Jing Zeng , Jin-Go Fn , b , ?

a Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20 0 092, China

b Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 20 0 092, China

The names of many diseases have changed over time, and the criteria of successfully changing the name of a disease should make sense, be easy to say and write, get quick endorsement by professional societies, and keep the same acronym. In general, a change in the name of a disease usually represents an improvement in the understanding of the disease, whether on clinical settings and natural history or pathophysiological aspects. The successful renamed liver diseases in history include from non-A non-B hepatitis, non-B non-C hepatitis, primary biliary cirrhosis to hepatitis C, hepatitis E and primary biliary cholangitis, respectively.Therefore, the rename of the disease that is finally used usually clearly indicates its main characteristics.

The term “fatty liver” was first used by Thomas Addision in 1845 during the autopsy. With liver biopsy widely used for the diagnosis of diffuse liver diseases since 1958, hepatic steatosis or steatohepatitis was found to be the common histological change.In 1970, Beringer and Thaler reported that biopsy-proven fatty liver was very common in patients with type 2 diabetes mellitus(T2DM) and the prevalence of liver cirrhosis was also significantly increased in these patients [1] . Then the term “nonalcoholic steatohepatitis (NASH)” was first proposed by Dr. Ludwig and his colleagues in 1980 on 20 patients with steatohepatitis but neither evidence of chronic alcoholism nor other secondary causes [2] . Most of them were moderately obese, and also had T2DM, cholelithiasis, hyperlipoproteinemia, hypertension, or a history of heart diseases. In 1986, the term “nonalcoholic fatty liver disease (NAFLD)”was proposed by Schaffner and Thaler as they found that inflammation was often absent in patients with biopsy-proven hepatic steatosis, and they suggested NASH as a subgroup of NAFLD [3] .In 1999, Marchesini et al. [4] reported a case-control study including 46 NAFLD patients with normal glucose tolerance, and 1:2 age- and sex-matched controls. They found that insulin resistance assessed by the homeostasis model assessment method,fasting plasma triglyceride level, and 3-h blood glucose level were independently associated with NAFLD regardless of overweight or obesity. Since 20 0 0, NAFLD has become one of the most important chronic liver diseases in the world [5] . According to the results of Global Burden of Disease study, liver-related mortality increased 11.4% from 2012 to 2017 [6] . Although chronic viral hepatitis remains the most common cause of liver-related deaths, NAFLD is the most rapidly growing contributor to liver-related mortality and morbidity. In addition to the long-term liver outcomes, NAFLD is associated with increased risk for T2DM, cardiovascular disease(CVD), cerebrovascular disease, chronic kidney disease, and extrahepatic tumors [7] . Based on the current diagnostic criteria for obesity, around 40% of NAFLD patients worldwide are not obese,and 19.2% are even lean [8] . Non-obese or lean NAFLD is also a manifestation of metabolic syndrome in the liver and may be in the progressive condition [9] .

Currently, the diagnosis of NAFLD requires exclusion of all other etiologies of hepatic steatosis or steatohepatitis. And numerous related studies over the decades have shown that the term “NAFLD”overemphasizes the role of alcohol and underemphasizes the importance of metabolic dysfunctions in the disease. The heterogeneous pathogenesis of NAFLD and inaccuracies in the disease terminology and definition make the reappraisal of nomenclature urgently needed. In 2020, a novel comprehensive redefinition of fatty liver disease (FLD) was proposed by an international panel of experts [10] . They recommended that NAFLD should be renamed metabolic dysfunction-associated fatty liver disease (MAFLD), and the diagnosis of MAFLD should be based on the presence of metabolic dysfunction. From this aspect, MAFLD can coexist with alcoholic liver disease and other liver diseases, and it does. MAFLDrelated cirrhosis is no longer a cryptogenic cirrhosis.

