Steatosis and hepatitis C virus: Mechanisms and significance for hepatic and extrahepatic disease

doi:10.1053/j.gastro.2003.11.020

Gastroenterology

Volume 126, Issue 2, February 2004, Pages 586-597

https://doi.org/10.1053/j.gastro.2003.11.020 Get rights and content

Abstract

Nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV)-related liver disease are common in the general population, but their concurrence is 2- to 3-fold higher than would be expected by chance alone. In patients with chronic HCV infection, steatosis is attributable to a variable combination of the mechanisms considered to play a role in the pathogenesis of NAFLD—insulin resistance in the obese and in the lean subject—along with a direct effect of HCV on hepatic lipid metabolism that leads to triglyceride accumulation through inhibition of export proteins that are required for very low density lipoprotein (VLDL) assembly and secretion. Accumulating evidence suggests that steatosis contributes to the progression of fibrosis in HCV-related disease in a pattern similar to that observed in NAFLD. Potential mechanisms of this effect include the increased sensitivity of steatotic livers to oxidative stress and cytokine-mediated injury. Steatosis-related hepatic insulin resistance may also play a role through the profibrogenic effects of the compensatory hyperinsulinemia and provides a potential explanation for the association between HCV and type 2 diabetes mellitus. Indeed, an appreciation of the importance of fat in HCV has recently led to trials of adjuvant therapy for HCV directed at steatosis-associated disease mechanisms, with encouraging results reported for various modalities, including weight loss and antioxidants. Future therapy should be aimed at exploiting the interactions of HCV with host insulin and lipid metabolism, particularly in nonresponders to standard antiviral schedules.

Section snippets

Epidemiology

Is the concurrence of HCV infection and steatosis a chance or causal association? The precise prevalence of NAFLD in the general population is unknown. Epidemiologic studies using ultrasonography both from Japan19, 20 and Italy21, 22 have reported that the prevalence of “fatty liver syndromes” (fatty liver and steatohepatitis of alcoholic and nonalcoholic etiology) in the general population is around 20% (reviewed in Loria et al.23). An ad hoc analysis of the NHANES III database suggests that

Insulin resistance

It has recently been shown that the presence of steatosis in some patients with chronic HCV infection is associated with risk factors for NASH rather than with alcohol consumption.31 This finding implies that steatosis in the context of HCV chronic infection may represent a host-related reaction and enables us to anticipate that conditions associated with NAFLD, principally insulin resistance and its clinical correlates, including obesity, diabetes, and arterial hypertension, will also be

Steatosis and progression of chronic hepatitis C

Given that steatosis is common in chronic HCV, what is the evidence that it plays a role in disease progression? Similar to studies in NAFLD,58, 59 indirect evidence supporting a role for steatosis in progression of chronic HCV has come from several studies showing that the severity of steatosis on index biopsy or its worsening are independent predictors of both the severity and the progression of fibrosis in HCV-positive patients with and without genotype 3.40, 43, 60, 61, 62, 63 Further

Mechanisms of fibrosis associated with steatosis in HCV

If, as seems likely, steatosis is involved in the fibrotic progression of HCV, what are the potential mechanisms of this effect? A recent study has reported that steatohepatitis-type lesions, sinusoidal fibrosis, and ballooning degeneration are present in 16% and 19% of patients with chronic HCV, respectively, and, along with age and the presence of T2DM, correlate with the severity of fibrosis.42 A second study has confirmed that the pattern of fibrosis in HCV (subsinusoidal and central vein)

Type 2 diabetes mellitus and NAFLD

Previous studies have reported that between 21% and 55% of patients with NAFLD have either overt T2DM or hyperglycemia.87 More recent studies have reported that insulin resistance is present in almost all patients with NAFLD irrespective of the coexistence of impaired glucose tolerance or obesity,35, 81, 88, 89 leading to the suggestion that NAFLD/NASH is the liver manifestation of the insulin resistance or metabolic syndrome.88 Contrary to previous reports, these studies showed that the

Steatosis, HCV, and atherosclerosis

The observation that arterial hypertension is highly prevalent in subjects with ultrasonographic evidence of steatosis114, 115 further supports the notion that NAFLD is part of the metabolic syndrome. More unexpectedly, hypertension has been shown to be an independent predictor of advanced fibrosis in obesity-associated NAFLD, attributed by the authors of the study to a potential fibrogenic effect of angiotensin II.68 Hypertension, along with other features of the metabolic syndrome,

Current therapy for NAFLD

If it is accepted that the steatosis occurring in association with chronic HCV infection is important in disease progression and possibly some of the extrahepatic manifestations, can this be used to inform treatment strategies for this growing number of patients? Optimal therapy for NAFLD has not been established but traditionally includes dietary intervention and correction of comorbid risk factors.6, 7, 13, 117, 118 Weight loss achieved by a moderately restricted diet, with or without

