Effect of 12-week intermittent calorie restriction compared to standard of care in patients with nonalcoholic fatty liver disease: a randomized controlled trial

(2023) 24:490 Lee et al. Trials https://doi.org/10.1186/s13063-023-07444-4 Trials Open Access STUDY PROTOCOL Effect of 12‑week intermittent calorie restriction compared to standard of care in patients with nonalcoholic fatty liver disease: a randomized controlled trial Han Ah Lee1 , Hyeyoung Moon2, Yuri Kim2, Hye Ah Lee3 and Hwi Young Kim1*    Abstract Background Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD can result in various complications. Owing to the lack of effective pharmacological therapies, lifestyle modifications are the cornerstone treatment for NAFLD. However, there has been no recommendation for a specific dietary therapy. Because no significant effects have been observed in previous studies. Intermittent calorie restriction (ICR) consists of alternating phases of extreme energy restriction and regular energy intake. Recent studies have demonstrated a significantly higher reduction in liver fat content in the ICR group than in the standard of care (SOC) or continuous calorie restriction groups in patients with NAFLD. However, critical weaknesses limit the broader application of ICR in clinical practice; those are a lack of appropriate assessment tools, different cutoffs of body mass index (BMI) used to define obesity, and different food portions. Thus, we report a protocol for a prospective, randomized controlled trial. The trial will evaluate the effect of 12-week ICR on improving liver fat content in NAFLD patients (Nonalcoholic Fatty Liver Disease-Intermittent Calorie Restriction [FLICR]). Methods We will include adult (19–75 years) NAFLD patients. NAFLD will be diagnosed by histologic assessment or magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 8%. A total of 72 patients will be classified according to BMI (obese group: BMI ≥ 25 kg/m2 [n = 36] and non-obese group: BMI < 25 kg/m2 [n = 36]). Participants will be followed up for 24 weeks. Participants will be randomly assigned to one of the two groups: the SOC or ICR group. The primary objective will be the change in liver fat content measured using MRI-PDFF from baseline to 12 weeks. Discussion This FLICR study may provide clinical evidence on ICR in the treatment of NAFLD in both obese and nonobese patients. The use of ICR in patients with NAFLD will improve the clinical outcomes of patients facing a shortage of effective medical therapy. Trial registration This trial was registered at the United States National Library of Medicine (NLM) at the National Institutes of Health. ClinicalTrials.gov NCT05309642. Registered on April 4, 2022. Keywords Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Intermittent calorie restriction, Steatosis, Fibrosis, MRI-proton density fat fraction, Elastography, Weight reduction, Dietary therapy *Correspondence: Hwi Young Kim Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lee et al. Trials (2023) 24:490 Introduction Background and rationale Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, affecting approximately 25% of the world’s population [1]. In Korea, the prevalence of NAFLD has been reported from 20 to 30% [2]. The broad spectrum of NAFLD encompasses simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis in 15–20% of affected patients, as well as the development of hepatocellular carcinoma (HCC) and death [3, 4]. NAFLD is an independent risk factor for the development of various extrahepatic diseases, including cardiovascular disease (CVD) and malignant tumors [2]. Therefore, proper and active management is required to reduce intrahepatic inflammation and fibrosis and to treat comorbid metabolic diseases in patients with NAFLD. However, because effective pharmacological therapies for NAFLD have not yet been approved, non-pharmacologic therapies including weight reduction through dietary control and exercise are the cornerstone treatment for both obese and non-obese NAFLD patients, based on the results of previous studies [5–7]. Although recent studies have evaluated the association between specific nutrients or dietary habits including low carbohydrate/high-fat diet or intermittent fasting and the development or progression of NAFLD, these studies have been conducted on only a small number of patients, and few have shown significant improvement in hepatic inflammation or fibrosis [8–12]. Intermittent calorie restriction (ICR), comprising phases of extreme energy restriction and regular energy intake, is a novel dietary approach for NAFLD treatment [13]. Significantly higher reductions in liver steatosis with ICR than with the standard of care (SOC) or continuous calorie restriction (CCR) have been reported in NAFLD patients [14– 17]. Although promising findings have been reported in previous studies of 6–12 weeks of dietary intervention, the lack of appropriate assessment tools, different cutoffs of body mass index (BMI) used to define obesity, and different food portions between studies are the major limitations [14–17]. Objectives Therefore, we hypothesized that ICR would be effective in reducing liver fat content measured using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) compared to SOC in patients with NAFLD. Finally, we developed a prospective, randomized controlled trial (RCT) to evaluate the effect of 12-week ICR on improving liver fat content in NAFLD, stratifying patients into obese and non-obese groups. Page 2 of 8 Trial design The Nonalcoholic Fatty Liver Disease-Intermittent Calorie Restriction trial was designed as a prospective, two-arm, open-label RCT to investigate the efficacy of 12-week ICR in reducing liver fat content in NAFLD patients. Methods: participants, interventions, and outcomes Study setting The study will recruit 72 patients who (...truncated)