Liver disease is a serious worldwide problem linked to approximately two million deaths per year and in many cases is entirely preventable (Sumeet et al, 2019). One of the most common causes of chronic liver disease is non-alcoholic fatty liver disease (NAFLD), which affects one billion people and is a major cause of liver-related morbidity and mortality (Younossi, 2020).

NAFLD was termed in the early 1980’s for a group of patients that showed characteristics of alcoholic fatty liver disease but denied excessive alcohol consumption (Fouad et al, 2020). Since then, an improved understanding of the disease has encouraged calls to change the nomenclature to “metabolic associated fatty liver disease” (MAFLD), in an attempt to better reflect its underlying pathology. However, this proposed change has been met with some hesitation. This area of scientific discussion is particularly of interest to innovators in liver research whose goal is to improve the lives of millions of liver patients across the world. Ultimately, the question is, what’s in the name? Is it important and if so, which name, NAFLD or MAFLD better serves the field to achieve their goals?


 

What is NAFLD?

The main defining factor of NAFLD is fat accumulation in the liver (steatosis) and this is the major risk factor for disease progression. NAFLD is also influenced by other risk factors including: obesity, age above 50 years old, high cholesterol, type 2 diabetes, high blood pressure and smoking (Rowell & Anstee, 2015). However, the contribution of each risk to the overall disease is less well understood, with NAFLD diagnosed in patients without any of the above risk factors, including children, highlighting the complexity of the disease.

Figure adapted from (Tilg and Effenberger, 2020). Original available here:

Symptoms are not usually present in early cases of NAFLD but with more advanced stages, patients can experience weakness, extreme tiredness, or unexplained weight loss1. Twenty percent of patients diagnosed with NAFLD develop non-alcoholic steatohepatitis (NASH), the severest form of the disease spectrum, which can progress to cirrhosis and liver cancer (Sass et al, 2005).

There are, at present, no approved therapies for the treatment of NAFLD and management of the disease begins with changes to lifestyle including alcohol avoidance, weight loss and changes to the diet. Said lifestyle changes are put forward to improve cardiovascular risk, steatosis and inflammation (Rowell & Anstee, 2015).

The case for a name change (to MAFLD)

As previously mentioned, the primary case for NAFLD’s name change to MAFLD is to reflect the extensive and continued research in the field, and therefore better conceptualize the disease for improved patient care. Since its original naming, scientists have a better understanding of its heterogeneity; caused by metabolic dysfunction and numerous genetic factors, which all need to be considered to develop effective treatment. It has been observed that this “one size fits all” approach has hindered the development of NAFLD therapy, and the appreciation of heterogeneity allows for a more targeted approach. Therefore, the term MAFLD could better represent the multiple sub-phenotypes and emphasize their metabolic backgrounds.

In the current nomenclature, research has shown stigmatization and misunderstanding associated with “non-alcoholic”, through its affiliation with alcohol consumption (Younossi, 2020). Not only does this terminology group together a wide variety of fatty liver diseases, but the stigma has shown to result in negative patient behaviours such as being less likely to seek medical attention and less consideration in health policy (Eslam et al, 2020; Fouad et al, 2020). In addition, the current guidance for diagnosis requires exclusion of significant daily intake of alcohol, however what is decided as ‘significant’ remains debated and defining this value with some patient populations can be irrelevant, for example with children, or for religious and social reasons (Fouad et al, 2020).

The case against a name change (to MAFLD)

Though the name change to MAFLD may advance the identification of new therapeutic targets and potentially improve patient behaviours, the name change could confuse awareness of the disease, and potentially disrupt several drugs in late phase development ahead of regulatory approval decisions. The general discussions on the definition of “metabolic health” have observed that adding “metabolic” does not necessarily help to identify the aetiology of the spectrum of diseases. Furthermore, MAFLD will still be used as an umbrella term, so as Dr Younossi (2020) suggests, researchers will likely never be fully accurate in assigning a single name to a disease as heterogenous as NAFLD (Younossi, 2020).

