Clinical Liver Disease - 2022 - Memel - Intermittent Fasting As A Treatment For Nonalcoholic Fatty Liver Disease What Is

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Review
Intermittent Fasting as a Treatment

for Nonalcoholic Fatty Liver
Disease: What Is the Evidence?
Zoe N. Memel, M.D.,*,† Jeffrey Wang, B.S.,‡ and
Kathleen E. Corey, M.D., M.P.H., M.M.Sc.*,†,‡
Key Points: in NAFLD, losing weight is difficult to achieve and adhere

• Studies in humans suggest that intermittent fasting (IF) to long-term. Thus, continued investigation of strategies
in patients with NAFLD is safe and efficacious for weight to treat NAFLD are needed.
loss and may improve NAFLD as assessed by non-invasive
Intermittent fasting (IF) is a term used to describe eating
tests.
patterns that limit food consumption for a predetermined
• IF may impact NAFLD through weight loss independent
amount of time to allow the body to enter a period of fast-
mechanisms including shifting metabolic processes
ing. Alternate day fasting consists of normal consumption
away from hepatic lipogenesis and improving insulin re-
for 24 hours and fasting for the next 24 hours. The 5:2
sistance and metabolic syndrome.
fasting is severely reducing caloric intake for 2 days (~500
• Time-restricted fasting, alternate-day fasting, and pro-
calories/day) followed by 5 days of normal consumption.
longed fasting may each be beneficial in NAFLD but the
whereas periodic fasting is intermittent fasting for 2+
best method of IF in NAFLD is not yet known.
days with minimal caloric intake (≤ 500 calories) without
repeated fasts. Time-restricted fasting (TRF) is eating only
Nonalcoholic fatty liver disease (NAFLD), a spectrum
during certain hours of the day (eg, 12 pm-8 pm).
from steatosis and nonalcoholic steatohepatitis (NASH) to
cirrhosis, is the leading cause of liver disease. Currently, It is hypothesized that IF may have metabolic bene-
there are no agency-approved pharmacologic therapies for fits on the liver, independent of caloric restriction and
NAFLD. While weight loss can improve histologic outcomes weight loss, this may also improve NAFLD histology.
From the * Harvard Medical School, Boston, MA; † Department of Medicine, Massachusetts General Hospital, Boston, MA; and
‡
Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA.
Potential conflict of interest: KC consults for Novo Nordisk. She also consults for and received grants from Bristol-Myers Squibb.
ZM own stock in Novo Nordisk.
Received May 31, 2021; accepted September 22, 2021.
View this article online at wileyonlinelibrary.com

© 2021 by the American Association for the Study of Liver Diseases
101
| Clinical Liver Disease, VOL 19, NO 3, MARCH 2022 An Official Learning Resource of AASLD
20462484, 2022, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.1172 by CochraneUnitedArabEmirates, Wiley Online Library on [01/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Review Intermittent Fasting as a Treatment for Non-Alcoholic Fatty Liver Disease Memel et al.
Induced by extended periods without food, fasting shifts non-pharmacological strategy for improving insulin resis-
the metabolic circuitry to increase hepatic lipid oxidation, tance and hepatic steatosis without difficult to achieve
decrease lipogenesis, and use ketones as the primary weight loss and caloric restrictions.1
energy source (Fig. 1).1 Ketones not only serve as fuel
but impact cellular machinery, enhancing the efficacy While pre-clinical models provide mechanistic insight
of mammalian target of rapamycin (mTOR) and AMP- into the benefits of fasting, clinical studies testing the
activated protein kinase (AMPK) pathways, and improve efficacy of fasting on humans with NAFLD are limited
the liver’s ability to breakdown excess triglycerides.1,2 (Table 1). Most studies on intermittent fasting in NAFLD
While not yet studied extensively in humans, alternate have occurred during the Muslim month of Ramadan,
day fasting in rodents protects against hepatic steatosis focusing on TRF, where people fast during the daylight
by selective stimulation of beige fat development within (12-14 hours) for ~30 days. The results have largely been
white adipose tissue likely via changes in the microbi- positive, finding that after 30 days, daily TRF significantly
ome leading to increasing beta- oxidation, improving improved non-invasive markers of fatty liver disease (in-
insulin resistance, and decreasing hepatic lipogenesis cluding Fibrosis-4 Index (FIB- 4) score, NAFLD Fibrosis
(Fig. 1).3 Furthermore, fasting may be an efficacious Score & BARD Score), reduced insulin resistance,4,5
4
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 ®.
102
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
103
Daily time-restricted fasting
(Ramadan fasting)
Review
Mari 20214 n = 155 Biopsy-proven NASH (74 30 days HOMA-IR, NFS, BARD scores, FIB4 In fasting group vs. non-fasting*
fasting) scores -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 20209 n = 83 NAFLD (42 fasting)† 30 days Anthropometric parameters, lipid - ↓ BMI fasting group (−0.80) vs. non-fasting (−0.02) (P < 0.001)
profiles, liver enzymes, VAI, AIP - ↓ 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 20175 n = 83 NAFLD (42 fasting)† 30 days Anthropometric parameters, fast- -↓ BMI in fasting group (0.80) vs. non-fasting (0.02) (P < 0.001)
ing glucose, plasma insulin, -↓ Body fat % in fasting (0.68) vs. non-fasting (0.29) (P = 0.003)
insulin resistance -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 20198 n = 697 with NAFLD, 38 (NAFLD& 10 days Anthropometric measurements, -Fasting induced weight loss (−4.37 kg, P < 0.001), ↓ BMI (−1.51,
T2DM) hbA1c, lipid panel, LFTs, FLI P < 0.001)
-HbA1c ↓ after fasting (−1.76, P < 0.001)
| Clinical Liver Disease, VOL 19, NO 3, MARCH 2022

