Effect of cofactors on NAFLD/NASH and MAFLD - a paradigm illustrating the pathomechanics of organ dysfunction

Abstract

Primary nonalcoholic fatty liver disease (NAFLD) is bi-directionally associated with the metabolic syndrome and its constitutive features (“factors”: impaired glucose disposal, visceral obesity, arterial hypertension, and dyslipidemia). Secondary NAFLD occurs due to endocrinologic disturbances or other cofactors. This nosography tends to be outdated by the novel definition of metabolic associated fatty liver disease (MAFLD). Irrespective of nomenclature, this condition exhibits a remarkable pathogenic heterogeneity with unpredictable clinical outcomes which are heavily influenced by liver histology changes. Genetics and epigenetics, lifestyle habits [including diet and physical (in)activity] and immunity/infection appear to be major cofactors that modulate NAFLD/MAFLD outcomes, including organ dysfunction owing to liver cirrhosis and hepatocellular carcinoma, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. The identification of cofactors for organ dysfunction that may help understand disease heterogeneity and reliably support inherently personalized medicine approaches is a research priority, thus paving the way for innovative treatment strategies.

Keywords

Alcohol / diet / HBV / HCV / HIV / infection / immunity / MAFLD / NAFLD / NASH / metabolic syndrome / HCC / maternal obesity / microbiota / personalized medicine / physical activity / sex differences

References

[1] Association for the Study of the Liver (EASL)., European Association for the Study of Diabetes (EASD)., European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol2016;64:1388-402

[2] Association for the Study of the Liver (AISF). AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions.Dig Liver Dis2017;49:471-83

[3] Diehl AM,Ishak KG.Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury.Gastroenterology1988;95:1056-62

[4] Lonardo A.Perspectives of nonalcoholic fatty liver disease research: a personal point of view.Explor Med2020;1:85-107

[5] Craciun A,Cortez-Pinto H.Nonalcoholic fatty liver disease versus alcohol-related liver disease: is it really so different?.Curr Pharm Des2020;26:1093-109

[6] Singal AK.Similarities and differences between non-alcoholic fatty liver disease (NAFLD) & alcohol-associated liver disease (ALD).Transl Gastroenterol Hepatol2021;6:1 PMCID:PMC7792989

[7] Younossi ZM,Yu ML.Global NASH CouncilClinical and patient-reported outcomes from patients with nonalcoholic fatty liver disease across the world: data from the global Non-Alcoholic Steatohepatitis (NASH)/ Non-Alcoholic Fatty Liver Disease (NAFLD) registry.Clin Gastroenterol Hepatol2021;S1542-3565(21)01183

[8] Sayiner M,Golabi P,Farhat F.Extrahepatic manifestations and healthcare expenditures of non-alcoholic fatty liver disease in the Medicare population.Hepatol Int2020;14:556-66

[9] Gordon S, Fraysse J, Li S, Ozbay AB, Wong RJ. Disease severity is associated with higher healthcare utilization in nonalcoholic steatohepatitis medicare patients.Am J Gastroenterol2020;115:562-74

[10] Wong RJ,Martinez DJ,Ozbay AB.Real-world comorbidity burden, health care utilization, and costs of nonalcoholic steatohepatitis patients with advanced liver diseases.J Clin Gastroenterol2021;55:891-902 PMCID:PMC8500367

[11] Lonardo A,Alswat KA.History of nonalcoholic fatty liver disease.Int J Mol Sci2020;21:5888 PMCID:PMC7460697

[12] Lonardo A,Marchesini G,Loria P.Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome.Dig Liver Dis2015;47:181-90

[13] Liebe R,Bock HH.Diagnosis and management of secondary causes of steatohepatitis.J Hepatol2021;74:1455-71

[14] Adinolfi LE,Guerrera B.NAFLD and NASH in HCV infection: prevalence and significance in hepatic and extrahepatic manifestations.Int J Mol Sci2016;17:803 PMCID:PMC4926337

