Prevention and control of risk factors in metabolic and alcohol-associated steatotic liver disease

Abstract

Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), is the primary cause of illness and mortality. In particular, MASLD affects more than 30% of the global population, while ALD accounts for 5.1% of all diseases and injuries worldwide. The SLD spectrum includes a variety of clinical conditions, from mild fatty liver and inflammation to different stages of liver fibrosis. Additionally, both conditions (MASLD and ALD) can be complicated by hepatocellular carcinoma (HCC), while around one-third of ALD patients can also develop at least one alcohol‐associated hepatitis (AH) episode. Both of these diseases are also associated with multiple extrahepatic complications, such as cardiovascular disease, chronic kidney disease, and malignancies. In MASLD, the rapid rise in global obesity and type 2 diabetes mellitus (T2DM) prevalence due to Westernized lifestyles has led to an increase in the prevalence of MASLD. Thus, the prevention and control of cardiometabolic risk factors (CMRFs) are the cornerstone of its treatment. Hypertension and atherogenic dyslipidemia are also important CMRFs associated with MASLD. Susceptible individuals with MASLD are adversely affected by even a small amount of alcohol consumption (though there is no agreed definition of a small amount), increasing the risk of severe outcomes and a faster progression of liver disease. This review explores factors that play a role in the development of SLD, especially focusing on the management of CMRFs and levels of alcohol use to prevent liver disease progression.

Keywords

Alcohol / alcohol use disorder / metabolic dysfunction-associated steatotic liver disease / alcohol-associated liver disease (ALD)

References

[1] Devarbhavi H,Arab JP,Pose E.Global burden of liver disease: 2023 update.J Hepatol2023;79:516-37

[2] Díaz LA,Louvet A,Arrese M.The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease.Nat Rev Gastroenterol Hepatol2023;20:764-83

[3] Rinella ME, Lazarus JV, Ratziu V, et al; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature.Ann Hepatol2024;29:101133

[4] Zhang YN,Hamilton G.Liver fat imaging-a clinical overview of ultrasound, CT, and MR imaging.Br J Radiol2018;91:20170959 PMCID:PMC6223150

[5] Nassir F,Hammoud GM.Pathogenesis and prevention of hepatic steatosis.Gastroenterol Hepatol2015;11:167-75 PMCID:PMC4836586

[6] Younossi ZM,Paik JM,Van Dongen C.The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.Hepatology2023;77:1335-47 PMCID:PMC10026948

[7] Ng CH,Chew NWS.Hypertension is prevalent in non-alcoholic fatty liver disease and increases all-cause and cardiovascular mortality.Front Cardiovasc Med2022;9:942753 PMCID:PMC9393330

[8] World Health Organization. Global status report on alcohol and health 2018. Available from: https://play.google.com/store/books/details?id=qnOyDwAAQBAJ. [Last accessed on 23 Jul 2024]

[9] Roberts A,Mason R.Alcohol and other substance use during the COVID-19 pandemic: a systematic review.Drug Alcohol Depend2021;229:109150 PMCID:PMC8559994

[10] Crabb DW,Szabo G,Lucey MR.Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the study of liver diseases.Hepatology2020;71:306-33

[11] Åberg F,Pirola CJ,Sookoian S.Alcohol consumption and metabolic syndrome: clinical and epidemiological impact on liver disease.J Hepatol2023;78:191-206

[12] Kalligeros M,Vassilopoulos S,Mylonakis E.Prevalence of steatotic liver disease (MASLD, MetALD, and ALD) in the United States: NHANES 2017-2020.Clin Gastroenterol Hepatol2024;22:1330-2.e4

[13] Riazi K,Charette JH.The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol2022;7:851-61

[14] Makri E,Polyzos SA.Epidemiology, pathogenesis, diagnosis and emerging treatment of nonalcoholic fatty liver disease.Arch Med Res2021;52:25-37

[15] Younossi ZM,de Avila L.The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis.J Hepatol2019;71:793-801

[16] Mitra S,Chowdhury A.Epidemiology of non-alcoholic and alcoholic fatty liver diseases.Transl Gastroenterol Hepatol2020;5:16 PMCID:PMC7063528

[17] Huang DQ,Cortez-Pinto H.Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors.Nat Rev Gastroenterol Hepatol2023;20:37-49 PMCID:PMC9579565

[18] Prata JC,Lopes I,Rocha-Santos T.Environmental exposure to microplastics: an overview on possible human health effects.Sci Total Environ2020;702:134455

[19] Blaser MJ.Antibiotic use and its consequences for the normal microbiome.Science2016;352:544-5 PMCID:PMC4939477

[20] Gabbia D.Targeting the adipose tissue-liver-gut microbiota crosstalk to cure MASLD.Biology2023;12:1471 PMCID:PMC10741127

[21] Lavrado NC,Cardoso CRL.Impact of PNPLA3 and TM6SF2 polymorphisms on the prognosis of patients with MASLD and type 2 diabetes mellitus.Liver Int2024;44:1042-50

