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

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Key Points:

• Studies in humans suggest that intermittent fasting (IF) in patients with NAFLD is safe and efficacious for weight loss and may improve NAFLD as assessed by non‐invasive tests.

• IF may impact NAFLD through weight loss independent mechanisms including shifting metabolic processes away from hepatic lipogenesis and improving insulin resistance and metabolic syndrome.

• Time‐restricted fasting, alternate‐day fasting, and prolonged fasting may each be beneficial in NAFLD but the best method of IF in NAFLD is not yet known.

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 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 rapamycin (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

FIG 1.

Proposed Metabolic Benefits of Fasting: Restricting food consumption for 14 hours or more depletes the body’s glycogen stores, activating lipolysis within adipocytes and breaking down triglycerides into free fatty acids (FFAs) and glycerol. FFAs are converted into ketone bodies within the liver and activate several powerful transcription factors PPAR‐alpha (Peroxisome Proliferator‐Activated Receptor Alpha) and Activating Transcription Factor 4 (ATF4) that stimulate the release of fibroblast growth factor 21 (FGF21). FGF21 is a protein that has pleiotropic effects on the body including improving insulin resistance and inhibiting hepatic lipogenesis. ² During fasting, AMP‐Activated protein kinase (AMPK), a master regulator of energy metabolism, activates fatty acid oxidation and breakdown. ¹ Reduction in circulating amino acids with fasting also represses the activity of mammalian target of rapamycin (mTOR), inhibiting further anabolic processes and promoting autophagy which helps clear excess lipids from the liver. ² Additionally, animal models suggest that fasting regimens selectively stimulate the conversion of white adipose tissue (WAT) into beige adipose tissue through changes in the gut microbiome composition that allow for an increase in acetate & lactate, upregulating monocarboxylate transporter 1 expression in WAT cells. Beige adipose tissue has increased thermogenesis and improves insulin resistance through increased metabolic activity. This process is independent of FGF21 effects on fasting. ³ Made with assistance from Biorender ®.

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.

TABLE 1.

Studies Performed on Patients with NAFLD/NASH Analyzing the Impact of Fasting on Fatty Liver Disease

