Fatty Liver Disease – A Multifaceted Disease With More Than One Name?

Jörn M. Schattenberg; Christian Labenz


Liver International. 2020;40(12):2937-2938. 

Fatty liver disease is increasingly prevalent and constitutes a well-established morbidity and mortality risk. While abusive alcohol consumption has long been recognized as the major cause of hepatic steatosis, the notion that fatty liver and steatohepatitis arise in the absence of abusive drinking or even complete abstinence has been emerging in the 80th of the last century.[1] The term nonalcoholic fatty liver disease (NAFLD) was subsequently used to characterize patients on 'clinical grounds' in the absence of a detailed knowledge of the underlying pathophysiology. Moving forward the definition for NAFLD was developed in a consensus process and subgroups with distinct clinical outcome were defined.[2] These definitions were subsequently refined and adapted by regulators to guide the development of diagnostics and therapeutics.[3,4] While the term NAFLD – defining a disease spectrum in the absence of a difficult to assess detail of the medical history – is far from perfect, its value comes from the broad agreement among stakeholders and the increasing recognition outside of hepatology. As for non-A, non-B hepatitis – subsequently named hepatitis C – it is important to define a name in order to be recognized and studied as a clinical entity – even if imperfect – to develop the field.

Considering the inaccuracy and difficulties linked to the term NAFLD, an important academic discussion focusing at a more precise terminology for NAFLD has been re-initiated recently and is support by us.[5] The term metabolic-dysfunction associated fatty liver disease (MAFLD) was brought forward by Asian and European investigators to more accurately capture the underlying risk factors and dampen the importance of the exclusionary definition that involves the amounts of alcohol consumed. The term MAFLD combines several important risk factors with a basic diagnostic approach using ultrasound to define patients and thus widens the spectrum considerably (Figure 1). Through MAFLD the well-recognized aspect of the co-existence with other liver disease or additive injury form socially accepted, non-abusive alcohol consumption is highlighted. In a recent analysis from Japan using MAFLD, mild alcohol consumption was associated with more significant fibrosis stages in MAFLD when compared to the NAFLD definition. This is achieved by excluding patients without metabolic comorbidities.[6]

Figure 1.

(A) Terminologies of fatty liver disease requiring the presence of metabolic risk factors, and allowing more hepatic comorbidities as seen in MAFLD vs NAFLD fall short to define more specific disease sub-types (B) which could be of pathophysiological importance and underlie disease progression

The most important shortcoming of the MAFLD definition – which is likewise true for NAFLD – is the lack of understanding the relevant pathophysiological drivers beyond the presence of metabolic risk factors. At the current stage of knowledge with rapidly expanding insight including the validation of non-invasive tests in large clinical study consortia[7] this is one argument why a change in the nomenclature is premature. We believe that smaller subgroups beyond simple dichotomous classification looking at steatohepatitis vs non-steatohepatitis will guide clinical decision making in the future and importantly it will be backed by emerging non-invasive diagnostics. A more granular view on subcategories of NASH (Figure 1B) will be helpful to guide preventive and therapeutic measures. These subgroups could be defined according to the speed of progression in disease stage (eg rapid vs normal progessor's), the underlying activity (eg highly inflammatory vs stable disease) or the underlying pathophysiology (eg hepatic hypothyroidism-associated NASH vs hepatic eu-thyroid NASH). Thus, it is our believe that at this time, the focus should be on the identification or relevant (and smaller) subgroups that do reach clinical endpoints. In the end an umbrella term like MAFLD is useful – but it will need refinement based on ongoing discovery science and the change in disease-defining terminology is not ready to happen today.