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Intermittent fasting for the management of NAFLD: Is there enough evidence?

Intermittent fasting for the management of NAFLD: Is there enough evidence? Acta Marisiensis - Seria Medica 2023;69(1):3-10 DOI: 10.2478/amma-2023-0001 REVIEW Intermittent fasting for the management of NAFLD: Is there enough evidence? 1,2* 3 Simona Cernea , Florina Ruţa 1. Department M3, Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania 2. Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania 3. Department of Community Nutrition and Food Safety, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania The pathogenesis of the non-alcoholic fatty liver disease (NAFLD) has been described as multifactorial, with genetic and environmental factors acting synergistically and causing excessive hepatic lipid accumulation, insulin resistance, and downstream pathogenetic insults. High-calorie diets, particularly those rich in foods with high (saturated) fat and sugar content, and sugar-sweetened beverages, are among the behavioral risk factors with a crucial role in the disease pathogenesis. In addition, meal frequency and meal timing appear to be relevant factors associ- ated with NAFLD. Current guidelines recommend a hypocaloric, preferably Mediterranean diet as the main dietary intervention approach, but various other dietary models have been evaluated in patients with NAFLD. Among these, several intermittent fasting regimens have shown promising results. Diets based on Time-Restricted Feeding and Intermittent Energy Restriction have demonstrated some improvements in body adiposity, liver enzymes, and hepatic steatosis, but most studies included a small number of subjects, were of relatively short-duration, and used surrogate markers of NAFLD. The best intermittent fasting regimen for NAFLD is not yet known, and further well-designed research that evaluates the feasibility (mainly on long-term), safety and efficacy outcomes of these dietary interventions is still needed. Our review has evaluated the up-to-date information regarding the intermittent fasting dietary intervention in NAFLD and generated some key-point messages that are relevant to physicians and dietitians involved in the care of patients with NAFLD. Keywords: NAFLD, dietary intervention, intermittent fasting, time-restricted feeding Received 7 December 2022 / Accepted 26 December 2022 Introduction netic and environmental factors act synergically and lead The non-alcoholic fatty liver disease (NAFLD) has emerged to excessive and dysfunctional adiposity, lipid accumula- as a major cause of chronic liver disease, affecting about a tion in the liver and lipotoxicity, insulin resistance, further quarter of the adult general population worldwide [1, 2]. causing inflammation, oxidative stress, hepatocellular ap - Moreover, the global prevalence of NAFLD is double in optosis and fibrosis [7, 8]. patients with type 2 diabetes mellitus (T2DM) [3]. Among the lifestyle risk factors, diet/diet composition NAFLD is characterized by an excessive accretion of li- has a crutial role in NAFLD pathogenesis [9]. The exces - pids in the liver (hepatic steatosis) affecting >5% of hepat - sive caloric intake appears to be a distinctive dietary fea- ocytes, in the absence of other secondary causes (including ture in patients with NAFLD and experimental overfeed- viral hepatitis, or alcohol intake exceeding 20 g/day for ing studies demonstrated that hypercaloric diets promoted women and 30 g/day for men) [4]. The hepatic lipid accu - hepatic fat accumulation [10, 11]. mulation is associated with insulin resistance, which is in Although it is more difficult to distinguish the effect of fact a key pathogenetic mechanism in NAFLD, and with a specific macronutrient/dietary component on modulat - components of the metabolic syndrome (obesity, T2DM, ing the risk of liver steatosis, overall data seem to indi- dyslipidemia) [5]. NAFLD in fact comprises several condi- cate that the intake of foods rich in fats (mainly saturated tions: simple steatosis (nonalcoholic fatty liver (NAFL)), fats), sugar (mainly fructose, but also glucose) and sugar- nonalcoholic steatohepatitis (NASH) (without or with sweetened beverages favors lipid accumulation in the liver, various grades of fibrosis, including hepatic cirrhosis), and insulin resistance, and increases the likelihood of NAFLD hepatocellular carcinoma (HCC) [4, 6]. [10-14]. Apparently, the negative effect of fructose on the intrahepatocellular lipids and transaminases is mainly The role of diet in the pathogenesis of NAFLD seen in the context of hypercaloric diets [15]. Dietary car- The pathogenesis of NAFLD is multifactorial, and a num - bohydrates stimulate de novo lipogenesis, increase the free ber of genetic/epigenetic, demographic, and environmen- fatty acid pool in the liver, and may also have pro-inflam - tal/lifestyle risk factors have been identified. The complex matory effects [10, 15, 16]. The intervention studies also interaction between these factors is responsible for the ini- support the findings from the observational studies, show - tiation and development of the pathogenetic mechanisms ing greater reduction of hepatic steatosis with low-carb/ of the disease. According to the “multiple-hit” theory, ge- sugar diets and with low-fat diets [17-23]. A meta-analysis of 11 studies showed no significant differences between low-carbohydrate diet and low-fat diet on the hepatic fat * Correspondence to: Simona Cernea E-mail: simonacernea@yahoo.com content and transaminases levels in subjects with NAFLD 4 Acta Marisiensis - Seria Medica 2023;69(1) [24]. However, the type of dietary fats is relevant since stay of intervention in NAFLD, recommended by current the saturated fats increase hepatic liver accumulation and guidelines [4, 6, 46]. This is associated with amelioration insulin resistance more than polyunsaturated fats [25- of insulin resistance. A histologic reference study has dem- 29]. Studies have shown that the monounsaturated fat- onstrated that weight loss through lifestyle intervention enriched diets and the Mediterranean diet (based on olive (low-fat hypocaloric diet and physical activity) in patients oil consumption as a main source of fat, which is rich in with NASH resulted in liver benefits (steatosis reduction, monounsaturated fats) are associated with lower intrahe- NASH resolution, and fibrosis regression), in direct re - patic triglyceride content [30-32]. Moreover, diets rich in lationship with the degree of weight loss (OR: 1.1-2.0, insoluble fibers and fruit fiber consumption in the context p<0.01) [47]. The NASH-related histologic improvements of energy restriction improve liver health (decrease liver were seen with a minimum 5% weight loss, and patients steatosis and transaminases) [33]. The protective effects of that obtained ≥10% weight loss also presented regression dietary fibers might be due to direct anti-inflammatory ef - of hepatic fibrosis [47]. Thus, the current guidelines gen - fects and/or indirect ones (through modulation of the gut erally recommend a hypocaloric diet for the management microbiome) [11]. Data on dietary protein is less consist- of NAFLD [6, 46]. The Mediterranean diet is a preferred ent. There is some evidence that red meat/animal protein dietary pattern in patients with NAFLD, as it is associated intake is also associated with liver steatosis, but the in- with improvement of liver steatosis and insulin resistance tervention studies showed that high protein diets reduced [48, 49]. However, other dietary interventions (DASH liver fat [34-39]. diet, low-carb diet, low-fat diet, ketogenic diet, etc.) have In addition to diet composition, meal frequency and been investigated and seem to bring liver-specific ben - meal timing appear to be other significant factors associ - efits, but choosing the best dietary intervention for each ated with hepatic steatosis/NAFLD. A randomized con- NAFLD patients is still a challenging task [50]. Nutrition- trolled trial (RCT) in patients with NAFLD has demon- al interventions based on time-restricted feeding/intermit- strated that in the context of a hypercaloric diet, higher tent fasting are novel and potentially promising approaches meal frequency, but not meal size, was associated with in- for NAFLD, that deserve attention. creased intrahepatic triglyceride content (mean relative in- crease of 45%, p=0.016), suggesting that snacking is an in- Intermittent fasting – regimens and dependent contributor to hepatic steatosis [40]. The same