In general studies examining the effect of weight loss in fatty liver disease have been uncontrolled or of short duration, providing limited guidance for long-term management. Most have not used sophisticated measurements to assess insulin secretion or action, nor performed liver biopsies before and after to correlate weight loss with histological improvement, but have rather used surrogate markers such as liver transaminases or imaging. It is also unclear what kind of exercise would best improve hepatic insulin sensitivity and/or lead to the greatest loss of liver fat or histological improvement. It is also evident that until we better understand the mechanisms that lead to hepatic steatosis, inflammation, and fibrosis, exercise prescriptions (frequency, duration, what kind of exercise program, etc.) in NAFLD will not have a clear target and will remain rather empiric.
Beyond these limitations, there appears to be benefit from lifestyle modification involving increased physical activity and/or weight loss to reverse fatty liver disease, although the results have been variable (349-351). Intervention studies in patients with NAFLD illustrate the same kind of difficulties in achieving and maintaining weight loss that clinicians face in clinical practice. In a meta-analysis of 13 weight reduction studies spanning between the years 1967 through 2000, Wang et al. (349) found that most studies were typically small (only 3 had more than 50 patients while 9 had 25 or fewer subjects enrolled), uncontrolled (10 were case series), and frequently used a surrogate primary end point (i.e., liver aminotransferase levels instead of liver histology in 8 of the 13 trials). In the few studies that performed a liver biopsy before and after weight loss, only steatosis improved, but not necroinflammation or fibrosis. Moreover, improvement in aminotransferase levels did not necessarily translate into improved liver histologic scores, something well documented in a recent trial we performed in patients with NASH (64).
The effect of exercise per se (independent of weight loss) in NAFLD has not been well studied. Most of the intervention studies in NAFLD have concentrated on the effect of weight loss alone, although a few studies have included exercise as part of the treatment program ( 349, 352-356). Studies have been small (15-65 patients), of short duration (12-16 weeks) and largely used as the primary endpoint surrogate markers (i.e., AST/ALT and/or ultrasound). Only Ueno et al. performed liver biopsies before and after 3 months of diet and exercise and found a reduction in steatosis (354). Moreover, none of these studies were designed to examine the effects of exercise per se from that of weight loss, but rather how both interventions were applied as part of an integrated lifestyle intervention. Recently, this issue was addressed by Tamura et al. (357) in 14 patients with T2DM exposed to a 2-week hypocaloric diet with or without moderate exercise (30-min exercise program - five to six times per week). Limitations of the study included the small sample size, short duration of the study, and unclear monitoring/compliance regarding the diet and activity program. Overall metabolic effects were small but insulin sensitivity slightly improved by exercise although such an exercise program had no significant impact on liver fat, being equally reduced in both groups by 27% (357).
Recently, Huang et al. (358) reported a trend toward a histologic improvement but not a significant benefit after a year-long, intense nutritional counseling program in patients with nonalcoholic steatohepatitis. Those that lost more weight overall did better, but weight reduction was overall modest (-2.9 kg) in the two-thirds of patients who successfully completed the study. In a 6-month randomized controlled trial of weight loss plus pioglitazone or placebo, we only observed a mild reduction in inflammation in the diet-plus-placebo arm and a trend toward reduction in steatosis in the subjects. The results were overall similar in only those who lost a significant amount of weight were analyzed (unpublished). Nevertheless, weight reduction must be emphasized in NAFLD and NASH patients, with some studies reporting a significant reduction in liver steatosis as measured by MRS in small (n = 7-10), short-term low-fat calorie restriction studies lasting anywhere from 2 (357, 359) to 12 weeks (360) and involving nondiabetic obese (357, 360) or T2DM (359) patients with NAFLD.
Dietary composition may be another important but frequently overlooked aspect related to excessive hepatic fat deposition, as been suggested in single case reports (361) and small case series (n = 5) (362) in which low-carbohydrate diets were of particular benefit to rapidly reduce steatosis and elevated ALT in subjects with NAFLD. Recently, Ryan et al. (363) examined the effect of two hypocaloric diets containing either 60% carbohydrate/25% fat or 40% carbohydrate/45% fat (15% protein) for 16 weeks in 52 insulin-resistant obese subjects. While both diets resulted in significant decreases in weight, insulin resistance, and serum ALT concentrations, the low carbohydrate diet improved all three parameters significantly more than the high carbohydrate diet. Reduction of steatosis and of plasma triglycerides concentration by low carbohydrate diets is likely related to downregulation of hepatic sterol regulatoryelement-binding proteins (SREBP) activity by the amelioration of chronic hyperinsulinemia and by lowering the postprandial glucose load that stimulates hepatic ChREBP de novo lipogenesis (335). However, long-term controlled trials using histologic findings as the primary endpoint remain very much needed. Of note, there was some concern from early studies (304, 364) that abrupt and/or massive weight loss with bariatric surgery could be detrimental in terms of paradoxically exacerbating liver inflammation and fibrosis. This concern has abated considerably as more recent bariatric surgery series report significant histological improvements, possibly associated with less malnutrition and procedure-related complications (365) . Furthermore, bariatric surgery is now backed by large, long-term follow-up studies showing a significant decrease in overall- and diabetes-related mortality by these procedures (366, 367).
Weight loss remains the standard of care in NAFLD because no pharmacological therapy has conclusively proven to be effective in the long term. Pharmacological therapies with modest benefit have included pentoxifilline, orlistat, vitamin E, cytoprotective agents, ursodeoxycholic acid, and lipid-lowering agents (368) , while insulin sensitizers such as metformin (369) and thiazolidinediones yielded provocative results in small uncontrolled studies in NASH (332, 370, 371). We recently demonstrated in a randomized, double-blind, placebo-controlled trial that pioglitazone treatment for 6 months in patients with T2DM and NASH significantly improved glycemic control, glucose tolerance, insulin sensitivity, and systemic inflammation (64). This was associated with a 50% decrease in steatohepatitis (p < 0.001) and a 37% reduction of fibrosis within the pioglitazone-treated group (-37%, p < 0.002), although this fell short of statistical significance when compared with placebo (p = 0.08). Our results provided "proof-of-principle" that pioglitazone may be the first agent capable of altering the natural history of the disease. However, definitive proof requires establishing its safety and efficacy in a large long-term clinical trial.
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