Obesity, diabetes fuel liver disease epidemic

Many physicians do not consider liver disease and liver cancer classic complications of obesity, type 2 diabetes, or metabolic syndrome, but they should.

Research findings over the past decade offer substantial evidence for links between obesity, diabetes, or metabolic syndrome and the earliest hepatic manifestation of these derangements: nonalcoholic fatty liver disease (NAFLD). Equally compelling links tie obesity, diabetes, and metabolic syndrome to more advanced liver pathology: nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer, especially hepatocellular carcinoma (HCC).

^{Courtesy UCLA Health System}

Dr. Ronald Busutti

Although the link between obesity, diabetes, or metabolic syndrome and NASH or liver cancer is not yet strong enough to justify major changes in disease surveillance or management, the link between these metabolic disorders and NAFLD is powerful and common enough to warrant routinely considering these patients as having NAFLD, say experts. And if NAFLD is found, the next step is deciding if a patient is the right candidate for NASH or cirrhosis assessment; and if those disorders develop, cancer screening follows.

A new dimension of obesity and diabetes morbidity

"For decades, attention to the patient with type 2 diabetes focused on the control of hyperglycemia and of risk factors associated with macrovascular disease. The epidemic of obesity now presents endocrinologists with new challenges. Among them is the need to identify early complications related to obesity in the setting of type 2 diabetes. NAFLD is a common complication of patients with type 2 diabetes that ... does not fit into the traditional realm of diabetic complications," Dr. Romina Lomonaco and Dr. Kenneth Cusi wrote in a recently published book chapter ("Evidence-based Management of Diabetes," chapter 21; TFM Publishing, 2012).

Not until recently has NAFLD been recognized as another common complication of patients with type 2 diabetes that requires special attention. NAFLD’s low profile as a complication of obesity and diabetes contrasts with its ubiquity. About 70% of patients with type 2 diabetes have NAFLD (compared with about 20% of all American adults), and perhaps up to 90% of morbidly obese patients have NAFLD. The prevalence of impaired fasting glucose and of newly diagnosed type 2 diabetes is about threefold higher in patients with NAFLD than in those without liver disease.

"Insulin resistance and obesity are probably the biggest factors" causing NAFLD, said Dr. Cusi, professor of medicine and chief of adult endocrinology, diabetes, and metabolism at the University of Florida in Gainesville. Moreover, "diabetes will worsen NAFLD, producing more fibrosis and an increased rate of cirrhosis," he said in an interview.

That’s significant because it is NAFLD progression that poses the biggest risk. NAFLD severity can range from mild, early-stage disease in an asymptomatic patient with normal liver enzyme levels to the development of inflammation –NASH – which can cause liver injury and fibrosis, lead to cirrhosis, and set up progression to organ failure or development of HCC or other liver cancer.

Overall, about 40% of patients with NAFLD progress to NASH, but both obesity and diabetes ratchet up NAFLD progression, and so roughly half of all patients with diabetes have NASH. Patients with type 2 diabetes also have a two- to fourfold increased risk of developing advanced liver disease, cirrhosis, and HCC compared with people without diabetes. "About 15% of NASH patients develop cirrhosis, and a significant percent also develop cancer," Dr. Cusi said.

Dr. Kenneth Cusi

"NASH represents the hepatic manifestation of the metabolic syndrome, a constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia. It is projected that 25 million Americans will develop NASH by 2025, with 20% progressing to cirrhosis, hepatocellular carcinoma, or both, that may require liver transplantation," wrote Dr. Vatche G. Agopian and his associates from the Dumont-University of California, Los Angeles (UCLA), Transplant and Liver Cancer Center in a recent report (Ann. Surg. 2012;256:624-33).

From 2001 to 2009, the nationwide frequency of NASH as the primary indication for liver transplantation rose from 1% to 10%, with NASH becoming the third most common U.S. indication for liver transplantation (Gastroenterology 2011;141:1249-53). The UCLA surgeons reviewed their experience with 1,294 patients who underwent primary liver transplantation at their center between January 2002 and August 2011, and found 136 patients (11%) who met NASH criteria. But during the 10-year period studied, NASH as the trigger for liver transplant soared from 3% of transplants in 2002 to 19% in 2011, a jump that by 2011 made NASH the second most common cause for liver transplant at UCLA, trailing only hepatitis C virus. In fact, NASH "is poised to surpass hepatitis C as the leading indication in the next 10-20 years," wrote Dr. Agopian, a liver surgeon, and Dr. Busuttil, professor and chief of liver and pancreatic transplantation at UCLA, and their associates (Ann. Surg. 2012;256:624-33).