[15] Lonardo A,Restivo L.Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen.World J Gastroenterol2014;20:7089-103 PMCID:PMC4064057

[16] Polyzos SA,Tsochatzis EA.Commentary: nonalcoholic or metabolic dysfunction-associated fatty liver disease?.Metabolism2020;113:154413

[17] Guaraldi G,Ballestri S.Human immunodeficiency virus is the major determinant of steatosis and hepatitis C virus of insulin resistance in virus-associated fatty liver disease.Arch Med Res2011;42:690-7

[18] Liu D,Zhang R.Prevalence and risk factors of metabolic associated fatty liver disease among people living with HIV in China.J Gastroenterol Hepatol2021;36:1670-8

[19] Angulo P.Nonalcoholic fatty liver disease.N Engl J Med2002;346:1221-31

[20] Lonardo A,Lugari S.NAFLD in some common endocrine diseases: prevalence, pathophysiology, and principles of diagnosis and management.Int J Mol Sci2019;20:2841 PMCID:PMC6600657

[21] Azzaroli F,Marchesini G,Petroni ML.Fatty liver in pregnancy: a narrative review of two distinct conditions.Expert Rev Gastroenterol Hepatol2020;14:127-35

[22] Reja D,Visaria A,Rustgi V.Blood lead level is associated with advanced liver fibrosis in patients with non-alcoholic fatty liver disease: a nationwide survey (NHANES 2011-2016).Ann Hepatol2020;19:404-10

[23] Heindel JJ,Cave M.Metabolism disrupting chemicals and metabolic disorders.Reprod Toxicol2017;68:3-33 PMCID:PMC5365353

[24] Cano R,Dávila LA.Role of Endocrine-Disrupting chemicals in the pathogenesis of non-alcoholic fatty liver disease: a comprehensive review.Int J Mol Sci2021;22:4807 PMCID:PMC8125512

[25] Lammert C,Teal E.Patients with chronic liver disease suggestive of nonalcoholic fatty liver disease may be at higher risk for drug-induced liver injury.Clin Gastroenterol Hepatol2019;17:2814-5

[26] Tarantino G,Basile V.A prospective study of acute drug-induced liver injury in patients suffering from non-alcoholic fatty liver disease.Hepatol Res2007;37:410-5

[27] Eslam M,George J.International Consensus PanelMAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology2020;158:1999-2014.e1

[28] Eslam M,Sarin SK.A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.J Hepatol2020;73:202-9

[29] Méndez-sánchez N,Gish RG.Global multi-stakeholder endorsement of the MAFLD definition.Lancet Gastroenterol Hepatol2022;7:388-90

[30] Ballestri S,Romagnoli D.The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment.Hepatol Res2016;46:1074-87

[31] Spengler EK.Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.Mayo Clin Proc2015;90:1233-46 PMCID:PMC4567478

[32] Hilzenrat N,Shrier I,Deschênes M.The effect of information level and coping style on pain and anxiety in needle liver biopsy.Can J Gastroenterol2006;20:597-600 PMCID:PMC2659946

[33] Midia M,Shuster A,Muir J.Predictors of bleeding complications following percutaneous image-guided liver biopsy: a scoping review.Diagn Interv Radiol2019;25:71-80 PMCID:PMC6339629

[34] Neuberger J,Caldwell H.Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology.Gut2020;69:1382-403 PMCID:PMC7398479

[35] Ratziu V,Heurtier A.LIDO Study GroupSampling variability of liver biopsy in nonalcoholic fatty liver disease.Gastroenterology2005;128:1898-906

[36] Takahashi Y.Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.World J Gastroenterol2014;20:15539-48 PMCID:PMC4229519

[37] Hagström H,Ekstedt M.Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD.J Hepatol2017;67:1265-73

[38] Harvey BE.NASH: regulatory considerations for clinical drug development and U.S. FDA approval.Acta Pharmacol Sin2022;43:1210-4 PMCID:PMC9061714