[22] Risch N.The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches.Cancer Epidemiol Biomarkers Prev2001;10:733-41

[23] Roerecke M,Hasan OSM.Alcohol consumption and risk of liver cirrhosis: a systematic review and meta-analysis.Am J Gastroenterol2019;114:1574-86 PMCID:PMC6776700

[24] Bertha M,Mellinger J.Diagnosis and treatment of alcohol-associated liver disease: a patient-friendly summary of the 2019 AASLD guidelines.Clin Liver Dis2021;17:418-23 PMCID:PMC8340354

[25] Birková A,Čižmárová B.Current view on the mechanisms of alcohol-mediated toxicity.Int J Mol Sci2021;22:9686 PMCID:PMC8472195

[26] Meroni M,Rametta R.Genetic and epigenetic modifiers of alcoholic liver disease.Int J Mol Sci2018;19:3857 PMCID:PMC6320903

[27] Akhavan Rezayat A,Ghasemi Nour M.Association between smoking and non-alcoholic fatty liver disease: a systematic review and meta-analysis.SAGE Open Med2018;6:2050312117745223 PMCID:PMC5788091

[28] Azzalini L,Ramalho LN.Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats.Hepatology2010;51:1567-76

[29] Fouda S,Pappachan JM.Pregnancy and metabolic-associated fatty liver disease: a clinical update.J Clin Transl Hepatol2022;10:947-54 PMCID:PMC9547252

[30] Kwon I,Moon JH.Effects of moderate alcohol drinking in patients with nonalcoholic fatty liver disease.Gut Liver2019;13:308-14 PMCID:PMC6529167

[31] Blomdahl J,Ekstedt M.Moderate alcohol consumption is associated with significant fibrosis progression in NAFLD.Hepatol Commun2023;7:e0003 PMCID:PMC9833449

[32] Tokushige K,Ono M.Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020.J Gastroenterol2021;56:951-63 PMCID:PMC8531062

[33] Mbaye B,Borentain P.Increased fecal ethanol and enriched ethanol-producing gut bacteria Limosilactobacillus fermentum, Enterocloster bolteae, Mediterraneibacter gnavus and Streptococcus mutans in nonalcoholic steatohepatitis.Front Cell Infect Microbiol2023;13:1279354 PMCID:PMC10687429

[34] Cusi K,Barb D.American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the study of liver diseases (AASLD).Endocr Pract2022;28:528-62

[35] Hrncir T,Kverka M.Gut microbiota and NAFLD: pathogenetic mechanisms, microbiota signatures, and therapeutic interventions.Microorganisms2021;9:957 PMCID:PMC8146698

[36] Aderinto N,Kokori E,Isarinade T.Recent advances in bariatric surgery: a narrative review of weight loss procedures.Ann Med Surg2023;85:6091-104 PMCID:PMC10718334

[37] Lee Y,Yu J.Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis.Clin Gastroenterol Hepatol2019;17:1040-60.e11

[38] Franklin BA,Pandey A,Toth PP.Physical activity, cardiorespiratory fitness, and cardiovascular health: a clinical practice statement of the American Society for Preventive Cardiology Part II: physical activity, cardiorespiratory fitness, minimum and goal intensities for exercise training, prescriptive methods, and special patient populations.Am J Prev Cardiol2022;12:100425 PMCID:PMC9586849

[39] Armandi A.Dietary and pharmacological treatment in patients with metabolic-dysfunction associated steatotic liver disease.Eur J Intern Med2024;122:20-7

[40] Zhang ZJ,Shi R,Jiang Q.Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis.J Clin Endocrinol Metab2012;97:2347-53

[41] Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet2015;385:956-65 PMCID:PMC4447192

[42] Vell MS,Krishnan A.Association of statin use with risk of liver disease, hepatocellular carcinoma, and liver-related mortality.JAMA Netw Open2023;6:e2320222 PMCID:PMC10293910

[43] Bril F,Kalavalapalli S.Role of vitamin e for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.Diabetes Care2019;42:1481-8

[44] Cusi K.Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions.Diabetologia2016;59:1112-20 PMCID:PMC4861748

[45] Raj H,Palui R.SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: a systematic review.World J Diabetes2019;10:114-32 PMCID:PMC6379733

[46] Shibuya T,Kawai M.Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study.Diabetes Obes Metab2018;20:438-42

[47] Newsome PN, Buchholtz K, Cusi K, et al; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.N Engl J Med2021;384:1113-24

[48] Petit JM,Loffroy R.Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the Lira-NAFLD study.J Clin Endocrinol Metab2017;102:407-15

[49] Napoli R,Formoso G.Beneficial effects of glucagon-like peptide 1 receptor agonists on glucose control, cardiovascular risk profile, and non-alcoholic fatty liver disease. An expert opinion of the Italian diabetes society.Nutr Metab Cardiovasc Dis2021;31:3257-70