There are similarities and differences between the diagnostic criteria of NAFLD and MAFLD [ 11 , 12 ]. The presence of hepatic steatosis is required in both criteria. In addition to that,NAFLD requires the exclusion of alcoholic and other liver diseases,whereas MAFLD is a relatively positive diagnosis based on the presence of overweight/obesity, or T2DM, or the existence of two or more metabolic risk factors. The term “MAFLD” highlights the important role of obesity, insulin resistance, dyslipidemia, T2DM and systemic inflammation in the occurrence and development of FLD [13] . Therefore, the clinical classification of FLD needs to be redefined according to the different criteria and definitions. Although most patients can be classified as both MAFLD and NAFLD(MAFLD + NAFLD + ), there are still some patients with NAFLD only(MAFLD-NAFLD + ) or MAFLD only (MAFLD + NAFLD-) [14] . That is,not all NAFLD can be directly classified as MAFLD, andviceversa.

In most clinical and epidemiological studies, the prevalences of NAFLD and MAFLD are different, with the MAFLD prevalence generally being slightly higher [12] . A multicenter cross-sectional study from China including 246 biopsy-proven NAFLD patients showed that 84% were identified as NASH, and 97% met the diagnostic criteria of MAFLD [15] . The proportions of NASH and significant fibrosis were both increased significantly with the increase of the number of metabolic components. The percent of NASH in the NAFLD only group was significantly less than that in the MAFLD group. In the MAFLD group, overweight was related to steatohepatitis, and T2DM was related to significant fibrosis. Importantly,insulin resistance index was the strongest powerful predictor for both hepatic inflammation and fibrosis. We once also conducted an epidemiology study of T2DM and FLD among 9980 adults in Shanghai, China [16] . The prevalence rates of NAFLD and MAFLD were 36.9% and 40.3%, respectively. There was 5.2% of patients diagnosed with MAFLD only as coexisting with other liver diseases. As Prof. Tarantino mentioned that a little more than 10% of MAFLD patients were not diagnosed as having NAFLD in our previous study, and it could be because most patients with MAFLD only coexist with alcoholic liver disease [17] . We could find that 94.6% of alcoholic liver disease also met the diagnostic criteria of MAFLD, suggesting that most of them were both alcohol-related and metabolic-associated FLD. In addition, there were 181 subjects with NAFLD only, and 82.9% of them had one metabolic component, which made us wonder if they were in the early stage of MAFLD. It is interesting that one epidemiology study of FLD in Hong Kong, China showed that the prevalences of NAFLD and MAFLD were almost the same [18] . And the incidence of MAFLD was 25%, lower than that of NAFLD, partly because lean people were common in this study.

In a cross-sectional study with 765 Japanese adults with FLD enrolled, the proportion rates of NAFLD and MAFLD were 70.7%and 79.6%, respectively [19] . Liver stiffness measured by shear wave elastography was higher in MAFLD compared to that in NAFLD. In logistic regression analysis, MAFLD, alcohol intake, and NAFLD were independently associated with non-invasive diagnostic significant fibrosis. By decision-tree analysis, MAFLD was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher in MAFLD than in NAFLD. Therefore, the MAFLD definition better identifies a group with FLD associated significant fibrosis. According to a Korean nationwide health screening database, the prevalence of MAFLD was significantly higher than that of NAFLD (37.3% vs. 28.0%) [20] . Nearly 9 million participants were followed 10 years for incident CVD event. NAFLD and MAFLD were each associated with a significantly higher risk for CVD events. When taking the neither-FLD group as the reference, multivariable-adjusted hazard ratios for CVD events gradually increased from the MAFLD-NAFLD+ group to the MAFLD+ NAFLDgroup, and then to the MAFLD + NAFLD + group. During 7 years of follow-up in another prospective study including 2985 patients with FLD, Niriella et al. also found that it was the MAFLD + NAFLDgroup not the MAFLD-NAFLD + group that was associated with incident CVD events [21] . The change from NAFLD to MAFLD criteria may thus identify a greater number of individuals with MAFLD and an increased risk for future CVD events.

