Management of patients with metabolic-associated fatty liver disease: an endocrinologist’s view

• Alexander S. Ametov
• Ksenya A. Amikishieva
• Irina V. Gurieva

Abstract

The metabolic syndrome, emerging as a consequence of the steadily increasing obesity pandemic, resulted in a substantial increase in the prevalence of metabolic-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM). Insulin resistance (IR) is associated with both the pathogenesis of MAFLD and its progression from steatosis to steatohepatitis, cirrhosis and even hepatocellular carcinoma, which is known to be the leading developmental mechanisms of T2DM. In addition, MAFLD exacerbates or induces IR, impairs glycemic control, and increases the risk of the development of the cardiovascular complications. To date, awareness of this antibiosis is often overlooked by both gastroenterologists and endocrinologists. The tactics of management of such patients should be complex and include the principle of interdisciplinary approach. This review discusses the peculiarities of the pathogenesis of MAFLD and T2DM, diagnostic criteria and perspectives of therapy of MAFLD, including the use of ademetionine.

Keywords: metabolic-associated fatty liver disease; insulin resistance; type 2 diabetes mellitus; obesity; hepatoprotectors; ademetionine

References

1. Le M.H., Yeo Y.H., Li X., Li J., Zou B., Wu Y., et al. 2019 Global NAFLD Prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022; 20: 2809–17.e28.

2. Peeters A., Barendregt J., Willekens F., Mackenbach J., Al Mamun A., Bonneux L. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003; 138: 24–32. DOI: https://doi.org/10.7326/0003-4819-138-1-200301070-00008

3. Powell E.E., Wong V.W., Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021; 397: 2212–24. DOI: https://doi.org/10.1016/S 0140-6736(20)32511-3

4. Minhas A.M.K., Jain V., Maqsood M.H., Pandey A., Khan S.S., Fudim M., et al. Non-alcoholic fatty liver disease, heart failure, and long-term mortality: insights from the national health and nutrition examination survey. Curr Probl Cardiol. 2022; 47: 101333.

5. Rojas Y.A.O., Cuellar C.L.V., Barrón K.M.A., Arab J.P., Miranda A.L. Non-alcoholic fatty liver disease prevalence in Latin America: a systematic review and meta-analysis. Ann Hepatol. 2022; 27: 100706.

6. Younossi Z.M., Koenig A.B., Abdelatif D., Fazel Y., Henry L., Wymer M. Global epidemiology of nonalcoholic fatty liver disease – meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64: 73–84.

7. Bril F., Sanyal A., Cusi K. Metabolic syndrome and its association with nonalcoholic steatohepatitis. Clin Liver Dis. 2023; 27 (2): 187–210. DOI: https://doi.org/10.1016/j.cld.2023.01.002

8. Lomonaco R., Godinez Leiva E., Bril F., et al. Advanced liver fibrosis is common in patients with type 2 diabetes followed in the outpatient setting: the need for systematic screening. Diabetes Care. 2021; 44 (2): 399–406. DOI: https://doi.org/10.2337/dc20-1997

9. Younossi Z.M., Golabi P., Paik J.M., Henry A., Van Dongen C., Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023; 77 (4): 1335–47. DOI: https://doi.org/10.1097/HEP.0000000000000004

10. Nogueira J.P., Cusi K. Role of insulin resistance in the development of nonalcoholic fatty liver disease in people with type 2 diabetes: from bench to patient care. Diabetes Spectr. 2024; 37 (1): 20–8. DOI: https://doi.org/10.2337/dsi23-0013

11. Stefan N., Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022; 10 (4): 284–96. DOI: https://doi.org/10.1016/S 2213-8587(22)00003-1

12. Habibullah M., Jemmieh K., Ouda A., Haider M.Z., Malki M.I., Elzouki A.N. Metabolic-associated fatty liver disease: a selective review of pathogenesis, diagnostic approaches, and therapeutic strategies. Front Med (Lausanne). 2024; 11: 1291501. DOI: https://doi.org/10.3389/fmed.2024.1291501 PMID: 38323033; PMCID: PMC 10845138.

13. Barrera F., Uribe J., Olvares N., Huerta P., Cabrera D., Romero-Gómez M. The Janus of a disease: diabetes and metabolic dysfunction-associated fatty liver disease. Ann Hepatol. 2024. Apr 15. 101501. DOI: https://doi.org/10.1016/j.aohep.2024.101501 Epub ahead of print. PMID: 38631419.