Summary

Steatosis is common in patients with chronic HCV infection because of a combination of the usual risk factors for NAFLD and to a direct steatogenic effect of some genotypes of the virus. The capacity of HCV to induce steatosis directly through interference with lipid metabolism may teleologically represent a mechanism favoring the entry of HCV into hepatocytes with a subsequent increase in viral replication. A growing body of evidence supports the view that steatosis plays a role in the

Future research needs

Although a considerable body of work has been performed on the mechanisms and significance of steatosis occurring in patients with chronic HCV infection, a number of outstanding questions remain unanswered that clearly warrant further study. First, with respect to mechanisms of steatosis, more direct evidence of a role for insulin resistance in the pathogenesis of HCV-related steatosis should be sought by correlating steatosis severity with measures of hepatic, muscle, and adipose tissue

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CHB patients with hepatic steatosis (CHB + HS) were prospectively recruited with followed-up of 3 years. HS and liver fibrosis were assessed by transient elastography. HS was defined as controlled attenuation parameter (CAP) ≥248 dB/m, and fibrosis progression was defined with ≥1-stage fibrosis increment. Multivariate and propensity score matching (PSM) analysis were used to evaluate antiviral therapy effects on fibrosis progression.
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A total of 1496 CHB patients were included. Two hundred and ninety (19.4%) patients were diagnosed with NAFLD by liver biopsy. The proportions of significant liver fibrosis (52.8% vs. 63.9%, P<0.001), advanced liver fibrosis (27.2% vs. 36.5%, P=0.003), and cirrhosis (13.4% vs. 19.7%, P=0.013) was considerably lower in CHB patients with NAFLD compared to those without NAFLD. 273 patients were included in each group after PSM adjusted for age, sex, hepatitis B envelope antigen status, and hepatitis B virus DNA. Liver fibrosis remained less severe in CHB patients with NAFLD than those without NAFLD (P<0.05) after PSM. The presence of NAFLD was considered an independent negative factor of significant liver fibrosis (odds ratio (OR) 0.692, P=0.013) and advanced liver fibrosis (OR 0.533, P = 0.002) in CHB patients.
NAFLD is not uncommon in CHB patients with the prevalence of 19.4%. The presence of NAFLD is associated with less severe liver fibrosis in CHB patients.
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^☆: Supported in part by a grant from the Ministero dell’Istuzione, Università e Ricerca Scientifica (MIUR) Anno 2002 - prot. 2002062883_001 and _002.

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Special reports and reviewsSteatosis and hepatitis C virus: Mechanisms and significance for hepatic and extrahepatic disease☆

Abstract

Section snippets

Epidemiology

Insulin resistance

Steatosis and progression of chronic hepatitis C

Mechanisms of fibrosis associated with steatosis in HCV

Type 2 diabetes mellitus and NAFLD

Steatosis, HCV, and atherosclerosis

Current therapy for NAFLD

Summary

Future research needs

Gastroenterology

Hepatology

Hepatology

Gastroenterology

J Hepatol

J Hepatol

Gastroenterology

Hepatology

Hepatology

Hepatology

Hepatology

Hepatology

J Hepatol

Dig Liver Dis

Hepatology

J Hepatol

Hepatology

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Lancet

Gastroenterology

Gastroenterology

Am J Gastroenterol

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Hepatology

Balliere’s Best Pract Res Clin Gastroenterol

Gastroenterology

J Hepatol

Hepatology

Am J Gastroenterol

J Biol Chem

Gastroenterology

Nonalcoholic steatohepatitisMayo Clinic experiences with a hitherto unnamed disease

Mayo Clin Proc

Should nonalcoholic fatty liver be considered precirrhotic?

Verh Dtsch Inn Med

Nonalcoholic fatty liver with alcoholic hyalin after long-term glucocorticoid therapy

Acta Hepatogastroenterol

Dyslipoproteinemia and diabetes mellitus in a metabolic syndrome

Fortschr Med

Nonalcoholic fatty liver disease

N Engl J Med

Update on nonalcoholic fatty liver disease

J Clin Gastroenterol

Non-alcoholic steatohepatitis (NASH)where are we now and where are we going?

Gut

Cryptogenic cirrhosisclinical characterization and risk factors for underlying disease

Hepatology

Liver transplantationcurrent status and novel approaches to liver replacement

Gastroenterology

Recurrence of nonalcoholic steatohepatitis after liver transplantation

Liver Transpl Surg

Natural history of chronic hepatitis C

Hepatology

Hepatocellular carcinoma and hepatitis C in the United States

Hepatology

Special reports and reviews
Steatosis and hepatitis C virus: Mechanisms and significance for hepatic and extrahepatic disease☆