In order to examine and compare the clinical and histologic features of MAFLD versus NAFLD, Huang et al. conducted a study with 175 patients with biopsy-proven FLD and 10 with cryptogenic cirrhosis [22] . Finally, 76 patients were diagnosed with MAFLD + NAFLD + , 81 patients were MAFLD + NAFLD-, and 9 patients were MAFLD-NAFLD + . The criteria for MAFLD included an additional 39% of patients with FLD. Their study indicated that the patients in the MAFLD + NAFLD- group exhibited a higher degree of disease severity regarding histology and laboratory data than those in the MAFLD-NAFLD+ group. Furthermore, none of MAFLDNAFLD + patients had advanced fibrosis. The percentage of advanced fibrosis in MAFLD + NAFLD- patients was even significantly higher than that in MAFLD + NAFLD + patients. Meanwhile, a crosssectional cohort from Japan also showed the risk of significant fibrosis was significantly higher in the MAFLD group than in the NAFLD group [19] . Therefore, the diagnostic criteria of MAFLD can better identify those with severe liver disease who urgently need early intervention compared with NAFLD criteria.

It is well known that hepatic steatosis is common in patients with chronic hepatitis B (CHB), and steatosis in CHB is associated with metabolic dysfunction not the virus. The anti-hepatitis B core antibody (HBcAb) was used to detect the previous HBV infection. A multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related hepatocellular carcinoma (HCC)from Hong Kong, China indicated that positive HBcAb was associated with lower steatosis grade but higher stage of liver fibrosis [23] . During a mean follow-up of 6 years, NAFLD patients with positive HBcAb had a higher incidence of HCC or cirrhotic complications. The prevalence of advanced fibrosis in CHB patients with MAFLD was significantly higher than in CHB patients with NAFLD only [24] . Recently, our team reported the prevalence of NASH was 18% among 10 0 0 na?ve biopsy-proven CHB patients with significant fibrosis [25] . After 72-week entecavir treatment, 43% of patients with NASH achieved steatohepatitis resolution without progression of fibrosis. Among patients without NASH at baseline, 4% of patients developed steatohepatitis at the second biopsy. Overweight at baseline and subtle weight change during follow-up were related to the prevalence, resolution, and incidence of NASH in CHB patients.

In another retrospective cohort of NAFLD in the Veterans Administration of United States, some developed liver cirrhosis and HCC during 9-year follow-up [26] . At baseline, most of these patients had obesity, 29% had diabetes, 70% had hypertension, and 62% had dyslipidemia. The risk of liver disease progression was the lowest in MAFLD-NAFLD + patients. There was a stepwise increase in risk with each additional metabolic risk factor. Compared with patients without any metabolic risk factors, patients with both hypertension and dyslipidemia (that is MAFLD) had a 1.8-fold higher risk of progression to liver cirrhosis or HCC, and the risk was 2.6-fold higher in NAFLD patients with diabetes, obesity, dyslipidemia, and hypertension. Moreover, T2DM had the strongest association with HCC in these patients. The results suggested that the presence of two or more metabolic components significantly increased the risk of FLD related cirrhosis and HCC. Therefore,MAFLD is associated with liver cirrhosis and cancer instead of NAFLD only.

In conclusion, the old term “NAFLD” overemphasizes alcohol abuse and ignores the importance of metabolic dysfunction in this disease. The definition of MAFLD is simple, practical, and outperforms the former NAFLD definition in identifying patients at high risk for future hepatic and extrahepatic outcomes, and also increases the awareness of FLD. Over a couple years, increased position statements on the redefinition of FLD were issued by the professional societies and multi-stakeholder. Prevalence of MAFLD has been broadly matched to that reported for NAFLD, however, it is somewhat higher as its definition includes the coexistence of other liver diseases. The new definition of MAFLD is not just a change in name, patients with FLD will need to be reclassified with careful management in the future.

Acknowledgments

None.

CRediT authorship contribution statement

Jing Zeng : Data curation, Writing - original draft. Jian-Gao Fan :Conceptualization, Funding acquisition, Writing - review & editing.

Funding

This study was supported by grants from the National Key Research and Development Program of China (2021YFC2700802),the National Natural Science Foundation of China (81873565 and 82170593), and Clinical Research Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (17CSK04).

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.