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Steatosis in chronic hepatitis C
  1. M Guidi1,
  2. P Muratori1,
  3. A Granito1,
  4. L Muratori1,
  5. M Lenzi1,
  6. F B Bianchi1
  1. 1Departments of Internal Medicine, Cardioangiology, and Hepatology, University of Bologna, Bologna, Italy
  1. Correspondence to:
    Dr M Guidi
    University of Bologna, V Massarenti 9, 40138 Bologna, Italy; marcelloguidi{at}yahoo.it
  1. T Asselah2,
  2. L Rubbia-Brandt3,
  3. P Marcellin4,
  4. F Negro5
  1. 2Service d’Hépatologie and INSERM CRB3, Hôpital Beaujon, Clichy, University of Paris VII, France
  2. 3Service de Pathologie Clinique, Hôpital Universitaire, Genève, Switzerland
  3. 4Service d’Hépatologie and INSERM CRB3, Hôpital Beaujon, Clichy, University of Paris VII, France
  4. 5Service de Pathologie Clinique, and Services de Gastroentérologie et d’Hépatologie, Hôpital Universitaire, Genève, Switzerland

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We read with great interest the review by Asselah et al (Gut 2006;55:123–30) on the relevance of steatosis in chronic hepatitis C. They correctly reported that steatosis occurs more frequently in patients with chronic hepatitis C (55%) than in the general population (20–30%) of adults in the Western world,1 and that it is associated with various factors, including obesity, high alcohol consumption, diabetes mellitus, and hyperlipidaemia. They also discuss experimental models demonstrating that hepatitis C virus (HCV) proteins derived from genotype 1 isolates can induce steatosis.2–5 Among the conclusions, they claim the need for larger studies which take into account confounding factors for steatosis.

We have recently published our experience in assessing the impact of steatosis on antiviral treatment in a group of 102 naive patients with chronic hepatitis C of different genotypes.6 We excluded subjects with at least one of the following features: present or past alcohol consumption, body mass index of 30 or more (indicating obesity), hyperglycaemia, hypercholesterolaemia, and hypertriglyceridaemia. This was done to rule out possible concomitant metabolic disorders—namely, alcoholic hepatitis and non-alcoholic fatty liver disease. However, we observed that hepatic steatosis was present histologically in 51% of cases; we then hypothesised a potential direct pathogenic role of the virus in induction of liver steatosis, not limited to HCV genotype 3.

We also observed significantly higher necroinflammatory activity and a greater prevalence of the advanced stage of fibrosis in HCV patients with steatosis.

Interestingly, the presence of steatosis was not associated with a lower sustained virological response. To our knowledge, no previous work has reported on a selected population such as ours, and we obviously agree on the need for larger trials which could explain the mechanisms that promote the occurrence of steatosis in chronic hepatitis C.

References

Authors’ reply

We thank Guidi et al for their interest in our review on the relevance of steatosis in chronic hepatitis C (Gut 2006;55:123–30). We would like to make three points in relation to their comments: the prevalence of steatosis with regard to genotype; the role of necroinflammation; and the relationship between steatosis and treatment outcome.

Firstly, several studies have observed a significant association between hepatitis C virus (HCV) genotype 3 infection and the presence of steatosis.1,2 Steatosis is present in 73% of HCV genotype 3 patients and in 50% of patients infected with genotypes other than 3 (mainly genotype 1). In HCV genotype 1 patients, steatosis occurs more frequently than in the general population of adults in the Western world (estimated at 20–30%). Hence we agree with the hypothesis of a potential direct pathogenic role of the virus in induction of liver steatosis, not limited to HCV genotype 3.3,4 Furthermore, in a study by Abid et al, the HCV core protein, from patients with severe (genotype 3a) or no (other genotypes) liver steatosis, was expressed in Huh7 cells.5

Although triglyceride accumulation occurred with genotypes 1b, 3a, and 3h, genotype 3a core protein expression resulted in the highest level of accumulation. In another recent study, a positive correlation between steatosis and the number of infected hepatocytes was observed only in genotype 3 patients.6 In most cases the number of cells with steatosis greatly outnumbered that of HCV infected cells (HCV antigens using immunoperoxidase technique). The conclusion was that steatosis does not appear to be directly related to the presence of HCV antigens within single hepatocytes—an indirect, possibly cytokine mediated, mechanism might be operative.

Secondly, several studies have found a highly significant link between steatosis and necroinflammation activity on the one hand, and between necroinflammation activity and fibrosis on the other.1 Fatty accumulation is not fibrogenic per se. Steatosis in the presence of necroinflammation could increase the fibrosis progression rate. Furthermore, we conducted a meta-analysis on individual patient data from 3068 patients with histologically confirmed chronic hepatitis C from several centres.7 Steatosis was independently associated with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was independently associated with inflammatory activity, steatosis, male sex, and older age, while HCV genotype 2 was associated with reduced fibrosis. The association between steatosis and fibrosis was invariably dependent on a simultaneous association between steatosis and hepatic inflammation.

Thirdly, Guidi et al reported in a selected population with chronic hepatitis C that the presence of steatosis was not associated with a lower sustained virological response (SVR).3 The main interest in their study was that they ruled out possible concomitant metabolic disorders—namely, alcoholic hepatitis and metabolic factors associated with non- alcoholic fatty liver disease. In a large study involving 1428 naïve patients with chronic hepatitis C, the presence of steatosis was associated with a lower SVR rate, even after taking other factors into account (p<0.001).8 Absence of baseline steatosis, as well as end of follow up steatosis, was associated with a higher SVR, except in patients with genotype 3. In another retrospective analysis of 174 patients with chronic hepatitis C, obesity (and not steatosis) was a negative predictor of SVR.9 It could be that obesity (with increased plasma free fatty acid) causes steatosis, and then each independently diminishes the response to treatment. Obesity decreases interferon bioavailability and impairs the immune response to HCV. The opposite was found in a study involving non-diabetic European patients with HCV genotype 1 at low risk for the metabolic syndrome where the prevalence of steatosis was nearly 60%.10 Insulin resistant was a risk factor for moderate/severe steatosis, especially in men. Moderate/severe steatosis was found to be associated with hyporesponsiveness to treatment.

We obviously agree on the need for larger studies which could explain the mechanisms that promote the occurrence of steatosis in chronic hepatitis C, and the relationship with response to treatment.

References

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Footnotes

  • Conflict of interest: None declared.

Footnotes

  • Conflict of interest: None declared.

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