[39] Segura-Azuara NLÁ,Trinidad-Calderón PA.MAFLD/NAFLD biopsy-free scoring systems for hepatic steatosis, NASH, and fibrosis diagnosis.Front Med (Lausanne)2021;8:774079 PMCID:PMC8792949

[40] Arnts J,Roozen S.Diagnostic accuracy of biomarkers of alcohol use in patients with liver disease: a systematic review.Alcohol Clin Exp Res2021;45:25-37 PMCID:PMC7898850

[41] Greuter T,Gores GJ.Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis.JCI Insight2017;2:95354 PMCID:PMC5621906

[42] Idalsoaga F,Mousa OY,Arab JP.Non-alcoholic fatty liver disease and alcohol-related liver disease: two intertwined entities.Front Med (Lausanne)2020;7:448 PMCID:PMC7468507

[43] Vanni E,Mezzabotta L.Systemic complications of nonalcoholic fatty liver disease: when the liver is not an innocent bystander.Semin Liver Dis2015;35:236-49

[44] Targher G,Byrne CD.Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach.Lancet Gastroenterol Hepatol2021;6:578-88

[45] Suzuki A.Nonalcoholic steatohepatitis.Annu Rev Med2017;68:85-98

[46] Lonardo A.Sexual dimorphism of NAFLD in adults. Focus on clinical aspects and implications for practice and translational research.J Clin Med2020;9:1278 PMCID:PMC7288212

[47] Balakrishnan M,Dunn-Valadez S.Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: a systematic review and meta-analysis.Clin Gastroenterol Hepatol2021;19:61-71.e15 PMCID:PMC8796200

[48] Ballestri S,Nascimbeni F,Lonardo A.Extra-hepatic manifestations and complications of nonalcoholic fatty liver disease.Future Med Chem2019;11:2171-92

[49] Mantovani A,Beatrice G,Byrne CD.Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals.Gut2021;70:962-9

[50] Mantovani A,Beatrice G.Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.Gut2022;71:156-62

[51] Arrese M,Arab JP.Sarcopenia in the setting of nonalcoholic fatty liver.Metab Target Organ Damage2022;2:2

[52] Mantovani A,Benfari G,Simon TG.Risk of heart failure in patients with nonalcoholic fatty liver disease: JACC review topic of the week.J Am Coll Cardiol2022;79:180-91

[53] Mantovani A,Vinco G.Association between non-alcoholic fatty liver disease and decreased lung function in adults: a systematic review and meta-analysis.Diabetes Metab2019;45:536-44

[54] Lonardo A,Fabbri LM.Chronic obstructive pulmonary disease (COPD) and metabolic fatty liver syndromes: a dangerous but neglected liaison.Metab Target Organ Damage2022;2:6

[55] Mantovani A,Beatrice G.Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.Gut2022;71:778-88

[56] Lonardo F.Metabolism and cancer-select topics.Metab Target Organ Damage2022;2:8

[57] Vilar-Gomez E,Wai-Sun Wong V.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology2018;155:443-457.e17

[58] Selvaraj EA,Jayaswal ANA.LITMUS InvestigatorsDiagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: a systematic review and meta-analysis.J Hepatol2021;75:770-85

[59] Mózes FE,Selvaraj EA.LITMUS InvestigatorsDiagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.Gut2022;71:1006-19

[60] Ratziu V.Why do so many NASH trials fail?.Gastroenterology2020;S0016-5085(20)30680

[61] Lonardo A.Metabolomic signature: one step forward in the process of obtaining NAFLD patients’ metabolic identity card.Am J Clin Nutr2022;115:603-5

[62] Persico M,Costantino A,Almasio PL.The impact of antiviral therapy and the influence of metabolic cofactors on the outcome of chronic HCV infection.Int J Hepatol2011;2011:314301 PMCID:PMC3230116

