Intermittent Fasting as a Treatment for Nonalcoholic Fatty Liver Disease: What Is the Evidence?

Content available: Author Interview and Audio Recording Nonalcoholic fatty liver disease (NAFLD), a spectrum from steatosis and nonalcoholic steatohepatitis (NASH) to cirrhosis, is the leading cause of liver disease. Currently, there are no agency-approved pharmacologic therapies for NAFLD. While weight loss can improve histologic outcomes in NAFLD, losing weight is difficult to achieve and adhere to long-term. Thus, continued investigation of strategies to treat NAFLD are needed. Intermittent fasting (IF) is a term used to describe eating patterns that limit food consumption for a predetermined amount of time to allow the body to enter a period of fasting. Alternate day fasting consists of normal consumption for 24 hours and fasting for the next 24 hours. The 5:2 fasting is severely reducing caloric intake for 2 days (~500 calories/day) followed by 5 days of normal consumption. whereas periodic fasting is intermittent fasting for 2+ days with minimal caloric intake (≤ 500 calories) without repeated fasts. Time-restricted fasting (TRF) is eating only during certain hours of the day (eg, 12 pm-8 pm). It is hypothesized that IF may have metabolic benefits on the liver, independent of caloric restriction(definition) and weight loss, this may also improve NAFLD histology. Induced by extended periods without food, fasting shifts the metabolic circuitry to increase hepatic lipid oxidation, decrease lipogenesis, and use ketones as the primary energy source (Fig. 1).1 Ketones not only serve as fuel but impact cellular machinery, enhancing the efficacy of mammalian target of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) (mTOR) and AMP-activated protein kinase (AMPK) pathways, and improve the liver’s ability to breakdown excess triglycerides.1, 2 While not yet studied extensively in humans, alternate day fasting in rodents protects against hepatic steatosis by selective stimulation of beige fat development within white adipose tissue likely via changes in the microbiome leading to increasing beta-oxidation, improving insulin resistance, and decreasing hepatic lipogenesis (Fig. 1).3 Furthermore, fasting may be an efficacious non-pharmacological strategy for improving insulin resistance and hepatic steatosis without difficult to achieve weight loss and caloric restrictions.1 While pre-clinical models provide mechanistic insight into the benefits of fasting, clinical studies testing the efficacy of fasting on humans with NAFLD are limited (Table 1). Most studies on intermittent fasting in NAFLD have occurred during the Muslim month of Ramadan, focusing on TRF, where people fast during the daylight (12-14 hours) for ~30 days. The results have largely been positive, finding that after 30 days, daily TRF significantly improved non-invasive markers of fatty liver disease (including Fibrosis-4 Index (FIB-4) score, NAFLD Fibrosis Score & BARD Score),4 reduced insulin resistance,4, 5 induced weight loss,4 and improved inflammatory markers (including IL-6 & CRP)5 (Table 1). Despite these findings, using Ramadan as a model for TRF has several limitations: (1) participants often consume meals high in fat and sugar during night-time eating that may decrease the benefits of TRF and (2) alterations in sleep cycles during the holiday may not be generalizable. These limitations suggest that TRF in the absence of altered sleep and high fat meals may provide even greater metabolic benefits; well-designed randomized control trials are needed. To compare the efficacy of alternate day fasting (ADF) to daily TRF (16:8 hours), a randomized NAFLD control trial was performed comparing 97 patients on 12 weeks of the TRF diet to 95 patients on the ADF diet. The study found that ADF resulted in a more significant reduction in total fat mass (−3.48 kg) and total cholesterol (−14.6%) compared to TRF (−2.62 kg) and controls (−1.05 kg). Between the two fasting methods, however, there was no difference in fat free mass, body weight, other lipid levels, fasting insulin, or liver stiffness (measured by vibration-controlled transient elastography), suggesting that longer durations of fasting may not be required to observe metabolic benefits on the liver.6 An alternative approach to strict fasting studied by Johari et al. compared the benefits of modified alternate day caloric restriction (MACR) (where participants reduced their caloric intake by 70% every other day for 8 weeks) against the benefits of intermittent fasting in NAFLD patients. In contrast to controls on a regular diet, the MACR group had a significant reduction in weight, BMI, steatosis, and fibrosis as assessed by sheer wave elastography (Table 1).7 A similar prospective study that did not require prolonged periods without food consumption but simply periods with significant reduction in caloric intake for >2 days (periodic fasting) found that after a mean of 8.5 days (range 6-38) subjects had a significant improvement in their Fatty Liver Index (FLI) score, with over half of high-risk subjects (FLI > 60) shifting to a lower risk FLI category after fasting (mean reduction −14.02 points).8 For every additional day of fasting, participants’ FLI score improved by 0.48 points with a mean weight loss of −4.37 kg.8 These findings illustrate that both fasting in the form of severe intermittent caloric restriction and fasting without food intake improves markers of hepatic steatosis and inflammation compared to controls. Available evidence suggests that any form of caloric restriction may be beneficial and specific forms of IF should be tailored to the individual. Further studies are needed to help differentiate if one fasting method is superior to others and compared to well established dietary patterns such as the Mediterranean diet, regarding patient feasibility and improvement in metabolic outcomes. Additionally, it is important we investigate the possible risks of fasting in patients with cirrhosis, which is currently not recommended. In conclusion, current evidence suggests that intermittent fasting in patients with NA