-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 20197 n = 43 NAFLD (33 in MACR group, 8 weeks Anthropometric parameters, -Weight ↓ MACR vs. control group (−3.06, P = 0.001)
10 in control group) lipid panel, hbA1c, ultrasound -BMI ↓ MACR vs control group (1.08; 95% CI:0.16;2.00, P = 0.02)
& shear wave elastography -No change in lipid parameters both within-group and between groups
(SWE), dietary adherence (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)
An Official Learning Resource of AASLD

Intermittent Fasting as a Treatment for Non-Alcoholic Fatty Liver Disease Memel et al.
induced weight loss,4 and improved inflammatory mark-
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.
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
-Total cholesterol (−0.71; −14.5%) (P < 0.001) & TG ↓ (−0.64, −25%)
ers (including IL-6 & CRP)5 (Table 1). Despite these find-
-Body weight ↓ ADF (−4.04 kg; −5.4 %) & TRF (−3.25; -2.3%); ADF &
ence between groups (P = 0.165), fat free mass did not change in
ness, & blood pressure did not have a significant change between
-Change in fat free mass, HDL, LDL, fasting insulin, glucose, liver stiff-
-Fat mass ↓ ADF (−3.48 kg) & TRF (−2.62 kg; −8.6%); no sig differ-
ings, using Ramadan as a model for TRF has several
ADF & TRF (−0.58, −20%) compared to controls (P < 0.001)

limitations: (1) participants often consume meals high
in fat and sugar during night-time eating that may de-
crease the benefits of TRF and (2) alterations in sleep cy-
cles during the holiday may not be generalizable. These
limitations suggest that TRF in the absence of altered
Findings
sleep and high fat meals may provide even greater met-
abolic benefits; well-designed randomized control trials
TRF did not differ (P = 0.709)
are needed.
To compare the efficacy of alternate day fasting (ADF)

to daily TRF (16:8 hours), a randomized NAFLD control trial
any group
was performed comparing 97 patients on 12 weeks of the

groups
Participants started with a low-calorie transition day & were provided low calories fruit & vegetable broths throughout fasting period.
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%) com-
Anthropometric measurements,
pared to TRF (−2.62 kg) and controls (−1.05 kg). Between

the two fasting methods, however, there was no difference
Outcomes
in fat free mass, body weight, other lipid levels, fasting

lipids, fibroscan
Patients were randomized to alternate day fasting, time-restricted feeding or the control group for 12 weeks.
insulin, or liver stiffness (measured by vibration-controlled

transient elastography), suggesting that longer durations
of fasting may not be required to observe metabolic ben-
efits on the liver.6
Study Duration
An alternative approach to strict fasting studied by

Johari et al. compared the benefits of modified alter-
12 weeks
nate 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,
Sample Size & population
n = 95 TRF, n = 79 control)
the MACR group had a significant reduction in weight,

n = 271 NAFLD (n = 90 ADF,
*P values are comparing fasting group to their baseline scores.
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 con-
Same cohort of patients was used for both studies.
sumption 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 sig-
nificant improvement in their Fatty Liver Index (FLI) score,
Alternate-Day Fasting§ compared
with over half of high-risk subjects (FLI > 60) shifting to

