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Metabolic-Associated Fatty Liver Disease

Metabolic-Associated Fatty Liver Disease (MAFLD) is defined as the presence of hepatic steatosis (detected either histologically or by imaging techniques) in those individuals who have either type 2 diabetes or obesity.

  • NAFLD
  • MAFLD
  • metabolic syndrome

1. Introduction

Steatosis, i.e., the pathological accumulation of intra-hepatic fat content, has been known since 1845 thanks to the work by Addison, who described liver histology changes induced by alcohol [1]. In 1938, Connor pinpointed the potential for fatty liver disease, owing to either alcohol or diabetes, to progress to liver cirrhosis [2] and, in 1964, Dianzani clearly addressed the pathogenesis of steatosis [3]. However, it was not until the 1980s that the terms “nonalcoholic steatohepatitis” (NASH) and “nonalcoholic fatty liver disease” (NAFLD) were coined by Ludwig et al. [4], and Shaffner and Thaler [5], respectively. Following decades of research, we are now fully aware that NAFLD and NASH are pathogenically diverse, are common in the general population on a worldwide basis, exact a heavy toll in terms of medical-related as well as indirect expenditures and remain orphans of an effective and safe drug treatment [6][7][8][9]. Of concern, many NASH trials fail [10], suggesting that we are far from dominating this non-transmissible though epidemic liver disease. Recently, based on previous suggestions reviewed in [11], it has been proposed that NAFLD should be renamed as MAFLD, i.e., metabolic-(associated) fatty liver disease [12][13].

2. The NAFLD-MAFLD Debate

In trying to incorporate those proposals regarding the inaccuracy and possible negative consequences of using the term “NAFLD” that have accumulated over the past twenty years, a panel of experts from as many as 22 countries has recently proposed novel names and definitions for NAFLD in adults—namely, metabolic dysfunction-associated fatty liver disease (MAFLD) [12][13]. This proposal has rapidly gained consensus in Latin America, North Africa and the Middle East [14][15], indicating that the motivations to abandon the old nosography are universally believed to outnumber the reasons for maintaining it.

MAFLD is defined as the presence of hepatic steatosis (detected either histologically or by imaging techniques) in those individuals who have either type 2 diabetes or obesity. Interestingly, the presence of at least two, among the following criteria: abnormal abdominal adiposity (assessed with waist circumference above the sex-specific and ethnicity-specific threshold); arterial hypertension; hypertriglyceridemia; low HDL-cholesterol; pre-diabetes; insulin resistance (HOMA-IR); and subclinical systemic inflammatory state (high-sensitivity C-Reactive Protein), is deemed to be equivalent to either obesity or diabetes. It remains unproven whether NAFLD in the diabetic patient will follow the same course as in the metabolically healthy obese. Similarly, it remains to be seen whether individuals with borderline metabolic derangements will be prone to the same risk of developing those hepatic and extra-hepatic complications that we commonly find in association with overt diabesity. From the histological point of view, NAFLD and NASH were more rigorously defined [16] than MAFLD and defining liver histology remains a milestone in our capacity to predict clinical outcomes of disease [17][18]. However, clinicians and patients will undoubtedly appreciate the possibility of diagnosing MAFLD non-invasively given the many criticisms that can be attributed to liver biopsy [19]. Whether, and to what extent, steatosis/steatohepatitis/fibrosis seen in a dysmetabolic individual is MAFLD rather than “alcoholic-and-nonalcoholic liver disease” remains uncertain [20].

The panel of experts also issued a set of diagnostic criteria to establish the diagnosis of MAFLD- related cirrhosis, so avoiding the use of the term cryptogenic cirrhosis among dysmetabolic individuals [12][13]. Given that fatty changes may disappear over time [21], the panel suggested that patients with established cirrhosis, though in the absence of histological evidence of steatohepatitis, should be considered to have MAFLD-cirrhosis if they meet at least one of the following criteria: past or present evidence of dysmetabolic traits that satisfy the criteria to diagnose MAFLD (as reported above) with at least one of the following criteria in their medical history, namely previous biopsy-proven MAFLD, or previous evidence of hepatic steatosis via imaging techniques [12][13]. In this connection, it is worth remembering the seminal study in 1999 in which Caldwell, based on his personal series of 70 cases, was the first to suggest that “NASH plays an under-recognized role in many patients with cryptogenic cirrhosis, most of whom are older, type 2 diabetic and obese females” [22].