mechanisms of health benefits was shown by a Japanese community-based cross-sectional Fasting (i.e. restricted food intake) is an ancient practice study indicating that snacking ≥2 times/day significantly based on cultural and religious beliefs, and has also been increased the prevalence rate of NAFLD both in men and used for healing purposes in the past [51]. Religious fast- women (41.1% in men, and 15.3% in women) [41]. In- ing is practiced in Christianity, Judaism, Islam, and other terestingly, an Australian study has shown that a “grazing” religions, but it varies by dietary pattern (food selection) temporal eating pattern (defined as a more frequent inges - and fasting duration, and has been shown to bring cardio- tion of minimum 50 kcal, lower probability of eating at metabolic benefits (decrease in body weight, blood lipids, conventional meal times, also associated with later timing insulin resistance, etc.) [52]. of first food ingestion) was associated with a poorer diet Intermittent fasting (also known as periodic energy re- quality and higher overall and visceral adiposity in women striction) refers to dietary intervention strategies that re- (OR: 1.57 [95%CI: 1.15, 2.13], and 1.73 [95%CI: 1.19, strict food intake to certain periods of time (within a day 2.50], respectively) [42]. In contrast, a preliminary report or a week) [53, 54]. The periods of fasting/energy restric - that analyzed the third National Health and Nutrition tion are usually followed by periods when food is used ad Examination Survey (NHANES III) data indicated that libitum [55]. There are several regimens of intermittent rather more meals per day decreased the odds of severe liver fasting, which can be broadly categorized into two major steatosis, but skipping breakfast and lunch had an opposite groups (table I): effect (increased the odds of liver steatosis) [43]. Thus, al - – Time-Restricted Feeding (TRF), which implies a though evidence is still weak, it appears that circadian mis- restriction of feeding during certain daily time win- alignments favor visceral adiposity and hepatic steatosis/ dows, and NAFLD. Indeed, the circadian clock plays an important – Intermittent Energy Restriction (IER), which impli- role in regulating major metabolism pathways and other es short periods of energy restriction alternating with physiologic functions in the liver, which show diurnal vari- normal eating/diet; this category comprises several ations [44]. Thus, circadian disruption by improper meal regimens; a special form of IER is the alternate-day timing may cause major disturbances leading to insulin fasting (ADF), and its modified form; the energy re - resistance, increased levels of free fatty acids and triglycer- striction during the fasting time varies between 75% ides, eventually leading to NAFLD [44, 45]. and 100% [56]. The role of dietary intake is further substantiated by In addition to the main intermittent fasting regimens the fact that caloric restriction and weight loss through mentioned in table I, there are several other modified dietary interventions and physical exercise are the main- forms, including the combination of intermittent fasting Acta Marisiensis - Seria Medica 2023;69(1) 5 Table I. Characteristics of the intermittent fasting regimens [51-57]. Fasting period Eating period Time-Restricted Feeding (TRF) TRF (16:8; 15:9, etc) ≥14 h; usually ≤10 h; early TRF regimen is preferred (eating be- no energy intake is allowed; tween 8:00 am and 2:00 pm or up to 5:00 pm, depending on the regimen); ad libitum feeding; B2 regimen 14-16 h; 2 main meals per day: breakfast (06:00-10:00 a.m.) and no energy intake is allowed; lunch (12:00-04:00 p.m.); no dinner; ad libitum feeding; Ramadan (during the Islamic holy dawn to sunset; sunset to dawn; month) no energy intake (including drinking) is allowed; ad libitum feeding; Intermittent Energy Restriction (IER) Alternate-day fasting every other day (24 h); alternate day to fasting day; no energy intake is allowed; ad libitum feeding; Alternate day-modified fasting 20 h, every other day; alternate day to fasting day; up to 25% of daily energy intake (mid-day meal); ad libitum feeding; 5:2 (twice weekly fasting) 2 days (24 h) a week (usually non-consecutive); 5 days a week; up to 25% of daily energy intake or ~500 kcal/day; ad libitum feeding; Modified periodic fasting 5 consecutive days; at least 10 days following the fasting period; a very-low-caloric diet (up to 25% of daily energy intake); ad libitum feeding; and caloric restriction (i.e. one day of fasting and six days intake and free radicals production, and possibly by activa- of caloric restriction) [58]. tion of redox-sensitive transcription factors (shift of redox Intermittent fasting has proven to bring cardiovascular status) [63]. benefits (reductions in systolic and diastolic blood pressure, Thirdly, intermittent fasting might directly influence body weight, and ectopic fat depositions, improvements in the gut microbiota composition, which is also involved in blood lipids, insulin sensitivity and inflammatory mark - metabolic signaling and bile acid metabolism [56, 64, 65]. ers) [53, 57]. However, there is no clear superiority of the Finally, the circadian rhythm theory might well explain intermittent fasting regimens compared to the continuous the beneficial effects associated with some intermittent fast - caloric restrictions, suggesting that in fact the reduction of ing regimens (mainly TRF) [53]. When properly timed, it energy intake (energy deficit) might be the main reason allows the resynchronization between the body’s circadian for the observed health benefits, although some data also rhythm and the time of fasting-feeding [53, 66]. The cir - support the weight-loss independent effects of intermittent cadian rhythm allows the expression of clock-controlled fasting on cardiometabolic parameters [57]. genes that regulate many molecules involved in metabolic There are several proposed mechanisms for the effects of functions, and there is evidence supporting a strong re- intermittent fasting on health. During fasting, a switch in lationship between circadian clock and metabolism [65]. substrate utilization occurs (from carbohydrate to fat, and In fact, circadian rhythm disruption (i.e. in case of shift ketone body production and oxidation) [59]. Glucose is workers, jet leg, etc.) is associated with various metabolic the main energy fuel for most cells, and during fasting, in- diseases (obesity, impaired glucose tolerance/diabetes, etc.) sulin levels drops, and glucose is released through glycogen [67-70]. Animal data indicate that intermittent fasting breakdown from liver depots [55]. In addition, there is a (TRF regimens) can restore the oscillation of metabolic breakdown of triglycerides and free fatty acids release from regulators (such as AMPK, mTOR, CREB, etc) and their the adipose tissue, which undergo β-oxidation in the liver target gene expression [67, 71]. Moreover, the feeding/fast- [55]. In prolonged fasting periods, free fatty acids are me- ing rhythms and diet may modulate the cyclic fluctuations tabolized into ketone bodies, which are an alternative en- of the gut microbiome, which influence the secondary me - ergy substrate for extrahepatic tissues (i.e. brain and heart) tabolite production, involved in the maintenance of the [55]. Therefore, during (intermittent) fasting a ketogenic peripheral circadian rhythm [72]. state is induced, as evidenced by the elevation of blood  Nevertheless, the exact mechanisms through which the ketone levels [60, 61]. Thus, a switch from fat storage to various intermittent fasting regimens are associated with utilization occurs, promoting weight loss (intermittent health benefits are not fully deciphered, and probably metabolic switching/”keto-adaptation”) [53, 55]. Ketone many factors (i.e. diet composition, time of fasting, dura- bodies also promote the activation of the cellular stress re- tion of interventions) influence the results. sponses under fasting conditions, which result in removal of damaged organelles and proteins, improve mitochon- Intermittent fasting for the drial function, and promote cellular repair mechanisms management of NAFLD [51, 52, 55]. The nutritional ketosis induced by the inter - NAFLD is a complex disease associated with a variety mittent fasting regimens determines the keto-adaptation of metabolic disturbances, and dietary intervention and which is linked to many health benefits [55]. weight loss are at the core of its management. As men- A second hypothesis (proposed