Article Text

Download PDFPDF

Weighty issues in hepatitis C
  1. J Heathcote
  1. Toronto Western Hospital, University Health Network, 399 Bathurst St, 6B Fell Pavilion, Room 172, Toronto, Ontario M5T 2S8, Canada; jenny.heathcote{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Simple lifestyle changes, inducing weight reduction over three months, can potentially reduce both the morbidity and mortality related to hepatitis C infection

The paper by Hickman and colleagues1 in this issue of Gut[see page89] is important because it shows that simple lifestyle changes inducing weight reduction over three months can lead to a significant reduction in hepatic steatosis and markers of stellate cell activation with a trend to less liver fibrosis. This change in liver histology was associated with a reduction in insulin resistance. Unfortunately, many patients regained their weight at the end of the three months of weekly monitoring of calorie intake and exercise. Nevertheless, it is clear that simple lifestyle changes alone can potentially reduce both the morbidity (development of diabetes) and mortality (fibrosis leading to cirrhosis) related to hepatitis C infection.

These same authors previously showed that hepatic steatosis is common in individuals infected with hepatitis C and that the degree of steatosis and fibrosis correlates well with body mass index.2 It is also known that individuals infected with genotype 3 are more likely to have a fatty liver even when they are not overweight.3 A recent illustration demonstrated how eradication of hepatitis C virus following antiviral therapy can lead to disappearance of hepatic steatosis only to recur on viral relapse.4 Thus it would appear that hepatic steatosis in association with hepatitis C is not simply secondary to obesity. In this current study, even those individuals with genotype 3 infection who were not overweight at the start had a diminution in hepatic steatosis on weight reduction, without the addition of antiviral therapy.

Although the patients in this study had normal fasting glucose levels, most were insulin resistant, as judged by the homeostasis model of assessment (HOMA) test. Fasting insulin levels correlated well with baseline BMI. Weight reduction led to an improvement in the HOMA score in the majority. Insulin resistance, also calculated using the HOMA method, has been noted by others to be common in individuals with hepatitis C and correlated with older age, obesity, severe liver fibrosis, and a family history of diabetes.5

In peripheral tissues, insulin normally downregulates the hormone sensitive lipase (HSL) enzyme responsible for hydrolysis of stored triglycerides from free fatty acids within adipocytes. In patients who are insulin resistant, this enzyme is no longer suppressed. In addition, counterregulatory hormones such as catecholamines, glucagon, and growth hormone are increased in response to increased circulating insulin levels. These counterregulatory hormones stimulate HSL to hydrolyse more triglycerides into free fatty acids, the end result being an increased flux of dietary and stored free fatty acids away from the adipose tissues and towards the liver. Unfortunately, Hickman et al did not measure free fatty acid levels before or after the weight reduction programme. Within the liver, insulin upregulates esterification of free fatty acids to triglycerides. Once the triglycerides are formed, insulin downregulates the secretory pathways, thus favouring increased storage of triglycerides in the cytosolic pool. Furthermore, free fatty acids can themselves upregulate the esterification pathway. The net result is a positive feedback cycle contributing to an ever increasing amount of free fatty acids and triglycerides in the liver. Thus portal hyperinsulinaemia leads to hepatic steatosis.

It is unfortunate that the authors used two methods to achieve weight reduction simultaneously. Exercise induced lowering of plasma insulin causes mobilisation of free fatty acids from the liver6 but the effect of exercise alone on hepatic steatosis has not been tried in individuals with non-alcoholic steatohepatitis or hepatitis C. Hickman et al were able to collect liver tissue both at baseline and again within three months of cessation of the 12 week weight reduction programme in 10 of the 19 individuals who participated in this study. Weight loss was associated with both a significant reduction in the grade of hepatic steatosis and a significant reduction in stellate cell activity, as judged by the extent of α smooth muscle actin staining. A significant reduction in liver fibrosis was not seen—not surprising over a six month period. These authors have provided some excellent photos of liver histology showing the marked changes in hepatic steatosis observed in 9/10 patients who underwent a second biopsy. However, fat is often focal and with this small number of paired biopsies, sampling error could still explain these changes although this is unlikely as 90% showed improvement of hepatic fat after weight loss. There is another study from Japan which also combined dietary restriction and an exercise programme in patients with fatty liver (uncomplicated by hepatitis C). They also demonstrated that a three month programme of weight reduction led to a significant reduction in hepatic steatosis but no change in fibrosis.7 These authors did not examine stellate cell activation. Clearly, the next experiment should be to establish whether exercise alone will induce similar changes.

There is still a lot that we do not know about hepatic steatosis and hepatitis C. These studies have suggested that the presence of fat in patients with hepatitis C is associated with markers of progressive liver disease in that fat was associated with increased stellate cell activation, but the mechanism by which this takes place is uncertain. It is possible that this occurs secondary to saturation of beta oxidation pathways within mitochondria which then leads to free fatty acids becoming more available to intracellular microsomes where they undergo lipid peroxidation. There are three main products of microsomal lipid peroxidation: malondialdehyde, 4-hydroxynonenal, and hydrogen peroxide. Malondialdehyde has been shown to activate stellate cells to produce fibrin, and may be responsible at least in part for liver fibrosis in patients with non-alcoholic steatohepatitis.

Recent data indicate that obesity is correlated with an impaired response to antiviral therapy in hepatitis C.8 It has been shown that the efficacy of “combination” therapy is in part related to the dose of ribavirin. This nucleoside analogue has a large volume of distribution and therefore body weight influences serum concentrations of ribavirin. Interferon, both standard and pegylated, has to be given by injection. Whereas standard interferon also has a large volume of distribution, as the size of the interferon molecule is increased (with pegylation), the volume of distribution diminishes so that body weight should not have such a marked effect on antiviral activity. However, it is possible that the site of the injection may influence absorption of IFN. In patients with diabetes, absorption of insulin differs according to the site of injection—for example, less in a slender arm and greater in an obese abdomen. Thus potentially weight loss could indirectly alter drug metabolism. This point has been discussed by Giannini and colleagues.9 One wonders whether this is one explanation for impaired response to antiviral therapy in hepatitis C in African-Americans who have a high rate of central obesity and insulin resistance.

Hickman et al have opened yet another chapter in the complicated story of the mechanisms involved in disease progression and possibly to factors influencing resistance to therapy in patients with hepatitis C. We have a lot more to learn!

Simple lifestyle changes, inducing weight reduction over three months, can potentially reduce both the morbidity and mortality related to hepatitis C infection


Linked Articles