14. Polyakova O.A., Kozgunova L.D., Ostroumova O.D. Metabolically associated fatty liver disease: the role of ademetionine. Farmateka [Pharmateca]. 2023; 30 (1–2): 54–62. DOI: https://doi.org/10.18565/pharmateca.2023.1-2.54-62 (in Russian)

15. Ipsen D.H., Lykkesfeldt J., Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci. 2018; 75: 3313–27. DOI: https://doi.org/10.1007/s00018-018-2860-6

16. Newberry E.P., Xie Y., Kennedy S., Han X., Buhman K.K., Luo J., et al. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. J Biol Chem. 2003. 278: 51664–72. DOI: https://doi.org/10.1074/jbc.M309377200

17. Auinger A., Valenti L., Pfeuffer M., Helwig U., Herrmann J., Fracanzani A.L., et al. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm Metab Res. 2010; 42: 854–9. DOI: https://doi.org/10.1055/s-0030-1267186

18. Koonen D.P., Jacobs R.L., Febbraio M., Young M.E., Soltys C.L., Ong H., et al. Increased hepatic CD 36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes. 2007; 56: 2863–71. DOI: https://doi.org/10.2337/db07-0907

19. Moreno-Fernandez M.E., Giles D.A., Stankiewicz T.E., Sheridan R., Karns R., Cappelletti M., et al. Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease. JCI Insight. 2018; 3: 626. DOI: https://doi.org/10.1172/jci.insight.93626

20. Hinds T.D., Hosick P.A., Chen S., Tukey R.H., Hankins M.W., Nestor-Kalinoski A., et al. Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα. Am J Physiol Endocrinol Metab. 2017; 312: E 244–52. DOI: https://doi.org/10.1152/ajpendo.00396.2016

21. Francque S., Verrijken A., Caron S., Prawitt J., Paumelle R., Derudas B., et al. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015; 63: 164–73. DOI: https://doi.org/10.1016/j.jhep.2015.02.019

22. Stec D.E., Gordon D.M., Hipp J.A., Hong S., Mitchell Z.L., Franco N.R., et al. Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity. Am J Phys Regul Integr Comp Phys. 2019; 317: R 733–45. DOI: https://doi.org/10.1152/ajpregu.00153.2019

23. Hong S., Gordon D., Stec D.E., Hinds T.D. Bilirubin: a ligand of the PPARα nuclear receptor. In: M.Z. Badr (ed.). Nuclear Receptors: The Art and Science of Modulator Design and Discovery. Cham: Springer International Publishing, 2021: 463–82.

24. Knebel B., Haas J., Hartwig S., Jacob S., Köllmer C., Nitzgen U., et al. Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS One. 2012; 7: e31812. DOI: https://doi.org/10.1371/journal.pone.0031812

25. Iizuka K., Takao K., Yabe D. ChREBP-mediated regulation of lipid metabolism: involvement of the gut microbiota, liver, and adipose tissue. Front Endocrinol. 2020; 11: 587189. DOI: https://doi.org/10.3389/fendo.2020.587189

26. Dentin R., Benhamed F., Hainault I., Fauveau V., Foufelle F., Dyck J.R., et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in Ob/Ob mice. Diabetes. 2006; 55: 2159–70. DOI: https://doi.org/10.2337/db06-0200

27. Gurung M., Li Z., You H., Rodrigues R., Jump D.B., Morgun A., et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020; 51: 102590. DOI: https://doi.org/10.1016/j.ebiom.2019.11.051

28. Yuan J., Chen C., Cui J., Lu J., Yan C., Wei X., et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 2019; 30 (4): 675–88.e7. DOI: https://doi.org/10.1016/j.cmet.2019.08.018

29. Theofilis P., Vordoni A., Kalaitzidis R.G. Trimethylamine N-oxide levels in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Metabolites. 2022; 12 (12): 1243. DOI: https://doi.org/10.3390/metabo12121243

30. Ponziani F.R., Bhoori S., Castelli C., Putignani L., Rivoltini L., Del Chierico F., et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology. 2019; 69: 107–20. DOI: https://doi.org/10.1002/hep.30036

31. Trebicka J., Macnaughtan J., Schnabl B., Shawcross D.L., Bajaj J.S. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol. 2021; 75: S 67–81. DOI: https://doi.org/10.1016/j.jhep.2020.11.013

32. ElSayed N.A., Aleppo G., Aroda V.R., Bannuru R.R., Brown F.M., Bruemmer D., et al. 4. Comprehensive medical evaluation and assessment of comorbidities: standards of care in diabetes-2023. Diabetes Care. 2023; 46: S 49–67. DOI: https://doi.org/10.2337/dc23-S 004

33. Arrese M., Barrera F., Triantafilo N., Arab J.P. Concurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerations. Expert Rev Gastroenterol Hepatol. 2019; 13: 849–86. DOI: https://doi.org/10.1080/17474124.2019.1649981

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