mechanisms) is reduc- tioned, various dietary interventions have been evaluated tion of the oxidative stress, induced by a decrease of energy in patients with NAFLD, some (i.e., the Mediterranean 6 Acta Marisiensis - Seria Medica 2023;69(1) diet) proving clear benefits [73]. Recently, various inter - have search PubMed without language restrictions since mittent fasting regimens have been evaluated with regards database inception to December 2022 using the terms: to liver-related outcomes in NAFLD. “NAFLD” or “non-alcoholic fatty liver disease” and “in- We review here the up-to-date main findings from the termittent fasting” and subsequently, “time-restricted feed- clinical studies in patients with NAFLD (table II). We ing” or “Ramadan fasting” or “alternate-day fasting” or “in- Table II. The effects of different intermittent fasting regimens on anthropometric and liver-related outcomes in patients with NAFLD Reference/ Dietary intervention Patients Main findings study type Time-Restricted Feeding (TRF) Kord-Varkaneh TRF (16 h fasting/8 45 NAFLD patients In intervention group after versus baseline: H. et al /RCT h feeding) plus low- (22 intervention, 23 Body weight ↓(83.75 to 80.54 kg; p<0.001) sugar diet vs control, control) BMI ↓(29.13 to 28.02 kg/m ; p<0.0001) for 12 weeks Body fat ↓(26.69 to 24.22 kg; p=0.001) Waist ↓(104.59 to 101.91; p=0.042) Change in intervention group versus control group: ALT ↓(34.04 to 21.22 U/l) vs ↓(30.34 to 28.04 U/l); p=0.003 AST ↓ (26.31 to 20.5o U/l) vs (23.68 to 23.77 U/l); p=0.031 TG ↓(201.50 to 133.27 mg/dl) vs ↑(187.6 to 199.56 mg/dl); p<0.001 TC ↓(190.04 to 157.8 mg/dl) vs ↑(172.21 to 180.72 mg/dl); p<0.001 LDLc ↓(104.63 to 84.04 mg/dl) vs ↑(93.73 to 97.45 mg/dl); p=0.017 CK-18 ↓(1.35 to 1.16 ng/ml) vs ↑(1.32 to 1.85 ng/ml); p<0.001 Fibrosis score ↓(6.33 to 5.15 kPa) vs ↓(5.82 to 5.46 kPa); p=0.024 CAP ↓(322.90 to 270.90 dB/m) vs (311.52 to 306.00 dB/m); p<0.001 Hodge A. et TRF (16 h fasting 28 NAFLD patients Weight ↓(81.9 to 79.8 kg; p=0.0024) (TRF) and ↓(82.3 to 81 kg; p=0.0066) (SoC) 77 2 2 al (abstract from 8 pm to 12 pm (17 TRF, 15 SoC) BMI ↓(29 to 28 kg/m ; p=0.002) (TRF) and ↓(30 to 29 kg/m ; p=0.006) (SoC) only)/random- next day /8 h feeding) Total body fat mass ↓(29 to 28 kg; p=0.0001) (TRF) and ↓(31 to 29 kg; p=0.0031) (SoC) ized pilot study vs standard of care Liver stiffness (Fibroscan®) ↓(7.33 to 5.84 kPa; p=0.0088) (TRF) and (6.32 to 6.09 kPa; (SoC), for 12 weeks p=0.7305) (SoC) CAP ↓(287 to 263 dB/m; p=0.012) (TRF) and (268 to 268 dB/m; p=0.981) (SoC) Badran H. et Ramadan fasting (16 98 NAFLD patients Before vs after fasting: al hours), for 22-29 days (diagnosed based Weight ↓(97.44 to 96.69 kg; p≤0.01) /interventional on US) BMI ↓(37.03 to 36.74 kg/m ; p≤0.01) multicenter HbA1c ↓(6.1 to 5.9%; p≤0.01) study HOMA-IR ↓(2.13 to 1.96; p≤0.01) TC ↓(241.1 to 218.48 mg/dl; p≤0.01) TG ↓(171.01 to 157.49 md/dl; p≤0.01) HDLc ↑(45.3 to 48.5 md/dl; p≤0.01) ALT ↓(36.5 to 32.7 U/l; p≤0.01) AST ↓(38.5 to 32.8 U/l; p≤0.01) GGT ↓(41.1 to 37.1 U/l; p=0.047) FIB-4 ↓(1.48 to 1.33; p≤0.01) APRI ↓(0.61 to 0.52; p≤0.01) Rahimi H. et Ramadan fasting and 60 NAFLD patients Before vs after fasting (versus control): al low-fat low-calory diet (34 fasting, 26 not Body weight (-0.80 kg) (fasting) and (-0.89 kg) (control); p=0.936 2 2 /prospective fasting=control) BMI (-0.26 kg/m ) (fasting) and (-0.36 kg/m ) (control); p=0.749 study ALT ↑(+7.38 U/l) (fasting) and ↓(-0.12 U/l) (control) p=0.002 Arabi SM. et Ramadan fasting 50 NAFLD patients Before vs after fasting: 80 2 2 al (between 13 h and 35 (diagnosed based BMI (29.5 to 29.0 kg/m ; p=0.07) (M) and (34.15 to 33.4 kg/m ; p=0.09) (F) /prospective min and 14 h and 42 on US) TC ↑(190.60 to 220.72 mg/dl; p=0.001) (M) and ↑(199.95 to 229.1 mg/dl; p=0.001) (F) observational min), for 27.3 days HDLc (42.72 to 45.27 mg/dl; p=0.22) (M) and ↑(46.52 to 53.91 mg/dl; p=0.04) (F) study Fasting BG ↑(85.5 to 133.56 mg/dl; p<0.001) (M) and ↑(100.0 to 120.23 mg/dl; p<0.001) (F) ALT ↓(18.0 to 13.0; p<0.001) (M) and ↓(14.0 to 11.0; p=0.001) (F) Aliasghari F. Ramadan fasting 83 NAFLD patients Fasting vs control group (change before to after): et al / obser- (42 fasting, 41 not Weight ↓(-2.14 vs -0.08 kg; p<0.001) vational study fasting=control) BMI ↓(-0.80 vs -0.02 kg/m ; p<0.001) Waist ↓(-0.95 vs -0.036 cm; p<0.001) Fasting BG ↓(94.02 to 92.4 mg/dl; p<0.001) (fasting) vs (94.75 to 94.46 mg/dl; p=0.05) (control) HOMA-IR ↓(3.49 to 3.48; p=0.011) (fasting) vs (3.78 to 3.81; p=NS) (control) Mari A. et al Ramadan fasting 155 NAFLD patients Fasting group (before vs after interventions): /retrospective (diagnosed by US) BMI ↓(36.7 to 34.5 kg/m ; p<0.005) case-control (74 fasting, 81 not HbA1c ↓(5.89 to 5.28%; p<0.005) study fasting=control) HOMA-IR ↓(2.92 to 2.15; p<0.005) AST ↓(44.2 to 34.23 U/l; p<0.005) ALT ↓(51.43 to 39.23 U/l; p<0.005) GGT ↓(52.3 to 43.25 U/l; p<0.005) NFS ↓(0.45 to 0.23; p<0.005) BARD ↓(2.3 to 1.6; p<0.005) No significant changes in control group (Continued on p. 7) Acta Marisiensis - Seria Medica 2023;69(1) 7 (Continued from p. 6) Reference/ Dietary intervention Patients Main findings study type Ebrahimi S. et Ramadan fasting 83 NAFLD patients Fasting vs control group (change end vs before intervention): al /observa- (42 fasting, 41 not Weight ↓(-2.14 vs -0.08 kg; p<0.001) tional study fasting=control) BMI ↓(-0.80 vs -0.02 kg/m ; p<0.001) Body fat ↓(-0.68 vs -0.29%; p=0.003) TC ↓(-13.71 vs -7.80 mg/dl; p=0.016) AST ↓(-4.66 vs -2.36 U/l; p=0.031) ALT ↓(-3.43 vs +2.58 U/l; p=0.046) Severity of US hepatic steatosis between groups (p=0.024) Intermittent Energy Restriction (IER) Cai H. et al Alternate-day fasting 264 NAFLD patients Body weight ↓(-4.04 kg) (ADF) vs (-3.25 kg) (TRF) vs (-1.85 kg) (control) (p<0.001 vs control) /RCT (ADF) vs TRF (16:8) vs (90 vs 95 vs 79) Fat mass ↓(-3.48 kg) (ADF) vs (-2.62 kg) (TRF) vs (-1.05 kg) (control) (p<0.001 vs control) control, for 12 weeks TG ↓(-0.64 mmol/l) (ADF) vs (-0.58 mmol/l) (TRF) vs (-0.25 mmol/l) (control) (p<0.001 vs control) Ezpeleta M. et Modified ADF (600 NAFLD patients (n Body weight ↓(-5.3 %; p<0.05) (ADF) and (-4.9 %; p<0.05) (combination) and (-1.9 %; p=NS) al (abstract kcal on fast day) vs = 48) (exercise) vs (-0.3 %) (control) only) exercise vs combina- ALT ↓(-29 %; p<0.05) (combination) and (-9 %; p=NS) (ADF) and (1%; p=NS) (exercise) vs /randomized tion vs control (usual (17%) (control) study diet), for 12 weeks No change in liver fat Johari MI. et Alternate-day modified 43 NAFLD patients Body weight ↓(80.80 to 78.79 kg; p=0.003); MD=3.06; p=0.01 86 2 al fasting (ADMF) (70% (33 ADMF vs 10 BMI ↓(31.73 to 30.95 kg/m ; p=0.003) (ADMF); MD=1.08; p=0.02 /RCT calory restriction on control) ALT ↓(84.33 to 59.17 U/l; p=0.001) (ADMF); MD=18.6; p=0.02 fasting day; 2 meals AST ↓(51.40 to 42.77 U/l; p=0.004) (ADMF) at 2 pm and 8 pm) vs Fasting BG ↓(6.62 to 5.87 mmol/l; p=0.006) (ADMF) control, for 8 weeks Liver steatosis grade ↓(1.93 to 1.43; p=0.001) (ADMF); MD=0.38; p=0.01 SWE ↓(5.87 to 5.01 kPa; p=0.001) (ADMF); MD= 0.74; p=0.01 Holmer M. et 5:2 diet vs low-carb 74 NAFLD patients Change from baseline to end of treatment: al /RCT high-fat diet (LCHF) (1:1:1 ratio) Body weight ↓(-7.4 kg) (5:2 diet) vs (-7.3 kg) (LCHF) (-2.5 kg) vs (SoC) (p<0.0001 for all) vs standard of care HOMA-IR ↓(-3.2; p<0.001) vs ↓(-2.9; p=0.006) (LCHF) vs (−2.4; p=0.097) (SoC) (SoC), for 12 weeks ALT ↓(-17.6 U/l; p<0.001) (5:2 diet) vs ↓(-17.6 U/l; p=0.013) (LCHF) vs ↓(-11.8 U/l; p=0.006) (SoC) CAP ↓(−63.8 dB/m; p<0.001) (5:2 diet) vs ↓(-61.9 dB/m; p<0.001) (LCHF) vs (−20.2 dB/m; p=0.118) (SoC) Elastography ↓(-1.8 kPa; p<0.001) (5:2 diet) vs (-0.3 kPa; p=0.522) (LCHF) vs ↓(-1.5 kPa; p= 0.005) (SoC) Kord Varkaneh 5:2 diet vs control 44 NAFLD patients In the intervention group after versus baseline: H. et al /RCT (usual diet), for 12 (21 IF vs 23 control) Body weight ↓(86.65 to 82.94 kg; p<0.001) weeks BMI ↓(30.42 to 29.13 kg/m ; p<0.001) Waist ↓(103.52 to 100.52 cm; p=0.001) Fat mass ↓(26.64 to 23.85 kg; p=0.039) ALT ↓(41.42 to 28.38 U/l; p=0.043) AST ↓(34.19 to 25.95 U/l; p=0.013) TG ↑(171.23 to 128.04 mg/dl; p<0.001) CK-18 ↓(1.32 to 1.19 ng/ml; p<0.001) Fibrosis score (Fibroscan®) ↓(6.97 to 5.58 kPa; p=0.009) CAP ↓(313.09 to 289.95 dB/m; p<0.001), For ALT, ASL, TG, CK-18, Fibrosis score and CAP, p<0.05 versus the change in control group after adjustment for variables RCT= randomized controlled trial; TRF=Time-Restricted Feeding; NAFLD=non-alcoholic fatty liver disease; BMI=body mass index; ALT=alanine aminotransferase; AST=aspartate