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The use of very low‐calorie diets in subjects with obesity complicated with nonalcoholic fatty liver disease: A scoping review

Abstract This scoping review synthesizes the existing research on the use of very low‐calorie diets (VLCDs) in subjects with nonalcoholic fatty liver disease (NAFLD) and end‐stage liver disease (ESLD). 19 studies were included, of which 5 were clinical trials, 11 were cohort studies, 1 was a case‐control study, and 2 were case series totaling 968 subjects. About 17 studies were focused on patients with NAFLD while the two case series described in patients with ESLD on the transplant list or post‐liver transplant. Six studies included subjects managed with VLCDs prior bariatric surgery. Most studies were short term and demonstrated acute improvement of diverse liver biomarkers including liver function tests, indices of hepatosteatosis and reduction in liver size. Adherence rates in these studies were between 69% and 93%. Eight studies did not report any adverse events and four subjects were reported to have discontinued VLCD due to adverse effects in two different studies. Aggregated adverse events were mild. Treatments based on VLCD in subjects with NAFLD seem to be safe and tolerable but can result in mild adverse effects. The findings of this scoping review suggest that the use of VLCD in patients with obesity complicated with NAFLD and potentially in ESLD appear to be effective to induce weight loss and to acutely reduce hepatosteatosis.

Very low-calorie diets (VLCD) have been used since the 1920s but became more popular in the sixties. 3 The definition of VLCD has shifted over the years but in 1979 an expert panel working for the Life Sciences Research Office of the Federation of American Societies of Experimental Biology defined VLCD as those containing less than or equal to 800 kilocalories per day. 4 The current definition of a VLCD is a hypocaloric diet comprising 800 kcal per day or less that meets all the vitamin, mineral, electrolyte, and essential fatty acid needs of the individual.
VLCDs have been demonstrated to be effective and safe for short-term weight loss under medical supervision 4,5 and are commonly used to aid in weight loss and to reduce liver volume prior to bariatric surgery. 6 Studies have described the effect of VLCD-based treatments on reduction of hepatosteatosis. 7,8 However, this effect has not been systematically studied in this population.
Scoping review is a form of knowledge synthesis that addresses an exploratory research question aimed at mapping key concepts, types of evidence, and gaps in research related to a defined area or field by systematically searching, selecting, and synthesizing existing knowledge. 9 The aim of this scoping review is to summarize in a descriptive way the literature evaluating the efficacy, adherence, and safety of VLCD in individuals with NAFLD and chronic liver disease.
Given the paucity and heterogeneity of manuscripts addressing this topic, it was not possible to conduct a systematic review with meta-analysis. Furthermore, we aggregated studies that included subjects undergoing both clinical and surgical management of obesity complicated with NAFLD. Although the inclusion of both clinical and presurgical VLCD interventions add variability to our descriptive results, short-term presurgical studies can provide an insight of the acute effectiveness and safety of VLCD in bariatric surgery patients with NAFLD regarding liver outcomes.

| Protocol
Our review protocol was conducted using the methodological framework described by Arksey and O'Malley and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Protocols Extension for Scoping Reviews.

| Eligibility criteria
The following parameters aided the search of relevant articles and defined the inclusion criteria for reviewing abstracts: adults (≥18 years) with obesity who must either be liver transplant candidates or diagnosed with NAFLD, NASH, or chronic liver disease. Studies could consist of inpatients or outpatients, but the trials must report on weight loss. The articles must be written in English, Spanish, French, or Italian. All clinical trials, observational trials, cohort studies, case series, and case reports were included.
The intervention being reviewed was VLCD, which encompassed any type of planned manipulation of dietary intake that induced an energy deficit, given the intake was no greater than 900 kcal (3700 kJ) per day. We increased the caloric cutoff to 900 kcal/day (as opposed to the VLCD definition of 800 kcal/day) to include more studies that were borderline between a VLCD and lowcalorie diet (LCD).
To focus on the research of VLCD in chronic liver disease patients, the following exclusion criteria were agreed upon: studies on pregnant women, subjects <18 years, subjects with acute medical illnesses or terminally ill. Dietary interventions that included energy intake greater than 900 kcal (3700 kJ) per day, studies that did not include weight loss outcomes or liver disease outcomes, and studies in any language other than English, Spanish, French, or Italian were also excluded. Any publications in the form of editorials, letters to the editor, and comments were excluded.

