Race, insulin resistance and hepatic steatosis in chronic hepatitis C

Hepatic steatosis is common in chronic hepatitis C and has been linked to concurrent obesity, insulin resistance, diabetes, disease severity, and poor response to therapy. Racial differences in rates of obesity and diabetes may contribute to racial differences in hepatic steatosis and treatment response. The aim of the present study was to compare hepatic steatosis and its associations between African American (AA) and Caucasian American (CA) patients with chronic hepatitis C, genotype 1, participating in a prospective study of peginterferon and ribavirin therapy. Liver biopsy results were available from 194 AA patients and 205 CA patients. The 2 groups were compared for anthropometric, clinical, and biochemical features and insulin resistance estimated by the homeostasis model assessment index (HOMA-IR). Sixty-one percent of the AA patients and 65% of the CA patients had hepatic steatosis (P = 0.38). In univariable analysis, steatosis was associated with HOMA-IR, body mass index, waist circumference, serum triglycerides, aminotransferase level, and histological scores for inflammation and fibrosis. After adjusting for these features, AA patients had a lower risk of steatosis than did CA patients (OR 0.54, 95% CI 0.32-0.91, P = 0.02). Insulin resistance but not steatosis was associated with a lower rate of sustained virological response when adjusted for known factors that predict response (relative risk 0.87, 95% CI 0.77-0.99, P = 0.028). CONCLUSION: After adjusting for the higher prevalence of features associated with hepatic steatosis, AA patients had a lower prevalence of hepatic steatosis than did CA patients with chronic hepatitis C, genotype 1. Insulin resistance but not steatosis was independently associated with lower sustained virological response.     

Hepatitis C virus infection: molecular pathways to steatosis, insulin resistance and oxidative stress

The persistent infection with hepatitis C virus is a major cause of chronic liver disease worldwide. However, the morbidity associated with hepatitis C virus widely varies and depends on several host-related cofactors, such as age, gender, alcohol consumption, body weight, and co-infections. The objective of this review is to discuss three of these cofactors: steatosis, insulin resistance and oxidative stress. Although all may occur independently of HCV, a direct role of HCV infection in their pathogenesis has been reported. This review summarizes the current understanding and potential molecular pathways by which HCV contributes to their development.     

Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C

The interaction between insulin resistance (IR), steatosis and genotype to fibrosis in chronic hepatitis C virus (HCV) infection has not been comprehensively assessed. We hypothesized that IR is a key mediator for the development of both steatosis and fibrosis in 346 untreated, nondiabetic patients solely infected with either genotype 1 or 3. We examined for genotype-specific interactions between IR, steatosis and fibrosis by performing subgroup analyses. Because cirrhosis is known to cause IR, we repeated the analysis in a cohort of 313 noncirrhotic HCV-infected patients. We confirmed the impact of IR on fibrosis by analysis of 153 lean subjects in whom any effect of steatosis would be minimized. In HCV genotype 3 patients, increased steatosis was linked to high viral load (P = 0.001), and was not associated with fibrosis (P = 0.1). In contrast, body mass index (P = 0.04) and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.01) contributed directly to steatosis in HCV genotype 1. HOMA-IR rather than steatosis was independently associated with fibrosis for both HCV genotype 1 (OR, 3.22; P = 0.02) and genotype 3 (OR, 3.17; P = 0.04). Exclusion of cirrhotic subjects did not alter the findings with respect to the greater contribution of IR compared to hepatic steatosis, as a predictor of fibrosis (P = 0.02). Genotype-specific subgroup analyses did not alter this finding. The extent of HOMA-IR remained significantly associated with fibrosis in lean patients, independent of the confounding effect of body mass index on IR (OR, 8.02; P = 0.003). CONCLUSION: IR is a major independent determinant of fibrosis in chronic HCV infection, regardless of the genotype and the severity of liver damage.     