There is a strong argument that rather than focusing on nomenclature of the disease, the priority should be on both better defining the sub categories of NAFLD and developing better biomarkers to identify NAFLD severity and sub-types. Due to the heterogeneity observed in clinical practice, the non-invasive NAFLD fibrosis scores currently used for diagnosis are considered inaccurate in most cases. The scores have shown to vary with age – in younger adults a lower accuracy was seen compared to a lower specificity in older adults (McPherson et al, 2017). Other factors affecting the accuracy of the fibrosis score include ethnicity, diabetes and obesity (De Silva et al, 2018).

Considering these discussions have been ongoing for the past 18 years (Fouad et al, 2020), it is clear a better understanding of NAFLD is required. It is our belief that the focus should primarily be on improving the pre-clinical in vivo and in vitro NAFLD models, to better reflect the disease sub-types and improve understanding of their pathophysiology and management, before changing the name.

Liver-on-a-Chip and disease models for liver research

Whilst the change in terminology from NAFLD to MAFLD does not address the problem of classifying diseases that fall under the umbrella term of MAFLD, the name change may present an opportunity to catalyse future research and identify sub-categories of the disease. Ultimately, for a disease where there is currently no approved therapy and only management strategies including lifestyle changes such as weight loss, there is a need to focus efforts on developing a greater understanding of the disease, to advance successful drug discovery in the area and better support patients.

As an Organ-on-a-Chip company, we specialize in single and multi-organ microphysiological systems to enhance the development of tomorrow’s medicines, this includes our comprehensive Liver-on-a-Chip plate (Liver-MPS (LC12)) and disease models. Our expert team are dedicated to keeping our in vitro NAFLD/NASH assays at the forefront of liver research; incorporating ground-breaking research to most accurately represent disease pathology through which the mechanisms of disease onset, and progression can be explored (read a case study here). Additionally, through our NASH Fee-for-Services approach, we continue to provide the scientific community access to advanced 3D in vitro models for NAFLD, or should it be MAFLD, and a whole host of other liver applications, including for drug-induced liver toxicities, to help improve the accuracy, efficiency and translatability of novel therapeutic development.

AUTHOR

Gareth Guenigault

Senior Scientist, CN Bio

References

  1. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567  [Accessed 20th October 2020]

De Silva S, Li WH, Kemos P, et al. (2018) Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of South Asian descent. Frontline Gastroenterol; 9:115–121

Eslam, M., Sanyal, A. J., George, J. (on behalf of International Consensus Panel) (2001) MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 158 (7)

Fouad, Y. Waked, I., Bollipo, S., Gomaa, A., Ajlouni, Y., Attia, D. (2020) What’s in a name? Renaming ‘NAFLD’ to ‘MAFLD’. Liver International. 40, pp. 1254-1261

McPherson S, Hardy T, Dufour JF, et al. (2017) Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol; 112:740–751.

Rachel J Rowell, Quentin M Anstee Clinical Medicine (2015) An overview of the genetics, mechanisms and management of NAFLD and ALD, Clinical Medicine, 15 (Suppl 6) s77-s82; DOI: 10.7861/clinmedicine.15-6-s77

Stickel F, Hampe J.(2012) Genetic determinants of alcoholic liver disease. Gut; 61:150–9

Sumeet K. Asrani, Harshad Devarbhavi, John Eaton, Patrick S. Kamath (2019) Burden of liver diseases in the world, Journal of Hepatology, Volume 70, Issue 1, 2019, Pages 151-171

Tilg, H., Effenberger, M. (2020) From NAFLD to MAFLD: when pathophysiology succeeds. Nature Reviews: Gastroenterology and Hepatology. 17, July 2020, pp. 387-88

Younossi, Z. M. et al. (2020) From NAFLD to MAFLD: Implications of a premature change in terminology. Hepatology. DOI: 10.1002/hep.31420

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