Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.
Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.12 Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.13 (None of these studies included histology as an outcome measure.)
Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.
Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.14 Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.14 Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.
Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.15
The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.15
Liver-directed pharmacotherapy: Evidence is lacking for many agents
Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:
Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.16 Vitamin E was also associated with improved serum ALT.
Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.17 In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.
Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;18 however, a recent meta-analysis found that metformin failed to improve liver histology.19
Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.20 The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.16 However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.