Mortality Risk Higher in Lean Patients With NAFLD

Caroline Helwick

May 05, 2014

CHICAGO — Overall mortality is higher in lean patients with nonalcoholic fatty liver disease (NAFLD) than in overweight or obese patients with the disease, according to a retrospective study of patients around the world.

"We have underestimated the prognosis of lean patients with fatty liver. We need to take these patients seriously. Our study challenges the concept that obese patients are worse off," said senior investigator Paul Angulo, MD, section chief of hepatology at the University of Kentucky Medical Center in Lexington.

He described the study here at a press briefing held in advance of Digestive Disease Week (DDW) 2014.

Although most patients with NAFLD are overweight, the clinical and histologic profiles and long-term outcomes of patients who are not remain unclear. This study was designed to address this information gap.

"Ours was an international study conducted at 9 medical centers that have a particular interest in fatty liver disease," Dr. Angulo explained. "This is the first study to look at such a large number of lean patients with NAFLD."

Retrospective Study of 1090 Patients

Investigators evaluated 1090 patients with biopsy-confirmed NAFLD over a 20-year period. Extensive clinical and laboratory data were collected at the time of biopsy, and slides were read by experienced liver pathologists. Histologic features included steatosis, inflammation, hepatocyte ballooning, and fibrosis stage.

The team compared 125 patients who had a body mass index (BMI) below 25 kg/m² with 965 patients who had a BMI of at least 25 kg/m². Mean age of the cohort was 46 years, mean BMI of the lean group was 23 kg/m², and mean BMI of the nonlean group was 33 kg/m².

Lean NAFLD patients were more likely to be men and nonwhite than nonlean NAFLD patients, and were less likely to have diabetes, hypertension, hypertriglyceridemia, low high-density-lipoprotein cholesterol, central obesity, and metabolic syndrome (P < .004 for all).

Lean patients also had significantly lower levels of alanine aminotransferase, less insulin resistance, less steatosis, and less advanced fibrosis than nonlean patients, but they had more severe lobular inflammation (P < .03 for all).

There was no significant difference between the 2 groups in terms of age, hepatocyte ballooning, or prevalence of definitive nonalcoholic steatohepatitis.

Survival Outcomes Worse for Lean Patients

A subgroup analysis was conducted on 483 patients who underwent biopsy before 2005. Mean follow-up in this subgroup was 133 months.

Our study challenges the concept that obese patients are worse off.

The mortality rate in this subgroup was higher in lean than in nonlean patients (28% vs 14%; log-rank test, 5.6; P < .02). In fact, the risk of dying was almost 12 times higher in the lean group (P = .001).

"We looked at causes of death. Cardiovascular disease was number 1, the second was malignancy, and the third was liver-related conditions," Dr. Angulo reported. "Between the groups, we saw no differences in any of these causes of death," he said.

He acknowledged that the study might have been underpowered to detect differences in cause of death. "We are collecting more data and now have almost 1500 patients. Perhaps with a larger number of patients, we can do an analysis that looks at different causes," he explained.

Although the mechanism remains unclear, "our findings indicate that risk factors for fatty liver go beyond body weight and BMI," Dr. Angulo said.

His team plans to expand these findings by examining data beyond BMI, such as fat distribution and differences in cell signaling proteins, including cytokine and adipokine profiles. The team also plans to include patients who have not yet undergone biopsy.

Treatment Recommendations for Lean Patients

Clinicians should not assume that lean NAFLD patients won't benefit from targeted interventions, Dr. Angulo emphasized.

"We need to see how much liver injury they have and make a concerted effort to have them change their diet — eat less fat and carbohydrates — and increase their physical activity, not for the purpose of losing weight but to increase insulin sensitivity in the liver and muscle mass. When you exercise, even without losing weight, you get beneficial metabolic effects," he said.

These findings are "very surprising" and currently lack an explanation, said DDW council chair Lawrence Friedman, MD, who is chair of the Department of Medicine at Newton-Wellesley Hospital in Massachusetts.

Dr. Friedman indicated that he will "certainly pay attention to these findings" when treating lean NAFLD patients in his practice. "We had assumed the absence of obesity was a good thing, and now we learn that it may not be. I will follow Dr. Angulo's advice and encourage my patients to exercise more robustly," he said.

Ibrahim Hanouneh, MD, a hepatologist at the Cleveland Clinic, said he agrees with Dr. Friedman.

"Although obesity is undoubtedly one of the main risk factors for fatty liver, since its first description it has been known that fatty liver can also occur in nonobese subjects," he told Medscape Medical News.

"We need to pay more attention to these patients," said Dr. Hanouneh. "Further studies in this patient population are warranted but, until then, I agree on the need for better diet and robust exercise in these patients," he concluded.

At least some of these lean patients might have a lisosomal acid lipase deficiency, said Donald Jensen, MD, director of the Center for Liver Diseases at the University of Chicago. The disorder is marked by a deficiency in an enzyme that helps break down fatty cholesteryl esters and triglycerides, and is associated with an accumulation of fat.

Although this genetic disorder is seen most often in children, there is some evidence that polymorphisms can have an effect into adulthood, he explained. "This is one example of the need for genetic analysis and biomarkers to identify why these patients are so different," he said.

Dr. Angulo, Dr. Friedman, Dr. Hanouneh, and Dr. Jensen have disclosed no relevant financial relationships.

Digestive Disease Week (DDW) 2014: Abstract 379. Presented May 4, 2014.


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