fibrotic score than patients without hepatic steatosis (1.9 +/- 1.2 vs 1.3 +/- 1.0; P = 0.016). There were no significant differences in the severity of necroinflammation, the presence of lymphoid aggregation/follicle or bile duct damage between the two groups. Multivariate logistic regression analysis showed that independent predictors associated with hepatic steatosis were obesity or a histology fibrotic score of > or = 2. CONCLUSION: It was found that 52% of Chinese patients with chronic hepatitis C had hepatic steatosis. Patients with hepatic steatosis were more frequently obese and had more severe hepatic fibrosis.     

Insulin resistance and steatosis in hepatitis C virus infection

The relationship between hepatitis C virus (HCV), steatosis, and insulin resistance is genotype specific, and steatosis and insulin resistance are closely linked to the progression of liver disease in HCV infected patients.     

Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection

BACKGROUND: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non-alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection. METHODS: In 124 chronic hepatitis C patients, the association between liver histology and the following was investigated: demographic and anthropometric data, alcohol intake, alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, transferrin saturation, ferritin, insulin, c-peptide, glucose and insulin resistance (homeostasis model). RESULTS: By multivariate analysis, genotype 3 was associated with increased steatosis grade (P = 0.02). There were significant pairwise interactions between genotype 3 status and total cholesterol (P = 0.01), current alcohol intake (P = 0.04) and serum ALT (P = 0.01). This showed that the etiology of steatosis was different in patients with genotype 3 and those with non-genotype 3 chronic hepatitis C infection. In genotype 3 patients, the degree of steatosis was inversely associated with serum cholesterol (P = 0.005) and positively associated with serum triglyceride (P = 0.02). There was no association between body mass index (BMI) and the extent of steatosis. Among patients with other genotypes, the steatosis grade was strongly influenced by BMI (P < 0.0001) and serum ALT (P < 0.01). Independent predictors of fibrosis were age (P = 0.001), past alcohol intake (P = 0.04), ALT (P = 0.002), serum insulin (P = 0.001) and portal inflammation (P < 0.001). CONCLUSIONS: Hepatitis C genotype 3 may interfere with pathways of hepatic lipid metabolism, whereas increased BMI appears to be a more important pathogenic factor in other genotypes. Although steatosis and BMI were not associated with hepatic fibrosis, their relationship with serum insulin suggests that metabolic factors related to insulin action could influence fibrogenesis in hepatitis C.     

慢性丙型肝炎合并脂肪肝的发病机制

慢性丙型肝炎(CHC)合并脂肪肝是CHC患者的主要临床表现,脂肪肝对CHC患者病情发展及其抗病毒疗效都有重要影响,归纳了近年来CHC患者并发脂肪肝的病毒和宿主方面的因素及脂肪肝对CHC患者预后的影响。CHC合并脂肪肝的发生机制仍然有待于进一步深入研究。     

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

AIM: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection

Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis in other settings. In a prospective study in 130 chronic HCV carriers therefore, serum HA concentrations were compared with conventional liver function tests (including alanine aminotransferase (ALT), a-glutathione-S transferase (GST) and serum HCV RNA in order to determine which identified the stage of liver fibrosis as assessed by liver biopsy most accurately. The median HA concentrations according to the stage of fibrosis 0, 1&2, 3 and 4&5 were 17gl^–1 (range 5– 37), 17gl^–1 (5–80), 30gl^–1 (10–105) and 350gl^–1 (20–800) respectively. The median HA concentration in stage 4&5 was significantly greater than in stages 0, 1&2 or 3. Serum HA concentration rose with age, but even when adjusted for age the median HA at stage 4&5 was greater than all other groups (95% CI of difference between the medians exceeded 0). Thus, serum HA gave a sensitivity and specificity for stage 4&5 fibrosis of 85% and 88% respectively, exceeding those for ALT or GST. In contrast, serum ALT or GST levels were not correlated with the stage of fibrosis although ALT was significantly greater in the cirrhotic group when compared to the group with no fibrosis (stage 0). There was no correlation between serum HA and either the grade of inflammatory changes or serum HCV RNA. These results suggest that serum hyaluronic acid is a useful marker of liver fibrosis in patients with chronic HCV infection. It could therefore be used to monitor patients at risk of progressive fibrosis, in controlled clinical trials, as a measure of response to antifibrotic therapy and in those in whom liver biopsy is difficult or contraindicated.     

Familial clustering of hepatitis C virus infection and chronic liver disease

The present study was undertaken to assess the prevalence of HCV antibodies (anti-HCV) and of chronic liver disease in relatives of anti-HCV positive subjects suffering from chronic active liver disease. We studied 122 subjects from 24 families. Each family had at least one positive anti-HCV component with histologically proven chronic liver disease. Anti-HCV was found in 32% of subjects; 82% of these were suffering from chronic liver disease diagnosed on the basis of physical examination and biochemical parameters. Prevalence of anti-HCV was higher in spouses, parents, and siblings of the index case as compared to the offspring. In conclusion, the transmission of HCV infection and of HCV-related chronic liver disease is contributed to by factors associated with the familial environment.     

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection

AIM To clarify the prevalence of occult hepatitis B virus(HBV) infection(OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma(HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus(HCV) infection. METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection(chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or moredifferent viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome. RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively(P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase 40 IU/L, Child-Pugh score and sustained virologic response(SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development. CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.     

Pretreatment serum microRNA-122 is not predictive for treatment response in chronic hepatitis C virus infection

BackgroundMicroRNA-122 is a liver specific microRNA and is elevated in the sera of patients with chronic hepatitis C virus infection. Hepatic microRNA-122 levels have been described to be reduced in patients with non-response to antiviral treatment with pegylated interferon-α and ribavirin.AimAssessment of differences in serum microRNA-122 levels in patients with sustained virological response and non-response.MethodsRNA was extracted from pretreatment serum samples and microRNA-122 and microRNA-16 levels were measured by quantitative PCR and compared in patients with sustained virological response and non-response.ResultsThe levels of microRNA-122 and microRNA-16 in the sera did not differ between patients with sustained virological response and non-response.ConclusionSerum microRNA-122 is not a suitable marker for treatment response prediction to combination therapy with pegylated interferon-α and ribavirin in patients with chronic hepatitis C virus infection.     

The SHAP-hyaluronan complex in serum from patients with chronic liver diseases caused by hepatitis virus infection.

Our previous study suggested that the serum-derived hyaluronan associated protein (SHAP)-hyaluronan (HA) complex in the sera of patients with rheumatoid arthritis is useful as a marker that directly correlates with the degree of inflammation. Here, we have investigated the serum levels of the SHAP-HA complex in patients at various clinical stages of chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) caused by infection with the hepatitis C or hepatitis B virus. Both serum levels of the SHAP-HA complex and HA in those patients were significantly higher than those of the controls and increased in the order of CH相似文献   

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.