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

BACKGROUND/AIMS: 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. METHODS: IgG against malondialdehyde-albumin adducts and HOMA-IR were measured as markers of oxidative stress and insulin resistance, respectively, in 107 consecutive CHC patients. RESULTS: 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. CONCLUSIONS: 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.     

Role of obesity, insulin resistance, and steatosis in hepatitis C virus infection

Hepatitis C, nonalcoholic fatty liver characterized by hepatic steatosis, and obesity inflict significant health and economic burdens on the Western world. Insulin resistance is the key player in these disease processes. Complex interplay between these conditions results in the ultimate phenotype of liver disease. This article focuses on the current understanding of host and viral interactions as well as on consequent clinical implications.     

Steatosis during chronic hepatitis C: the role of insulin resistance and viral factors

Liver steatosis is frequent in patients with chronic hepatitis C. Two main types are described: (1) "viral steatosis" induced by the virus, especially genotype 3, which probably inhibits the "Microsomal Triglyceride Transfer Protein", thus decreasing "Very Low Density Lipoprotein" secretion and leading to triglyceride accumulation within hepatocytes; (2) "metabolic steatosis" which is a feature of the metabolic syndrome and insulin resistance, a systemic disorder associated with a high risk of cardiovascular disease and diabetes mellitus. Insulin resistance induces intrahepatic triglyceride accumulation due to excess free fatty acid flux from increased adipose tissue lipolysis as well as increased intrahepatic lipogenesis through activation of the "Sterol Response Element Binding Protein". Hepatitis C Virus itself can also be responsible for insulin resistance, possibly through impairment of the insulin signalling pathway because of increased"Tumor Necrosis Factor Alpha" levels and/or upregulated "Cytokine Signalling Suppressor" expression. Insulin resistance and steatosis, appear to be associated with fibrosis progression and impairment of sustained response to antiviral treatment.     

Interaction of IFNL3 with insulin resistance,steatosis and lipid metabolism in chronic hepatitis C virus infection

Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)infection.Further,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in CHC.The emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin resistance.This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.     

Pathophysiology of insulin resistance and steatosis in patients with chronic viral hepatitis

Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease.A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis.Due to the obesity epidemic,fatty liver is now a significant problem in clinical practice.Steatosis has an impact on the acceleration of liver damage in patients with chronic hepatitis due to other causes.An association between hepatitis C virus (HCV) infection,steatosis and the onset of insulin resistance ...     

Hepatitis C,insulin resistance,and steatosis

Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) are two frequently identified liver diseases worldwide. NAFLD is related to obesity and insulin resistance, which may also be a preexisting condition in patients with CHC. The complex relationship among obesity, steatosis, and insulin resistance as it pertains to the pathogenesis, treatment, and outcomes in CHC is discussed in this article.     

Chemerin,vaspin and insulin resistance in chronic hepatitis C

Summary. Adipocytokine profile seems to play a distinct role in the pathogenesis of chronic hepatitis C (CHC). Chemerin and vaspin are recently described adipocytokines with various suggested functions and potential to modulate inflammatory response and insulin resistance (IR). We assessed chemerin, vaspin and leptin serum concentration and studied their association with IR laboratory and morphological features in patients with hepatitis C. The study included 40 patients with hepatitis C and 20 healthy volunteers, similar in age and body mass index (43.6 ± 11.6 vs 40.9 ± 11.8 years and 25.0 ± 4.1 vs 23.9 ± 3.3 kg/m², respectively). Patients had to have a normal lipid profile, and diabetes was an exclusion criteria. Serum chemerin and leptin levels and IR were significantly higher in patients with hepatitis C when compared to the controls (P = 0.02, P = 0.02 and P = 0.02, respectively), whereas vaspin level was significantly decreased (P = 0.01). Serum chemerin was negatively associated with necro‐inflammatory grade (r = (–0.49), P = 0.01). The lowest levels of serum chemerin were found in patients with moderate/severe inflammation (P = 0.03). Serum leptin tended to be up‐regulated in patients with minimal inflammatory activity. Serum vaspin was higher, although not significantly, when fibrosis was more advanced. IR was positively associated with fibrosis stage (r = 0.33, P = 0.03). Serum chemerin and leptin were related to each other (r = 0.45, P = 0.02).Our findings support a complex interaction between the analysed adipokines and pathogenesis of inflammatory process in CHC. The role of chemerin and vaspin in pathogenesis of inflammatory response should be further investigated.     

