Non Alcoholic Fatty Liver Disease; Disease Burden, Management, and Future Perspectives

Peter Jerome Ishmael Villete Paulino *

Department of Biological Sciences, Vanguard University, Costa Mesa, California, US State.

Kimberly Morton Cuthrell

Saint James School of Medicine, Illinois, United States of America.

Nikolaos Tzenios

Public Health and Medical Research, Charisma University, Grace Bay, Turks and Caicos Islands, UK.

*Author to whom correspondence should be addressed.


Abstract

Non-alcoholic fatty liver disease (NAFLD) is a significant and pertinent human ailment linked to a modified way of life, characterized by a fast increasing occurrence and prevalence in the majority of countries worldwide. Non-alcoholic fatty liver disease (NAFLD) can lead to significant health problems at various stages of chronic liver disease, including cirrhosis and related consequences such as hepatocellular carcinoma (HCC) and decompensation (such as bleeding from esophageal varices, accumulation of fluid in the abdomen, and impaired brain function due to liver dysfunction). In addition to hepatic problems, non-alcoholic fatty liver disease (NAFLD) patients frequently experience the metabolic syndrome, type 2 diabetes (T2D), and cardiovascular disease (CVD). While the current  comprehension of the fundamental pathways in relation to NAFLD is growing, the precise pathophysiological impact of NAFLD on T2D and CVD remains incompletely known. One of the main theories suggests that a sub-clinical pro-inflammatory milieu is caused by lipotoxicity, insulin resistance (IR), and the intestinal microbiota. The primary foundation of the treatment involves lifestyle adjustment, which encompasses weight reduction, nutritional intervention, and consistent physical activity. While achieving this aim may be challenging for numerous patients, it is advisable for treating physicians to recommend and provide support for it. A variety of therapy choices, ranging from non-invasive management and medical intervention to surgical techniques (such as bariatric surgery), have been created with different results, particularly for the non-invasive treatment methods. The range of innovative therapeutic techniques is extensive, with several intriguing candidates. Collectively, NAFLD represents a significant healthcare concern that is projected to escalate in the future. Consequently, it is imperative for physicians from many disciplines to enhance their understanding of this condition to effectively address it with their patients.

Keywords: Non alcoholic, liver dysfunction, fatty liver disease, lipotoxicity, disease burden


How to Cite

Paulino, Peter Jerome Ishmael Villete, Kimberly Morton Cuthrell, and Nikolaos Tzenios. 2024. “Non Alcoholic Fatty Liver Disease; Disease Burden, Management, and Future Perspectives”. International Research Journal of Gastroenterology and Hepatology 7 (1):1-13. https://journalirjgh.com/index.php/IRJGH/article/view/92.


References

Abu-Shanab A, E. Quigley, the role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7.

Ahmed A, Wong RJ, Harrison SA, Nonalcoholic fatty liver disease review: Diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol. 2015;13.

Ajmera V, Belt P. Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis. Clin Gastroenterol Hepatol. 2018;16.

Batool S et al. Hepatocellular carcinoma in non-alcoholic fatty liver disease: Emerging burden. International Journal of Oncology. 2022;6:93-104.

Angula P, Hui JM, Marchesini G. The nafld fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45.

Angulo P. Obesity and nonalcoholic fatty liver disease. Nutr Rev. 2007;65.

Barsh G, Farooqi I, Rahilly SO. Genetics of body-weight regulation. Nature. 2000;404.

Bjelakovic G, Nikolova D, Gluud L. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis. JAMA. 2007;297.

Chalasani N, Younossi Z, Lavine JE. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the american association for the study of liver diseases. Hepatology. 2018;67.

Gawrieh S, Chalasani N. Emerging treatments for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin Liver Dis. 2018;22.

Kim D, Touros A, Kim WR. Nonalcoholic fatty liver disease and metabolic syndrome. Clin Liver Dis. 2018;22.

Tsochatzis EA. natural history of NAFLD: Knowns and unknowns. Nature Reviews Gastroenterology & Hepatology. 2022;19(3):151-152.

Loomba R, Lawitz E, Mantry PS. The ask1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology. 2018;67.

Alalwani J et al. The impact of health status, diet and lifestyle on non-alcoholic fatty liver disease: Narrative review. Clinical Obesity. 2022;12(4):e12525.

