Journal of Hepatology
Volume 40, Issue 3 , Pages 533-535, March 2004

Hepatitis C virus and liver steatosis: when fat is not beautiful

Division of Gastroenterology and Hepatology and of Clinical Pathology, University Hospital, 24 rue Micheli-du-Crest, 1211 Geneva, Switzerland

See Article, pages 484–490

Article Outline

 

The progression of chronic hepatitis C towards cirrhosis is a relentless process that may evolve over a period of decades. Several factors may accelerate the rate of progression of liver fibrosis. Many such factors, like male gender, prolonged alcohol abuse, co-infection with the immunodeficiency virus, and obesity are now well recognized [1], [2], [3]. Others, like smoke [4] and, possibly, some genetic polymorphisms [5], are slowly being unravelled. In this context, the role played by the liver steatosis as a disease modifier is suggested by an increasing number of observations. Indeed, judging from the number of papers appeared on this subject in recent years, steatosis is viewed as taking an increasingly important role in many aspects of the hepatitis C virus (HCV) infection: not only is it a diagnostic tool, but it may also significantly affect both liver disease progression and response to antiviral treatment.

The diagnostic significance of steatosis in chronic hepatitis C was proposed by early works [6], [7], and later confirmed by several authors, especially when it became clear that in many patients steatosis is a histological hallmark of a direct toxic effect of HCV on the hepatocyte. The evidence in favour of this comes from three observations: (1) steatosis is more frequent and severe in patients infected with the genotype 3 of HCV, suggesting the existence of specific ‘steatogenic’ sequences proper to this genotype [8], [9], [10], [11], [12], [13], (2) the degree of fat infiltration (especially in patients with the genotype 3) is correlated with the level of HCV replication and protein expression, as measured both in serum [10] and in liver tissue [9], [14], and 3) there is a close correlation, at least in some patients (again, especially among patients with genotype 3) between the disappearance of fat from the liver and the response to antiviral therapy [9], [12], [15]. In addition, the recurrence of HCV infection after an initially successful treatment is accompanied by the reappearance of steatosis [16].

In the present issue of the Journal, Patton et al. [17] add some strong evidence to this notion. They show, based on the largest chronic hepatitis C patients' population ever studied at a single centre, a number of solid correlations between steatosis and several clinical and virological parameters, including a negative effect on the rate of response to treatment, thus nicely confirming and extending previous studies. In addition, by means of a logistic regression analysis separately performed on subgroups of patients infected with different genotypes, they were able to add some evidence that steatosis may affect liver disease progression in a genotype-specific way, i.e. only among patients with genotype 1.

These results are important, due to the relevant size of the study. Nonetheless, they should be considered critically, the most important issue at stake being whether steatosis does indeed affect the rate of progression of liver fibrosis, and in which patients it may do so. That steatosis may correlate with fibrosis was first reported by Hourigan et al. [3] and then confirmed by several authors [9], [10], [11], [15], [18]. However, recent data suggest that this interaction is far more complex than previously thought. Furthermore, it is less and less clear whether steatosis, that may negatively influence liver disease progression, is due to HCV or rather to concomitant conditions unrelated to the virus. This issue is highly relevant, since understanding the histological findings in pathogenetic terms has always been critical to proper clinical management. So, we need to address the question: is steatosis seen in chronic hepatitis C always due to HCV? And, if not, what are the alternative mechanisms?

Several studies have provided good evidence in favour of the existence of multiple factors independently underlying the fatty liver in chronic hepatitis C [10], [12], [15]. There is a ‘viral’ steatosis, i.e. directly linked to HCV replication and mostly (but not exclusively) seen in patients with genotype 3, that disappears upon successful antiviral therapy. Since the pathogenesis of this kind of lipid accumulation seems to depend on a derangement of lipoprotein secretion [19], it can be identified by measuring the level of ApoB in serum before therapy [18]. Low ApoB values may suggest that HCV is responsible for most if not all steatosis seen in these cases, especially in the absence of other risk factors for a fatty liver. The altered lipid profile, usually consisting in a hypocholesterolemia, will revert to normal after therapy, provided that this is associated with eradication of HCV [13], [15], [18]. Then, there is a so-called metabolic steatosis. The severity of fat accumulation, in these cases, is proportional to the body mass index (BMI) [10], and is not responsive to antiviral therapy [12], [15]. Since obesity increases with age and patients with genotype 3 are usually younger, the metabolic type of steatosis is likely to affect more frequently patients infected with non-3 genotypes. A third, well known component of steatosis is alcohol abuse, but its contribution to the published series is variable. There are substantial differences in the referral patterns of chronic hepatitis C patients, the overall attitude of specialists who perform liver biopsies, and the specific inclusion and exclusion criteria of each single study. Many patients undergoing a diagnostic workup of their HCV infection may have already stopped drinking alcohol, either spontaneously or because of the suggestion of their physician, before a liver biopsy is carried out at the hepatology unit. In the study by Patton et al. [17], this kind of steatosis was unlikely to be significant, since ongoing alcohol abuse was an exclusion criterion for admission into the clinical trial. Diabetes and dyslipidemias may also contribute to steatosis of the liver, and, finally, it is not unexpected that a variable proportion of patients present with a mixed type steatosis, i.e. where viral and one or more metabolic factors overlap [15]. This is more likely to occur in populations where overweight is highly prevalent and tends to affect younger generations.