Author	Sample Size & population	Study Duration	Outcomes	Findings
Daily time‐restricted fasting (Ramadan fasting)
Mari 2021 4	n = 155 Biopsy‐proven NASH (74 fasting)	30 days	HOMA‐IR, NFS, BARD scores, FIB4 scores	In fasting group vs. non‐fasting*
				‐BMI ↓ 36.7 to 34.5 (P < 0.005)
				‐HbA1c ↓ 5.89 to 5.28 (P < 0.005)
				‐NFS ↓ 0.45 to 0.23 (P < 0.005)
				‐FIB4 scores ↓ 1.93 to 1.34 (P < 0.005)
				‐BARD score ↓ 2.3 to 1.6 (P < 0.005)
				‐HOMA‐IR ↓ 2.92 to 2.15 (P < 0.005)
Ebrahimi 2020 9	n = 83 NAFLD (42 fasting) †	30 days	Anthropometric parameters, lipid profiles, liver enzymes, VAI, AIP	‐ ↓ BMI fasting group (−0.80) vs. non‐fasting (−0.02) (P < 0.001)
				‐ ↓ Body fat % in fasting (0.68)vs. non‐fasting (0.29) (P = 0.003)
				‐ ↓ Total cholesterol in tfasting (13.71) vs. non‐fasting (7.80) (P = 0.016)
				‐ Triglycerides, VAI, AIP, LDL, HDL h non‐sig change between groups
				‐↓ Severity of hepatic steatosis (on US) between groups (P = 0.024)
Aliasghari 2017 5	n = 83 NAFLD (42 fasting) †	30 days	Anthropometric parameters, fasting glucose, plasma insulin, insulin resistance	‐↓ BMI in fasting group (0.80) vs. non‐fasting (0.02) (P < 0.001)
				‐↓ Body fat % in fasting (0.68) vs. non‐fasting (0.29) (P = 0.003)
				‐HOMA‐IR fasting vs. non‐fasting had sig change (P < 0.041)
				‐Blood pressure had non‐sig change between the 2 groups (P < 0.115)
				‐IL‐6 & hsCRP ↓ fasting group vs.non‐fasting (P < 0.001, P < 0.001)
Periodic fasting (6‐10 days)
Drinda 2019 8	n = 697 with NAFLD, 38 (NAFLD& T2DM)	10 days	Anthropometric measurements, hbA1c, lipid panel, LFTs, FLI	‐Fasting induced weight loss (−4.37 kg, P < 0.001), ↓ BMI (−1.51, P < 0.001)
				‐HbA1c ↓ after fasting (−1.76, P < 0.001)
				‐FLI ↓ −14.02 (P < 0.001) after fasting overall, more significant in T2DM ↓−19.15 vs no DM ↓ −13.7 (P < 0.002)
				‐120 subjects baseline FLI > 60 (high risk) shifted to lower FLI risk after fasting
				‐Liver enzymes & lipid panels improved after fasting ( P < 0.0001)
Modified Alternate‐Day Calorie Restriction ‡
Johari 2019 7	n = 43 NAFLD (33 in MACR group, 10 in control group)	8 weeks	Anthropometric parameters, lipid panel, hbA1c, ultrasound & shear wave elastography (SWE), dietary adherence	‐Weight ↓ MACR vs. control group (−3.06, P = 0.001)
				‐BMI ↓ MACR vs control group (1.08; 95% CI:0.16;2.00, P = 0.02)
				‐No change in lipid parameters both within‐group and between groups (P = 0.34)
				‐Liver steatosis ↓ MACR vs control group (−0.38, P = 0.01) & shear wave elastography ↓ for MACR group vs control ‐(0.74, P = 0.01)
				‐Liver Steatosis ↓ for pre vs post MACR group (−0.50, P = 0.001) & shear wave elastography ↓ for pre vs post MACR group ‐(0.87, P = 0.001)
Alternate‐Day Fasting § compared to TRF
Cai 2019 6	n = 271 NAFLD (n = 90 ADF, n = 95 TRF, n = 79 control)	12 weeks	Anthropometric measurements, lipids, fibroscan	‐Body weight ↓ ADF (−4.04 kg; −5.4 %) & TRF (−3.25; ‐ 2.3%); ADF & TRF did not differ (P = 0.709)
				‐Fat mass ↓ ADF (−3.48 kg) & TRF (−2.62 kg; −8.6%); no sig difference between groups (P = 0.165), fat free mass did not change in any group
				‐Total cholesterol (−0.71; −14.5%) (P < 0.001) & TG ↓ (−0.64, −25%) ADF & TRF (−0.58, −20%) compared to controls (P < 0.001)
				‐Change in fat free mass, HDL, LDL, fasting insulin, glucose, liver stiffness, & blood pressure did not have a significant change between groups

Abbreviations: ADF, alternate day fasting; AIP, Atherogenic Index of plasma; BMI, body‐mass index; FIB4, Fibrosis‐4; FLI, Fatty Liver Index; HDL, high density lipoprotein; HOMA‐IR, homeostatic model assessment of B‐cell function and insulin resistance; hsCRP, high sensitivity C‐Reactive Protein; LDL, low density lipoprotein; MACR, Modified Alternate Day Caloric Restriction; NAFLD, non‐alcoholic fatty liver disease; NASH, Non‐alcoholic Steatohepatitis; NFS, NAFLD Fibrosis score; SWE, shear wave elastography; T2DM, type 2 diabetes mellitus; TRF, time restrictive fasting; VAI, Visceral Adiposity index.

^* P values are comparing fasting group to their baseline scores.

^† Same cohort of patients was used for both studies.

^‡ Participants started with a low‐calorie transition day & were provided low calories fruit & vegetable broths throughout fasting period.

^§ Patients were randomized to alternate day fasting, time‐restricted feeding or the control group for 12 weeks.

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 NAFLD is a feasible, safe, and effective means for weight loss, with significant trends towards improvements in dyslipidemia and NAFLD as illustrated through non‐invasive testing (NIT). Minimal risks were observed including hunger, irritability, and reduced concentration. ² Given the small size, observational nature of most available studies, and use of NITs, it is difficult to deduce true causal inferences on the relationship between fasting and improvement in NAFLD histology. Moving forward, randomized control trials with comprehensive outcome assessment using validated NITs and/or liver biopsies are needed to compare the efficacy of different fasting strategies and determine the impact IF may have on NAFLD histology.