Lean or diabetic subtypes predict increased all-cause and disease-specific mortality in metabolic-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new conceptual definition of fatty liver disease that is based on metabolic abnormalities (regardless of the etiology of chronic liver disease) that emphasizes the role of metabolic dysfunction in the clinical outcomes of patients with hepatic steatosis [1, 2]. MAFLD is defined according to the presence of hepatic steatosis along with one or more of the following criteria: (i) overweight or obesity, (ii) diabetes mellitus (DM), or (iii) ≥ 2 metabolic abnormalities [3]. Recent studies have investigated the predictive role of MAFLD in cardiovascular disease (CVD) [4, 5] and all-cause mortality [6‐8].

However, MAFLD includes a heterogeneous group of patients, and the following subgroups should be recognized: lean and non-lean patients, alcoholic and nonalcoholic patients, and patients with isolated hepatic steatosis (vs. those with underlying liver disease) [9]. A previous study reported that MAFLDs are heterogeneous in terms of mortality outcomes and cardiovascular risk and that these outcomes vary according to the accompanying metabolic dysfunctions [10]. A previous study demonstrated that MAFLD better identifies cardiovascular risk than nonalcoholic fatty liver disease (NAFLD), which was attributed to the inclusion criteria of metabolic dysfunctions [11]. Moreover, a statistically significant difference in the degree of liver fibrosis has been reported among MAFLD subgroups, suggesting differential risks of advanced liver disease across MAFLD subgroups [12].

Since overweight/obesity is typically defined according to body mass index (BMI), it does not always entail metabolic abnormalities [13]. As MAFLD is a spectrum encompassing diverse disease groups defined according to metabolic abnormalities and overweight/obesity, there may be heterogeneity in clinical outcomes according to disease subcategorizations. Therefore, we aimed to investigate the differential risk of all-cause and disease-specific mortality according to MAFLD subgroups divided by metabolic risk factors and overweight/obesity status within a nationally representative Korean study population.

In this large nationwide, population-based cohort study, we calculated all-cause and disease-specific mortality in MAFLD subgroups using a database of health insurance claims in Korea. All-cause and disease-specific mortality were highest in the MAFLD-diabetes group, followed by the MAFLD-lean and MAFLD-overweight/obese groups, suggesting differential prognoses according to the MAFLD subtype. Interestingly, the liver-related mortality in the MAFLD-lean group was comparable to that in the MAFLD-diabetes group, emphasizing the poor liver-related prognosis in the MAFLD-lean group. The classification of MAFLD subtypes based on the metabolic phenotypes used in this study might help risk stratification of MAFLD patients.

Among the MAFLD subtypes, MAFLD-diabetes showed the highest increased risk for all-cause and disease-specific mortality. Diabetes is associated with a thrombotic and inflammatory condition and a higher incidence of atherosclerosis and carcinogenesis due to sustained hyperglycemia [28, 29]. As a consequence, diabetes has been recognized as a risk factor for all-cause and cause-specific mortality [30‐32]. The results of this study showing that MAFLD-diabetes can be a strong predictor of all-cause and disease-specific mortality are in line with previous literature.

In addition to diabetes, MAFLD subcategorizations according to overweight/obesity may help elucidate the differential mortality risk among MAFLD subtypes. However, since the proportion of lean MAFLD is relatively low in real clinical practice and it is difficult to collect enough samples, the clinical and prognostic features of lean MAFLD have not been defined well in prior work. In the current study, although the prevalence of MAFLD-lean was 1.9% of the total population, the characteristics of the nationwide population study design enabled reliable analysis by securing a significant sample size.

In this study, individuals in the MAFLD-lean group were at a higher risk of all-cause and disease-specific mortality than those in the MAFLD-overweight/obese group. Similar to our results, several studies have reported that the cumulative CVD incidence rate was higher in lean MAFLD than in overweight/obese MAFLD [4, 19], and the risk of all-cause mortality was higher in those with lean MAFLD without diabetes (HR: 2.34) than in overweight/obese MAFLD subjects without diabetes (HR: 1.23) [10]. These findings are in line with poor clinical outcomes previously documented in patients with lean NAFLD [33‐35]. A recent study reported that NAFLD subjects with normal BMI had a higher risk of all-cause mortality than those with obese NAFLD and that the major causes of death in this subgroup were cancer and CVD [36]. Similarly, people with lean NAFLD show a comparable risk of advanced liver disease, metabolic comorbidities, CVD, and liver-associated mortality to those with non-lean NAFLD without weight gain during follow-up and independent of genotype [37].