Is steatosis associated with chronic hepatitis C an innocent bystander or does it contribute to liver fibrosis progression? If so, is the natural history of virally related steatosis different from that of other types of fatty liver? Even if in some conditions the fibrogenesis may be activated in the absence of hepatitis and correlate with the severity of steatosis [20], evidence from cohort studies on patients with non-alcoholic fatty liver disease shows that a simple steatosis mostly runs a non-progressive clinical course [21], [22]. Since chronic hepatitis C cases always present with some degree of necroinflammation, the steatosis observed in these patients is likely to sustain a process triggered by causes that act irrespectively of the presence of fat. The relationship with necroinflammation is thus important, because this may provide the primum movens leading to fibrogenesis, with the steatosis playing a role as an incidental amplifier of the tissue damage. As said above, the association between steatosis and fibrosis in HCV infection has been reported by many authors, including Patton and co-workers [3], [9], [10], [11], [15], [17], [18]. However, recent data seems to suggest a more complex interaction. In a study [23], the association was denied, while in others [24], [25], [26] it seemed to hold true for only some patients' subgroups. As a matter of fact, Patton et al. [17] found an association between steatosis and fibrosis only among patients with genotype 1 infection, i.e. those more likely to suffer from metabolic steatosis, unresponsive to antiviral therapy. The lack of association in the subgroup infected with genotype 3 (84 patients, corresponding to 16% of the total) may however result from a type beta error. In our recent analysis [25] performed on 755 patients seen at three centers in Italy and Switzerland (178 with genotype 3, i.e. 23.6% of the total, and twice as many as reported by Patton et al. [17]), the opposite was true, as steatosis was independently associated with fibrosis only in patients with genotype 3. On the contrary, among the remaining 577 patients, infected with other genotypes, liver fibrosis was associated with intrahepatic necroinflammation, age and past alcohol abuse, whereas history of diabetes approached, without reaching, statistical significance. A relationship between fatty liver and advanced fibrosis in genotype 3-infected patients is suggested also by other studies [24], [26]. However, at closer inspection, these results are not necessarily conflicting. Again the baseline features of the study populations are quite different, as are the inclusion and exclusion criteria, the scoring systems for assessing histological and clinical variables (such as alcohol abuse) and even referral patterns at different locations. As a result, it is difficult to compare data. Discrepancies are most likely to be due to the relative proportion of patients with viral vs. non-viral steatosis. Patients populations studied in the United States [11], [17] or in Australia [12] are characterised by a higher average BMI and a lower prevalence of genotype 3, whereas European patients have a lower BMI (<25 in all studies) and are more frequently infected with genotype 3. Other factors, such genetic and dietary, may also play a role. Possibly, meta-analyses on individual data pooled from all studies of sufficient quality may help to address this issue. However, it has to be reminded that logistic regression analyses, no matter how extensive they are, invariably provide at best correlative evidence, rather than shedding light on pathogenesis. Several hypotheses have been put forward that may account for the mechanism linking steatosis and liver fibrogenesis: from the production of excess reactive oxygen species and lipid peroxides [27], [28] to the insulin resistance syndrome [29], [30]. These research domains, together with the study of the potential fibrogenic effect of leptin and angiotensin, will certainly constitute a major challenge in the field of hepatitis C infection in the next few years.

In conclusion, steatosis appears another factor in affecting chronic hepatitis C progression. Whether it affects all patients or only some subgroups of them, as a function of pathogenesis, remains to be elucidated. While prospective studies may address this question, measures aiming at reducing risk factors of fatty liver seem now an established acquisition in the clinical management of chronic hepatitis C patients.

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Acknowledgements 

The author's experimental work cited in the present manuscript is supported by contract no. 32-63549.00 from the Swiss National Science Foundation. The author is indebted to Laura Rubbia-Brandt and Roberto Genta for critical discussion.

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PII: S0168-8278(04)00022-4

doi:10.1016/j.jhep.2004.01.011

Journal of Hepatology
Volume 40, Issue 3 , Pages 533-535, March 2004

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