Marengo A, Jouness R, Bugianesi E. Progression and natural history of nonalcoholic fatty liver disease in adults. Clin Liver Dis. 2016;20.

Neuschwander-Tetri BA, Loomba R, AJ Sanyal, Farsenoid X. Nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (flint): A multicentre, randomised, placebo-controlled trial. Lancet. 2015;385.

Rich NE, Oji S, Mufti AR. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the united states: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2017;16.

Younossi ZM. et al. Clinical and economic burden of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin Liver Dis. 2018;22.

Mantovani A, Petracca G, Csermely A, Beatrice G, Bonapace S, Rossi A et al. Non-alcoholic fatty liver disease and risk of new-onset heart failure: An updated meta-analysis of about 11 million individuals. Gut; 2022.

Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569–582.

Climent M, Viggiani G, Chen YW, Coulis G, Castaldi A. microrna and ros crosstalk in cardiac and pulmonary diseases. Int J Mol Sci. 2020; 21.

Zhao Y, Wang Z. impact of trimethylamine n-oxide (TMAO) metaorganismal pathway on cardiovascular disease. J Lab Precis Med. 2020;5.

Roderburg C, Kostev K, Mertens A, Luedde T, Loosen SH. Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of extrahepatic cancer; 2022.

Adams LA et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66.

Afolabi PR et al. The characterisation of hepatic mitochondrial function in patients with non-alcoholic fatty liver disease (NAFLD) using the (13)c-ketoisocaproate breath test. J Breath Res. 2018;12.

Anstee QM et al. Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2018;15.

Aung LHH et al. Therapeutic potential and recent advances on targeting mitochondrial dynamics in cardiac hypertrophy: A concise review. Mol Ther Nucleic Acids. 2021;25.

Borges-Canha M et al. Association between nonalcoholic fatty liver disease and cardiac function and structure-a meta-analysis. Endocrine 2019;66.

Brown E et al. SGLT2 Inhibitors and glp-1 receptor agonists: Established and emerging indications. Lancet. 2021; 398.

Byrne CD, Targher G. Non-alcoholic fatty liver disease-related risk of cardiovascular disease and other cardiac complications. Diabetes Obes Metab. 2022;24.

Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) Metabolism. 2016;65(8):1038-1048.

Carlsson B et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51.

Chiu LS et al. The association of non-alcoholic fatty liver disease and cardiac structure and function-framingham heart study. Liver Int. 2020;40.

Dulai PS et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017;65.

Dunn MA et al. Hepatic steatosis in diabetic patients does not predict adverse liver-related or cardiovascular outcomes. Liver Int. 2013;33.

Eslam M et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73.

Estes C et al. Modeling NAFLD disease burden in china, france, germany, italy, japan, spain, united kingdom, and united states for the period. J Hepatol. 2018;69:2016–2030.

Houghton D et al. The degree of hepatic steatosis associates with impaired cardiac and autonomic function. J Hepatol. 2019;70.

Huber Y et al. Health-related quality of life in nonalcoholic fatty liver disease associates with hepatic inflammation. Clin Gastroenterol Hepatol. 2019;17.

Jacob JS, Ahmed A,. Cholankeril G. The impact of alteration in gut microbiome in the pathogenesis of nonalcoholic fatty liver disease. Curr Opin Infect Dis. 2021;34.

Jennison E, Byrne CD.The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2021;27.

Labenz C et al. Impact of non-alcoholic fatty liver disease on metabolic comorbidities in type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2022;130.

Lan Y et al. Outcomes of subjects who are lean, overweight or obese with nonalcoholic fatty liver disease: A cohort study in china. Hepatol Commun. 2022;6.

Li W et al. Association between non-alcoholic fatty liver disease and risk of incident heart failure: A meta-analysis of observational studies. Ther Adv Chronic Dis.2022;13.

Loosen SH et al. Heart failure and depression: A comparative analysis with different types of cancer. Eur J Prev Cardiol. 2022;29.

Mantovani A et al. Risk of heart failure in patients with nonalcoholic fatty liver disease: JACC review topic of the week. J Am Coll Cardiol. 2022;79.

Mantovani A, Byrne CD, Targher G. Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: A systematic review. Lancet Gastroenterol Hepatol. 2022;7.

Mantovani A et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: An updated systematic review and meta- analysis. Lancet Gastroenterol Hepatol. 2021;6.

