Pathogenesis and Clinical Management of Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic progressive liver disease with a substantial impact on global health. Given that MASLD has a complex etiology, it is a multisystemic disease, a multidisciplinary approach is required when treating MASLD. The optimal drug for MASLD should diminish steatosis, fibrosis and inflammation in the liver. Although the pharmaceutical industry is still lagging in developing an approved pharmacologic therapy for MASLD, research has recently intensified, and many molecules that are in the final stages of clinical trials are expected to be approved in the coming few years. The current review updated information related to the MASLD pathogenesis, diagnosis and therapeutic options, how patients are clinically managed nowadays, and what to expect in the near future.

Keywords: MASLD; NAFLD; diagnosis; lifestyle; pathogenesis; therapies.

Figure 1

Exacerbation of MASLD and pharmacotherapy to reverse the stage of fibrotic MASH to a healthy liver. MASLD: metabolic dysfunction-associated steatotic liver disease, MAFL: metabolic-associated fatty liver, MASH: metabolic-associated steatohepatitis, HCC: hepatocellular carcinoma. Dark arrow: worsening liver condition. Light red arrow: improving MASLD stages under MASLD pharmacotherapy.

Figure 2

Gut–liver axis in MASLD—FFA—free fatty acids; LPS—lipopolysaccharides; TLR—toll-like receptors.

Figure 3

TLR4 activation in MASLD—PAMPs—pathogen-associated molecular patterns; DAMPs—damage-associated molecular patterns; TLR4, triggered by endogenous DAMPs and exogenous PAMPs, is activated and initiates downstream signaling that stimulates NF-κB and leads to cytokine production, such as IL-17, fueling a pro-inflammatory state.

Figure 4

Role of IL17 in MASLD progression—Th17 cells, a subset of pro-inflammatory CD4+ T cells; IL-17 and IL-22 cytokines; DCs—dendritic cells, SCs—stellate cells in the liver.

Figure 5

Main therapeutic approaches for MASLD. GLP-1: Glucagon-Like Peptide-1, SGLT-2: Sodium-glucose co-transporter-2, PPAR: Peroxime Proliferator-Activated Receptor, FXR: Farnesoid-X receptor, FGF: Fibroblast growth factors, THR-beta: Thyroid hormone receptor beta.