Insulin resistance a culprit for non-alcoholic fatty liver disease

NEW ORLEANS — The prevalence of nonalcoholic fatty liver disease is high in patients with diabetes, and insulin resistance is the apparent cause, according to a keynote lecture at the National Lipid Association Scientific Sessions.

“Insulin resistance appears to be the underlying pathophysiological defect leading to [nonalcoholic fatty liver disease],” David E. Cohen, MD, PhD, Director of Hepatology at Brigham and Women’s Hospital, director of the Harvard–MIT division of health sciences and technology, and Robert H. Ebert Professor of Medicine at Harvard Medical School, said.

David E. Cohen

NAFLD is defined as an alcohol-like liver disease in people who do not excessively consume alcohol, and is divided into non-alcoholic fatty liver with steatosis (NAFL), with no inflammation; and non-alcoholic steatohepatitis (NASH), which is associated with increased hepatocyte death, inflammation and fibrosis, he said.

NAFL can lead to NASH, which can evolve to cirrhosis, but sometimes NASH leads to other outcomes, he said. Thirty percent of patients with NASH develop cirrhosis over 5 to 10 years, he said.

In the Dallas Heart Study of 2,200 participants, 31% had liver fat of more than 5.5%, the definition of steatosis. In the NHANES III cohort, 5.5% had NAFLD.

Of those with NAFLD, approximately 80% have NAFL and 20% have NASH, but NASH is more common in those with morbid obesity, type 2 diabetes or dyslipidemia.

Approximately half of patients with type 2 diabetes have NAFLD, with 87% of those with any form of the condition having NASH, he said. By 2020, NASH will be the leading reason for orthotopic liver transplantation, he said.

NAFLD is an independent risk factor for CVD and type 2 diabetes, he said.

“Steatosis is telling you that you have a very high cardiac risk,” he said.

Fatty liver is associated with diabetes, obesity and dyslipidemia, which “track back to insulin resistance,” Cohen said.

The oxidation and secretion processes in the liver aren’t able to dispose of the excess fats generated in the livers of patients with NAFLD, leading to excess lipids being stored, according to Cohen.

Insulin resistance is a major reason for accumulation of triglycerides in the liver, and glucose and insulin play roles in fatty acid synthesis, he said.

Genetic studies have revealed a number of genes implicated in different types of NAFLD, most notably PNPLA3, whose G allele is associated with hepatic steatosis, he said, noting that therapies targeting these genes are still in development.

Laboratory tests for NAFLD are not very specific, and are best used to rule out other liver diseases and to analyze markers of the metabolic syndrome that often appear in conjunction with NAFLD, Cohen said.

Prognosis usually depends on histology. Portal hypertension being a sign of increased risk for poor outcomes, he said. Blood tests are modestly helpful, imaging tests are not helpful, and liver biopsy is the gold standard for establishing severity.

The cornerstones of management of patients with NAFLD are diet and exercise. Weight loss leads to improvement in steatosis and severity of NASH, and weight loss surgery often leads to the resolution of NASH, he said. Exercise without weight loss also decreases steatosis, he said.

Vitamin E may be an appropriate therapy for nondiabetic NASH, because it decreases steatosis but does not impact fibrosis, but it should be used cautiously in men because of its link to prostate cancer, Cohen said. Pioglitazone has also been tested, but is not currently recommended.

Weight loss, avoidance of alcohol and tobacco and implementing CVD prevention measures are the most common recommendations for combating NAFLD. Lipid-lowering therapy, especially statins is important because this addresses the increased cardiac risk and could potential have a positive impact on the NAFLD, according to Cohen.

Novel drugs targeting fat accumulation in the liver and fibrosis are being developed, he noted. – by Erik Swain

Reference:

Cohen DE. Pathogenesis and Management of Non-Alcoholic Fatty Liver Disease. Presented at: National Lipid Association Scientific Sessions; May 19-22, 2016; New Orleans.
Disclosure: Cohen reports financial ties with Aegerion, Catabasis, Esperion, Genzyme, Intercept, Merck and Synegeva.