Neil Canavan

November 28, 2011

November 28, 2011 (San Francisco, California) — Nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation rose 5-fold from 2002 to 2009. Although metabolic changes related to NASH risk have increased in the general population as a whole, the criteria for establishing risk for NASH-related liver failure remain unclear, according to data presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

"NASH is increasingly an indication for liver transplant," said Danielle Brandman, MD, from the University of California at San Francisco. "Factors for this include the addition of NASH as a diagnosis in the UNOS [United Network for Organ Sharing] database, and increased awareness of NASH as a cause of end-stage liver disease." Up to half of all cases of cryptogenic cirrhosis are likely a result of unrecognized NASH, although Dr. Brandman noted that there are no uniform diagnostic criteria to define cryptogenic cirrhosis caused by NASH.

To identify the NASH-related risk factors driving this increase, the researchers conducted a comparison of pre- and post-MELD score measures.

The findings suggest that steep increases in the incidence of obesity and insulin resistance are the culprits, as opposed to the recorded rates of hypertension and dyslipidemia, which have remained essentially stable since 2002.

In addition to these changes occurring over time in the general population, "we must think about how patients with NASH undergoing liver transplant may be changing over time," said Dr. Brandman. This study is an investigation of changes in the characteristics of liver transplant recipients secondary to NASH over time, as well as patient survival after transplantation for NASH.

The data for this retrospective investigation were drawn from the UNOS database. The inclusion criteria included being 18 years or older and undergoing liver transplantation from 2002 to 2009. Exclusion criteria included retransplantation, HIV positivity, fulminant hepatic failure, and rare liver diseases.

Cases of NASH and "probably NASH" were combined for the analysis. NASH was determined using primary diagnostic code at liver transplantation, and probably NASH was defined as preliver transplant diabetes mellitus, preliver transplant hypertension, and/or a body mass index (BMI) of 40 kg/m² or higher.

After reviewing 30,182 charts, Dr. Brandman's team identified 1355 cases of NASH and 1537 cases of probably NASH. In the probably NASH group, 70% had diabetes, 32% were hypertensive, and 9% had a BMI of 40 kg/m² or higher. Many patients had more than 1 condition, and half of the remaining liver transplant recipients were positive for hepatitis C virus infection.

There were more females in the NASH/probably NASH group than in the no NASH group (43% vs 29%), more patients with a BMI of 40 kg/m² or higher (31.7% vs 27.5%), more white patients (31.7 vs 27.5), more preliver transplant diabetes (67% vs 19%), and more hypertension (43% vs 16%). Patients in the NASH/probably NASH group had a low prevalence of hepatocellular carcinoma but a high requirement for renal replacement therapy just before transplantation.

Five-year survival rates after liver transplantation in the 2 groups were the same (81.1%).

Matching temporal trends of these measures to risk and outcome has been problematic. "Since 2002, NASH is an increasing indication for liver transplant; it was responsible for just over 4% of transplants in 2002 and more than 12% in 2009," said Dr. Brandman. "At the same time, those identified as having NASH/probably NASH exhibited less preliver transplant diabetes and pretransplant hypertension over time, despite increases in these conditions in the general population."

Dr. Brandman surmises that the selection criteria for liver transplantation are likely being applied. "Additional studies are needed to determine what these criteria are, and which are the strongest predictors of outcome."

There's Something Happening Here

"NASH can definitely kill an individual," said Arun Sanyal, MD, chair of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University in Richmond. Patients with NASH have a 15% to 20% risk of progressing to cirrhosis and end-stage liver disease, and there is increasing evidence that NASH may be connected to the development of hepatocellular carcinoma, even in the absence of cirrhosis. "That has huge public health implications because this cancer has one of the fastest rising incidences in the country."

Dr. Sanyal concurs with Dr. Brandman that the factors driving the increase in NASH are not clear.

"The increasing incidence of obesity and insulin resistance are 2 factors certainly." Other suggested contributors are the consumption of high-fructose corn syrup and environmental exposure to pollution. "There are studies that have linked exposure to various hydrocarbons to the development of fat in the liver — one of the defining characteristics of NASH."

Genetics also play a role. "We know that African Americans have a high incidence of hypertension and diabetes, but seem to be protected from fatty liver disease. In contrast, Hispanics have a high rate of metabolic syndrome and fatty liver disease," Dr. Sanyal said.

What is the clinician to do for the obese or hypertensive patient regarding NASH? "This is an emerging trend, so we're not quite there yet with a general clinical recommendation." There is no set diagnostic criteria for the disease, and other than lifestyle interventions, there is no approved treatment, although vitamin supplements can help. "We published a study last year showing that vitamin E at 800 units/day reverses NASH in roughly 40% of patients [N Engl J Med. 2010;362:1675-1685]," Dr. Sanyal noted.

Dr. Brandman and Dr. Sanyal have disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 12. Presented November 8, 2011.


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