MIAMI BEACH — All patients with nonalcoholic steatohepatitis, as well as those at risk for developing the condition, should be counseled about the importance of diet and exercise, while more aggressive therapy should be considered in those who fail to achieve 10% weight loss with diet and exercise alone, Dr. Stephen A. Harrison said at a meeting on hepatobiliary disease sponsored by the University of Miami.

Studies suggest that people who are overweight or obese have a substantially higher risk of nonalcoholic steatohepatitis (NASH). For example, about 3% of the general population has NASH, compared with 20%–40% of those with body mass index greater than 35 mg/kg

Weight loss is the accepted standard for treatment, Dr. Harrison said. Studies consistently show that substantial weight loss results in improved histopathology. For example, in a recent randomized study evaluating the use of orlistat to augment weight loss, Dr. Harrison showed that patients in both the treatment and control groups who achieved greater than 9% weight loss had improvements in insulin resistance, steatosis, and inflammation, as well as significant reductions in NASH activity scores.

Control patients who were treated with dietary restrictions and vitamin E lost a mean of 6% of their body weight, compared with 8% weight loss in those also treated with orlistat, and no differences were seen between the groups with regard to histopathologic outcomes. Orlistat can be considered a tool to help augment weight loss, but it is those patients who achieve greater than 9% weight loss who will benefit, Dr. Harrison noted.

Exercise has also been shown to be helpful in these patients. In one study of more than 1,500 individuals who exercised at a gym at least 1 day per week and who followed a diet low in processed carbohydrates, 6% of patients lost at least 5% of body weight, and nearly half of all patients with abnormal alanine transaminase (ALT) levels had ALT normalization at 1 year. Every 5% decrease in weight was associated with a 3.6-fold decrease in ALT, and participants also experienced reductions in triglycerides, blood pressure, and fasting glucose.

Weight loss surgery is also an option, particularly for morbidly obese patients and those who are not able to lose enough weight through diet and exercise alone.

Data on adjustable gastric banding are quite provocative in terms of its effects on NASH, Dr. Harrison said. In one study of 36 patients who lost an average of 75 pounds by 25 months, 23 patients had NASH, and 82% of them had resolution of NASH.

Recent studies also appear to dispel the notion that the kind of rapid weight loss often associated with surgery can lead to worsening of steatohepatitis. Older data based on a single follow-up liver biopsy suggested that rapid weight loss was associated with increasing inflammation, but studies that are more recent have used serial biopsies, which showed an initial increase in inflammation, followed by resolution over time, he explained.

Pharmacotherapy is another option in those who can't or won't lose weight, Dr. Harrison said. Thiazolidinediones (glitazones) will form the foundation of therapy in the future in these patients, he said.

Studies of pioglitazone and rosiglitazone, are promising in regard to their effects on plasma glucose, hepatic insulin sensitivity, adiponectin levels, hepatic fat content, inflammation, steatosis, and fibrosis.

Other drugs, such as metformin, show promise, but studies suggest that metformin is not associated with the histopathologic improvements seen with the glitazones. Combination therapy, however, may be beneficial; metformin appears to mitigate the weight gain that can occur with the glitazones, Dr. Harrison said.

Who's at Risk for a NASH Diagnosis?

A composite index based on clinical and laboratory findings can help identify patients at risk of having NASH, Dr. Harrison said.

A study of 80 patients with biopsy-proven nonalcoholic fatty liver disease, including 39 with simple steatosis and 41 with NASH, showed that the index—including three of five of the following factors—has 74% sensitivity and 66% specificity for identifying patients at risk of NASH. The factors are aspartate transaminase (AST) of 45 U/L or over, body mass index of 30 kg/m

“So for instance, if you have a female over age 50 that's obese, her probability of having steatohepatitis is certainly greater than 50%,” he said.

In addition, in a recent study of 97 severely obese patients undergoing bariatric surgery, insulin resistance was shown to be more severe in patients with NASH, compared with those without NASH, and both AST level and the presence of diabetes were independently associated with a NASH diagnosis (Am. J. Gastroenterol. 2007;102:399–408).

Other studies have also shown an association between metabolic syndrome and NASH; one study found that 88% of patients with NASH had metabolic syndrome, Dr. Harrison noted.

Push Diet, Exercise; Consider Glitazones for NASH : Patients who achieved greater than 9% weight loss had improvements in NASH activity scores.