Although probably not the ultimate answer to all unmet clinical needs, the definition of MAFLD goes one step further in the attempt to better define NAFLD patients [20]. Indeed, the name “MAFLD” progresses from a “negative” (nonalcoholic) to a “positive” (metabolic-associated) qualification of fatty liver syndromes. Moreover, it is logical to differentiate NAFLD associated with (i.e., MAFLD) or dissociated from Metabolic Syndrome (i.e., genetic NAFLD), given that either may follow different outcomes, such as extensively discussed below. Moreover, the novel definition of MAFLD utilizes the lessons learnt regarding the ominous interaction of NAFLD with Metabolic Syndrome, an association which worsens liver histology, facilitates fibrosis progression, exposes to the risk of developing HCC and decreases life expectancy of patients with NAFLD [23][24][25][26]. However, the road ahead remains long given that, for example, we still know little, if anything, regarding the impact of other determinants of disease such as sex and gender [27], gut microbiota [28], the role of hyper-ferritinemia [29][30] and of genetic polymorphisms [31].

3. Conclusions

While research on NAFLD continues to be conducted and published, we are witnessing the dawn of a new era. NAFLD, originally based on the exclusion of competing causes of liver disease (i.e., a disease defined by negation) is increasingly recognized as a truly metabolic disease (hence MAFLD, namely a positive diagnosis). This implicitly takes into account the disappearance of Hepatitis C thanks to the Direct Antiviral Agents and, therefore, the globally changing scenario of risk factors for the development of chronic liver disease [32]. However, MAFLD itself retains elements of ambiguity [20] and words of caution against the risks of prematurely abandoning the old NAFLD definition have been given by eminent experts based on uncertainties regarding definition of metabolic health and given our incomplete understanding of the molecular pathogenesis of disease [33].

This suggests that additional studies will have to ascertain whether MAFLD and NAFLD are equivalent, given that preliminary evidence suggests that NAFLD may specifically identify those individuals with more progressive disease [34] and, therefore, could be more equivalent to the notion of NASH rather than to NAFLD. Challenged by the disappointing findings of many NASH trials [10], what we need is a more accurate definition of NAFLD pathobiology in the individual patient. Proposals to better articulate the diagnosis of NAFLD/MAFLD have recently been formulated [35]. The so called LDE system addresses NAFLD features as seen from the Liver (L), the Determinants of Disease (D) and its extra-hepatic manifestations and complications (E). The LDE system is only one example of how we might better describe our patient population and it is assumed that this will help to improve the so far disappointing attempts to cure NASH. However, this prediction cannot be ascertained unless this or similar classification systems are utilized and assessed in the NAFLD/NASH research arena.

