We have demonstrated, using a large multivariable logistic regression analysis stratified according to HCV genotype, that liver steatosis is associated with liver fibrosis only in chronic hepatitis C patients infected with genotype 3. In patients infected with other genotypes, age, prolonged alcohol abuse and possibly history of diabetes may prevail in determining the progression of liver disease.
These findings add to other analyses (mostly univariate6,7,13,19
and in two cases multivariate8,20
) published previously. There are some noteworthy differences as to their conclusions, partly due to discrepancies in scoring histological parameters or clinical variables such as alcohol abuse, but mostly due to major differences in patient baseline features. In a multivariable logistic regression from the USA,8
the only independent predictors of steatosis were BMI and genotype 3. However, excluding 17 patients with risk factors for non-alcoholic steatohepatitis, only genotype remained as a factor affecting steatosis. Moreover, steatosis and liver inflammation were the only independent predictors of liver fibrosis, thus excluding a likely role of a history of alcohol abuse. We partially confirmed these results but we also identified fibrosis score, ongoing alcohol abuse, and age as further independent predictors of steatosis, and age and past alcohol abuse as further predictors of fibrosis. These discrepancies may be due to different population features—that is, the relative proportion of patients with viral versus non-viral steatosis. Studies carried out in the USA8
were characterised by a higher BMI and a lower percentage of patients with genotype 3 whereas European patients had a lower BMI (<25 in all four studies)6,7,19,20
and were more frequently infected with genotype 3.
Our most significant finding was that the role of steatosis in affecting liver fibrosis seems to be limited to patients with genotype 3, in agreement with another recent small univariate analysis from Sweden.19
This is possibly due to the lower BMI of our patients compared with both American and Australian studies.8,13
This finding is even more significant if we consider that patients infected with genotype 3 were younger (and possibly had a shorter duration of disease) and had a lower BMI compared with patients with other genotypes. The shorter duration of disease in patients with genotype 3 is also indirectly proven by the fewer patients with decompensated liver disease at enrolment. In patients infected with non-3 genotypes, age and history of alcohol abuse were major determinants of fibrosis (apart from liver inflammation), with diabetes following closely behind. The mechanism linking steatosis and fibrosis in patients with genotype 3 is unclear. Interestingly, among these patients (at variance with those infected with non-3 genotypes), steatosis was associated with Metavir activity, suggesting that it may be a cofactor contributing to inflammation (and hence to fibrogenesis). The opposite situation—that is, that liver inflammation is the origin of steatosis—seems unlikely because there was no association between inflammation and steatosis in patients with comparable levels of liver disease activity and non-3 genotypes.
The relationship between steatosis and fibrosis deserves further comment in view of the peculiar scoring system we adopted to classify fibrosis stages. The 109 patients with decompensated cirrhosis recruited at the time of liver transplantation, albeit presenting with a Metavir score of F4,17
were considered as belonging to a more advanced phase of liver disease and given a distinct score. Also, the remaining classes of fibrosis were reclassified, and patients with Metavir scores of F1–F2 on the one hand, and F3–F4 scores on the other, were grouped together. This scoring system allowed us to observe an interesting phenomenon, consistent with our previous observations.20
The odds of having liver steatosis increased with progression of liver fibrosis, independent of viral genotype. However, when liver disease progressed to decompensation, the risk of having any degree of liver steatosis fell sharply to 4.6%, independent of viral genotype, suggesting that in late stages of hepatitis C steatosis disappears, independent of its cause, as is the case for other liver diseases.21–23
Whether this depends on reduced calorie intake, systemic shunting of portal blood, or sinusoidal capillarisation remains unclear.23
In conclusion, we have shown that in chronic hepatitis C, steatosis may influence liver fibrosis progression in a genotype specific way. In patients with genotype 3, the presence of steatosis, which is due to HCV replication and is frequently moderate to severe, correlates with the liver fibrosis score. In contrast, steatosis and fibrosis are not associated in patients with HCV genotypes other than 3, in whom steatosis is milder and unrelated to HCV replication. In these patients, progression of liver disease may depend on other factors, such as prolonged alcohol abuse or being overweight. These results have practical implications for patient clinical management. Patients infected with HCV genotype 3 and presenting with liver steatosis, especially if moderate to severe, should be offered antiviral therapy, irrespective of other considerations, especially knowing that the rate of success in this setting, with currently available regimens, is very high.24
Measures aimed at reducing the risk of liver disease progression in patients with genotypes other than 3, in addition to antiviral treatment, should also include strict abstinence from alcohol and body weight control.