aminotrans- ferase; GGT=gamma-glutamyl transferase; HDLc=high density lipoprotein cholesterol; LDLc=low density lipoprotein cholesterol; TG=triglyceride; TC=total cholesterol; HOMA-IR= Homeo- static Model Assessment for Insulin Resistance; NFS=NAFLD Fibrosis Score; ADF=alternate-day fasting; APRI=aspartate aminotransferase/platelet ratio; FIB-4=Fibrosis-4; CAP=controlled at- tenuation parameter; MD=mean difference; SWE=shear wave elastography; SoC=standard of care; CK-18=Cytokeratin-18; M=males; F=females; BG=blood glucose; LCHF=low-carb high-fat diet termittent energy restriction”, by selecting “meta-analysis”, term protection against NAFLD [74]. Although not per- “clinical trial”, “observational study” and “randomized formed in patients with NAFLD (but T2DM patients), clinical trial”. Duplicate articles were removed and the data the study by Kahleova H et al. demonstrated that a hy- were summarized descriptively. pocaloric B2 regimen (comprising two larger meals a day: There are several studies that have evaluated the effects breakfast and lunch) decreased the hepatic fat content to of TRF regimens, and most have in fact been focused on a slightly greater extent than a hypocaloric A6 (compris- Ramadan fasting. The meta-analysis by Faris M. et al. has ing 6 smaller meals) (-0.04% [95%CI: -0.041, -0.035] recently evaluated the effect of Ramadan diurnal intermit - vs -0.03% [95%CI: -0.033, -0.027]; p=0.009) [75]. Al- tent fasting (RDIF) on liver function tests in healthy in- though no similar study has been performed in patients dividuals (n=20 studies, 601 adults) and has shown that with NAFLD so far to our knowledge, this finding is worth RDIF was associated with small but significant reductions being mentioned. in aspartate aminotransferase (AST) (standardized mean The only RCT that primarily investigated a TRF (16:8) difference (SMD): -0.257 [95%CI: -0.381, -0.133]), regimen was the one performed by Kord-Varkaneh H. et alanine aminotransferase (ALT) (SMD: -0.105 [95%CI: al., which demonstrated benefits regarding body adiposity, -0.282, 0.07]), gamma glutamyl transpeptidase (GGT) liver enzymes, steatosis, with slight improvement in mark- (-0.533 [95%CI: -0.842, -0.224]), and may confer a short- ers of fibrosis (table II) [76]. Another small proof-of-con - 8 Acta Marisiensis - Seria Medica 2023;69(1) cept study published as abstract only has also indicated re- Potential risks associated with ductions in body adiposity with a TRF (16:8) regimen [77]. intermittent fasting This was also observed in the standard of care group, but The safety of the intermittent fasting regimens was rather with TRF there was also an improvement in liver steatosis less well investigated in the NAFLD studies (some did not and stiffness, as evaluated by transient elastography [77]. report any safety data, some indicated no adverse effects, The other studies were in fact observational, generally and one study reported a hypoglycemic event/pre-syncope small (some without a control group), and were evaluat- associated with intermittent fasting) [76-88]. Although ap- ing the effect of Ramadan fasting on various anthropo - parently this dietary intervention seems safe, it should be metric and laboratory markers [77-82]. They overall seem noted that it poses risk of hypoglycemia, mainly in patients to indicate modest improvements in BMI, liver enzymes, with diabetes treated with insulin and/or other glucose- and markers of steatosis (although not all findings were in lowering medications (and they should be carefully moni- concordance) (table II) [78-83]. It should be mentioned tored during the intervention), but also other possible ad- though that there is a major difference between “classic” verse events (malnutrition in patients with advanced liver TRF regimens and the Ramadan fasting, as the later does disease/cirrhosis or older individuals, binge eating, or other not synchronize the fasting period with the physiological psychologic adverse effects (i.e. mood swings), constipa - feeding/fasting time (as the fasting is diurnal). tion, headache etc.) [90-91]. For some patient categories Various Intermittent Energy Restriction regimens were (such as pregnant or lactating mothers, older individuals, assessed in several RCTs and they were associated with a those with advanced chronic diseases, with eating behavior decrease in body weight and fat mass, improvements in disorders) there is no sufficient safety data to even con - transaminases values and markers of liver steatosis, and sider advising this intervention, and it is prudent to refrain slight decreases in markers of liver fibrosis (although not all from doing so. More short- and long-term safety data is studies have investigated the latter two parameters) (table definitely needed in patients with NAFLD, as well as other II) [84-88]. Nevertheless, it should be mentioned that the patient categories, and these should be consistently evalu- studies were of relatively short duration (8-12 weeks), had ated in future studies. no histologic evaluation of NAFLD (they used surrogate markers of liver steatosis and fibrosis), and except for one Conclusions study (Cai H et al,.), all the others included a relatively There is limited but promising evidence so far regarding small number of patients. the beneficial effects of an intermittent fasting interven - Additional data worth mentioning here is that reported tion in patients with NAFLD. Most studies included by Drinda S. et al, although the study did not specifically a relatively small number of subjects, were of relatively include NAFLD patients, but individuals with or without short-duration, and used anthropometric parameters and T2DM undergoing periodic fasting (n=697) [89]. At base- surrogate markers of NAFLD (i.e. liver enzymes, ultraso- line, 37.9% of subjects had a Fatty Liver Index (FLI) ≥ 60 nography). Some of the regimens (mainly Time-Restrict- (indicating liver steatosis) [89]. The mean fasting duration ed Feeding and Intermittent Energy Restriction) showed was 8.5±4 days, and it allowed a maximum energy intake some improvements in body adiposity, liver enzymes, and of 250 kcal/day (consisting of fruit juice/vegetable broth) hepatic steatosis, but the best intermittent fasting regimen during the fasting period [89]. At the end of the interven- for NAFLD is not yet known. Further well-designed re- tion, 49.9% of subjects lost ≥5% of body weight, the BMI search that evaluates the feasibility (mainly on long-term), was reduced by -1.51 ± 0.82 kg/m , and the FLI decreased safety and efficacy outcomes of these dietary interventions significantly (-14.02 ± 11.67; p<0.0001), in correlation for patients with NAFLD is still needed. with number of fasting days and magnitude of BMI reduc- tion [89]. Authors contribution: Finally, a systematic review and meta-analysis of six SC contributed by conception of the review, research the studies (n=417 patients with NAFLD) that approached literature, drafted the paper, and revised it critically for im- various intermittent fasting regimens, has reported that portant intellectual content; final approval of the version these dietary interventions were associated with a small to be published. but significant decrease in weight (mean difference FR contributed to the design of the review paper; researched (MD): -2.45 [95%CI:-3.98, -0.91], p≤0.00), BMI (MD: the literature, revised the paper for important intellectual -0.50 [95%CI:-0.93, -0.07], p=0.02), ALT (MD: -10.54 content; final approval of the version to be published. [95%CI:-14.01, -7.08], p≤0.00), and AST (MD: -11.31 [95%CI:-14.30, -8.32], p≤0.00), but with no significant Conflict of interest changes in waist circumference, blood glucose, fasting None to declare. insulin and HOMA-IR, blood lipids or liver stiffness (al - though except for weight and BMI, all other analyses in- References 1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. cluded only 2-4 studies) [90]. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic Acta Marisiensis - Seria Medica 2023;69(1) 9 assessment of prevalence, incidence, and outcomes. Hepatology. fat/low-glycaemic index diet to reduce liver fat in older subjects. Br J 2016;64(1):73-84. Nutr. 2013;109(6):1096-104. 2. Younossi ZM, Marchesini G, Pinto-Cortez H, Petta S. Epidemiology 24. van Herpen NA, Schrauwen-Hinderling VB, Schaart G, Mensink RP, of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Schrauwen P. 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Intermittent fasting for the management of NAFLD: Is there enough evidence?

