April 9, 2015

Fatty Liver Disease – Part 2

The liver diseases seen in type 2 diabetes patients cover virtually the entire spectrum of liver disease.
Abnormal liver enzymes
Elevation of serum alanine aminotransferase (ALT), while uncommon (0.5%) in apparently normal subjects, is common in patients with type 2 diabetes.

The most common chronic liver disease in the U.S. is NAFLD. It is defined as fatty liver disease in the absence of less than 20 g alcohol/day. NAFLD, which resembles alcoholic liver disease, consists of a spectrum of liver disease from steatosis (fatty infiltration of the liver) to nonalcoholic steatohepatitis (NASH), which consists of steatosis plus inflammation, necrosis, and fibrosis. The prevalence of NAFLD in diabetes is estimated at 34–74% and, in diabetes with obesity, at virtually 100%. While once considered a benign process, NASH has been found to lead to cirrhosis and, in some cases, to hepatocellular carcinoma. Of patients with NAFLD, 50% have NASH and 19% have cirrhosis at the time of diagnosis. While these studies are subject to selection bias, the prevalence is undoubtedly very high.

NAFLD does not universally progress to NASH, and the precise pathogenesis of steatohepatitis is yet to be determined. However, dysregulation of peripheral lipid metabolism seems to be important. The natural history of NAFLD is similar to that of alcoholic liver disease.

Cirrhosis in diabetes
Cirrhosis is an important cause of death in diabetes. An autopsy study in the U.S. has shown that patients with diabetes have an increased incidence of severe fibrosis. The association of cirrhosis and diabetes is complicated by the fact that cirrhosis itself is associated with insulin resistance. Impaired glucose tolerance is seen in 60% and overt diabetes in 20% of patients with cirrhosis. Insulin-mediated glucose disposal has been shown to be reduced by ∼50% in cirrhotic patients. However, the onset of type 2 diabetes in cirrhotic patients is associated with decreased rather than increased insulin secretion. This interplay of associations has made it difficult to sort out the pathogenesis of cirrhosis in diabetes. Nevertheless, the association is incontrovertible and has implications for the treatment of diabetes in patients with cirrhosis.

Hepatocellular carcinoma in diabetes
Numerous studies have confirmed a fourfold increased prevalence of hepatocellular carcinoma in patients with diabetes as well as an increased prevalence of diabetes in patients with hepatocellular carcinoma. It is not known whether the increased prevalence of hepatocellular carcinoma is unique to diabetes or the increased prevalence of cirrhosis, the precursor lesion of hepatocellular carcinoma. The pathogenic sequence of events leading to hepatocellular carcinoma appears to be insulin resistance, increased lipolysis, lipid accumulation in the hepatocytes, oxidative stress, and cell damage followed by fibrosis and cell proliferation, which are procarcinogenic.

Acute liver failure
The incidence of acute liver failure appears to be increased in patients with diabetes: 2.31 per 10,000 person-years compared with 1.44 in the background population (53,54). It remains unclear whether it is diabetes, medications, or some other factor that accounts for the increased risk of acute liver failure.

Hepatitis C in diabetes

The prevalence of hepatitis C virus (HCV) is higher in patients with diabetes than in the general population. Specifically, the prevalence of HCV antibodies is 4.2% in the diabetic population compared with 1.6% in the comparator group. The relative odds of HCV-infected patients developing diabetes is 2.1 (95% CI 1.12–3.90). Patients with HCV are more likely to develop diabetes (21%) than patients with hepatitis B (10%), suggesting that HCV, rather than liver disease per se, predisposes patients to diabetes.

Finally, there is an association of diabetes with α-interferon treatment of HCV infection. Type 1 diabetes occurs more frequently in patients treated with interferon for HCV versus other conditions. The latency of diabetes ranges from 10 days to 4 years after starting treatment.

The interaction between HCV infection, diabetes, and interferon is the subject of intensive investigation. In the meantime, given the strong epidemiologic evidence for the increased prevalence of HCV in diabetes, it seems reasonable that all patients with type 2 diabetes and persistently elevated serum ALT should be screened for HCV.

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