[50] Enomoto M,Nishimura N.Rifaximin and lubiprostone mitigate liver fibrosis development by repairing gut barrier function in diet-induced rat steatohepatitis.Dig Liver Dis2022;54:1392-402

[51] Simon TG,Stoyanova S.Aspirin for metabolic dysfunction-associated steatotic liver disease without cirrhosis: a randomized clinical trial.JAMA2024;331:920-9 PMCID:PMC10951738

[52] Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med2015;373:2117-28

[53] Sinha B,Ghosal S.Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes.JGH Open2021;5:219-27 PMCID:PMC7857274

[54] Wettstein G,Poekes L.The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis.Hepatol Commun2017;1:524-37 PMCID:PMC5678909

[55] Lange NF,Caussy C.PPAR-targeted therapies in the treatment of non-alcoholic fatty liver disease in diabetic patients.Int J Mol Sci2022;23:4305 PMCID:PMC9028563

[56] Kokkorakis M,Hill MA.Resmetirom, the first approved drug for the management of metabolic dysfunction-associated steatohepatitis: trials, opportunities, and challenges.Metabolism2024;154:155835

[57] Petta S,Romeo S.The first MASH drug therapy on the horizon: Current perspectives of resmetirom.Liver Int2024;44:1526-36

[58] World Health Organization. Food-based dietary guidelines in the WHO European Region. 2003. Available from: https://iris.who.int/handle/10665/107490. [Last accessed on 23 Jul 2024]

[59] Moon JH,Jang H,Kim W.Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: a nationwide cohort study.EClinicalMedicine2023;65:102292 PMCID:PMC10632413

[60] Stahre M,Kanny D,Zhang X.Contribution of excessive alcohol consumption to deaths and years of potential life lost in the United States.Prev Chronic Dis2014;11:E109 PMCID:PMC4075492

[61] Hofer BS,Hartl L.Alcohol abstinence improves prognosis across all stages of portal hypertension in alcohol-related cirrhosis.Clin Gastroenterol Hepatol2023;21:2308-17.e7

[62] Mason BJ.Alcohol use disorder: the role of medication in recovery.Alcohol Res2021;41:07 PMCID:PMC8184096

[63] Glaser G. The irrationality of alcoholics anonymous. 2015. Available from: http://soberlawnews.com/wp-content/uploads/2015/03/The-Irrationality-of-Alcoholics-Anonymous-The-Atlantic.pdf. [Last accessed on 23 Jul 2024]

[64] Avery J.Naltrexone and alcohol use.Am J Psychiatry2022;179:886-7

[65] Skinner MD,Pham H.Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis.PLoS One2014;9:e87366 PMCID:PMC3919718

[66] Marroni CA,Fernandes SA.Liver transplantation and alcoholic liver disease: History, controversies, and considerations.World J Gastroenterol2018;24:2785-805 PMCID:PMC6048431

[67] Cuadrado A,Casafont F.Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease.Liver Transpl2005;11:420-6

[68] Marroni CA.Management of alcohol recurrence before and after liver transplantation.Clin Res Hepatol Gastroenterol2015;39:S109-14

[69] Arab JP,Altamirano J.Alcohol-related liver disease: clinical practice guidelines by the Latin American Association for the study of the liver (ALEH).Ann Hepatol2019;18:518-35

[70] Lazarus JV,Allen AM.on behalf of the Healthy LiversHealthy Lives CollaboratorsA global action agenda for turning the tide on fatty liver disease.Hepatology2024;79:502-23 PMCID:PMC10789386

[71] Addolorato G,Ferrulli A.Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.Lancet2007;370:1915-22

[72] Jophlin LL,Bataller R.ACG Clinical guideline: alcohol-associated liver disease.Am J Gastroenterol2024;119:30-54 PMCID:PMC11040545

[73] Louvet A,Kim DJ.Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo - a meta-analysis of individual data from controlled trials.Gastroenterology2018;155:458-68.e8

[74] Marot A,Moreno C.Granulocyte colony-stimulating factor for alcoholic hepatitis: a systematic review and meta-analysis of randomised controlled trials.JHEP Rep2020;2:100139 PMCID:PMC7396826

[75] Arab JP,Simonetto DA.An open-label, dose-escalation study to assess the safety and efficacy of IL-22 agonist F-652 in patients with alcohol-associated hepatitis.Hepatology2020;72:441-53 PMCID:PMC7250715

[76] Hassanein ,Flamm SL. Safety and efficacy of DUR-928: a potential new therapy for acute alcoholic hepatitis. Available from: https://durect.com/wp-content/uploads/2022/06/AASLD2019_DUR-928_For_Alcoholic_Hepatitis_PPT-1.pdf. [Last accessed on 23 Jul 2024]

[77] Fukuda T,Fukaishi T.Extent to which weight loss contributes to improving metabolic dysfunction-associated and metabolic and alcohol related/associated steatotic liver disease: a study on Japanese participants undergoing health checkups.Front Endocrinol2024;15:1392280 PMCID:PMC11109399