Cernea, Simona; Ruţa, Florina
Acta Marisiensis - Seria Medica , Volume 69 (1): 8 – Mar 1, 2023
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Acta Marisiensis - Seria Medica 2023;69(1):3-10 DOI: 10.2478/amma-2023-0001 REVIEW Intermittent fasting for the management of NAFLD: Is there enough evidence? 1,2* 3 Simona Cernea , Florina Ruţa 1. Department M3, Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania 2. Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania 3. Department of Community Nutrition and Food Safety, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania The pathogenesis of the non-alcoholic fatty liver disease (NAFLD) has been described as multifactorial, with genetic and environmental factors acting synergistically and causing excessive hepatic lipid accumulation, insulin resistance, and downstream pathogenetic insults. High-calorie diets, particularly those rich in foods with high (saturated) fat and sugar content, and sugar-sweetened beverages, are among the behavioral risk factors with a crucial role in the disease pathogenesis. In addition, meal frequency and meal timing appear to be relevant factors associ- ated with NAFLD. Current guidelines recommend a hypocaloric, preferably Mediterranean diet as the main dietary intervention approach, but various other dietary models have been evaluated in patients with NAFLD. Among these, several intermittent fasting regimens have shown promising results. Diets based on Time-Restricted Feeding and Intermittent Energy Restriction have demonstrated some improvements in body adiposity, liver enzymes, and hepatic steatosis, but most studies included a small number of subjects, were of relatively short-duration, and used surrogate markers of NAFLD. The best intermittent fasting regimen for NAFLD is not yet known, and further well-designed research that evaluates the feasibility (mainly on long-term), safety and efficacy outcomes of these dietary interventions is still needed. Our review has evaluated the up-to-date information regarding the intermittent fasting dietary intervention in NAFLD and generated some key-point messages that are relevant to physicians and dietitians involved in the care of patients with NAFLD. Keywords: NAFLD, dietary intervention, intermittent fasting, time-restricted feeding Received 7 December 2022 / Accepted 26 December 2022 Introduction netic and environmental factors act synergically and lead The non-alcoholic fatty liver disease (NAFLD) has emerged to excessive and dysfunctional adiposity, lipid accumula- as a major cause of chronic liver disease, affecting about a tion in the liver and lipotoxicity, insulin resistance, further quarter of the adult general population worldwide [1, 2]. causing inflammation, oxidative stress, hepatocellular ap - Moreover, the global prevalence of NAFLD is double in optosis and fibrosis [7, 8]. patients with type 2 diabetes mellitus (T2DM) [3]. Among the lifestyle risk factors, diet/diet composition NAFLD is characterized by an excessive accretion of li- has a crutial role in NAFLD pathogenesis [9]. The exces - pids in the liver (hepatic steatosis) affecting >5% of hepat - sive caloric intake appears to be a distinctive dietary fea- ocytes, in the absence of other secondary causes (including ture in patients with NAFLD and experimental overfeed- viral hepatitis, or alcohol intake exceeding 20 g/day for ing studies demonstrated that hypercaloric diets promoted women and 30 g/day for men) [4]. The hepatic lipid accu - hepatic fat accumulation [10, 11]. mulation is associated with insulin resistance, which is in Although it is more difficult to distinguish the effect of fact a key pathogenetic mechanism in NAFLD, and with a specific macronutrient/dietary component on modulat - components of the metabolic syndrome (obesity, T2DM, ing the risk of liver steatosis, overall data seem to indi- dyslipidemia) [5]. NAFLD in fact comprises several condi- cate that the intake of foods rich in fats (mainly saturated tions: simple steatosis (nonalcoholic fatty liver (NAFL)), fats), sugar (mainly fructose, but also glucose) and sugar- nonalcoholic steatohepatitis (NASH) (without or with sweetened beverages favors lipid accumulation in the liver, various grades of fibrosis, including hepatic cirrhosis), and insulin resistance, and increases the likelihood of NAFLD hepatocellular carcinoma (HCC) [4, 6]. [10-14]. Apparently, the negative effect of fructose on the intrahepatocellular lipids and transaminases is mainly The role of diet in the pathogenesis of NAFLD seen in the context of hypercaloric diets [15]. Dietary car- The pathogenesis of NAFLD is multifactorial, and a num - bohydrates stimulate de novo lipogenesis, increase the free ber of genetic/epigenetic, demographic, and environmen- fatty acid pool in the liver, and may also have pro-inflam - tal/lifestyle risk factors have been identified. The complex matory effects [10, 15, 16]. The intervention studies also interaction between these factors is responsible for the ini- support the findings from the observational studies, show - tiation and development of the pathogenetic mechanisms ing greater reduction of hepatic steatosis with low-carb/ of the disease. According to the “multiple-hit” theory, ge- sugar diets and with low-fat diets [17-23]. A meta-analysis of 11 studies showed no significant differences between low-carbohydrate diet and low-fat diet on the hepatic fat * Correspondence to: Simona Cernea E-mail: simonacernea@yahoo.com content and transaminases levels in subjects with NAFLD 4 Acta Marisiensis - Seria Medica 2023;69(1) [24]. However, the type of dietary fats is relevant since stay of intervention in NAFLD, recommended by current the saturated fats increase hepatic liver accumulation and guidelines [4, 6, 46]. This is associated with amelioration insulin resistance more than polyunsaturated fats [25- of insulin resistance. A histologic reference study has dem- 29]. Studies have shown that the monounsaturated fat- onstrated that weight loss through lifestyle intervention enriched diets and the Mediterranean diet (based on olive (low-fat hypocaloric diet and physical activity) in patients oil consumption as a main source of fat, which is rich in with NASH resulted in liver benefits (steatosis reduction, monounsaturated fats) are associated with lower intrahe- NASH resolution, and fibrosis regression), in direct re - patic triglyceride content [30-32]. Moreover, diets rich in lationship with the degree of weight loss (OR: 1.1-2.0, insoluble fibers and fruit fiber consumption in the context p<0.01) [47]. The NASH-related histologic improvements of energy restriction improve liver health (decrease liver were seen with a minimum 5% weight loss, and patients steatosis and transaminases) [33]. The protective effects of that obtained ≥10% weight loss also presented regression dietary fibers might be due to direct anti-inflammatory ef - of hepatic fibrosis [47]. Thus, the current guidelines gen - fects and/or indirect ones (through modulation of the gut erally recommend a hypocaloric diet for the management microbiome) [11]. Data on dietary protein is less consist- of NAFLD [6, 46]. The Mediterranean diet is a preferred ent. There is some evidence that red meat/animal protein dietary pattern in patients with NAFLD, as it is associated intake is also associated with liver steatosis, but the in- with improvement of liver steatosis and insulin resistance tervention studies showed that high protein diets reduced [48, 49]. However, other dietary interventions (DASH liver fat [34-39]. diet, low-carb diet, low-fat diet, ketogenic diet, etc.) have In addition to diet composition, meal frequency and been investigated and seem to bring liver-specific ben - meal timing appear to be other significant factors associ - efits, but choosing the best dietary intervention for each ated with hepatic steatosis/NAFLD. A randomized con- NAFLD patients is still a challenging task [50]. Nutrition- trolled trial (RCT) in patients with NAFLD has demon- al interventions based on time-restricted feeding/intermit- strated that in the context of a hypercaloric diet, higher tent fasting are novel and potentially promising approaches meal frequency, but not meal size, was associated with in- for NAFLD, that deserve attention. creased intrahepatic triglyceride content (mean relative in- crease of 45%, p=0.016), suggesting that snacking is an in- Intermittent fasting – regimens and dependent contributor to hepatic steatosis [40]. The same mechanisms of health benefits was shown by a Japanese community-based