| Search methods
The searches were developed and conducted by a health sciences and Embase were limited to references in English, Italian, French, and Spanish. No date limits were applied to any databases. Database records were de-duplicated in EndNote. 10 The search strategies are available in the appendix.

| Study selection and data management
All abstracts of studies retrieved for selection after de-duplication were split in two and each half reviewed by two reviewers. The reviewers were to independently decide which studies should be included based on the pre-agreed inclusion and exclusion criteria. -511 software (Rayyan®) was used to support the review screening process. The results of the screening process can be found in After thoroughly selecting the studies, data extraction was performed, and the following variables were recorded: author(s), year of publication, research design, sample size, location, and outcomes. The primary outcomes of interest included timing and effect measures (length of time on diet), degree of weight loss, change in liver disease burden and eligibility for liver transplant. The percentages of patients who dropped out of studies and patients experiencing major side effects when starting VLCD were carefully noted. Data were collected on many different subgroups based on their age, race, body mass index (BMI), dietary intervention, and transplant candidate status. Data collection was conducted by one reviewer and verified by a second reviewer.
We organized the included manuscripts by study design and number of participants in each category to give a better idea of the hierarchical relevance and contribution of a particular study in the current aggregate knowledge about this topic.

| Types of studies and participant description
The four databases yielded 2620 records, which after abstract screening left 197 full text studies to review. Of these, 178 were excluded for the following reasons: 63 studies did not have a VLCD (<900 kcal/day), 37 studies did not include participants with chronic liver disease or liver transplant candidates, 34 studies were the incorrect study types (i.e., reviews, commentaries, etc.), 15 studies were poster abstracts without full text, 21 studies were duplicates, 4 studies were incomplete or unpublished clinical trials, and 4 studies were in another language (i.e., not English, Spanish, French, or Italian).
This screening yielded 19 studies that met our inclusion criteria ( Figure 1). These studies included 5 randomized trials, 11 cohort studies, 1 case-control study, and 2 case series. About 17 of the studies were focused on subjects with NAFLD and NASH, while two case reports included patients with end-stage liver disease (ESLD) on F I G U R E 1 Flow diagram of scoping review 512the transplant list or post-transplant. A summary of these studies is presented in Tables 1-3. All five randomized clinical trials included participants with NAFLD. Three of those trials recruited subjects with obesity and NAFLD, and two studies enrolled bariatric surgery candidates ( In the trial by Baldry et al. 14  In the trial by Cunha et al. 7 subjects were recruited with a BMI ≥ 30 kg/m 2 while exclusion criteria were diabetes diagnosis during the study, inability to complete the program, history of alcohol abuse, or contraindications to MRI. Of the 11 cohort studies, 9 were prospective cohorts and 2 were retrospective cohort studies (Tables 2 and 3). The study conducted by Schwenger et al. 15 included subjects who had been confirmed for bariatric surgery and underwent variable periods of weight loss prior to the procedure to improve surgical access. In the study by Hohenester et al. 16 subjects with BMI ≥ 30 kg/m 2 were recruited while active in a lifestyle intervention program. In the study by D'Abbondanza et al., the subjects had a BMI ≥ 40 kg/m 2 or BMI ≥ 35 kg/m 2 with obesity related comorbidities (i.e., metabolic disorders, respiratory disease, cardiovascular disease, and osteoarthritis).
Exclusion criteria were type 1 diabetes, severe chronic kidney disease (estimated glomerular filtration rate <30 ml/min), psychiatric disorders, severe liver failure, severe heart failure, excessive alcohol consumption, and chronic hepatitis. 17 In the study by Watanabe et al., 18 the subjects were required to have BMI ≥ 30 kg/m 2 , stable body weight over 3 months, and a positive screening for fatty liver based on hepatic steatosis index above 36. Exclusion criteria were type 1 diabetes, previous bariatric surgery, or severe cardiac, liver, renal, or hepatic diseases.
In the prospective study by Colles et al., the subjects were recruited if weight was stable over 3 months, with total weight <155 kg, and BMI was ≥40 kg/m 2 for men and ≥50 kg/m 2 for women.
Exclusion criteria included severe hepatic, renal, cardiac diseases, or excessive alcohol intake. 19 In the trial by Scragg 24 included all potential liver donors with hepatic steatosis ≥10% at baseline, who were placed on a VLCD, and had liver biopsies at follow up.
One case-control and two case series studies were included ( Table 3). The case-control study by Ministrini et al. examined subjects with obesity referred to a bariatric surgery with BMI ≥ 35 kg/m 2 and obesity-related comorbidities or BMI ≥ 40 kg/m 2 .
The control group comprised of 20 healthy, normal-weight subjects. Another group of 20 subjects with grade 1 obesity and no related comorbidities were used as a sham control group. These patients were given nutritional and lifestyle advice at the moment of enrollment. 25 In the case series by Bhatti et al. 26 inclusion criteria included a BMI ≥ 30 kg/m 2 , either a liver biopsy indicating hepatosteatosis or biopsy confirmed NAFLD, at least 6 months post-liver transplant and not taking corticosteroids. Temmerman et al. reported two cases of patients with obesity who needed to lose weight to make it to the liver transplant list. One patient was a man with alcohol-related cirrhosis, whereas the second patient was a woman with NASH.
The BMI goal for both patients was <37 kg/m 2 for transplant eligibility. 27

