Management of Nonalcoholic Fatty Liver Disease and Metabolic Syndrome

Lifestyle Modifications

Dietary modifications alone have been shown to be beneficial in the treatment of NAFLD, but good short-term success has not been shown to translate into sustained weight loss over time. Weight reduction is the ultimate goal of most lifestyle modification programs, and sustained weight loss has been correlated to improved hepatic histologic features and laboratory parameters with a decrease in or normalization of serum ALT, AST, fasting glucose, fasting insulin, triglyceride, and free fatty acids levels. A well-conducted prospective randomized study of 31 NASH patients demonstrated that intensive lifestyle modification with diet and exercise produced a 9.3% reduction in body weight compared with 0.2% in the control group and resulted in significant reduction in hepatic necroinflammation as determined by the NAS.

A subsequent larger prospective study of 293 biopsy-proven NASH patients who underwent 52 weeks of lifestyle modification confirmed the benefits of weight loss with regard to hepatic histologic features. All of those who lost 10% or more of their body weight showed reductions in the NAS and 90% of these individuals showed resolution of NASH, with 45% showing regression of fibrosis. Unfortunately, only 30% of patients lost 5% or more of their body weight, although even a 5% weight loss was associated with 2-point reduction in the NAS in 82% of patients. This suggests that moderate weight loss, although difficult to achieve, results in relief of NAFLD in most individuals.

Other studies have also shown histologic benefits with weight loss in NAFLD patients, and a meta-analysis of eight randomized controlled trials (RCTs) suggested that weight loss of 5% or more reduced hepatic steatosis and weight loss of 7% or more reduced the NAS. In total, these studies suggest that sustained weight loss on the order of 5% to 10% of body weight is effective in treating NASH, with the caveat that intensive intervention and long-term follow-up were involved in all of these trials. It is discouraging that even in the context of a clinical trial with close follow-up, only a minority of individuals (30% in the largest study) successfully lost 5% to 10% of their body weight at 1 year of follow-up. Data are lacking for longer-term studies in NAFLD patients to ascertain the feasibility of sustained weight loss, but multiple large studies have demonstrated maintaining weight loss over multiple years is an elusive goal, with only approximately 20% of individuals able to maintain significant long-term weight loss defined by 5 kg or more at 5 years. Despite maintained weight loss failures, recent evidence suggests the number of clinical encounters improves weight reduction and that more frequent clinic visits appear to correlate with weight loss success.

Although weight loss is generally the goal of most lifestyle modification trials, low-carbohydrate or low-fat diets are alternative approaches that have been investigated with and without caloric reduction. One small study demonstrated that decreasing daily caloric and carbohydrate intake in individuals with NAFLD increased hepatic insulin sensitivity and decreased intrahe­patic triglyceride concentration. A longer study comparing reduced-fat and reduced-carbohydrate diets demonstrated similar reductions between the groups in intrahepatic lipid content as measured by spectroscopy. These and other studies have suggested that overall caloric reduction rather than either a low-carbohydrate or low-fat diet predicted improvements in hepatic histologic features.

Specific macronutrient composition may also be important in addition to net calories consumed as diets high in saturated fatty acids have been shown to be an independent risk factor for the development of fatty liver disease. Conversely, diets high in polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids have been associated with NAFLD reduction. The Mediterranean diet, high in monounsaturated fatty acids, has been shown to reduce cardiovascular disease and has been associated with decreased IR and lower alanine aminotransferase (ALT) levels in obese individuals with type 2 diabetes. A more recent study by Ryan et al. showed increased insulin sensitivity and decreased hepatic steatosis after just 6 weeks of adherence to the Mediterranean diet. Similarly, a 2014 study by Kontogianni et al. showed a decrease in the severity of NAFLD in those who adhered to the Mediterranean diet. Although these data are encouraging, further study is needed to determine if the Mediterranean diet reduces hepatic fibrosis or improves outcomes in NAFLD patients.

PUFAs have also shown potential benefit in NAFLD populations, with a 2012 meta-analysis demonstrating significant reduction in hepatic steatosis with PUFA supplementation. This was also supported by a double-blind randomized placebo-controlled trial where 3 g of n -3 fish oil daily reduced hepatic steatosis but not the NAS. Further evidence beyond isolated steatosis reduction is required before the Mediterranean diet or PUFA supplementation can be recommended as primary NAFLD therapy.

The intake of fructose has also been associated with activation of stress response kinases that leads to hepatic inflammation, apoptosis, fibrosis and down-regulation of hepatic insulin signaling. Both animal and human models have associated fructose consumption with NAFLD and NASH, leading to the idea that dietary restriction of fructose may prove a useful adjunct to more conventional treatments. Limiting high-fructose corn syrup intake is thought to be beneficial as numerous studies have demonstrated an association between fructose intake and NASH, although prospective treatment trials are lacking. Alternatively, some authors have suggested that excessive calories rather than specifically fructose are the culprit, and current recommendations include limiting dietary fructose in NAFLD patients within the context of overall caloric reduction.

Caffeinated coffee intake is a unique dietary adjunct that has been associated with decreased hepatic fibrosis in NASH patients as well as a 40% decreased incidence of hepatocellular carcinoma in NAFLD and viral hepatitis. It is uncertain what components provide the apparent antiinflammatory, antioxidant, and antifibrotic properties specific to caffeinated drip coffee as these benefits have not been associated with decaffeinated coffee, tea, or espresso. In the absence of prospective data, it is reasonable to encourage the drinking of one cup to two cups of caffeinated drip coffee daily by NAFLD patients as an adjunct to other lifestyle modification.

Exercise

Globally decreased levels of physical activity have contributed to increased rates of obesity as well as NAFLD, and interventions that include exercise either alone or in combination with dietary modification are a logical treatment approach as exercise has been shown to decrease IR and improve metabolic parameters (improved oral glucose tolerance test, fasting serum glucose, and increased insulin sensitivity with decreased lipogenesis and intrahepatic lipid concentrations) associated with NAFLD. A systematic review and meta-analysis by Keating et al. demonstrated that exercise alone decreases the amount of intrahepatic fat, regardless of achieving weight loss. A subsequent RCT assessed four lifestyle modification approaches in biopsy-proven NAFLD patients: standard-of-care diet education, moderate exercise alone, low-fat diet with moderate exercise, and moderate-fat and low-carbohydrate diet for 6 months. The study, although limited by low overall numbers, found improvement in liver histologic features in all patients who modified their lifestyle regardless of the group, suggesting no one approach was superior. Programs using resistance training independent of weight loss also have shown benefit, with even 8 weeks of resistance training demonstrating decreased IR as well as hepatic steatosis. Additional RCTs are needed in regard to developing optimal exercise programs best suited to improve NASH histologic features, but adequate evidence exists to encourage exercise as a component of any NAFLD treatment regimen.