High-Protein Diet for Improving Alcoholic Fatty Liver Disease

Official title

Efficacy and Safety of a High-Protein Diet Versus a Standard Diet in Patients With Alcoholic Fatty Liver Disease: A Randomized Controlled Trial

Overview

Alcohol-associated liver disease (ALD) is a major cause of mortality from malignant liver diseases, accounting for 47.9% of cirrhosis-related deaths and 30% of liver cancer-related deaths annually. In China, both alcohol consumption and the prevalence of ALD (approximately 5.15%) are on the rise, making ALD an increasingly significant health concern for the population. Alcohol-associated fatty liver disease (AFLD), as the initial and most reversible stage of ALD, is primarily characterized by excessive hepatic lipid deposition, mild liver injury accompanied by mild inflammation. It can progressively develop into alcoholic hepatitis, and in some patients, advance to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Currently, there is a lack of effective clinical treatments for AFLD. Although alcohol abstinence remains the optimal choice for reversing AFLD, it is often difficult for individuals with alcohol dependence to maintain. A high-protein diet generally refers to a dietary pattern where protein accounts for more than 20% of total energy intake. A protein contribution of 30% is a common ratio in research investigating high-protein dietary interventions for metabolic diseases. Population-based intervention studies have demonstrated that a high-protein diet at this ratio significantly reduces hepatic fat content. For instance, a study published in Gastroenterology (2017) reported that a 6-week isocaloric high-protein diet (macronutrient distribution: 30% protein, 40% carbohydrates, 30% fat) significantly improved hepatic lipid deposition in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Research in Diabetologia (2019) showed that a 6-week isocaloric high-protein diet (30% protein, 30% carbohydrates, 40% fat) significantly reduced hepatic fat content in patients with T2DM. Additionally, a study in Liver International (2020) indicated that a 3-week energy-restricted high-protein diet (30% protein, 35%-45% carbohydrates, 25%-30% fat) significantly decreased hepatic fat content in NAFLD patients. Importantly, none of the aforementioned studies reported adverse events associated with the high-protein dietary interventions. Furthermore, a population-based intervention study published in Annals of Internal Medicine revealed that a low-carbohydrate, high-fat diet was more effective than a high-carbohydrate, low-fat diet in reducing hepatic fat content over a 6-month period in patients with NAFLD and T2DM. These findings suggest that increasing the percentage of energy from protein by reducing carbohydrate intake may yield superior improvements. Based on the macronutrient distributions from the referenced population interventions, and considering that a 30% fat energy contribution closely aligns with the typical dietary fat intake of the Chinese AFLD population, we established the macronutrient distribution for the high-protein diet group as 30% protein, 40% carbohydrates, and 30% fat. This study intends to conduct a randomized controlled trial to investigate the effects of increasing the percentage of energy from protein under an isocaloric dietary pattern on liver function, hepatic fat content, and glucose-lipid metabolism in individuals with AFLD. The aim is to elucidate the mechanisms underlying its beneficial effects on AFLD, thereby providing population-based evidence and strategies for health promotion in this patient group.

Interventions

• Dietary supplement high protein diet
  high protein diet
• Dietary supplement control diet
  control diet
• Dietary supplement perilla peptide dietary group
  perilla peptide dietary group

Primary outcome measures

• Magnetic Resonance Imaging proton density fat fraction in hepatic steatosis [Time frame: Baseline, up to 60 days of the study]

Secondary outcome measures (3)

• Liver function [Time frame: Baseline, up to 60 days of the study]
• Glucose metabolism [Time frame: Baseline, up to 60 days of the study]
• Lipid metabolism [Time frame: Baseline, up to 60 days of the study]

Eligibility criteria

Inclusion criteria

• Aged between 30 and 65 years old.
• Able to understand the study and voluntarily sign the informed consent form.
• Meet the clinical diagnostic criteria for alcohol-associated fatty liver disease (AFLD): a history of alcohol consumption for ≥5 years, with an average daily ethanol intake of ≥20 g/d; clinically diagnosed with fatty liver (indicated by abdominal ultrasound or a liver MRI proton density fat fraction \[MRI-PDFF\] ≥5.2%).