This entry is adapted from 10.3390/jcm10030492

References

  1. Addison, T. Observations on fatty degeneration of the liver. Guys Hosp. Rep. 1836, 1, 485.
  2. Connor, C.L. Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism. Am. J. Pathol. 1938, 14, 347–364.
  3. Dianzani, M.U. Sulla patogenesi dell’accumulo del grasso nella steatosi epatica. Rass. Med. Sarda 1964, 66, 67–90.
  4. Ludwig, J.; Viggiano, T.R.; McGill, D.B.; Oh, B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 1980, 55, 434–438.
  5. Schaffner, F.; Thaler, H. Nonalcoholic fatty liver disease. Prog. Liver Dis. 1986, 8, 283–298.
  6. Suzuki, A.; Diehl, A.M. Nonalcoholic steatohepatitis. Annu. Rev. Med. 2017, 68, 85–98.
  7. 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.
  8. Allen, A.M.; Van Houten, H.K.; Sangaralingham, L.R.; Talwalkar, J.A.; McCoy, R.G. Healthcare cost and utilization in nonalcoholic fatty liver disease: Real-World data from a large, U.S. claims database. Hepatology 2018, 68, 2230–2238.
  9. Rinella, M.E.; Sanyal, A.J. Management of NAFLD: A stage-based approach. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 196–205.
  10. Ratziu, V.; Friedman, S.L. Why do so many NASH trials fail? Gastroenterology 2020, 18, S0016-5085(20)30680-6.
  11. Fouad, Y.; Waked, I.; Bollipo, S.; Gomaa, A.; Ajlouni, Y.; Attia, D. What’s in a name? Renaming ‘NAFLD’ to ‘MAFLD’. Liver Int. 2020, 40, 1254–1261.
  12. Eslam, M.; Sanyal, A.J.; George, J. International consensus panel. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020, 158, 1999–2014.e1.
  13. Eslam, M.; Newsome, P.N.; Sarin, S.K.; Anstee, Q.M.; Targher, G.; Romero-Gomez, M.; Zelber-Sagi, S.; Wong, V.W.-S.; Dufour, J.F.; Schattenberg, J.M.; et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol. 2020, 73, 202–209.
  14. Mendez-Sanchez, N.; Arrese, M.; Gadano, A.; Oliveira, C.P.; Fassio, E.; Arab, J.P.; Chávez-Tapia, N.C.; Dirchwolf, M.; Torre, A.; Ridruejo, E.; et al. The Latin American association for the study of the liver (ALEH) position statement on the redefinition of fatty liver disease. Lancet Gastroenterol. Hepatol. 2021, 6, 65–72.
  15. Shiha, G.; Alswat, K.; Al Khatry, M.; Sharara, A.I.; Örmeci, N.; Waked, I.; Benazzouz, M.; Al-Ali, F.; Hamed, A.E.; Hamoudi, W.; et al. Nomenclature and definition of metabolic-associated fatty liver disease: A consensus from the Middle East and north Africa. Lancet Gastroenterol. Hepatol. 2021, 6, 57–64.
  16. Nascimbeni, F.; Ballestri, S.; Machado, M.V.; Mantovani, A.; Cortez-Pinto, H.; Targher, G.; Lonardo, A. Clinical relevance of liver histopathology and different histological classifications of NASH in adults. Expert Rev. Gastroenterol. Hepatol. 2018, 12, 351–367.
  17. Vilar-Gomez, E.; Calzadilla-Bertot, L.; Wai-Sun Wong, V.; Castellanos, M.; Aller-de la Fuente, R.; Metwally, M.; Eslam, M.; Gonzalez-Fabian, L.; Alvarez-Quiñones Sanz, M.; Conde-Martin, A.F.; et al. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients with Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology 2018, 155, 443–457.
  18. Lonardo, A.; Nascimbeni, F.; Maurantonio, M.; Marrazzo, A.; Rinaldi, L.; Adinolfi, L.E. Nonalcoholic fatty liver disease: Evolving paradigms. World J. Gastroenterol. 2017, 23, 6571–6592.
  19. Lonardo, A.; Ballestri, S. Perspectives of nonalcoholic fatty liver disease research: A personal point of view. Explor. Med. 2020, 1.
  20. Polyzos, S.A.; Kang, E.S.; Tsochatzis, E.A.; Kechagias, S.; Ekstedt, M.; Xanthakos, S.; Lonardo, A.; Mantovani, A.; Tilg, H.; Côté, I.; et al. Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name. Metabolism 2020, 113, 154413.