[63] Long MT,Massaro JM.Parental non-alcoholic fatty liver disease increases risk of non-alcoholic fatty liver disease in offspring.Liver Int2019;39:740-7 PMCID:PMC6758911

[64] Botello-Manilla AE,Uribe M.Genetics and epigenetics purpose in nonalcoholic fatty liver disease.Expert Rev Gastroenterol Hepatol2020;14:733-48

[65] Arrese M,Barrera F,Valenti L.Insights into nonalcoholic fatty-liver disease heterogeneity.Semin Liver Dis2021;41:421-34 PMCID:PMC8492194

[66] Petäjä EM.Definitions of normal liver fat and the association of insulin sensitivity with acquired and genetic NAFLD-A systematic review.Int J Mol Sci2016;17:633 PMCID:PMC4881459

[67] Lonardo A,Targher G.Not all forms of NAFLD were created equal. Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis?.Atherosclerosis2017;257:253-5

[68] Romeo S,Xing C.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet2008;40:1461-5 PMCID:PMC2597056

[69] Yuan L.PNPLA3 and nonalcoholic fatty liver disease: towards personalized medicine for fatty liver.Hepatobiliary Surg Nutr2020;9:353-6 PMCID:PMC7262620

[70] Pirazzi C,Burza MA.Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro.J Hepatol2012;57:1276-82

[71] Kozlitina J,Stender S.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.Nat Genet2014;46:352-6 PMCID:PMC3969786

[72] Luo F,Martin SA.Hepatic TM6SF2 is required for lipidation of VLDL in a Pre-Golgi compartment in mice and rats.Cell Mol Gastroenterol Hepatol2022;13:879-99 PMCID:PMC8804273

[73] Mancina RM,Petta S.The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent.Gastroenterology2016;150:1219-1230.e6 PMCID:PMC4844071

[74] Thangapandi VR,Brosch M.Loss of hepatic Mboat7 leads to liver fibrosis.Gut2021;70:940-50 PMCID:PMC8040158

[75] Helsley RN,Brown AL.Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease.Elife2019;8:e49882 PMCID:PMC6850774

[76] Schaftingen E. A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate.Eur J Biochem1989;179:179-84

[77] Campo JA, Gallego-Durán R, Gallego P, Grande L. Genetic and epigenetic regulation in Nonalcoholic Fatty Liver Disease (NAFLD).Int J Mol Sci2018;19:911 PMCID:PMC5877772

[78] Rodríguez-Sanabria JS,Rosas-Campos R,Sandoval-Rodríguez A.An update in epigenetics in metabolic-associated fatty liver disease.Front Med (Lausanne)2021;8:770504 PMCID:PMC8787199

[79] Thompson MD.Developmental programming of NAFLD by parental obesity.Hepatol Commun2020;4:1392-403 PMCID:PMC7527686

[80] Hagström H,Roelstraete B,Söderling J.Maternal obesity increases the risk and severity of NAFLD in offspring.J Hepatol2021;75:1042-8

[81] Lomas-Soria C,Rodríguez-González GL.Maternal obesity has sex-dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring.J Physiol2018;596:4611-28 PMCID:PMC6166072

[82] Soderborg TK,Mulligan CE.The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD.Nat Commun2018;9:4462 PMCID:PMC6203757

[83] Lonardo A,Arrese M.Perspectives on precision medicine approaches to NAFLD diagnosis and management.Adv Ther2021;38:2130-58 PMCID:PMC8107169

[84] Cespiati A,Tourna A.Genetics and epigenetics in the clinic: precision medicine in the management of fatty liver disease.Curr Pharm Des2020;26:998-1009

[85] Zelber-Sagi S.Dietary treatment for NAFLD: new clinical and epidemiological evidence and updated recommendations.Semin Liver Dis2021;41:248-262

[86] Machado MV.What should we advise MAFLD patients to eat and drink?.Metab Target Organ Damage2021;1:9

