In the large population-based study of 17,595 participants, SLD was diagnosed in 7,538 (42.8%) participants. Of them, 7,274 (96.5%) were MASLD and 264 (3.5%) were cryptogenic SLD. Compared with cryptogenic SLD patients, MASLD patients were older and had a higher percentage of male. Propensity score matching for age and sex showed worse metabolic profiles, greater severity of liver markers and higher percentage of carotid plaques in MASLD patients, justifying the exclusion of cryptogenic SLD from NAFLD according to the diagnostic criteria of MASLD.
Cryptogenic SLD, by definition, primarily involves the participants having hepatic steatosis without metabolic dysfunction. This means that individuals with this condition do not exhibit any abnormal measurements in cardio-metabolic risk factors. In our study, cryptogenic SLD patients display favorable metabolic and cardiovascular risk. As for hepatic aspect, individuals with cryptogenic SLD show relatively lower values of liver inflammatory enzymes, FLI, and NFS than MASLD patients. Taken all these findings together, cryptogenic SLD patients have lower risk of liver, metabolic or cardiovascular complications than MASLD patients.
In this study, the definition of health controls refers to individuals who do not have hepatic steatosis and also do not exhibit metabolic dysfunction. When compared to the healthy controls, individuals with cryptogenic SLD show poorer results in terms of anthropometric measurements and lipid profiles. Regarding atherosclerotic indicators, the proportions of carotid plaques are similar between the two groups. As for the liver aspect, both the liver inflammation markers including ALT, GGT, and FLI are higher, but NFS is lower. Our study showed those with cryptogenic SLD had worse metabolic factors and liver inflammatory markers than healthy controls; comparable risk of atherosclerosis; and less severity of hepatic fibrosis markers, suggesting although hepatic steatosis alone induces adverse impact on metabolic and liver inflammation in those without metabolic dysfunction, there is no evidence of adverse outcome on the risk of liver fibrosis and atherosclerosis.
This study reveals that cryptogenic SLD accounts for approximately 3.5% of NAFLD patients. If alcohol-related and hepatitis B and C cases are not excluded, the proportion of cryptogenic SLD patients is 1.2% among the entire population. The change in terminology from NAFLD to MASLD only excludes a very small portion of patients. Among the SLD patients in this study, since other chronic liver diseases have been ruled out, strictly speaking, those with metabolic dysfunction should be referred to as pure MASLD. According to the previously mentioned algorithm of SLD classifications, MASLD encompasses not only pure MASLD but also cases involving alcohol and other specific etiologies. For the sake of clinical utility and communication, it is suggested to use the term "MASLD" as a general label for these three subtypes. Other subtype names including pure MASLD (pMASLD), MASLD with alcoholic liver disease (MetALD) and MASLD combined with other etiologies (cMASLD) should be placed before it, along with annotations and abbreviations for differentiation (Fig. 2). This approach offers the advantage of avoiding confusion and facilitating clinical communication [18]. In conclusion, this study not only identifies the small proportion of cryptogenic SLD within the population of NAFLD but also provides evidence to support the rationale for the change of disease name and diagnostic criteria from NAFLD to MASLD.
This study has several strengths. Firstly, this is the first study to investigate the clinical characteristics and outcomes of MASLD and cryptogenic SLD patients. Secondly, the large-scale population-based study confirms that the clinical severity of cryptogenic SLD patients, the excluded population from NAFLD, is lower than MASLD patients. In addition, there is no increased risk of liver fibrosis and atherosclerosis compared with healthy controls. These findings provide a reasoned and evidence-based solution to disputes over the change of diagnostic name and criteria. Thirdly, This study found that hepatic steatosis alone still exerts influences on metabolism and liver inflammation even in those without metabolic dysfunction. However, some weakness should also be addressed. Firstly, the diagnosis of hepatic steatosis is mainly based on liver ultrasound rather than biopsy. However, biopsy is a more invasive examination and is not well suited for population-based studies [19]. Secondly, the diagnosis of hepatic steatosis by ultrasound is not sensitive for patients with mild severity of fatty liver under histology [20]. Thirdly, since cryptogenic SLD could be only diagnosed after excluding other specific etiology SLDs, the possibility of drug-induced liver injury or monogenic diseases cannot be completely excluded due to having no relevant inspection and information in our cohort.
In summary, this large population-based study found that MASLD contained 96.5% of NAFLD patients and better identified a high-risk population of advanced liver fibrosis and atherosclerosis. Cryptogenic SLD patients, the excluded population, occupied only 3.5% in NAFLD patients or 1.2% in the whole population. This study confirms that by incorporating patients with cardio-metabolic risk factors, not only does MASLD accurately reflect the underlying causes and enhance the degree of homogeneity, but it also allows for the selection of high-risk patients. This ensures that clinically significant cases are not overlooked, thereby providing evidence for the rationale behind the change of disease name and diagnostic criteria from NAFLD to MASLD.