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Therapeutic fasting strategies have been recognized for their potential health benefits, which are achieved through multiple pathways, from increasing autophagy¹ to optimizing mitochondrial function.² Research studies have investigated different types of intermittent fasting for a range of clinical applications, including weight reduction and the improvement of metabolic health.^3-5

In the past few years, intermittent fasting approaches have been discussed in relation to the management of non-alcoholic fatty liver disease (NAFLD), yet few fasting-related clinical trials have included NAFLD-specific populations to evaluate the outcomes, efficacy, and safety parameters.^6,7 Recently, however, two randomized controlled trials (RCTs) assessed the benefits of intermittent fasting, specifically alternate-day fasting and time-restricted eating, for patients diagnosed with NAFLD.^8,9 Both reported compelling results.

Alternate-Day Fasting + Exercise

The 2023 Ezpeleta et al RCT is reportedly one of the first studies to examine the effect of intermittent fasting combined with exercise on NAFLD outcomes.⁸ Specifically, this three-month study explored the impact of alternate-day fasting and moderate-intensity aerobic exercise on both intrahepatic triglyceride (IHTG) content, an indicator of liver fat accumulation, and metabolic risk factors. The trial included 80 patients with obesity and NAFLD (mean age of 44 years; primarily Hispanic and Black females), and participants were randomized into one of the following four groups:⁸

• Alternate-day fasting (ADF) plus aerobic exercise intervention: Participants in this combination group alternated fasting days (consumed 600 kcal as a dinner between 5:00-8:00 pm) and “feasting” days (ate food as desired). In addition, they engaged in a moderate-intensity aerobic exercise session five times per week (60 minutes per session).
• ADF-only intervention: Participants in this group only alternated fasting days (consumed 600 kcal as a dinner between 5:00-8:00 pm) and “feasting” days (ate food as desired).
• Exercise-only intervention: Participants in this group only engaged in the moderate-intensity aerobic exercise session held five times per week (60 minutes per session).
• Control group with no intervention: Participants in this group were instructed to maintain their body weight throughout the trial and to also maintain their usual eating or exercise habits.

After three months, researchers found that IHTG content was significantly reduced by 5.48% in the combination group (95% CI, -7.77% to -3.18%) compared to the exercise-only group (-1.30%) and the control group (-0.17%).⁸ Of interesting note, the IHTG content reduction in the combination group was not significantly different than the reduction in the ADF-only group (-2.25%; 95% CI, -4.46% to -0.04%). Further research may help to clarify whether a combination intervention of fasting and exercise would reduce IHTG content to a significantly greater extent than fasting alone in patients with NAFLD.

In regard to metabolic risk factors, the combination intervention of ADF and exercise reduced body weight and fat mass to a greater extent compared to the exercise-only and control groups; however, these factors were not significantly different between the combination and ADF-only groups.⁸ In addition, waist circumference and insulin resistance (measured by HOMA-IR) were significantly reduced in the combination group compared with controls but were not significantly different between the combination, ADF-only, and exercise-only groups.⁸

Overall, the Ezpeleta et al RCT demonstrated the significant effectiveness of ADF combined with exercise to reduce hepatic steatosis, body weight, fat mass, waist circumference, alanine transaminase (ALT), fasting insulin, and insulin resistance and to increase insulin sensitivity for patients with obesity and NAFLD compared to controls.⁸

Time-Restricted Eating + Low-Sugar Diet

In another recent trial, Kord-Varkaneh et al examined the impact of time-restricting feeding (TRF) plus a low-sugar diet on NAFLD outcomes and metabolic health indicators.⁹ This intervention explored the potential benefits associated with optimizing circadian rhythms within an NAFLD treatment plan.

In this 12-week RCT, 45 middle-aged patients with NAFLD were recruited from a medical center in Iran (mean BMI of 29.9) and randomized to either the intervention group (followed a daily circadian fasting/TRF pattern of 16-hour fasting and 8-hour feeding in addition to a low-sugar diet) or the control group (followed an isocaloric control diet based on traditional meal distribution and eating patterns).⁹ While the intake of total energy (kcal/day) was not significantly different between the two groups, the intervention group consumed less carbohydrates than the control group due to their prescribed low-sugar diet (free sugar intake restricted to less than 3% of daily calories).

