These results demonstrate for the first time that weight reduction in patients with chronic HCV may reduce hepatic steatosis, irrespective of viral genotype. The reduction in steatosis may be accompanied by a significant decrease in stellate cell activation and in some cases (5/9) regression of hepatic fibrosis was demonstrated.
Most patients with chronic HCV and steatosis were in the overweight or obese weight range (26–35 kg/m2
) and had significant visceral adiposity, as demonstrated by an elevated waist circumference (>94 cm in males and >80 cm in females).12, 13
In these patients, loss of as little as 2.6% body weight resulted in a reduction in steatosis, with a significant association between the amount of body weight lost and the degree of change in steatosis. However, at least two patients with HCV genotype 3 were not overweight, suggesting that their steatosis may be due to a cytopathic effect of the virus, as previously described.5, 14–17
Interestingly, even in these lean patients with HCV genotype 3, weight loss was accompanied by a significant reduction in steatosis.
Steatosis was accompanied by mild fine subsinusoidal fibrosis with a chicken wire appearance similar to that seen in steatohepatitis. We have previously shown in chronic HCV that the extent of α-SMA staining (as a marker of stellate cell activation) is correlated with the degree of portal inflammation and the stage of portal fibrosis, but not with the grade of hepatic steatosis.18
In the current study, we again demonstrated a wide variation between individuals in the extent of α-SMA staining. This suggests that in clinical samples (as opposed to rodent models) there may be some dissociation between stellate cell activation and collagen deposition, probably reflecting differences between individuals and also in collagen turnover. However, following weight loss, there was a striking reduction in stellate cell activation in some patients and this was seen in both the acini and portal tracts. Resolution of fibrosis following removal of injurious agents is thought to occur via apoptosis of hepatic stellate cells.19
Although weight loss is recommended in the management of obese patients with fatty liver disease, there has been little evidence to support a beneficial effect on the progression of liver disease. Our study is the first to demonstrate histological improvement following weight loss in patients with fatty liver as a cofactor associated with a primary liver disease. A previous study has shown a decline in ALT and an improvement in symptoms and physical findings following ≥10% weight loss in a small group of overweight patients with chronic hepatitis.20
In a study of obese patients with primary fatty liver disease, repeat liver biopsy after a three month trial of dietary restriction and exercise showed a reduction in steatosis, and a trend towards a reduction in inflammation and fibrosis that was not statistically significant.21
The mechanisms by which weight loss and a reduction in steatosis improve portal inflammation and fibrosis in chronic HCV remain to be determined. Steatosis is associated with an increased production of reactive oxygen species which initiate lipid peroxidation, resulting in activation of hepatic stellate cells. The mechanism for this is not precisely known although recently steatosis has been shown to alter the expression of mitochondrial membrane proteins, including uncoupling protein 2.22
This protein has been implicated in the generation of reactive oxygen species and lipid metabolism.23
Irrespective of its effect on steatosis, energy restriction may also have a direct effect on the inflammatory response associated with HCV. In various rodent models, calorie restriction has been shown to reduce the intensity of inflammation and levels of proinflammatory cytokines.24, 25
In our patients, energy restriction was modest, and the effect of the dietary intervention in the absence of steatosis was not addressed.
Despite the overall decrease in ALT with weight loss, this was not correlated to the reduction in steatosis in our patients. In these patients with steatosis and chronic HCV, fasting serum insulin levels were mildly elevated and significantly associated with BMI. Fasting hyperinsulinaemia and HOMA score are commonly used as surrogate markers for insulin resistance and occur frequently in overweight individuals. It has been suggested that insulin resistance may contribute to hepatic steatosis by a number of mechanisms. In lean individuals, insulin inhibits hormone sensitive lipase, providing control over the release of free fatty acids from adipocytes. In contrast, in obesity the loss of insulin sensitivity at the level of the adipocyte results in increased movement of fatty acids from peripheral stores to the liver. In addition, one of the actions of insulin in the liver is to increase the transcription of genes involved in fatty acid synthesis.26
This stimulation may be responsible for the increase in triglyceride levels in the liver and plasma that accompany hyperinsulinaemia.
Compliance in this cohort of patients was very good, with a mean weight loss of 5.9 kg over a 12 week period. This was achieved by a combination of intensive weekly intervention by a dietitian, restriction in energy intake, and an increase in daily activity. The contribution of each component to the change in liver biochemistry and histology could not be differentiated in our patients but will be of great interest in future studies. Maintenance of this weight loss may be challenging, as in a recent review of long term outcomes after lifestyle interventions alone, individuals regained around 60% of the weight they had originally lost after one year.27
However, our follow up to date has been encouraging, and perhaps the motivation of patients with a chronic disease and no other immediate treatment options may improve compliance with dietary and lifestyle modifications.
This study has demonstrated that weight loss in patients with chronic HCV is achievable and may result in a reduction in hepatic steatosis, irrespective of viral genotype. A small amount of weight loss may be associated with a reduction in abnormal liver enzymes and an improvement in fibrosis, despite the persistence of the virus. We believe that weight reduction may provide an important new adjunct treatment strategy for patients with chronic HCV.