Obesity, diabetes fuel liver disease epidemic

Pioglitazone received endorsement from the AASLD panel for treating NASH in their 2012 NAFLD management recommendations. The recommendations cautioned that most NASH patients who received pioglitazone treatment in trials did not have diabetes, and that long-term safety and efficacy of pioglitazone in NASH patients are not established.

The AASLD guidelines also call for using vitamin E at a daily dosage of 800 IU, but only for patients with biopsy-proven NASH and no diabetes; the guidelines call it "first line" in this setting. But the guidelines also specifically caution against using vitamin E in patients with NASH and diabetes, patients with NAFLD who have not undergone a liver biopsy, patients with NASH and cirrhosis, and those with cryptogenic cirrhosis. The guidelines also caution against using metformin to treat NASH. No other drug intervention gets guideline endorsement for treating NASH.

"You can say diet and exercise minimize the risk of fatty liver, but beyond that drug therapy is unclear," said Dr. Caldwell. "I think as we see treatment evolve, we’ll see more interest [in treating NAFLD and NASH] by endocrinologists," he predicted.

The intervention picture changes when the goal is preventing liver cancer. "Effective treatment of insulin resistance and hyperinsulinemia may be critical to prevent hepatocarcinogenesis," wrote Dr. Baffy, Dr. Brunt, and Dr. Caldwell in their recent review (J. Hepatology 2012;56:1384-91). "Insulin sensitizing agents in diabetes may reduce the risk of HCC." They especially cited the epidemiologic evidence supporting a role for thiazolidinediones, which were linked to a 70% reduction in HCC incidence among patients with diabetes compared with patients treated with insulin or a sulfonylurea in a case-control study (Cancer 2010;116:1938-46). The same study also showed a similar, 70% reduction in HCC among patients treated with a biguanide like metformin.

"While current guidelines for the management of HCC have no specific recommendations for cases associated with NAFLD, obesity, and diabetes, the use of insulin-sensitizing drugs and avoidance of treatments that contribute to hyperinsulinemia are likely to enhance prevention and improve disease outcomes of HCC," said Dr. Baffy, Dr. Brunt, and Dr. Caldwell.

Similar evidence recently came from other epidemiologic studies that suggest damping down of HCC development in patients treated with a thiazolidinedione or metformin. A report last year that analyzed health records of about 98,000 Taiwan residents found that treatment with a thiazolidinedione or with metformin reduced the rate of HCC in patients with diabetes by about 50% compared with other treatments (Am. J. Gastroenterol. 2012;107:46-52). More evidence supporting protection from metformin against formation of both HCC and a second, less common type of liver cancer, intrahepatic cholangiocarcinoma, came in two studies reported last May at the annual Digestive Disease Week in San Diego.

"Metformin has not proved useful in the therapy of NAFLD, but it is helpful in decreasing the risk of HCC in patients with obesity- or diabetes-associated liver disease. Metformin should be part of antidiabetic management whenever possible," Dr. Baffy said in an interview.

But other experts regard the evidence accumulated so far as too preliminary to guide management. "It is premature to recommend using [metformin or a thiazolidinedione] for the primary reason of HCC prevention," said Dr. El-Serag.

"I don’t think the evidence is convincing at this point" regarding preventing HCC, said Dr. Caldwell. "The thiazolidinediones seem to retard progression of NASH fibrosis, but they also have adverse effects and their popularity has decreased."

Early days for a complex pathology

It seems as if the links between obesity, diabetes, and metabolic syndrome and NAFLD, NASH, and liver cancer are so tangled that it will take more time to fully resolve the etiologic relationships and the implications for diagnosis and management. The bottom line today is that a growing segment of American adults face risks for significant liver disease because of obesity, type 2 diabetes, and other elements of the metabolic syndrome.

"We see more and more patients over the last decade with liver cancer who didn’t have hepatitis or alcohol use but have diabetes and obesity. It’s a changing demographic," said Dr. Hezel. "We increasingly see liver cancer in patients without one of the classic risk factors. There are two possible mechanisms. Fibrosis and inflammation" caused by NAFLD and NASH trigger cancer formation and growth, "or it could be a more direct effect of high insulin levels or other hormonal effects. This is an emerging area; it follows on the epidemic of obesity and diabetes."

Dr. Cusi, Dr. Caldwell, Dr. Baffy, Dr. El-Serag, Dr. Busuttil, and Dr. Hezel all said that they had no relevant disclosures.