Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread global disease with significant health burden. Unhealthy lifestyle, obesity, diabetes mellitus (DM), insulin resistance, and genetics have been implicated in the pathogenesis of MASLD. A significant degree of heterogeneity exists among each of above-mentioned risk factors. Heterogeneity of these risk factors translates into the heterogeneity of MASLD. On the other hand, MASLD can itself lead to insulin resistance and DM. Such heterogeneity makes it difficult to assess the natural course of an individual with MASLD in clinical practice. At present MASLD is considered as one disease despite the variability of etiopathogenic processes, and we lack the consensus definitions of unique subtypes of MASLD. In this review, pathogenic processes of MASLD are discussed and a need of subtyping is recommended.

Keywords: Diabetes; Genetics; Insulin resistance; Metabolic dysfunctions-associated steatotic liver disease; Visceral obesity.

Figure 1

Overlap of metabolic comorbidities. This diagram shows a hypothetical overlap of metabolic risk factors to highlight the heterogeneity of metabolic overlap. Metabolic risk factors are represented with colors: Obesity; yellow, DM; green, dyslipidemia; blue and metabolic dysfunction-associated steatotic liver disease (MASLD); red. The proportion of overlaps were based upon the data from epidemiological studies. Blue arrow represents MASLD patients and green arrow represents non-MASLD patients but has metabolic risk factors. MASLD: Metabolic dysfunction-associated steatotic liver disease; DM: Diabetes mellitus.

Figure 2

The key modulators of carbohydrate and fat metabolism. Red arrow indicates negative relationship and blue arrow indicates positive relationship. FA: Fatty acid; GLP1: Glucagon like peptide 1; GIP1: Gastric inhibitory peptide 1; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor.

Figure 3

Diversity of pathogenetic mechanisms leading to metabolic dysfunction-associated steatotic liver disease. MASLD: Metabolic dysfunction-associated steatotic liver disease; DNL: De novo lipogenesis.

Figure 4

Estimated prevalence of metabolic dysfunction-associated steatotic liver disease subtypes. MASLD: Metabolic dysfunction-associated Steatotic liver disease, US: Ultrasound: DM: Diabetes mellitus; BMI: Body mass index.

Figure 5

Bidirectional connection between two pathogenetic pathways leading to insulin resistance.