288 ANNALS OF 2005,S.P. 18(3):288-290 DOURAKIS

Editorial

Hepatitis C and steatohepatitis: Is there any relationship?

S.P. Dourakis

Nonalcoholic fatty disease (NAFLD) represents improve with successful treatment of C.7,8 the hepatic manifestation of the in Insulin resistance is now recognized as the main cause the great majority of cases. The diagnosis requires a care- of NAFLD. Insulin is an important regulator of lipid ful exclusion of alcoholic by clinical evalua- balance and and promotes lipogenesis tion. NAFLD and are two common (the prev- while inhibiting lipolysis. In addition, certain cytokines alence in general population approximately 20 and 1- known as adipokines are produced in areas of inflam- 2% respectively) liver diseases and coexistence of the two mation and promote lipogenesis or lipolysis. In those pa- is to be expected. However, hepatic is a com- tients infected with HCV infection genotype 1, steatosis is mon histological finding occurring in more than 50% of associated with features of metabolic syndrome, in partic- patients with chronic hepatitis C, in contrast to chronic ular Body Mass Index (BMI) associated with insulin re- hepatitis B viral infection. So, the prevalence of coexist- sistance and an increased supply of fatty acids to the liv- ent hepatitis C and fatty liver is 2-3 times higher than er.9 In addition, mice expressing the HCV core protein would be expected, indicating that hepatitis C predisposes 1-3 develop NAFLD. HCV infection may directly cause insu- to NAFLD. Both host and viral factors have been dem- lin resistance by impairing the insulin receptor substrate – onstrated to play an important role in the development 1 (IRS-1) mechanism of insulin signal transduction, due of alterations in lipid and carbohydrate metabolism, liv- to Tumor Necrosis Factor-a (TEN-a) secretion.10,11 er steatosis and fibrosis in chronic HCV infection.4,5 The association between HCV and mellitus The association of HCV and steatosis seems to be type 2, has been reported by groups all over the world. genotype-specific. The virus has a direct cytopathic, st- HCV infection can mediate diabetes mellitus in geneti- eatogenic effect, particularly (two thirds) evident in pa- cally susceptible individuals. HCV is diabetogenic tients with HCV genotype 3 (viral steatosis). In this case, through an extra hepatic effect, which might be either HCV may directly interfere with trafficking through direct, through the core protein, or immune mediated. the liver and induce steatosis without a state of insulin Alternatively and more commonly, the virus can cause resistance. Both HCV core and NS-5 proteins are asso- glucose intolerance and diabetes by the induction of pro- ciated with lipid droplets apolipoprotein A and micro- longed insulin resistance and associated hepatic steato- somal triglyceride transfer protein impairing triglycer- sis. So, type 2 diabetes mellitus is another extra hepatic ide export from hepatocytes in the form of very low-den- manifestation of HCV infection.12,13 sity lipoprotein (VLDL), leading to steatosis.6 Moreo- ver, patients with genotype 3 infection tend to have low- An association between HCV infection and carotid er circulating lipid levels, indicating impaired secretion artery plaque formation and carotid intima-media thick- 14 of hepatic VLDL. Viral steatosis and serum lipid levels ening has been reported . The role of steatosis in the development of atheroma in HCV seems worthy of fur- ther study. 2nd Department of Medicine, Medical School, Athens University, Hippokration General Hospital, Athens. Steatosis in patients with hepatitis C predisposes to accelerated fibrosis progression and an increased risk of 15-17 Author for correspondence: hepatocellular carcinoma. Fatty liver is more vulner- S.P Dourakis, 28 Achaias st, 115 23 Athens, Greece, able to damage induced by factors (abnormalities in the Tel 210 6918464, 6932272477, fax: 210 6993693, mitochondria, peroxisomes, cytochrome P450 system, e-mail: [email protected] and various enzyme pathways) that increase Hepatitis C and steatohepatitis: Is there any relationship? 289 hepatic oxidant production. So, HCV core protein may important new adjunct treatment strategy for patients induce oxidative stress directly through an effect on mi- with chronic HCV infection irrespective of genotype or tochondrial electron transport. The antiviral inflamma- virological response. The potential benefit of treating tory response may provide an additional source of oxi- fatty liver in slowing the progression of liver disease in dative stress leading to increased lipid peroxidation, pro- patients with hepatitis C and improving the response to duction of pro-inflammatory cytokines and cell death. treatment requires further investigation. Treatments di- Moreover, in the presence of steatosis, increasing apop- rected at either oxidant stress (vitamin E) or insulin re- tosis was associated with activation of stellate cells and sistance (metformin, thiazolinediones-pioglitazone, ros- fibrosis.18 Hepatic fibrosis probably develops as a conse- iglitazone) are under way. quence of hepatic stellate activation by inflammatory cytokines. Moreover, insulin resistance can directly pro- mote fibrogenesis possibly through the expression of REFERENCES TNF-a and cytochrome P450 CYP2E1 isoenzyme. Nev- 1. Dev A, Patel K, McHutchison JG. 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