-Contributed by Abi Kasberg, PhD
Changes have arrived to the field of hepatic steatosis!
In efforts to destigmatize and enhance the identification of steatotic liver diseases, several worldwide governing bodies (AASLD, EASL, and ALEH) recently came together to form a multi-stage Delphi panel that assessed, edited, and published changes to the standard nomenclature and diagnostic criteria surrounding fatty liver disease. In short, NAFLD became MASLD, NASH became MASH, and a new branch of steatotic liver disease was created, named MetALD. The support for the nomenclature change was largely driven for the following reasons:
- Stigmatizing and negative verbiage: The terms “alcoholic” and “fatty” can be stigmatizing. Global and local cultures frequently associate damaging or shameful stereotypes with these terms, which can leave individuals feeling marginalized or discriminated against. While some patients do not feel stigmatized by the previous nomenclature, efforts were made to close any door open to stigma in favor of clear, affirmative language for accurate names and diagnoses.
- Acknowledgment of the combined impact that metabolic risk factors and alcohol consumption have on the liver: Previous nomenclature and diagnostic criteria fell short of accounting for the contributions of alcohol consumption on a NAFLD or NASH liver. It was common practice in clinical research to exclude patients from NAFLD/NASH clinical trials who consumed alcohol above a designated low threshold. Likewise, metabolic risk factors were not a comorbidity that was well tracked or considered while treating alcohol-associated liver disease.
Tell me more about these new terms…
The updated SLD nomenclature comes with replacement terms for established diseases, such as MASLD for NAFLD and MASH for NASH. Importantly, a brand-new term called MetALD has been created to better capture individuals with both metabolic risk factors and exposure to alcohol (Fig. 1).
Figure 1: Flow of nomenclature stemming from the new umbrella term steatotic liver disease (SLD). Grey dotted line arrows indicate uncertainty regarding how progressive forms of MetALD will be classified.
Steatotic Liver Disease (SLD)
Steatotic liver disease (SLD) replaces fatty liver disease as an overarching term that is characterized by the accumulation of fat in liver cells. SLD encompasses the following liver disease states, MASLD, MASH, MetALD, and other causes of SLD.
Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)
Metabolic dysfunction-associated steatotic liver disease (MASLD) replaces NAFLD while better capturing the metabolic impacts to liver disease. Diagnostic criteria include the presence of hepatic steatosis with the addition of 1 or more cardiometabolic risk factors (Table 1).
Metabolic Dysfunction–associated Steatohepatitis (MASH)
Metabolic dysfunction-associated steatohepatitis (MASH) replaces NASH to characterize a high risk of developing hepatic fibrosis and increased mortality rates.
Metabolic Alcohol-associated Liver Disease (MetALD)
MetALD is a new term to SLD that describes the occurrence of MASLD plus significant alcohol consumption (20-50 g/day for females; 30-60 g/day for males). This new nomenclature is revolutionary in creating a designated space to research and clinically investigate the synergistic impacts of metabolic disorders with alcohol-associated liver disease. MetALD is a continuum where the metabolic-related or alcohol-related contributions to liver steatosis can fluctuate in predominance. It has not yet been clearly defined in the literature what progressive forms of MetALD are classified as; MASH or AH, or perhaps even both.
Alcohol-associated Liver Disease (ALD)
Alcohol-associated liver disease (ALD) is not novel to the new nomenclature, yet it holds an important place within SLDs. Historically, ALD has a similar clinical presentation as NAFLD, yet they are treated differently and have differences in prognoses (Staufer and Stauber 2023). Therefore, it is important to be able to distinguish ALD from metabolic liver disease.
Specific Etiology SLD
Specific etiology SLD encompasses liver steatosis caused by other diseases or injuries. This includes drug-induced liver disease (DILI), Wilson’s disease, and viral hepatitis infections.
Cryptogenic SLD describes hepatic steatosis of unknown causes.
Cardiometabolic Risk Factors*
*Specific values with adjustments for ethnicity, gender, and age can be found at Rinella et al. 2023.
Table 1: List of cardiometabolic risk factors.
Anticipated impacts on research and medicine
The updated SLD nomenclature is nurturing an environment where SLD research, drug development, and treatment options can grow. These benefits will manifest in diverse ways. For one, disease awareness will be enhanced due to the loss of stigma. Individuals may be more willing to pursue a diagnosis and confide with friends and family when the disease name contains affirmative, non-stigmatizing language.
A greater resolution to the specific causes underlying each disease subgroup will lead to improved diagnostic clarity and patient identification. Under the previous nomenclature, patients with NAFLD risk factors were routinely excluded from clinical trials and treatment options if the individual consumed more than a narrow threshold of alcohol (Fig. 2) (Rinella et al. 2023). This has resulted in a considerable patient pool that has been omitted from clinical trials and has been ineligible for the best treatment options.
Figure 2: Comparison of the previously used fatty liver nomenclature against the new SLD nomenclature. (A) The fatty liver nomenclature focused on the impact of hepatic steatosis with underlying metabolic risks, without room for consideration of alcohol consumption. The dotted box represents subject populations who are excluded from participating in NAFLD and NASH clinical trials due to alcohol consumption at quantities greater than the allowable amount (B) The new SLD nomenclature accounts for the contribution of cardiometabolic risk factors in addition to alcohol consumption through the creation of the new term MetALD. MetALD represents a spectrum between metabolic risks and alcohol-induced injury to the liver. Other SLDs include specific etiologies for SLD (DILI, Wilson’s, etc.) and cryptogenic SLD (causes unknown).
With the updated SLD nomenclature comes clearly defined pathways for research projects to travel upon. This will enable research studies to tease apart disease mechanisms underlying each SLD subgroup. Clinical trial subject pools will be more accurately stratified, increasing the number of participants and enhancing the representation of each SLD subgroup within clinical studies. Thus, disease states will be more accurately reflected in the data, which in turn will drive the development of SLD subgroup-specific therapies. For these reasons, the new nomenclature will have a life-changing impact on the treatment opportunities and future health of individuals with SLDs.
Realistically, adoption of the nomenclature will take time and will be a financial hardship for many organizations to update names and materials in order to clearly communicate changes to stakeholders. I am confident it will be worth the effort. If even one life is saved due to reduced stigma or approved treatment, it is a worthwhile pursuit.
The updated SLD nomenclature creates an inclusive framework on which research and development can expand upon. Ultimately, these nomenclature updates will enhance opportunities for growth, and lives will be saved due to the improved ability to identify patients and treat them appropriately.
Rinella, Mary E et al. “A multi-society Delphi consensus statement on new fatty liver disease nomenclature.” Annals of hepatology, 101133. 20 Jun. 2023, doi:10.1016/j.aohep.2023.101133
Staufer, Katharina, and Rudolf E Stauber. “Steatotic Liver Disease: Metabolic Dysfunction, Alcohol, or Both?.” Biomedicines vol. 11,8 2108. 26 Jul. 2023, doi:10.3390/biomedicines11082108