Impact of steatosis on insulin secretion in chronic hepatitis C patients

OBJECTIVES: Liver steatosis is frequently observed in patients with chronic hepatitis C (CHC) and is an identified risk factor for progression of liver fibrosis. This study aimed to evaluate the relationship between steatosis and host/viral factors, and the correlation between steatosis and insulin secretion in CHC patients with normal glucose tolerance (NGT). METHODS: A total of 212 CHC patients were enrolled in this study. Insulin resistance and insulin secretion were determined in response to oral loading of 75 g glucose. Liver fibrosis and steatosis were quantified by the image analysis. RESULTS: Of the 212 CHC patients, 165 (78%) had steatosis, mostly of a mild degree. Multiple ordinal regression analysis revealed body mass index (BMI) (P= 0.011) as the main factor associated with severe steatosis. Of the 212 CHC patients, 148 (61%) showed NGT, and the serum insulin response to oral glucose loading in these NGT patients with steatosis was significantly different from that in patients with NGT but no steatosis. The peak insulin response occurred at 60 min in cases of mild steatosis, and at 90 min in patients with moderate or severe steatosis. The insulin level at 120 min in patients with severe steatosis was higher than that in those without steatosis. The total area under the response curve of insulin during OGTT in the patients with steatosis is higher than that in those without steatosis. CONCLUSION: Exaggerated insulin secretion was observed even in CHC patients with mild steatosis and NGT, suggesting the presence of insulin resistance. Exaggerated insulin secretion may accelerate the progression of liver fibrosis in CHC patients.     

Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C.

Aim: The mechanisms by which metabolic disorders develop in patients with chronic hepatitis C are unknown. Our study aimed to test whether oxidative stress contributes to these mechanisms. Methods: The index of homeostasis model assessment-insulin resistance (HOMA-IR) and serum and hepatic levels of thioredoxin (Trx), which are markers of oxidative stress, were evaluated in 203 biopsy-proven chronic hepatitis C patients with hepatitis C virus (HCV) genotype 1 or 2 infection. HOMA-IR and Trx levels were compared with baseline values after phlebotomy in 23 patients. Results: HOMA-IR and serum Trx levels were significantly correlated with disease stage (HOMA-IR, P < 0.00001; Trx, P < 0.0001) and independently predicted fibrosis scores (HOMA-IR, P < 0.05; Trx, P < 0.005). Steatosis (%) was significantly correlated with HOMA-IR (P < 0.00005) and Trx (P < 0.001) stage (P < 0.00001). Serum Trx levels were significantly correlated with HOMA-IR (P < 0.05), even after adjustment for body mass index (P < 0.05). Furthermore, the mRNA levels of hepatic Trx were significantly correlated with HOMA-IR (P < 0.05) and independently-predicted HOMA-IR (P < 0.05). The alanine aminotransferase (P < 0.00001), Trx (P < 0.05), and HOMA-IR (P < 0.05) serum levels decreased significantly after phlebotomy; these effects were similar even in non-responders to interferon. Conclusion: Oxidative stress contributed to the development of IR irrespective of obesity in patients with HCV genotype 1 or 2 infection. This study could contribute to our understanding of how metabolic disorders develop and how they should be treated in chronic hepatitis C patients.     