| Interventions
The interventions implemented in the manuscripts were heterogeneous with varying caloric targets and duration of VLCD. In the clinical trial by Lin  or 800 kcal/day for 12 weeks. They also performed ultrasound for NAFLD and assessed a host of measures including waist circumference, hip circumference, body composition with electrical impedance, resting metabolic rate, fasting glucose, and lipid profile at baseline and at week 12. 11 In the trial by Contreras et al., subjects were randomized to 21 days of either 800 kcal/day meal replacements or 1200 kcal/day diets prior to bariatric surgery. They measured body weight change and composition, liver volume, and surgical complications during bariatric surgery. 12 In the trial by Chong et al., participants were allowed 600 kcal/day for 4 weeks and were then randomized into three groups (i.e., metronidazole and inulin, placebo and inulin, and double placebo) to investigate whether metronidazole and/or inulin would further reduce ALT and maintain weight loss after the VLCD. 13 The outcomes of this study included maintenance of weight loss ≥7% at 16 weeks, changes in ALT, elastography, and gut microbiome in response to the dietary and pharmacological interventions. 13 In the trial by Baldry et al., participants consumed an 800 kcal/ day diet for 2 weeks but were randomized to consume these calories as either meal replacements or through natural foods. Weight loss, technical challenges of surgery, and liver biopsies were assessed in this clinical trial. 14 In the trial by Cunha et al., participants were randomized to 2 months of either low carbohydrate (i.e., <50 g/day) 600-800 kcal/ day diet or a diet with a 15% caloric deficit from calculated requirements resulting on a calorie intake of 1400-1800 kcal/day. They measured body weight change, abdominal MRI, and elastography to assess liver stiffness. 7 In the prospective cohort study by Schwenger et al., each participant was given replacement meals as shakes consisting of 900 kcal/day, lasting 1 week for every 100 lbs of body weight. The mean duration of the intervention was of 2.6 weeks. Besides insulin resistance evaluation, liver histology, and metabolic biomarkers including HbA1c, insulin, glucose, liver enzymes, lipid profile, and platelets were measured in this cohort. 15 In the cohort study by Hohenester et al., participants were on an 800 kcal/day diet for 12 weeks followed by a normal diet for a total of 52 weeks. Response to therapy was defined as a 5% weight loss for BMI < 35 kg/m 2 and a 10% weight loss for BMI ≥ 35 kg/m 2 .
Measurements of LFTs and abdominal ultrasound were used to calculate the fatty liver index (FLI). 16 In the study by D'Abbondanza et al., participants were placed on a low carbohydrate diet with 800 kcal/day for 25 days. They measured changes in body weight, body composition, abdominal ultrasound, liver enzymes, hemoglobin A1c, and homeostatic model assessment for insulin resistance (HOMA-IR). 17 In the cohort by Watanabe  steatosis by ultrasound declined from 86.6% to 38.6% of participants.
Eighty one percent of participants exhibited an elevated ALT before the intervention, which declined to 50.5% after VLCD. 16 In the prospective study by D'Abbondanza et al., there was an average weight loss of 13 kg for men and 10 kg for women. Grade 3 steatosis decreased from 58.3% to 18.8% in men and from 41.7% to 18.2% in women. 17 In the cohort study by Watanabe  Altogether, these results confirm VLCD-dependent weight loss in subjects with NAFLD and suggest improvement in liver steatosis.
Body weight losses of 5% or more are common with VLCD lasting at least 2 weeks.