As lean NAFLD represents a unique subset related to the interaction of genetics, underlying medical conditions, and environmental exposures [38], the mechanism-related poor prognosis in lean MAFLD is not completely elucidated. Although lean and obese NAFLD share common altered metabolic and cardiovascular profiles, NAFLD patients having normal body weight show excess abdominal adipose tissue and metabolic abnormalities [39]. Recent studies reported that the progression of lean NAFLD is affected by multiple epigenetic mechanisms such as modification of cytosine and histones and changes in nucleosome localization [40], and circulating histones may discriminate the severity of steatosis in lean MAFLD patients [41]. In addition, a previous study reported that lean MAFLD subjects had lower fatty tissue index, lean tissue index, and total body water than did non-lean MAFLD subjects, which means that lean MAFLD subjects had less adiposity and less muscle mass compared to obese MAFLD subjects [42]. These results suggest that sarcopenia, which is the loss of muscle mass and function with aging, is a possible underlying reason for poor prognosis in people with lean MAFLD.

Because MAFLD is closely related to metabolic diseases, various pharmacological approaches that have been attempted to manage NAFLD’s metabolic traits, such as anti-obesity, antidiabetic, antioxidants, and cytoprotective agents, may also be effective in MAFLD. Emerging data from various clinical trials with drugs targeting diverse molecular mechanisms show promising results [43], and a recent phase II trial reported that semaglutide might be an attractive potential therapeutic option for NASH [44]. Future potential treatments for NAFLD include agents that act through peroxisomal proliferator-activated receptors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, or farnesoid X receptor agonists, and several investigating agents have entered phase III clinical trials [45].

Overweight/obesity increases the risk for CVD, cancer, and liver-associated adverse outcomes. However, subjects in the MAFLD-overweight/obese group showed better prognoses than did those in the MAFLD-lean group in the present study. This phenomenon may be associated with the obesity paradox (i.e., elevated BMI may improve survival in individuals with CVD, primarily those with congestive heart failure [46, 47], cancer [48, 49], and type 2 DM [50]). Potential explanations for the obesity paradox include reverse causation, the inability to distinguish fat tissue from muscle mass using BMI, and even the possibility that adipose tissue may provide some level of protection. Although the evidence for an obesity paradox is mixed for individuals with a BMI between 22 and 24.9 kg/m² [51, 52], the findings of increased mortality in individuals with lower BMI values are indisputable.

Our study presents the substantial strengths of a large sample size, a population-based design, and the categorization of MAFLD considering diabetes and metabolic risk factors in addition to BMI. This study provides new insights into the understanding of mortality-related outcomes of MAFLD, which can be used for risk stratification strategies in patients with MAFLD. However, we also acknowledge some limitations of the present work. First, although histological or radiological methods are more accurate for detecting hepatic steatosis than FLI, we used FLI as a surrogate marker of fatty liver and, thus, cannot accurately quantify the presence and severity of steatosis [53]. In addition, FLI has different cut-offs for men and women and bears a large gray zone of undetermined presence/absence of hepatic steatosis [26, 27]. However, similar results were observed when we used two different sex-specific cut-off values of FLI. Moreover, the use of FLI is practical for screening the general population in epidemiologic studies [10, 54], and FLI is regarded as an acceptable surrogate for diagnosing hepatic steatosis in MAFLD [55]. Second, our study cannot establish a causal relationship because of its population-based observational design. Third, there might be residual confounding factors such as family history or occupational exposures related to cancer development since the NHIS does not collect these data. Fourth, although most studies used BMI to define lean NAFLD/MAFLD [38], total body fat quantity (assessed based on BMI) does not reflect regional body fat distribution. Because visceral adiposity can be a target for interventions in the treatment of MAFLD, future studies need to consider visceral adiposity. Finally, it is possible that the evaluated conditions were under- or overestimated because the diagnoses were based on claims data (ICD-10 codes). However, the definitions we used in this study were validated in several previous studies [21, 22]. Further replicative research is warranted to validate and elucidate our results’ underlying mechanisms.

Lean or diabetic MAFLD showed a poor prognosis for all-cause and disease-specific mortality. Classifying MAFLD subgroups based on metabolic phenotypes that account for integrated metabolic disorders might help risk stratification of patients with MAFLD.