cross-sectional Fasting (i.e. restricted food intake) is an ancient practice study indicating that snacking ≥2 times/day significantly based on cultural and religious beliefs, and has also been increased the prevalence rate of NAFLD both in men and used for healing purposes in the past [51]. Religious fast- women (41.1% in men, and 15.3% in women) [41]. In- ing is practiced in Christianity, Judaism, Islam, and other terestingly, an Australian study has shown that a “grazing” religions, but it varies by dietary pattern (food selection) temporal eating pattern (defined as a more frequent inges - and fasting duration, and has been shown to bring cardio- tion of minimum 50 kcal, lower probability of eating at metabolic benefits (decrease in body weight, blood lipids, conventional meal times, also associated with later timing insulin resistance, etc.) [52]. of first food ingestion) was associated with a poorer diet Intermittent fasting (also known as periodic energy re- quality and higher overall and visceral adiposity in women striction) refers to dietary intervention strategies that re- (OR: 1.57 [95%CI: 1.15, 2.13], and 1.73 [95%CI: 1.19, strict food intake to certain periods of time (within a day 2.50], respectively) [42]. In contrast, a preliminary report or a week) [53, 54]. The periods of fasting/energy restric - that analyzed the third National Health and Nutrition tion are usually followed by periods when food is used ad Examination Survey (NHANES III) data indicated that libitum [55]. There are several regimens of intermittent rather more meals per day decreased the odds of severe liver fasting, which can be broadly categorized into two major steatosis, but skipping breakfast and lunch had an opposite groups (table I): effect (increased the odds of liver steatosis) [43]. Thus, al - – Time-Restricted Feeding (TRF), which implies a though evidence is still weak, it appears that circadian mis- restriction of feeding during certain daily time win- alignments favor visceral adiposity and hepatic steatosis/ dows, and NAFLD. Indeed, the circadian clock plays an important – Intermittent Energy Restriction (IER), which impli- role in regulating major metabolism pathways and other es short periods of energy restriction alternating with physiologic functions in the liver, which show diurnal vari- normal eating/diet; this category comprises several ations [44]. Thus, circadian disruption by improper meal regimens; a special form of IER is the alternate-day timing may cause major disturbances leading to insulin fasting (ADF), and its modified form; the energy re - resistance, increased levels of free fatty acids and triglycer- striction during the fasting time varies between 75% ides, eventually leading to NAFLD [44, 45]. and 100% [56]. The role of dietary intake is further substantiated by In addition to the main intermittent fasting regimens the fact that caloric restriction and weight loss through mentioned in table I, there are several other modified dietary interventions and physical exercise are the main- forms, including the combination of intermittent fasting Acta Marisiensis - Seria Medica 2023;69(1) 5 Table I. Characteristics of the intermittent fasting regimens [51-57]. Fasting period Eating period Time-Restricted Feeding (TRF) TRF (16:8; 15:9, etc) ≥14 h; usually ≤10 h; early TRF regimen is preferred (eating be- no energy intake is allowed; tween 8:00 am and 2:00 pm or up to 5:00 pm, depending on the regimen); ad libitum feeding; B2 regimen 14-16 h; 2 main meals per day: breakfast (06:00-10:00 a.m.) and no energy intake is allowed; lunch (12:00-04:00 p.m.); no dinner; ad libitum feeding; Ramadan (during the Islamic holy dawn to sunset; sunset to dawn; month) no energy intake (including drinking) is allowed; ad libitum feeding; Intermittent Energy Restriction (IER) Alternate-day fasting every other day (24 h); alternate day to fasting day; no energy intake is allowed; ad libitum feeding; Alternate day-modified fasting 20 h, every other day; alternate day to fasting day; up to 25% of daily energy intake (mid-day meal); ad libitum feeding; 5:2 (twice weekly fasting) 2 days (24 h) a week (usually non-consecutive); 5 days a week; up to 25% of daily energy intake or ~500 kcal/day; ad libitum feeding; Modified periodic fasting 5 consecutive days; at least 10 days following the fasting period; a very-low-caloric diet (up to 25% of daily energy intake); ad libitum feeding; and caloric restriction (i.e. one day of fasting and six days intake and free radicals production, and possibly by activa- of caloric restriction) [58]. tion of redox-sensitive transcription factors (shift of redox Intermittent fasting has proven to bring cardiovascular status) [63]. benefits (reductions in systolic and diastolic blood pressure, Thirdly, intermittent fasting might directly influence body weight, and ectopic fat depositions, improvements in the gut microbiota composition, which is also involved in blood lipids, insulin sensitivity and inflammatory mark - metabolic signaling and bile acid metabolism [56, 64, 65]. ers) [53, 57]. However, there is no clear superiority of the Finally, the circadian rhythm theory might well explain intermittent fasting regimens compared to the continuous the beneficial effects associated with some intermittent fast - caloric restrictions, suggesting that in fact the reduction of ing regimens (mainly TRF) [53]. When properly timed, it energy intake (energy deficit) might be the main reason allows the resynchronization between the body’s circadian for the observed health benefits, although some data also rhythm and the time of fasting-feeding [53, 66]. The cir - support the weight-loss independent effects of intermittent cadian rhythm allows the expression of clock-controlled fasting on cardiometabolic parameters [57]. genes that regulate many molecules involved in metabolic There are several proposed mechanisms for the effects of functions, and there is evidence supporting a strong re- intermittent fasting on health. During fasting, a switch in lationship between circadian clock and metabolism [65]. substrate utilization occurs (from carbohydrate to fat, and In fact, circadian rhythm disruption (i.e. in case of shift ketone body production and oxidation) [59]. Glucose is workers, jet leg, etc.) is associated with various metabolic the main energy fuel for most cells, and during fasting, in- diseases (obesity, impaired glucose tolerance/diabetes, etc.) sulin levels drops, and glucose is released through glycogen [67-70]. Animal data indicate that intermittent fasting breakdown from liver depots [55]. In addition, there is a (TRF regimens) can restore the oscillation of metabolic breakdown of triglycerides and free fatty acids release from regulators (such as AMPK, mTOR, CREB, etc) and their the adipose tissue, which undergo β-oxidation in the liver target gene expression [67, 71]. Moreover, the feeding/fast- [55]. In prolonged fasting periods, free fatty acids are me- ing rhythms and diet may modulate the cyclic fluctuations tabolized into ketone bodies, which are an alternative en- of the gut microbiome, which influence the secondary me - ergy substrate for extrahepatic tissues (i.e. brain and heart) tabolite production, involved in the maintenance of the [55]. Therefore, during (intermittent) fasting a ketogenic peripheral circadian rhythm [72]. state is induced, as evidenced by the elevation of blood  Nevertheless, the exact mechanisms through which the ketone levels [60, 61]. Thus, a switch from fat storage to various intermittent fasting regimens are associated with utilization occurs, promoting weight loss (intermittent health benefits are not fully deciphered, and probably metabolic switching/”keto-adaptation”) [53, 55]. Ketone many factors (i.e. diet composition, time of fasting, dura- bodies also promote the activation of the cellular stress re- tion of interventions) influence the results. sponses under fasting conditions, which result in removal of damaged organelles and proteins, improve mitochon- Intermittent fasting for the drial function, and promote cellular repair mechanisms management of NAFLD [51, 52, 55]. The nutritional ketosis induced by the inter - NAFLD is a complex disease associated with a variety mittent fasting regimens determines the keto-adaptation of metabolic disturbances, and dietary intervention and which is linked to many health benefits [55]. weight loss are at the core of its management. As men- A second hypothesis (proposed mechanisms) is reduc- tioned, various dietary interventions have been evaluated tion of the