Pre-MASLD: Should it be defined separately?

Hang-Kai Huang,You-Ming Li,Cheng-Fu Xu

Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases,yet it has not received sufficient attention [1].Over the past two decades,the overall global prevalence of NAFLD has risen from 25% to 37% [2].The disease burden of NAFLD is fueled by the epidemic of obesity and diabetes [3].It is estimated that more than half of patients with diabetes have NAFLD,and nearly one-third have nonalcoholic steatohepatitis,a progressive stage of the disease [4].NAFLD is a major risk factor for end-stage liver disease,including liver cirrhosis and hepatocellular carcinoma [5].In recent years,the etiology of hepatocellular carcinoma has shown a shift from viral to nonviral factors,especially NAFLD.The prevalence of NAFLD-related hepatocellular carcinoma has tripled in the last decade in Asia [6].NAFLD is not a condition with effects limited to the liver but rather a multisystem disease [7].NAFLD is a driver of kidney disease,with a hazard ratio of 1.41 for incident chronic kidney disease [8].The risk of cardiovascular disease is 1.64 times higher in patients with NAFLD and 2.58 times higher in those with severe NAFLD [9].Patients with NAFLD are also at higher risk of all-cause mortality,cardiovascular mortality,and liver-related mortality,which are increased with the histological progression of NAFLD [10].

NAFLD has been defined for decades [11].In 1980,Ludwig et al.[12]first proposed the term “nonalcoholic steatohepatitis” to depict the histology of excess liver fat deposition without heavy drinking.This term was derived from similar pathological findings of alcoholic liver disease,with scarce understanding of its underlying pathophysiology for the time.With the development of science and technology,the pathogenesis of NAFLD is gradually clear,especially for its close link with systemic metabolic dysfunction [13].The term of NAFLD seems not suitable for these patients.

Metabolic dysfunction-associated fatty liver disease (MAFLD)was proposed by a panel of international experts to replace NAFLD in 2020 [14].The definition of MAFLD is liver fat accumulation in the presence of at least one of the following metabolic conditions: overweight/obese,type 2 diabetes,or two of seven metabolic risk factors.The prominence of MAFLD compared with NAFLD is that it emphasizes the contribution of systemic metabolic dysfunction and removes the need to rule out other concomitant liver diseases [15].The diagnosis label “nonalcoholic” sounds that the disease is unimportant [16].

Since the introduction of MAFLD,there has been a debate about the utility of the new term [17].Numerous observational studies have compared the performance of MAFLD and NAFLD in identifying comorbidities and disease prognosis risk of fatty liver patients [18–25].In these studies,MAFLD definition is demonstrated to be more practical for identifying comorbidities than NAFLD in fatty liver patients [24].In addition,researchers evaluated the utility of the new nomenclature in identifying patients with high risks of extrahepatic diseases and poor longterm outcomes.Patients with MAFLD have higher risk of chronic kidney diseases [26],cardiovascular events [27],and all-cause mortality,including cardiovascular and cancer-related,than patients with NAFLD [19–21].Collectively,most studies provided evidence that MAFLD criteria identify patients with worse metabolic traits [24,28],more advanced liver fibrosis [29]and higher mortality risks compared with the NAFLD criteria [19–21].However,some studies show inconsistent results [22,23].

Endorsement of the MAFLD definition should be treated with caution.The complexity of diagnosing metabolic dysfunction by three dimensions (overweight/obesity,type 2 diabetes or two of seven metabolic risk factors) cannot be ignored,and therefore,its clinical utility needs to be carefully evaluated.In addition,the level of C-reactive protein and homeostasis model assessment for insulin resistance (HOMA-IR) included in the seven metabolic risk factors are not routinely measured in clinical practice [30].The pivotal role of hyperuricemia in the development of fatty liver has been established by substantial evidence [31].On this basis,our team developed a simplified definition of MAFLD as fatty liver accompanied by two of the six metabolic abnormalities,including obesity,hyperglycemia,elevated blood pressure,decreased highdensity lipoprotein cholesterol (HDL-C),increased triglyceride and hyperuricemia [32].We compared the utility of the simplified definition with the existing definition and found that the former was better at identifying fatty liver patients with higher risks of allcause mortality.In a prospective cohort study of 13 786 Chinese adults with 7-year follow-up,we found that the simplified criterion was superior in predicting the development of type 2 diabetes,carotid atherosclerosis plaque and hypertension [33].

