Impact of Obesity on Hepatitis C and Treatment of HCV

By Liz Highleyman

It is increasingly clear that obesity and associated metabolic abnormalities play a role in the progression of liver disease and poor response to hepatitis C treatment.

Obesity and the metabolic syndrome -- a cluster of conditions including insulin resistance and elevated blood fat levels -- is associated with steatosis (fatty liver), which in turn is linked with more severe liver fibrosis and a greater risk of cirrhosis and hepatocellular carcinoma.

As reported in the May 2006 issue of Gastroenterology, for example, a meta-analysis of data from more than 3,000 patients at 10 clinics in Italy, Switzerland, France, Australia, and the United States found that steatosis was "significantly and independently" associated with fibrosis in people with chronic HCV infection, and that addressing metabolic factors "appears important in the management of chronic hepatitis C."

Similarly, a study presented at the Digestive Disease Week 2006 conference in May confirmed the link between steatosis and liver disease progression. In a retrospective review of medical records from 223 chronic hepatitis C patients, researchers observed a significant relationship between steatosis and fibrosis, leading them to suggest that, "Efforts to control steatosis may therefore have an important role in halting HCV liver disease progression, particularly in persons who are non-responders to antiviral therapy."

How Do Obesity and Metabolic Factors Promote Liver Damage?

The mechanisms by which obesity and metabolic abnormalities promote steatosis and fibrosis are not well understood, but inflammation, autoimmunity, and altered levels of cytokines and hormones such as leptin and adiponectin may play a role.

A study reported in the April 2006 Journal of Hepatology showed that alanine aminotransferase (ALT) levels -- and whether ALT decreased with successful treatment with pegylated interferon/ribavirin -- were associated with markers of the metabolic syndrome, including high body mass index and elevated blood pressure, blood glucose, and blood fat levels. The authors concluded that ALT elevation (a marker for liver inflammation) "partially depends on the degree of derangement of fat and carbohydrate metabolism."

In the June 2006 issue of Hepatology, researchers from the Mayo Clinic reviewed mechanisms that may explain the link between obesity and liver disease progression.

Fat tissue secretes hormones called adipokines (including leptin and adiponectin) that regulate metabolism of glucose and lipids in the liver, and also modulate immune activity. Some adipokines promote the release of pro-inflammatory cytokines. Leptin appears to activate signaling pathways in hepatic stellate cells that contribute to inflammation and fibrogenesis. Obesity can cause insulin resistance, which promotes the accumulation of fat in liver cells; HCV, too, appears to directly induce insulin resistance, so obese patients with hepatitis C may have an additive effect. Oxidative stress related to inflammation, as well as elevated insulin levels, may interfere with interferon-signaling pathways. Finally, excess fat tissue reduces the amount of circulating interferon in the body during treatment, possibly due to impaired absorption after injection.

Different HCV genotypes seem to be associated with steatosis through differing mechanisms. Genotype 3 HCV appears to directly promote the build-up of fat in liver cells, while steatosis in genotype 1 patients appears to be linked with co-existing metabolic conditions such as insulin resistance.

Management of Obesity

The Mayo Clinic researchers reported that reducing body weight and improving underlying metabolic factors may help "overcome the low sustained viral response rates observed in obese patients infected with HCV."

The first-line approach to managing obesity involves lifestyle modification, including exercise and a healthy, balanced diet. Weight loss has been shown to improve insulin sensitivity, lower ALT levels, and improve liver histology.

If such measures are not adequate, anti-diabetes drugs such as metformin (Glucophage), pioglitazone (Actos), and rosiglitazone (Avandia) may also be used to increase insulin sensitivity, which may help reduce fat accumulation in the liver. While these medications have not yet been studied extensively in people with hepatitis C, there is data suggesting that they are associated with reduced ALT and improved liver histology in HCV negative patients with non-alcoholic fatty liver disease.

The authors also suggested that use of higher doses of pegylated interferon and ribavirin for extended periods might help overcome the lower response rates observed in obese patients. Weight-based dosing and longer treatment durations are currently the subject of considerable research, but the authors also suggested higher dosing based on levels of insulin resistance or amount of visceral fat, rather than body weight alone.

Together, these studies suggest that liver disease progression should be considered among the deleterious outcomes of obesity and the metabolic syndrome, along with diabetes and cardiovascular disease.

7/28/06

References

G Leandro, A Mangia, J Hui, and others. Relationship Between Steatosis, Inflammation, and Fibrosis in Chronic Hepatitis C: A Meta-Analysis of Individual Patient Data. Gastroenterology 130(6): 1636-1642. May 2006.

K Corey, A K Bhan, R T Chung. Steatos is Associated with More Severe Fibrosis in Chronic Hepatitis C. Abstract S1056. Digestive Disease Week. May 20-25, 2006. Los Angeles, CA.

D Prati, M L Shiffman, M Diago, and others. Viral and Metabolic Factors Influencing Alanine Aminotransferase Activity in Patients with Chronic Hepatitis C. Journal of Hepatology 44(4): 679-685. April 2006.

M R Charlton, P J Pockros, S A Harrison. Impact of Obesity on Treatment of Chronic Hepatitis C. Hepatology 43(6): 1177-1186. June 2006.