oxidative stress, induced by a decrease of energy in patients with NAFLD, some (i.e., the Mediterranean 6 Acta Marisiensis - Seria Medica 2023;69(1) diet) proving clear benefits [73]. Recently, various inter - have search PubMed without language restrictions since mittent fasting regimens have been evaluated with regards database inception to December 2022 using the terms: to liver-related outcomes in NAFLD. “NAFLD” or “non-alcoholic fatty liver disease” and “in- We review here the up-to-date main findings from the termittent fasting” and subsequently, “time-restricted feed- clinical studies in patients with NAFLD (table II). We ing” or “Ramadan fasting” or “alternate-day fasting” or “in- Table II. The effects of different intermittent fasting regimens on anthropometric and liver-related outcomes in patients with NAFLD Reference/ Dietary intervention Patients Main findings study type Time-Restricted Feeding (TRF) Kord-Varkaneh TRF (16 h fasting/8 45 NAFLD patients In intervention group after versus baseline: H. et al /RCT h feeding) plus low- (22 intervention, 23 Body weight ↓(83.75 to 80.54 kg; p<0.001) sugar diet vs control, control) BMI ↓(29.13 to 28.02 kg/m ; p<0.0001) for 12 weeks Body fat ↓(26.69 to 24.22 kg; p=0.001) Waist ↓(104.59 to 101.91; p=0.042) Change in intervention group versus control group: ALT ↓(34.04 to 21.22 U/l) vs ↓(30.34 to 28.04 U/l); p=0.003 AST ↓ (26.31 to 20.5o U/l) vs (23.68 to 23.77 U/l); p=0.031 TG ↓(201.50 to 133.27 mg/dl) vs ↑(187.6 to 199.56 mg/dl); p<0.001 TC ↓(190.04 to 157.8 mg/dl) vs ↑(172.21 to 180.72 mg/dl); p<0.001 LDLc ↓(104.63 to 84.04 mg/dl) vs ↑(93.73 to 97.45 mg/dl); p=0.017 CK-18 ↓(1.35 to 1.16 ng/ml) vs ↑(1.32 to 1.85 ng/ml); p<0.001 Fibrosis score ↓(6.33 to 5.15 kPa) vs ↓(5.82 to 5.46 kPa); p=0.024 CAP ↓(322.90 to 270.90 dB/m) vs (311.52 to 306.00 dB/m); p<0.001 Hodge A. et TRF (16 h fasting 28 NAFLD patients Weight ↓(81.9 to 79.8 kg; p=0.0024) (TRF) and ↓(82.3 to 81 kg; p=0.0066) (SoC) 77 2 2 al (abstract from 8 pm to 12 pm (17 TRF, 15 SoC) BMI ↓(29 to 28 kg/m ; p=0.002) (TRF) and ↓(30 to 29 kg/m ; p=0.006) (SoC) only)/random- next day /8 h feeding) Total body fat mass ↓(29 to 28 kg; p=0.0001) (TRF) and ↓(31 to 29 kg; p=0.0031) (SoC) ized pilot study vs standard of care Liver stiffness (Fibroscan®) ↓(7.33 to 5.84 kPa; p=0.0088) (TRF) and (6.32 to 6.09 kPa; (SoC), for 12 weeks p=0.7305) (SoC) CAP ↓(287 to 263 dB/m; p=0.012) (TRF) and (268 to 268 dB/m; p=0.981) (SoC) Badran H. et Ramadan fasting (16 98 NAFLD patients Before vs after fasting: al hours), for 22-29 days (diagnosed based Weight ↓(97.44 to 96.69 kg; p≤0.01) /interventional on US) BMI ↓(37.03 to 36.74 kg/m ; p≤0.01) multicenter HbA1c ↓(6.1 to 5.9%; p≤0.01) study HOMA-IR ↓(2.13 to 1.96; p≤0.01) TC ↓(241.1 to 218.48 mg/dl; p≤0.01) TG ↓(171.01 to 157.49 md/dl; p≤0.01) HDLc ↑(45.3 to 48.5 md/dl; p≤0.01) ALT ↓(36.5 to 32.7 U/l; p≤0.01) AST ↓(38.5 to 32.8 U/l; p≤0.01) GGT ↓(41.1 to 37.1 U/l; p=0.047) FIB-4 ↓(1.48 to 1.33; p≤0.01) APRI ↓(0.61 to 0.52; p≤0.01) Rahimi H. et Ramadan fasting and 60 NAFLD patients Before vs after fasting (versus control): al low-fat low-calory diet (34 fasting, 26 not Body weight (-0.80 kg) (fasting) and (-0.89 kg) (control); p=0.936 2 2 /prospective fasting=control) BMI (-0.26 kg/m ) (fasting) and (-0.36 kg/m ) (control); p=0.749 study ALT ↑(+7.38 U/l) (fasting) and ↓(-0.12 U/l) (control) p=0.002 Arabi SM. et Ramadan fasting 50 NAFLD patients Before vs after fasting: 80 2 2 al (between 13 h and 35 (diagnosed based BMI (29.5 to 29.0 kg/m ; p=0.07) (M) and (34.15 to 33.4 kg/m ; p=0.09) (F) /prospective min and 14 h and 42 on US) TC ↑(190.60 to 220.72 mg/dl; p=0.001) (M) and ↑(199.95 to 229.1 mg/dl; p=0.001) (F) observational min), for 27.3 days HDLc (42.72 to 45.27 mg/dl; p=0.22) (M) and ↑(46.52 to 53.91 mg/dl; p=0.04) (F) study Fasting BG ↑(85.5 to 133.56 mg/dl; p<0.001) (M) and ↑(100.0 to 120.23 mg/dl; p<0.001) (F) ALT ↓(18.0 to 13.0; p<0.001) (M) and ↓(14.0 to 11.0; p=0.001) (F) Aliasghari F. Ramadan fasting 83 NAFLD patients Fasting vs control group (change before to after): et al / obser- (42 fasting, 41 not Weight ↓(-2.14 vs -0.08 kg; p<0.001) vational study fasting=control) BMI ↓(-0.80 vs -0.02 kg/m ; p<0.001) Waist ↓(-0.95 vs -0.036 cm; p<0.001) Fasting BG ↓(94.02 to 92.4 mg/dl; p<0.001) (fasting) vs (94.75 to 94.46 mg/dl; p=0.05) (control) HOMA-IR ↓(3.49 to 3.48; p=0.011) (fasting) vs (3.78 to 3.81; p=NS) (control) Mari A. et al Ramadan fasting 155 NAFLD patients Fasting group (before vs after interventions): /retrospective (diagnosed by US) BMI ↓(36.7 to 34.5 kg/m ; p<0.005) case-control (74 fasting, 81 not HbA1c ↓(5.89 to 5.28%; p<0.005) study fasting=control) HOMA-IR ↓(2.92 to 2.15; p<0.005) AST ↓(44.2 to 34.23 U/l; p<0.005) ALT ↓(51.43 to 39.23 U/l; p<0.005) GGT ↓(52.3 to 43.25 U/l; p<0.005) NFS ↓(0.45 to 0.23; p<0.005) BARD ↓(2.3 to 1.6; p<0.005) No significant changes in control group (Continued on p. 7) Acta Marisiensis - Seria Medica 2023;69(1) 7 (Continued from p. 6) Reference/ Dietary intervention Patients Main findings study type Ebrahimi S. et Ramadan fasting 83 NAFLD patients Fasting vs control group (change end vs before intervention): al /observa- (42 fasting, 41 not Weight ↓(-2.14 vs -0.08 kg; p<0.001) tional study fasting=control) BMI ↓(-0.80 vs -0.02 kg/m ; p<0.001) Body fat ↓(-0.68 vs -0.29%; p=0.003) TC ↓(-13.71 vs -7.80 mg/dl; p=0.016) AST ↓(-4.66 vs -2.36 U/l; p=0.031) ALT ↓(-3.43 vs +2.58 U/l; p=0.046) Severity of US hepatic steatosis between groups (p=0.024) Intermittent Energy Restriction (IER) Cai H. et al Alternate-day fasting 264 NAFLD patients Body weight ↓(-4.04 kg) (ADF) vs (-3.25 kg) (TRF) vs (-1.85 kg) (control) (p<0.001 vs control) /RCT (ADF) vs TRF (16:8) vs (90 vs 95 vs 79) Fat mass ↓(-3.48 kg) (ADF) vs (-2.62 kg) (TRF) vs (-1.05 kg) (control) (p<0.001 vs control) control, for 12 weeks TG ↓(-0.64 mmol/l) (ADF) vs (-0.58 mmol/l) (TRF) vs (-0.25 mmol/l) (control) (p<0.001 vs control) Ezpeleta M. et Modified ADF (600 NAFLD patients (n Body weight ↓(-5.3 %; p<0.05) (ADF) and (-4.9 %; p<0.05) (combination) and (-1.9 %; p=NS) al (abstract kcal on fast day) vs = 48) (exercise) vs (-0.3 %) (control) only) exercise vs combina- ALT ↓(-29 %; p<0.05) (combination) and (-9 %; p=NS) (ADF) and (1%; p=NS) (exercise) vs /randomized tion vs control (usual (17%) (control) study diet), for 12 weeks No change in liver fat Johari MI. et Alternate-day modified 43 NAFLD patients Body weight ↓(80.80 to 78.79 kg; p=0.003); MD=3.06; p=0.01 86 2 al fasting (ADMF) (70% (33 ADMF vs 10 BMI ↓(31.73 to 30.95 kg/m ; p=0.003) (ADMF); MD=1.08; p=0.02 /RCT calory restriction on control) ALT ↓(84.33 to 59.17 U/l; p=0.001) (ADMF); MD=18.6; p=0.02 fasting day; 2 meals AST ↓(51.40 to 42.77 U/l; p=0.004) (ADMF) at 2 pm and 8 pm) vs Fasting BG ↓(6.62 to 5.87 mmol/l; p=0.006) (ADMF) control, for 8 weeks Liver steatosis grade ↓(1.93 to 1.43; p=0.001) (ADMF); MD=0.38; p=0.01 SWE ↓(5.87 to 5.01 kPa; p=0.001) (ADMF); MD= 0.74; p=0.01 Holmer M. et 5:2 diet vs low-carb 74 NAFLD patients Change from baseline to end of treatment: al /RCT high-fat diet (LCHF) (1:1:1 ratio) Body weight ↓(-7.4 kg) (5:2 diet) vs (-7.3 kg) (LCHF) (-2.5 kg) vs (SoC) (p<0.0001 for all) vs standard of care HOMA-IR ↓(-3.2; p<0.001) vs ↓(-2.9; p=0.006) (LCHF) vs (−2.4; p=0.097) (SoC) (SoC), for 12 weeks ALT ↓(-17.6 U/l; p<0.001) (5:2 diet) vs ↓(-17.6 U/l; p=0.013) (LCHF) vs ↓(-11.8 U/l; p=0.006) (SoC) CAP ↓(−63.8 dB/m; p<0.001) (5:2 diet) vs ↓(-61.9 dB/m; p<0.001) (LCHF) vs (−20.2 dB/m; p=0.118) (SoC) Elastography ↓(-1.8 kPa; p<0.001) (5:2 diet) vs (-0.3 kPa; p=0.522) (LCHF) vs ↓(-1.5 kPa; p= 0.005) (SoC) Kord Varkaneh 5:2 diet vs control 44 NAFLD patients In the intervention group after versus baseline: H. et al /RCT (usual diet), for 12 (21 IF vs 23 control) Body weight ↓(86.65 to 82.94 kg; p<0.001) weeks BMI ↓(30.42 to 29.13 kg/m ; p<0.001) Waist ↓(103.52 to 100.52 cm; p=0.001) Fat mass ↓(26.64 to 23.85 kg; p=0.039) ALT ↓(41.42 to 28.38 U/l; p=0.043) AST ↓(34.19 to 25.95 U/l; p=0.013) TG ↑(171.23 to 128.04 mg/dl; p<0.001) CK-18 ↓(1.32 to 1.19 ng/ml; p<0.001) Fibrosis score (Fibroscan®) ↓(6.97 to 5.58 kPa; p=0.009) CAP ↓(313.09 to 289.95 dB/m; p<0.001), For ALT, ASL, TG, CK-18, Fibrosis score and CAP, p<0.05 versus the change in control group after adjustment for variables RCT= randomized controlled trial; TRF=Time-Restricted Feeding; NAFLD=non-alcoholic fatty liver disease; BMI=body mass index; ALT=alanine aminotransferase; AST=aspartate aminotrans- ferase; GGT=gamma-glutamyl transferase; HDLc=high density lipoprotein cholesterol; LDLc=low density lipoprotein