Impact of obesity,hepatic steatosis,and insulin resistance on hepatitis C treatment outcomes

Hepatitis C virus (HCV) infection is commonly associated with hepatic steatosis, an important factor predicting disease severity in all genotypes. There appears to be a strong association between the presence of steatosis and insulin resistance (IR) in HCV infection, especially in genotype 1 infection. Obesity, hepatic steatosis, and IR all appear to negatively influence response to antiviral therapy. IR is important not only in the development of hepatic steatosis, but also in fibrosis severity. Recent studies also suggest that IR is a significant independent predictor of sustained virologic response to antiviral therapy, not only in genotype 1 infection but also in hepatitis C genotypes 2 and 3. It remains to be seen whether interventions such as weight loss, hepatic steatosis reduction, and improvement in IR will increase the response to antiviral therapy and/or delay disease progression in chronic hepatitis C.     

Insulin resistance,steatosis and hepatitis C virus

Epidemiological studies have shown an increased occurrence of metabolic disorders such as insulin resistance (IR) and steatosis in patients with hepatitis C virus (HCV) infection. IR is believed to represent one of the central clinical features of the “metabolic syndrome” and the major pathogenetic factor for type 2 diabetes mellitus. In patients with chronic HCV hepatitis, IR may have several dangerous consequences such as accelerated progression of liver fibrosis, resistance to antiviral therapy and development of hepatocellular carcinoma. According to recent evidence, the global epidemic of metabolic disorders related to incorrect diets will lead physicians to deal with 1.2 billion patients with diabetes in the world in 2025. Given the high prevalence of HCV infection in several countries, metabolic manifestations will contribute to increasing morbidity and mortality in patients with HCV chronic infection in the near future. HCV treatment, shown able to decrease both the occurrence of HCV-related IR and diabetes, may reduce the risk of the associated morbidities.     

Impact of obesity, steatosis and insulin resistance on progression and response to therapy of hepatitis C

Summary.  Clinical progression of chronic hepatitis C depends on several cofactors, which also have a negative affect on the rate of response to interferon-α-based therapy. Given the current worldwide prevalence of the metabolic syndrome, the impact of obesity and insulin resistance, and of their histopathological correlate, hepatic steatosis, on the natural history and management of chronic hepatitis C is undoubtedly very important. We will review some of the current knowledge on the clinical consequences of overweight/obesity, steatosis and insulin resistance on chronic hepatitis C, and discuss how this issue may be dealt with in clinical practice.     

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.     

Association of inflammatory and anti‐inflammatory cytokines with insulin resistance in chronic hepatitis C

Background: The pathogenetic basis for the association between hepatitis C virus (HCV) infection and type‐2 diabetes remains uncertain. It has been reported that insulin resistance (IR) plays an essential role. We investigated the association of inflammatory [tumour necrosis factor (TNF)‐α, interleukin (IL)‐6] and anti‐inflammatory cytokines (adiponectin and IL‐10) with IR in chronic HCV infection. Methods: Eighty‐one consecutive non‐diabetic chronic hepatitis C patients (37 men and 44 women, mean age of 51.9±12.2 years) and 40 age, sex and body mass index (BMI)‐matched healthy individuals were collected. IR was evaluated by the homoeostasis model assessment (HOMA). Serum levels of cytokines were measured by enzyme‐linked immunosorbent assay. Results: Patients with chronic hepatitis C have a higher HOMA‐IR, TNF‐α, IL‐6, adiponectin and IL‐10, as compared with controls. By multiple linear regression analysis, moderate/severe steatosis grade, total cholesterol level and adiponectin was significantly associated with HOMA‐IR, whereas, TNF‐α, IL‐6 and IL‐10 was not. Male gender, BMI and HOMA‐IR was inversely correlated with the serum adiponectin level. Serum adiponectin was positively correlated with TNF‐α level, which was significantly associated with higher degree of hepatic necroinflammation. Conclusion: Our data suggest that chronic HCV infection is associated with increased IR, which is correlated inversely with the serum adiponectin level. The complex role of adiponectin in the pathogenesis of IR and hepatic necroinflammation in chronic HCV infection merit further investigation.