Impact and Management of Insulin Resistance in Patients with Hepatitis C

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Impact and Management of Insulin Resistance in Patients with Hepatitis C

By Liz Highleyman

Metabolic complications, including insulin resistance, have become an increasingly important aspect of the management of chronic hepatitis C. Insulin resistance is a condition in which higher-than-normal insulin levels are needed to process glucose.

Diabetes is a known complication of all types of liver disease, but research indicates that hepatitis C virus (HCV) infection plays a more direct role in abnormal glucose metabolism - an association that appears to differ based on HCV genotype. Studies have shown that HCV infection is associated with a higher rate of diabetes, and that blood glucose abnormalities, in turn, are linked to more severe fibrosis. Sustained responders to interferon-based therapy typically experience improved insulin sensitivity - though patients with insulin resistance are less likely to respond to anti-HCV treatment.

Two recent reports examined the connection between insulin resistance and liver steatosis (fat accumulation) and fibrosis, while another provided an overview of the management of insulin abnormalities and metabolic syndrome in people with chronic hepatitis C.

Study 1

In the first study, republished in the December 2006 issue of Hepatology, researchers from the University of Turin analyzed the relationship between clinical characteristics, insulin resistance (using the homeostasis model assessment of insulin resistance, or HOMA-IR), and histological parameters in 132 patients with "viral" steatosis associated with genotype 3 HCV infection and 132 subjects with "metabolic" steatosis associated with non-alcoholic fatty liver disease (NAFLD). Participants were matched by age, body mass index (BMI), and degree of fat accumulation in liver cells.Results

Tests of liver function were comparable in the 2 study populations. Features of insulin resistance were more common in the NAFLD patients, who also had higher HOMA-IR scores (P = 0.008). Logistic regression analysis found that in patients with genotype 3 HCV, steatosis was associated with:- high HCV viral load;- low serum cholesterol. In NAFLD patients, steatosis was associated with:- high aminotransferase (ALT and AST) levels;- elevated glucose levels;- levels of ferritin (a protein that stores iron);- hypertriglyceridemia (elevated triglycerides). In a univariate analysis, advanced fibrosis was associated with steatosis in NAFLD patients, but not genotype 3 HCV patients. Other parameters related to fibrosis severity in genotype 3 HCV patients were:- higher HOMA-IR score;- low platelet count. Factors related to fibrosis severity in NAFLD patients were:- high aminotransferase levels;- higher HOMA-IR score;- ferritin level;- low high-density lipoprotein (HDL, or "good") cholesterol. In a multivariate analysis, only low platelet count (OR = 0.78; 95% CI 0.67-0.92) and HOMA-IR score (OR = 2.98; CI 1.13-7.89) were independent predictors of advanced fibrosis in genotype 3 HCV patients. In NAFLD patients, severe fibrosis was predicted by degree of liver fat accumulation (OR = 3.03; CI 1.41-6.53), ferritin level (OR = 1.13; CI 1.03-1.25), and HOMA-IR score (OR = 1.16; CI 1.02-1.31).

In conclusion, the authors wrote, "insulin resistance is an independent predictor of advanced fibrosis in both NAFLD and [genotype 3 chronic HCV infection], but the extent of steatosis contributes to advanced disease only in NAFLD. Virus-induced hepatic steatosis as seen in [genotype 3 chronic HCV infection] does not contribute significantly to liver fibrosis."Study 2

In the second study, described in the October 6, 2006 online edition of the American Journal of Gastroenterology, researchers from the Nagasaki University School of Medicine in Japan investigated the association between liver fibrosis and glucose intolerance in 83 chronic HCV-infected patients.

The investigators measured insulin sensitivity in a fasting state using HOMA-IR and beta-cell function (cells in the pancreas that produce insulin) using the homeostasis model assessment of beta-cell function (HOMA-beta). They also measured insulin sensitivity after subjects consumed 75 g oral glucose using the whole-body insulin sensitivity index (WBISI) and delta-insulin/delta-glucose 30.

Results

In a multivariate analysis, severe fibrosis was the only independent factor associated with insulin resistance. There were significant differences in both HOMA-IR (P = 0.0063) and WBISI (P = 0.0159) scores between patients with mild fibrosis (n = 34) and those with severe fibrosis (n = 49). Although HOMA-beta increased significantly in subjects with severe fibrosis compared to those with mild fibrosis (P = 0.0169), delta-insulin/delta-glucose 30 showed no significant difference related to stage of liver fibrosis.

Our findings suggest that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients," the authors wrote. However, they noted that the data suggest "an uncertain association between liver fibrosis and beta-cell function."

Managing Insulin Resistance

In the October 2006 Journal of Hepatology, Francesco Negro, MD, of University Hospital in Geneva, Switzerland, presented an overview of new knowledge about insulin resistance and the metabolic syndrome, and how this influences clinical management of chronic hepatitis C.

The metabolic syndrome refers to a constellation of factors including insulin resistance, abdominal obesity, high blood pressure, elevated triglycerides, low HDL, and a pro-inflammatory/pro-thrombotic state that promotes blockage and blood clots in the arteries. It is becoming more common as the population grows ever more obese. Fatty liver is increasingly recognized as a component of the syndrome. The process is not fully understood, but appears to involve altered levels of various cytokines or hormones, such as adiponectin and leptin, that regulate fat and sugar metabolism.

"It should be said that the correct management of the metabolic syndrome should be undertaken in all affected patients and this independently of the existence of liver disease," Negro wrote. "Control of excess body weight and increased physical exercise constitute the mainstays of any therapeutical intervention."

"Interestingly, some moderate physical exercise and weight loss may not only reduce the insulin resistance state, but also improve the fatigue that so often accompan[ies] chronic hepatitis C, via the antagoni[sm] of leptin and pro-inflammatory adipokines," she continued.

Beyond lifestyle changes, medications may be also used to manage insulin resistance, including metformin (Glucophage) and the thiazolidinediones or "glitazones," such as rosiglitazone (Avandia) and pioglitazone (Actos). Studies have shown that by sensitizing the liver to insulin, metformin appears to reduce steatosis in leptin-deficient mice and in humans with NAFLD, whereas glitazones shift body fat distribution from visceral to subcutaneous areas, which improves insulin sensitivity in the liver. These agents also appear to influence levels of metabolic hormones. At this time, however, more research is needed on metabolic manifestations and their management in people with hepatitis C.

"Undoubtedly today we have one more reason to investigate the presence of the metabolic syndrome in chronic hepatitis C patients, especially those more at risk like the aged and the obese," Negro concluded. "The role of lifestyle changes in increasing insulin sensitivity will never be emphasized enough, but the introduction of insulin sensitizers should be - for the time being - confined to randomized clinical trials."

12/08/06

References

E Bugianesi, G Marchesini, E Gentilcore, and others. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosis. Hepatology 44(6): 1648-1655. December 2006.

N Taura, T Ichikawa, K Hamasaki, and others. Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. American Journal of Gastroenterology. October 6, 2006 [Epub ahead of print].

F Negro. Insulin resistance and HCV: Will new knowledge modify clinical management? Journal of Hepatology 45(4): 514-519. October 2006.

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