  21. van der Poorten, D.; Samer, C.F.; Ramezani-Moghadam, M.; Coulter, S.; Kacevska, M.; Schrijnders, D.; Wu, L.E.; McLeod, D.; Bugianesi, E.; Komuta, M.; et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: Are alterations in serum adiponectin the cause? Hepatology 2013, 57, 2180–2188.
  22. Caldwell, S.H.; Oelsner, D.H.; Iezzoni, J.C.; Hespenheide, E.E.; Battle, E.H.; Driscoll, C.J. Cryptogenic cirrhosis: Clinical characterization and risk factors for underlying disease. Hepatology 1999, 29, 664–669.
  23. Kang, H.; Greenson, J.K.; Omo, J.T.; Chao, C.; Peterman, D.; Anderson, L.; Foess-Wood, L.; Sherbondy, M.A.; Conjeevaram, H.S. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am. J. Gastroenterol. 2006, 101, 2247–2253.
  24. Francque, S.; De Maeght, S.; Adler, M.; Deltenre, P.; de Galocsy, C.; Orlent, H.; Van Steenbergen, W.; Bastens, B.; Wain, E.; Langlet, P.; et al. High prevalence of advanced fibrosis in association with the metabolic syndrome in a Belgian prospective cohort of NAFLD patients with elevated ALT. Results of the Belgian NAFLD registry. Acta Gastroenterol. Belg. 2011, 74, 9–16.
  25. Negro, F. Natural history of NASH and HCC. Liver Int. 2020, 40 (Suppl. 1), 72–76.
  26. Golabi, P.; Otgonsuren, M.; de Avila, L.; Sayiner, M.; Rafiq, N.; Younossi, Z.M. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine (Baltimore) 2018, 97, e0214.
  27. Lonardo, A.; Suzuki, A. Sexual dimorphism of NAFLD in adults. focus on clinical aspects and implications for practice and translational research. J. Clin. Med. 2020, 9, 1278.
  28. Aron-Wisnewsky, J.; Vigliotti, C.; Witjes, J.; Le, P.; Holleboom, A.G.; Verheij, J.; Nieuwdorp, M.; Clément, K. Gut microbiota and human NAFLD: Disentangling microbial signatures from metabolic disorders. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 279–297.
  29. Zelber-Sagi, S.; Nitzan-Kaluski, D.; Halpern, Z.; Oren, R. NAFLD and hyperinsulinemia are major determinants of serum ferritin levels. J. Hepatol. 2007, 46, 700–707.
  30. Trombini, P.; Piperno, A. Ferritin, metabolic syndrome and NAFLD: Elective attractions and dangerous liaisons. J. Hepatol. 2007, 46, 549–552.
  31. Eslam, M.; George, J. Genetic contributions to NAFLD: Leveraging shared genetics to uncover systems biology. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 40–52.
  32. Terrault, N.A.; Pageaux, G.P. A changing landscape of liver transplantation: King HCV is dethroned, ALD and NAFLD take over! J. Hepatol. 2018, 69, 767–768.
  33. Younossi, Z.M.; Rinella, M.E.; Sanyal, A.; Harrison, S.A.; Brunt, E.; Goodman, Z.; Cohen, D.E.; Loomba, R. From NAFLD to MAFLD: Implications of a premature change in terminology. Hepatology 2020.
  34. Lin, S.; Huang, J.; Wang, M.; Kumar, R.; Liu, Y.; Liu, S.; Wu, Y.; Wang, X.; Zhu, Y. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver Int. 2020, 40, 2082–2089.
  35. Soto-Angona, O.; Anmella, G.; Valdés-Florido, M.J.; De Uribe-Viloria, N.; Carvalho, A.F.; Penninx, J.H.; Berk, M. Non-Alcoholic fatty liver disease (NAFLD) as a neglected metabolic companion of psychiatric disorders: Common pathways and future approaches. BMC Med. 2020, 18, 261.
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    Lonardo, A. Metabolic-Associated Fatty Liver Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/7437 (accessed on 27 May 2022).
    Lonardo A. Metabolic-Associated Fatty Liver Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/7437. Accessed May 27, 2022.
    Lonardo, Amedeo. "Metabolic-Associated Fatty Liver Disease," Encyclopedia, https://encyclopedia.pub/entry/7437 (accessed May 27, 2022).
    Lonardo, A. (2021, February 22). Metabolic-Associated Fatty Liver Disease. In Encyclopedia. https://encyclopedia.pub/entry/7437
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