[87] Semmler G,Reiberger T.Diet and exercise in NAFLD/NASH: beyond the obvious.Liver Int2021;41:2249-68 PMCID:PMC9292198

[88] Chang Y,Kim Y.Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study.Hepatology2019;69:64-75

[89] Long MT,Hoffmann U,Naimi TS.Alcohol use is associated with hepatic steatosis among persons with presumed nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol2020;18:1831-1841.e5 PMCID:PMC7569606

[90] Åberg F,Salomaa V.Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts.Hepatology2020;71:835-48

[91] Kashiwagi K,Shiba S.Moderate alcohol consumption is not associated with subclinical cardiovascular damage but with hepatic fibrosis in non-alcoholic fatty liver disease.Alcohol2020;89:1-7

[92] Lange NF,Dufour JF.Prevention of NAFLD-associated HCC: role of lifestyle and chemoprevention.J Hepatol2021;75:1217-27

[93] New-Aaron M,Dagur RS,Poluektova LY.Pancreatogenic diabetes: triggering effects of alcohol and HIV.Biology (Basel)2021;10:108 PMCID:PMC7913335

[94] Osna NA,Seth D,Kidambi S.Second hits exacerbate alcohol-related organ damage: an update.Alcohol Alcohol2021;56:8-16 PMCID:PMC7768623

[95] Osna NA,Dagur RS.A review of alcohol-pathogen interactions: new insights into combined disease pathomechanisms.Alcohol Clin Exp Res2022;46:359-70 PMCID:PMC8920772

[96] Youssef NA,Binks M.Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease.Liver Int2013;33:1062-70

[97] Gu Y,Hu Y,Shi J.Association between nonalcoholic fatty liver disease and depression: a systematic review and meta-analysis of observational studies.J Affect Disord2022;301:8-13

[98] Weinstein AA,Kannan S.Interrelationship between physical activity and depression in nonalcoholic fatty liver disease.World J Hepatol2022;14:612-22 PMCID:PMC9055201

[99] Kleef LA, Hofman A, Voortman T, de Knegt RJ. Objectively measured physical activity is inversely associated with nonalcoholic fatty liver disease: the rotterdam study.Am J Gastroenterol2022;117:311-8 PMCID:PMC8812433

[100] Chun HS,Lee HA.Association of physical activity with risk of liver fibrosis, sarcopenia, and cardiovascular disease in nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol2022;S1542-3565(22)00001

[101] Adenote A,Madrid C,Nordstrom CW.NAFLD and infection, a nuanced relationship.Can J Gastroenterol Hepatol2021;2021:5556354 PMCID:PMC8087474

[102] Machado MV,Cortez-Pinto H.Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients.J Gastroenterol Hepatol2011;26:1361-7

[103] Wang CC,Kao JH.Systematic review: chronic viral hepatitis and metabolic derangement.Aliment Pharmacol Ther2020;51:216-30

[104] Guaraldi G,Maia L.Metabolic concerns in aging HIV-infected persons: from serum lipid phenotype to fatty liver.AIDS2017;31 Suppl 2:S147-56

[105] Krahn T,Sapir-Pichhadze R.Nonalcoholic fatty liver disease and the development of metabolic comorbid conditions in patients with human immunodeficiency virus infection.J Infect Dis2020;222:787-97

[106] Targher G,Byrne CD.Risk of severe illness from COVID-19 in patients with metabolic dysfunction-associated fatty liver disease and increased fibrosis scores.Gut2020;69:1545-7

[107] Portincasa P,Smyk W,Di Ciaula A.COVID-19 and non-alcoholic fatty liver disease: two intersecting pandemics.Eur J Clin Invest2020;50:e13338 PMCID:PMC7361203

[108] Milic J,Gozzi L.Metabolic-associated fatty liver disease is highly prevalent in the postacute COVID syndrome.Open Forum Infect Dis2022;9:ofac003 PMCID:PMC8826155

