Obesity, diabetes fuel liver disease epidemic

In their report, Dr. Agopian and Dr. Busuttil called the current surge in liver transplants for patients with NASH "the new epidemic."

"The future of [liver] transplantation is here with these patients who have nonalcoholic steatohepatitis and subsequent cirrhosis," commented Dr. John P. Roberts, professor and chief of transplant surgery at the University of California, San Francisco. "Currently, there are about 6,000 [liver] transplants [per year] in the United States. Half of those are done for hepatitis C. In the overall population of the United States, 1.3% have hepatitis C, and that provides about half of liver transplant patients. Twelve percent of the U.S. population have nonalcoholic steatohepatitis, a 10-fold increase over the percentage of the population with hepatitis C. Due to the kinetics of the hepatitis C epidemic, we are going to see a falloff in the number of patients with hepatitis C eligible for transplantation in the next 10 years. [Patients with NASH] are going to replace them, potentially by 10-fold," said Dr. Roberts, who commented on the report by Dr. Agopian and Dr. Busuttil on the UCLA experience during the 2012 annual meeting of the American Surgical Association in San Francisco.

The NAFLD, NASH, and HCC connections

"The link between obesity, NASH, cirrhosis, and HCC is very strong" said Dr. Stephen H. Caldwell, professor of medicine and director of hepatology at the University of Virginia in Charlottesville.

"What remains unknown is whether NASH and hepatic scar formation are essential to cause cancer, or can carcinomas arise in a noncirrhotic, non-NASH fatty liver? Scar formation itself is a carcinogenic process, especially when it progresses to stage 3 – bridging fibrosis – or to stage 4," when cirrhosis occurs.

"It’s difficult to justify screening all patients with a fatty liver; that would be a huge undertaking," Dr. Caldwell said in an interview. "The more important clinical message is to consider whether a patient has NASH, but that is hard to diagnose without a liver biopsy."

So far, no markers have been unquestionably accurate for diagnosing NASH. Any patient who is obese or has metabolic syndrome should be considered for NASH, said Dr. Caldwell. Signs of more advanced liver injury include cirrhosis or portal hypertension. Other, more subtle signs include spider angiomas, reddening of the palms, declining platelet counts, or a family history of liver disease. Any of these could be a reason to look for NASH, he said.

Last year, guidelines issued by the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology, and the American Gastroenterological Association recommended against routinely testing for NAFLD, even among patients in diabetes or obesity clinics. Evidence was lacking for routine screening, even of high-risk patients, the guidelines said, with no data on cost effectiveness and uncertainties about diagnostic tests and treatment options (Hepatology 2012;55:2005-32).

But the guidelines do call for targeted assessment of NAFLD, and targeting NASH workups for selected NAFLD patients. The guidelines recommend ruling out all other possible etiologies and establishing NAFLD by histology or imaging. When a patient is diagnosed with NAFLD, the guidelines say that "as the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its presence can be used to target patients for liver biopsy." The 2012 guidelines also highlighted the NAFLD Fibrosis Score (Hepatology 2007;45:846-54) as another useful tool to identify NAFLD patients at increased risk for NASH or cirrhosis. The guidelines called the plasma biomarker cytokeretin-18 "promising," but cautioned that it was "premature to recommend in routine clinical practice."

Major issues for patients who develop NASH are their risk for cirrhosis and liver failure, as well as that for liver cancer. Although the case already exists for obesity, diabetes, and metabolic syndrome as factors leading to NAFLD and NASH, evidence also links each of these three conditions to an increased rate of HCC and other liver cancer, such as cholangiocarcinoma.

"The evidence supports both an independent role for obesity, insulin resistance, and diabetes, as well as boosting the risk from other major risk factors such as hepatitis. The missing evidence is it has not been shown that treatment of diabetes or weight loss can reduce the risk of liver cancer," said Dr. Hashem B. El-Serag, professor and chief of gastroenterology and hepatology at the Baylor College of Medicine in Houston. "Screening for fatty liver by liver enzymes and ultrasound is probably a prudent first step" for obese or insulin-resistant patients, noted Dr. El-Serag. But surveillance for HCC by twice-annual ultrasound exams is only for patients with demonstrated advanced fibrosis or cirrhosis, he said in an interview.