Exclusion criteria

• Average daily ethanol intake >80 g/d.
• Presence of other hepatobiliary diseases, such as autoimmune liver disease, viral hepatitis, liver fibrosis, or cirrhosis.
• Presence of severe cardiovascular or cerebrovascular diseases, or renal insufficiency.
• Patients with tumors or other severe systemic diseases.
• Patients with gastrointestinal disorders, or those with known protein allergy or intolerance.
• Long-term use of medications known to cause hepatic steatosis or steatohepatitis (e.g., amiodarone or tamoxifen), nutritional supplements, or probiotics.
• Total daily energy intake (excluding energy from alcohol) <1900 kcal or ≥2900 kcal.
• Participation in another interventional study within the past year, or scheduled to receive non-study treatments during the trial period.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Marin-Alejandre BA, Abete I, Cantero I, Monreal JI, Elorz M, Herrero JI, Benito-Boillos A, Quiroga J, Martinez-Echeverria A, Uriz-Otano JI, Huarte-Muniesa MP, Tur JA, Martinez JA, Zulet MA. The Metabolic and Hepatic Impact of Two Personalized Dietary Strategies in Subjects with Obesity and Nonalcoholic Fatty Liver Disease: The Fatty Liver in Obesity (FLiO) Randomized Controlled Trial. Nutrients. 2 PMID 31652512
• Papakonstantinou E, Triantafillidou D, Panagiotakos DB, Koutsovasilis A, Saliaris M, Manolis A, Melidonis A, Zampelas A. A high-protein low-fat diet is more effective in improving blood pressure and triglycerides in calorie-restricted obese individuals with newly diagnosed type 2 diabetes. Eur J Clin Nutr. 2010 Jun;64(6):595-602. doi: 10.1038/ejcn.2010.29. Epub 2010 Mar 10. PMID 20216558
• Sun P, Huang L, Shuai P, Wan Z, Liu Y, Xue J, Liu Y. Effect of a High Protein, Low Glycemic Index Dietary Intervention on Metabolic Dysfunction-Associated Fatty Liver Disease: A Randomized Controlled Trial. Front Nutr. 2022 Apr 27;9:863834. doi: 10.3389/fnut.2022.863834. eCollection 2022. PMID 35571881
• Xu C, Markova M, Seebeck N, Loft A, Hornemann S, Gantert T, Kabisch S, Herz K, Loske J, Ost M, Coleman V, Klauschen F, Rosenthal A, Lange V, Machann J, Klaus S, Grune T, Herzig S, Pivovarova-Ramich O, Pfeiffer AFH. High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels. Liver Int. 2020 Dec;40(12):2982-2997. doi: 10.1111/liv.14596. Epub PMID 32652799
• Skytte MJ, Samkani A, Petersen AD, Thomsen MN, Astrup A, Chabanova E, Frystyk J, Holst JJ, Thomsen HS, Madsbad S, Larsen TM, Haugaard SB, Krarup T. A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial. Diabetologia. 2019 Nov;62(11):2066-2078. doi: 10.1007/s00125-019-4956-4. Epub 2019 Jul 23. PMID 31338545
• Markova M, Pivovarova O, Hornemann S, Sucher S, Frahnow T, Wegner K, Machann J, Petzke KJ, Hierholzer J, Lichtinghagen R, Herder C, Carstensen-Kirberg M, Roden M, Rudovich N, Klaus S, Thomann R, Schneeweiss R, Rohn S, Pfeiffer AF. Isocaloric Diets High in Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2 Diabetes. Gastroenterology. 2017 Feb;152(3):571-585.e8. doi PMID 27765690
• Mackowiak B, Fu Y, Maccioni L, Gao B. Alcohol-associated liver disease. J Clin Invest. 2024 Feb 1;134(3):e176345. doi: 10.1172/JCI176345. PMID 38299591

Identifiers

NCT: NCT07632222 · HP-AFLD-RCT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