Mohamed-Ali V et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82.

Moschen AR et al. Anti-inflammatory effects of excessive weight loss: Potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut. 2010;59.

Patel VB et al. Role of the ace2/angiotensin axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118:1–7

Rathmann W et al. Basic characteristics and representativeness of the german disease analyzer database. Int J Clin Pharmacol Ther. 2018;56.

Roderburg C et al. Heart failure is associated with an increased incidence of cancer diagnoses. ESC Heart Fail. 2021;8.

Romeo S et al. Genetic variation in pnpla3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40.

Romero-Gómez M, Zelber-Sagi S, Trenell M. treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67.

Schiattarella GG et al. Gut microbe-generated metabolite trimethylamine-n-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J. 2017;38.

Simon TG et al. Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: Results from a nationwide histology cohort. Gut. 2022;71.

Sookoian S et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology. 2015;61.

Stahl EP et al. Nonalcoholic fatty liver disease and the heart: Jacc state-of-the-art review. J Am Coll Cardiol. 2019;73.

Targher G et al. association between non-alcoholic fatty liver disease and impaired cardiac sympathetic/parasympathetic balance in subjects with and without type 2 diabetes-the cooperative health research in south tyrol (CHRIS)-NAFLD sub-study. Nutr Metab Cardiovasc Dis. 2021;31.

Targher G, Tilg H, Byrne CD. Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol. 2021;6.

VanWagner LB et al. longitudinal association of non-alcoholic fatty liver disease with changes in myocardial structure and function: The CARDIA study. J Am Heart Assoc. 2020;9.

Zou B et al. Fatty liver index and development of cardiovascular disease: findings from the uk biobank. Dig Dis Sci. 2021;66.

Anstee QM, Day CP. the genetics of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10.

Younossi Z et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019;69.

Zhou J et al. Nonalcoholic fatty liver disease and cardiac remodeling risk: Pathophysiological mechanisms and clinical implications. Hepatology. 2021;74.

Araki O et al. Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms. Mol Endocrinol. 2009;23.

Armstrong MJ et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (lean): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387.

Artwohl M et al. Different mechanisms of saturated versus polyunsaturated ffa-induced apoptosis in human endothelial cells. J Lipid Res. 2008;49.

Ashraf NU, Sheikh TA. Endoplasmic reticulum stress and oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Free Radic Res. 2015;49.

Asrih M, Jornayvaz FR. Diets and nonalcoholic fatty liver disease: The good and the bad. Clin Nutr. 2014;33.

Baar MJB et al. SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care. 2018;41.

Balboa E et al. Mln64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content. Redox Biol. 2017;12.

Barber MC, Price NT, Travers MT. Structure and regulation of acetyl-coa carboxylase genes of metazoa. Biochim Biophys Acta. 2005;1733.

Barbero-Camps E et al. Endoplasmic reticulum stress mediates amyloid beta neurotoxicity via mitochondrial cholesterol trafficking. Am J Pathol. 2014;184.

Basaranoglu M, Basaranoglu G, Bugianesi E. Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction. Hepatobiliary Surg Nutr. 2015;4.

BasuRay S et al. the PNPLA3 variant associated with fatty liver disease (I148m) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017;66.

BasuRay S et al. Accumulation of pnpla3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci U S A. 2019;116.

Baumeister SE et al. Impact of fatty liver disease on health care utilization and costs in a general population: A 5-year observation. Gastroenterology. 2008; 134.

Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: Epidemiology, pathophysiology, and management. JAMA. 2002;287.

Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol. 2009;8.

Bellentani S et al. Prevalence of and risk factors for hepatic steatosis in northern italy. Ann Intern Med. 2000;132.

Bieghs V et al. Nash and atherosclerosis are two aspects of a shared disease: Central role for macrophages. atherosclerosis. 2012;220.

Bieghs V et al. trapping of oxidized LDL in lysosomes of kupffer cells is a trigger for hepatic inflammation. Liver Int. 2013;33.

Bijnen M et al. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Gut. 2018;67.

Bittencourt MS, Cerci RJ. Statin effects on atherosclerotic plaques: Regression or healing? BMC Med. 2015;13.

Adams LA et al. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: A community-based cohort study. Am J Gastroenterol. 2010;105.

Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013;10.

Wong RJ et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015; 148.