Recently,a multinational Delphi consensus recommended a new nomenclature,metabolic dysfunction-associated steatotic liver disease (MASLD),to replace NAFLD [34].The diagnosis of MASLD is based on hepatic steatosis along with at least one of five metabolic risk factors.Similar to the definition of MAFLD,MASLD highlights a close link with metabolic dysfunction.MASLD does not require to exclude other causes of liver disease.In contrast,the diagnosis of metabolic abnormalities in MASLD is simplified and does not need to be evaluated from three aspects,and measurement of Creactive protein and HOMA-IR is not included in the assessment of metabolic abnormalities.The definition of MASLD also has a lower diagnostic threshold of metabolic dysfunction.In addition,the stigmatized “fatty” label is removed from the criteria of MASLD,which may have a deleterious impact on self-esteem and reduce adherence to healthcare recommendations and self-management [13].

There are debates whether MASLD is superior to MAFLD or NAFLD [30].A study based on data from the third National Health and Nutrition Examination Survey reported that in the general population,20% and 15% of adults were diagnosed with MAFLD and MASLD,respectively [35].Both MAFLD and MASLD were positively associated with the risk of all-cause mortality,with the former being more strongly associated.Individuals meeting both MAFLD and MASLD criteria and meeting only MAFLD criteria showed an increased risk of all-cause mortality,while those with MASLD only did not.More studies are needed to compare the utility of the new and existing definitions in risk stratification.

The five metabolic risk factors included in the MASLD diagnosis are derived from the definition of metabolic syndrome,namely,obesity,hyperglycemia,increased triglyceride,reduced HDL-C and elevated blood pressure [36].The diagnostic criterion of metabolic syndrome is three or more of these components.Previous studies reported that the more the components of metabolic syndrome there were,the higher the risk of poor long-term outcomes in patients with NAFLD [20].Given that only one metabolic risk factor is needed to reach the diagnosis of metabolic dysfunction in MASLD,we speculated that the diagnostic threshold is relatively low and may capture individuals with a desirable prognosis who do not need premature monitoring.Therefore,we recently developed a new term named MASLD-2,which requires at least two of the five metabolic risk factors on the basis of hepatic steatosis.Drawing lessons from the definition of prediabetes as patients with hyperglycemia but not reaching a diabetes diagnosis,we named individuals with hepatic steatosis but not meeting MASLD-2 as “pre-MASLD”.Pre-MASLD refers to individuals with either no or only one metabolic risk factor along with hepatic steatosis.

In comparison with the performance between MASLD-2 and MASLD in identifying individuals with worse prognosis,we found that MASLD-2 was significantly associated with an increased risk of all-cause mortality,while MASLD was not (data not shown).Based on this,we speculated that the MASLD-2 criteria would be better in capturing the long-term outcomes of patients with hepatic steatosis.Furthermore,we evaluated whether it was reasonable to define pre-MASLD separately.We divided participants into the nonhepatic steatosis,pre-MASLD and MASLD-2 groups and observed an increased risk of all-cause mortality in patients with MASLD-2 but not in individuals with pre-MASLD compared with nonhepatic steatosis.These findings suggested that individuals with pre-MASLD had more favorable outcomes;thus,early surveillance may place an unnecessary burden on strained health and economic resources.The superiority of the MASLD-2 criteria over MASLD and the necessity of defining pre-MASLD separately warrant further investigation.

In conclusion,there are still debates on renaming and redefining fatty liver disease.More evidence is needed to assess the benefits as well as detriments of using the new nomenclature MAFLD or MASLD in terms of improving public awareness of the disease,risk stratification,biomarker discovery and treatment development.

Acknowledgments

None.

CRediT authorship contribution statement

Hang-Kai Huang:Data curation,Methodology,Investigation,Writing– original draft,Writing– review &editing.You-Ming Li:Conceptualization,Methodology,Investigation,Writing– review &editing.Cheng-Fu Xu:Conceptualization,Funding acquisition,Methodology,Investigation,Project administration,Supervision,Writing– original draft,Writing– review &editing.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82370574 and 82070585).

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.All authors declare no conflicts of interest.