cholesterol; TG=triglyceride; TC=total cholesterol; HOMA-IR= Homeo- static Model Assessment for Insulin Resistance; NFS=NAFLD Fibrosis Score; ADF=alternate-day fasting; APRI=aspartate aminotransferase/platelet ratio; FIB-4=Fibrosis-4; CAP=controlled at- tenuation parameter; MD=mean difference; SWE=shear wave elastography; SoC=standard of care; CK-18=Cytokeratin-18; M=males; F=females; BG=blood glucose; LCHF=low-carb high-fat diet termittent energy restriction”, by selecting “meta-analysis”, term protection against NAFLD [74]. Although not per- “clinical trial”, “observational study” and “randomized formed in patients with NAFLD (but T2DM patients), clinical trial”. Duplicate articles were removed and the data the study by Kahleova H et al. demonstrated that a hy- were summarized descriptively. pocaloric B2 regimen (comprising two larger meals a day: There are several studies that have evaluated the effects breakfast and lunch) decreased the hepatic fat content to of TRF regimens, and most have in fact been focused on a slightly greater extent than a hypocaloric A6 (compris- Ramadan fasting. The meta-analysis by Faris M. et al. has ing 6 smaller meals) (-0.04% [95%CI: -0.041, -0.035] recently evaluated the effect of Ramadan diurnal intermit - vs -0.03% [95%CI: -0.033, -0.027]; p=0.009) [75]. Al- tent fasting (RDIF) on liver function tests in healthy in- though no similar study has been performed in patients dividuals (n=20 studies, 601 adults) and has shown that with NAFLD so far to our knowledge, this finding is worth RDIF was associated with small but significant reductions being mentioned. in aspartate aminotransferase (AST) (standardized mean The only RCT that primarily investigated a TRF (16:8) difference (SMD): -0.257 [95%CI: -0.381, -0.133]), regimen was the one performed by Kord-Varkaneh H. et alanine aminotransferase (ALT) (SMD: -0.105 [95%CI: al., which demonstrated benefits regarding body adiposity, -0.282, 0.07]), gamma glutamyl transpeptidase (GGT) liver enzymes, steatosis, with slight improvement in mark- (-0.533 [95%CI: -0.842, -0.224]), and may confer a short- ers of fibrosis (table II) [76]. Another small proof-of-con - 8 Acta Marisiensis - Seria Medica 2023;69(1) cept study published as abstract only has also indicated re- Potential risks associated with ductions in body adiposity with a TRF (16:8) regimen [77]. intermittent fasting This was also observed in the standard of care group, but The safety of the intermittent fasting regimens was rather with TRF there was also an improvement in liver steatosis less well investigated in the NAFLD studies (some did not and stiffness, as evaluated by transient elastography [77]. report any safety data, some indicated no adverse effects, The other studies were in fact observational, generally and one study reported a hypoglycemic event/pre-syncope small (some without a control group), and were evaluat- associated with intermittent fasting) [76-88]. Although ap- ing the effect of Ramadan fasting on various anthropo - parently this dietary intervention seems safe, it should be metric and laboratory markers [77-82]. They overall seem noted that it poses risk of hypoglycemia, mainly in patients to indicate modest improvements in BMI, liver enzymes, with diabetes treated with insulin and/or other glucose- and markers of steatosis (although not all findings were in lowering medications (and they should be carefully moni- concordance) (table II) [78-83]. It should be mentioned tored during the intervention), but also other possible ad- though that there is a major difference between “classic” verse events (malnutrition in patients with advanced liver TRF regimens and the Ramadan fasting, as the later does disease/cirrhosis or older individuals, binge eating, or other not synchronize the fasting period with the physiological psychologic adverse effects (i.e. mood swings), constipa - feeding/fasting time (as the fasting is diurnal). tion, headache etc.) [90-91]. For some patient categories Various Intermittent Energy Restriction regimens were (such as pregnant or lactating mothers, older individuals, assessed in several RCTs and they were associated with a those with advanced chronic diseases, with eating behavior decrease in body weight and fat mass, improvements in disorders) there is no sufficient safety data to even con - transaminases values and markers of liver steatosis, and sider advising this intervention, and it is prudent to refrain slight decreases in markers of liver fibrosis (although not all from doing so. More short- and long-term safety data is studies have investigated the latter two parameters) (table definitely needed in patients with NAFLD, as well as other II) [84-88]. Nevertheless, it should be mentioned that the patient categories, and these should be consistently evalu- studies were of relatively short duration (8-12 weeks), had ated in future studies. no histologic evaluation of NAFLD (they used surrogate markers of liver steatosis and fibrosis), and except for one Conclusions study (Cai H et al,.), all the others included a relatively There is limited but promising evidence so far regarding small number of patients. the beneficial effects of an intermittent fasting interven - Additional data worth mentioning here is that reported tion in patients with NAFLD. Most studies included by Drinda S. et al, although the study did not specifically a relatively small number of subjects, were of relatively include NAFLD patients, but individuals with or without short-duration, and used anthropometric parameters and T2DM undergoing periodic fasting (n=697) [89]. At base- surrogate markers of NAFLD (i.e. liver enzymes, ultraso- line, 37.9% of subjects had a Fatty Liver Index (FLI) ≥ 60 nography). Some of the regimens (mainly Time-Restrict- (indicating liver steatosis) [89]. The mean fasting duration ed Feeding and Intermittent Energy Restriction) showed was 8.5±4 days, and it allowed a maximum energy intake some improvements in body adiposity, liver enzymes, and of 250 kcal/day (consisting of fruit juice/vegetable broth) hepatic steatosis, but the best intermittent fasting regimen during the fasting period [89]. At the end of the interven- for NAFLD is not yet known. Further well-designed re- tion, 49.9% of subjects lost ≥5% of body weight, the BMI search that evaluates the feasibility (mainly on long-term), was reduced by -1.51 ± 0.82 kg/m , and the FLI decreased safety and efficacy outcomes of these dietary interventions significantly (-14.02 ± 11.67; p<0.0001), in correlation for patients with NAFLD is still needed. with number of fasting days and magnitude of BMI reduc- tion [89]. Authors contribution: Finally, a systematic review and meta-analysis of six SC contributed by conception of the review, research the studies (n=417 patients with NAFLD) that approached literature, drafted the paper, and revised it critically for im- various intermittent fasting regimens, has reported that portant intellectual content; final approval of the version these dietary interventions were associated with a small to be published. but significant decrease in weight (mean difference FR contributed to the design of the review paper; researched (MD): -2.45 [95%CI:-3.98, -0.91], p≤0.00), BMI (MD: the literature, revised the paper for important intellectual -0.50 [95%CI:-0.93, -0.07], p=0.02), ALT (MD: -10.54 content; final approval of the version to be published. [95%CI:-14.01, -7.08], p≤0.00), and AST (MD: -11.31 [95%CI:-14.30, -8.32], p≤0.00), but with no significant Conflict of interest changes in waist circumference, blood glucose, fasting None to declare. insulin and HOMA-IR, blood lipids or liver stiffness (al - though except for weight and BMI, all other analyses in- References 1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. cluded only 2-4 studies) [90]. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic Acta Marisiensis - Seria Medica 2023;69(1) 9 assessment of prevalence, incidence, and outcomes. Hepatology. fat/low-glycaemic index diet to reduce liver fat in older subjects. Br J 2016;64(1):73-84. Nutr. 2013;109(6):1096-104. 2. Younossi ZM, Marchesini G, Pinto-Cortez H, Petta S. Epidemiology 24. van Herpen NA, Schrauwen-Hinderling VB, Schaart G, Mensink RP, of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Schrauwen P. 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Journal

Acta Marisiensis - Seria Medica – de Gruyter

Published: Mar 1, 2023

Keywords: NAFLD; dietary intervention; intermittent fasting; time-restricted feeding

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