[109] Arrese M,Kalergis AM.Innate immunity and inflammation in NAFLD/NASH.Dig Dis Sci2016;61:1294-303 PMCID:PMC4948286

[110] Parthasarathy G,Malhi H.Pathogenesis of nonalcoholic steatohepatitis: an overview.Hepatol Commun2020;4:478-92 PMCID:PMC7109346

[111] Dalekos GN,Koukoulis GK.Non-alcoholic steatohepatitis or autoimmune hepatitis?.BMJ Case Rep2020;13:e238400

[112] Dalekos GN,Zachou K.NAFLD and autoimmune hepatitis: do not judge a book by its cover.Eur J Intern Med2020;75:1-9

[113] Kim HJ,Park HK,Suh K.Association of thyroid autoimmunity with nonalcoholic fatty liver disease in euthyroid middle-aged subjects: a population-based study.J Gastroenterol Hepatol2022;37:1617-23

[114] Bessone F,Rodil MA,Roma MG.Review article: drug-induced liver injury in the context of nonalcoholic fatty liver disease - a physiopathological and clinical integrated view.Aliment Pharmacol Ther2018;48:892-913

[115] Allard J,Begriche K.Drug-induced liver injury in obesity and nonalcoholic fatty liver disease.Adv Pharmacol2019;85:75-107

[116] Wang R,Li B,Schnabl B.Gut microbiome, liver immunology, and liver diseases.Cell Mol Immunol2021;18:4-17 PMCID:PMC7852541

[117] Duan Y,Lang S.Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.Nature2019;575:505-11 PMCID:PMC6872939

[118] Alferink LJM,Erler NS.Microbiomics, metabolomics, predicted metagenomics, and hepatic steatosis in a population-based study of 1,355 adults.Hepatology2021;73:968-82

[119] Loomba R,Li W.Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease.Cell Metab2017;25:1054-1062.e5 PMCID:PMC5502730

[120] Yamamura S,Kawaguchi T.MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.Liver Int2020;40:3018-30

[121] Liang Y,Liu Y.Association of MAFLD with diabetes, chronic kidney disease, and cardiovascular disease: a 4.6-year cohort study in China.J Clin Endocrinol Metab2022;107:88-97 PMCID:PMC8684479

[122] Tsutsumi T,Kawaguchi T.MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: generalized estimating equation approach.Hepatol Res2021;51:1115-28

[123] Miao L,Guo LS.Metabolic Dysfunction-associated fatty liver disease is associated with greater impairment of lung function than nonalcoholic fatty liver disease.J Clin Transl Hepatol2022;10:230-7 PMCID:PMC9039714

[124] Lee H,Kim SU.Metabolic dysfunction-associated fatty liver disease increases colon cancer risk: a nationwide cohort study.Clin Transl Gastroenterol2022;13:e00435 PMCID:PMC8806363

[125] Liu Z,Shi O.The health impact of MAFLD, a novel disease cluster of NAFLD, is amplified by the integrated effect of fatty liver disease-related genetic variants.Clin Gastroenterol Hepatol2022;20:e855-75

[126] Quek J,Tang ASP.Metabolic associated fatty liver disease increases the risk of systemic complications and mortality. A Meta-Analysis and Systematic Review of 12 620 736 Individuals.Endocr Pract2022;28:667-72

[127] Semmler G,Bachmayer S.Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)-rather a bystander than a driver of mortality.J Clin Endocrinol Metab2021;106:2670-7

[128] Nasr P,Kechagias S.Modifiers of liver-related manifestation in the course of NAFLD.Curr Pharm Des2020;26:1062-78

[129] Lonardo A.Separating the apples from the oranges: from NAFLD heterogeneity to personalized medicine.Explor Med2021;2:435-42

[130] Lonardo A,Targher G.Precision medicine approaches in metabolic disorders and target organ damage: where are we now, and where are we going?.Metab Target Organ Damage2021;1:3