| Safety
Eight of the reviewed studies did not mention or report on any adverse events during VLCD. In the Lin et al. clinical trial, 103 adverse events were reported and 60 of those were considered to be related to the VLCD. However, no serious adverse events were reported. 11 30 Of note, none of these medicines are approved by the FDA for management of NAFLD.
In the absence of effective pharmacological treatments specifically targeting the liver disease, interventions that promote substantial weight loss can be helpful in the management of NAFLD and NASH. Bariatric surgery is the most effective intervention for weight loss and has been associated with improvement of liver steatosis and fibrosis. 31 However, bariatric surgery is not widely available and might be contra-indicated in patients with portal hypertension and advanced liver dysfunction. Furthermore, short-and long-term 520morbidity and mortality in patients with cirrhosis undergoing bariatric surgery seems to be higher as compared with patients without this condition. 32  The pre-operatory VLCD treatment did not significantly reduce perioperative or intraoperative complications and the long-term liver disease prognosis was not reported. 37 Whereas bariatric surgery seems to resolve or improve NAFLD and NASH overtime, 38,39 the impact of pre-operatory VLCD on these outcomes is unknown.
In 13 of the 19 studies of this scoping review reported completion rates that ranged from 72% to 90% of the participants, suggesting good adherence to the intervention among subjects with NAFLD. However, VLCD-based interventions typically last only 3-4 months and sustained weight loss is a concern. In one study HERRINGTON ET AL.
-521 listed in this scoping review, 53% of participants lost more than 10% of their weight after 8-10 weeks of VLCD, whereas only 34% of participants sustained weight loss greater than 10% after 9 months. 8 Nevertheless, it has been shown that complementary interventions such as intermittent meal replacements and antiobesity medicines can improve sustainability of weight loss after dietary interventions with less than 1000 kcal daily. 40 Whether VLCD-dependent weight loss is sustainable in subjects with NAFLD concomitantly treated with anti-obesity medications is a matter of future investigation.
In 12 of the 19 studies, no adverse events were reported, even though it is not clear whether this information was omitted, or subjects did not in fact experience adverse effects. In the largest ran-

| CONCLUSIONS
The findings of this scoping review suggest that VLCD in patients with NAFLD and potentially with ESLD appear to be effective and safe to induce weight loss and short-term reductions in hepatosteatosis. However, the impact of VLCD on liver fibrosis is unknown. Adherence rates in these studies ranged between 69% and 93% and over longer time periods, we would expect adherence to decrease. However, it is expected that combination therapies including intensive lifestyle modifications, anti-obesity pharmacotherapy and VLCD might extend the sustainability of weight loss and reduced hepatosteatosis. Limitations of the scoping review include great heterogeneity between studies including dietary interventions and liver disease outcome measurements. VLCDs seem to improve liver disease markers and may allow selected patients to be removed from transplant list.