From Nonalcoholic Fatty Liver to Metabolic – dysfunction associated Fatty Liver Disease (MAFLD)

22 Jun 2020

In 1836 the term fatty liver was described for the first time by Thomas Addison (England)1. In subsequent years other authors hypothesized a causative correlation between hepatic fat accumulation and cirrhosis (1884 and 1885) and other researchers observed the progression from fatty liver to cirrhosis in diabetic patients (1938)2. The term Non Alcoholic Fatty Liver Disease (NAFLD) was coined for the first time in 1980 by Ludwig, who described 20 patients who denied misuse of alcohol but had chronic liver disease with histological characteristics of alcoholic fatty liver disease2.
In the following 40 years researchers firstly identified the role of oxidative stress as the driver of liver inflammation (the “two hits” theory) 3, then Marchesini et al., discovered the association between insulin resistance and NAFLD4, and the possible role of fatty liver as the hepatic manifestation of the metabolic syndrome5. In the same time, in clinical practice NAFLD has grown to become one of the leading cause of liver disease and liver transplantation2, as well as being responsible of cardiovascular and oncological sequalae, affecting nearly one billion people globally, with increasing prevalence mostly in children and adolescents6 . Until now the exclusion of other chronic liver diseases, including “excess” alcohol intake, was necessary for the diagnosis of NAFLD, but the growing body of evidence that linked NAFLD to a condition of metabolic disfunction raised the urgent need to renew the term of the disease introducing positive criteria.
In 2020 a consensus of global representative experts applied a carefully designed Delphi method and recommended to use a new practical definition as “metabolic associated fatty liver disease” (MAFLD), instead of NAFLD 6,7.
MAFLD is present if hepatic steatosis is accompanied by either:

1. Obesity or overweight (BMI >25 kg/m2 in white and >23 kg/m2 in Asian individuals),

2. Type 2 diabetes mellitus or

3. Evidence of metabolic dysregulation.

At least two metabolic risk factors should be present for definition of metabolic dysregulation: waist circumference ≥102/88 cm in white men and women or ≥90/80 cm in Asian men and women; prediabetes; inflammation with elevated high-sensitive serum C-reactive protein level; elevated blood pressure or specific drug treatment; decreased HDL-cholesterol levels; increased plasma triglycerides levels; and homeostasis model assessment (HOMA)-insulin resistance score ≥2.56,7.
Among the main novelties of this new definitions we mention:

1. The exclusion of other significant alcohol intake or other chronic liver disease is not perquisite for the diagnosis of MAFLD anymore.

2. The proposal to forsake the dichotomous classification (steatosis vs steatohepatitis), as the disease process in MAFLD is best described by the grade of activity and the stage of fibrosis.

3. The inclusion of high-sensitive C-reactive protein levels as one of the metabolic risk factors, as it is well established that this biomarker is relevant in metabolic disorders.

A recent study retrospectively evaluated the characteristics of patients with MAFLD and NAFLD using data from the third National Health and Nutrition Examination Surveys of the United States8. MAFLD patients were significantly older, had higher BMI level, higher proportions of metabolic comorbidities (diabetes, hypertension), and higher HOMA-IR, lipid and liver enzymes. There were more cases with advance fibrosis in MAFLD patients with alcohol consumption8.
One concern about this new definition of MAFLD is that it may hide the relevant role of alcohol consumption as mechanism of chronic liver disease, thus reducing in some patients the relevance of alcohol as major trigger of liver disease. Further research is warranted for the clinical validation of these new criteria in prospective studies, confirming their utility in routine clinical practice and for the clinical trial recruitment.


  1. Addison T. Observations on fatty degeneration of the liver. Guys Hosp Rep. 1836;1(476):485.
  2. 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
  3. Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).
  4. Marchesini, G. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 107, 450–455 (1999).
  5. Marchesini, G. et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50, 1844–1850 (2001).
  6. Eslam M, Arun J Sanyal, Jacob George, International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020 May;158(7):1999-2014.e1.
  7. Eslam M, et al. A New Definition for Metabolic Dysfunction-Associated Fatty Liver Disease: An International Expert Consensus Statement. J Hepatol. 2020 Apr 8;S0168-8278(20)30201-4. Online ahead of print.
  8. Su Lin et al. Comparison of MAFLD and NAFLD Diagnostic Criteria in Real World. Liver Int. 2020 Jun 1. doi: 10.1111/liv.14548. Online ahead of print.