TABLE 1. (CONTINUED)
a lower risk FLI category after fasting (mean reduction

−14.02 points).8 For every additional day of fasting, par-
ticipants’ 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 re-
striction and fasting without food intake improves mark-
Cai 20196
to TRF
ers of hepatic steatosis and inflammation compared to

Author
†
‡
§
controls. Available evidence suggests that any form of
104
caloric restriction may be beneficial and specific forms REFERENCES

of IF should be tailored to the individual. Further studies
1) Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S,
are needed to help differentiate if one fasting method is et al. Time-restricted feeding without reducing caloric intake pre-
superior to others and compared to well established vents metabolic diseases in mice fed a high- fat diet. Cell Metab.
dietary patterns such as the Mediterranean diet, regard- 2012;15:848-860.
ing patient feasibility and improvement in metabolic out- 2) de Cabo R, Mattson MP. Effects of intermittent fasting on health,
comes. Additionally, it is important we investigate the aging, and disease. N Engl J Med 2019;381(26):2541-2551.
possible risks of fasting in patients with cirrhosis, which is
3) Li G, Xie C, Lu S, et al. Intermittent fasting promotes white adipose
currently not recommended. browning and decreases obesity by shaping the gut microbiota. Cell
Metab 2017;26:801.
In conclusion, current evidence suggests that intermit-
tent fasting in patients with NAFLD is a feasible, safe, and 4) Mari A, Khoury T, Baker M, Said Ahmad H, Abu Baker F, Mahamid M.
The impact of ramadan fasting on fatty liver disease severity: a retro-
effective means for weight loss, with significant trends
spective case control study from Israel. Isr Med Assoc J 2021;23:94-98.
towards improvements in dyslipidemia and NAFLD as il-
lustrated through non-invasive testing (NIT). Minimal risks 5) Aliasghari F, Izadi A, Gargari BP, Ebrahimi S. The Effects of ramadan
fasting on body composition, blood pressure, glucose metabolism,
were observed including hunger, irritability, and reduced
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concentration.2 Given the small size, observational nature trial. J Am Coll Nutr. 2017;36:640-645.
of most available studies, and use of NITs, it is difficult to
6) Cai H, Qin YL, Shi ZY, et al. Effects of alternate-day fasting on body
deduce true causal inferences on the relationship between
weight and dyslipidaemia in patients with non-alcoholic fatty liver dis-
fasting and improvement in NAFLD histology. Moving ease: a randomised controlled trial. BMC Gastroenterol. 2019;19:219.
forward, randomized control trials with comprehensive
outcome assessment using validated NITs and/or liver biop- 7) Johari MI, Yusoff K, Haron J, et al. A randomised controlled trial on the
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sies are needed to compare the efficacy of different fast- tion in improving activity of non-alcoholic fatty liver disease. Sci Rep.
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NAFLD histology.
8) Drinda S, Grundler F, Neumann T, et al. Effects of periodic fasting on fatty
CORRESPONDENCE liver index—a prospective observational study. Nutrients. 2019;11:2601.
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105

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20462484, 2022, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.1172 by CochraneUnitedArabEmirates, Wiley Online Library on [01/03/2023].

Intermittent Fasting as a Treatment

Key Points: in NAFLD, losing weight is difficult to achieve and adhere

View this article online at wileyonlinelibrary.com

| Clinical Liver Disease, VOL 19, NO 3, MARCH 2022

An Official Learning Resource of AASLD

induced weight loss,4 and improved inflammatory mark-

ADF & TRF (−0.58, −20%) compared to controls (P < 0.001)

To compare the efficacy of alternate day fasting (ADF)

was performed comparing 97 patients on 12 weeks of the

TRF diet to 95 patients on the ADF diet. The study found

pared to TRF (−2.62 kg) and controls (−1.05 kg). Between

in fat free mass, body weight, other lipid levels, fasting

insulin, or liver stiffness (measured by vibration-­controlled

An alternative approach to strict fasting studied by

nate day caloric restriction (MACR) (where participants

n = 95 TRF, n = 79 control)

the MACR group had a significant reduction in weight,

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

BMI, steatosis, and fibrosis as assessed by sheer wave

sumption but simply periods with significant reduction

with over half of high-­risk subjects (FLI > 60) shifting to

a lower risk FLI category after fasting (mean reduction

ers of hepatic steatosis and inflammation compared to

controls. Available evidence suggests that any form of

caloric restriction may be beneficial and specific forms REFERENCES

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| Clinical Liver Disease, VOL 19, NO 3, MARCH 2022

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