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 dysfunction-associated steatotic liver disease (MASLD), 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 MASLD better serves the field to achieve its 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. 20 % 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 MASLD)
As previously mentioned, the primary case for NAFLD’s name change to MASLD and NASH’s to Metabolic dysfunction-associated steatohepatitis (MASH) 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 Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to 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).
More recent research (Rinella et al, 2023) established that the term “fatty” was also stigmatizing which brought about the more recent call for nomenclature to be changed to MASLD.
The case against a name change (to MASLD)
Though the name change to MASLD 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, MASLD 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 decades (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 MASLD does not address the problem of classifying diseases that fall under the umbrella term of MASLD, 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 Multi-chip Liver plates and disease models. Our expert team are dedicated to keeping our PhysioMimix® in vitro NAFLD/NASH (or should it be MASLD/MASH) 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).
Adopting our models into your workflow
We have developed a unique product called NASH in-a-box, which is tailored for use with our PhysioMimix® OOC range of microphysiological systems. The kit includes all the primary human cells, media and consumables required to recreate our NASH model in your laboratory. Combined with software-guided protocols (which walk you through the experimental process step-by-step), the kit streamlines the entire workflow, enabling rapid adoption. Alternatively, you can access the model through our portfolio of Contract Research Services. More information can be found here.
In December 2023, we were delighted to announce that our PhysioMimix NASH assay was used to provide human-relevant data on compound efficacy to support the initiation of Inipharm’s Phase 1 clinical trial for INI-822. The submission represents the first example of an OOC provider’s data supporting the clinical progression of a drug for NASH and demonstrates the transformative potential of these models to provide human-relevant insights within preclinical programs.
updated 2024
AUTHOR
Gareth Guenigault
Senior Scientist, CN Bio
References
https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567 [Accessed 20th October 2020]
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Younossi, Z. M. et al. (2020) From NAFLD to MAFLD: Implications of a premature change in terminology. Hepatology. DOI: 10.1002/hep.31420