Among the statistically significant results, investigators reported that compared to controls, the TRF plus low-sugar diet intervention:⁹

• Reduced body fat, body weight, waist circumference, and body mass index.
• Reduced circulating level of fasting blood glucose and liver-related enzymes (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase).
• Reduced both the fibrosis score as well as the steatosis score/controlled attenuation parameter (CAP).
• Reduced lipids, including total cholesterol.
• Reduced inflammatory markers, including high-sensitivity C-reactive protein and cytokeratin-18 (a biomarker of steatohepatitis).¹⁰

The researchers noted that while the 12-week TRF/low-sugar diet did not cure NAFLD, the reduction in CAP as well as the reduction in liver stiffness measurements suggested clinical relevance in the management of the disease and related cardiometabolic dysfunction.⁹ In addition, the TRF component of the intervention explored the relationship between circadian rhythms, nutrition, and metabolism and suggested metabolic benefit when aligning lifestyle behaviors such as food timing with the body’s internal clock.

Conclusion

The standard of care for NAFLD focuses on lifestyle interventions that improve dietary patterns and exercise habits in the support of weight reduction or management.^11,12 Therapeutic fasting approaches may be appropriate as part of a patient’s personalized treatment or prevention plan. Larger NAFLD study populations and longer intervention durations are needed to clarify the clinical magnitude of fasting benefits in NAFLD management, the sustainability of such interventions, and any population-specific long-term safety concerns. However, results from these recent RCTs highlight the health improvement possibilities due to therapeutic fasting relevant to this chronic disease and its related cardiometabolic disorders.

Related Articles

Probiotics & NAFLD/NASH: Emerging Therapeutic to Enhance Standard of Care

Supporting Liver Function With Nutrition

Fasting and Mitochondrial Health

Circadian Fasting and Precursors to Heart Health

References

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2. Zhao Y, Jia M, Chen W, Liu Z. The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function. Free Radic Biol Med. 2022;182:206-218. doi:1016/j.freeradbiomed.2022.02.021
3. Patikorn C, Roubal K, Veettil SK, et al. Intermittent fasting and obesity-related health outcomes: an umbrella review of meta-analyses of randomized clinical trials. JAMA Netw Open. 2021;4(12):e2139558. doi:1001/jamanetworkopen.2021.39558
4. Elortegui Pascual P, Rolands MR, Eldridge AL, et al. A meta-analysis comparing the effectiveness of alternate day fasting, the 5:2 diet, and time-restricted eating for weight loss. Obesity (Silver Spring). 2023;31(Suppl 1):9-21. doi:1002/oby.23568
5. Ezzati A, Rosenkranz SK, Phelan J, Logan C. The effects of isocaloric intermittent fasting vs daily caloric restriction on weight loss and metabolic risk factors for noncommunicable chronic diseases: a systematic review of randomized controlled or comparative trials. J Acad Nutr Diet. 2023;123(2):318-329.e1. doi:1016/j.jand.2022.09.013
6. Lavallee CM, Bruno A, Ma C, Raman M. The role of intermittent fasting in the management of nonalcoholic fatty liver disease: a narrative review. Nutrients. 2022;14(21):4655. doi:3390/nu14214655
7. Sripongpun P, Churuangsuk C, Bunchorntavakul C. Current evidence concerning effects of ketogenic diet and intermittent fasting in patients with nonalcoholic fatty liver. J Clin Transl Hepatol. 2022;10(4):730-739. doi:14218/JCTH.2021.00494
8. Ezpeleta M, Gabel K, Cienfuegos S, et al. Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial. Cell Metab. 2023;35(1):56-70.e3. doi:1016/j.cmet.2022.12.001
9. Kord-Varkaneh H, Salehi-Sahlabadi A, Tinsley GM, Santos HO, Hekmatdoost A. Effects of time-restricted feeding (16/8) combined with a low-sugar diet on the management of non-alcoholic fatty liver disease: a randomized controlled trial. Nutrition. 2023;105:111847. doi:1016/j.nut.2022.111847
10.  Wong VW, Adams LA, de Lédinghen V, Wong GL, Sookoian S. Noninvasive biomarkers in NAFLD and NASH – current progress and future promise. Nat Rev Gastroenterol Hepatol. 2018;15(8):461-478. doi:1038/s41575-018-0014-9
11.  Kang SH, Lee HW, Yoo JJ, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2021;27(3):363-401. doi:3350/cmh.2021.0178
12.  National Institute of Diabetes and Digestive and Kidney Diseases. Eating, diet, & nutrition for NAFLD & NASH: how can my diet help prevent or treat NAFLD? National Institutes of Health. Reviewed April 2021. Accessed March 9, 2023. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/eating-diet-nutrition