Editorial
MAFLD and ASCVD: Plasma Heparin Cofactor II Activity as an Anti-liver Fibrosis Biomarker
2023 Volume 30 Issue 8 Pages 853-854
Details
2023 Volume 30 Issue 8 Pages 853-854
See article vol. 30: 871-883
Metabolic dysfunction–associated fatty liver disease (MAFLD) was proposed as a new nomenclature for nonalcoholic fatty liver disease (NAFLD) considering the metabolic overload independently of the presence of other liver diseases1). The criteria are based on evidence of hepatic steatosis in addition to one of the following three criteria: overweight/obesity, presence of type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation1). Although the definitions of NAFLD and MAFLD differ based on history of binge drinking, both are based commonly on evidence of liver fat accumulation (liver steatosis)1). Liver steatosis as well as ectopic fat accumulation in the skeletal muscle and cardiovascular system can be a major cause of insulin resistance and its consequences such as T2DM2), dyslipidemia, and atherosclerotic cardiovascular disease (ASCVD)3).
Evidence revealed a significant association between NAFLD and MAFLD, with increased risk of cardiovascular disease morbidity and mortality4-6).
Thrombin acts as an enzyme capable of forming fibrin clot, and it also activates platelets, vascular endothelial cells, vascular smooth muscle cells, and macrophages to augment procoagulation, chemotaxis, mitogenesis, and proliferation. Thrombin signals in the blood stream cause atherosclerosis by thrombosis and vascular inflammation via activation of thrombin receptors known as protease activated receptors7) (Fig.1). Reportedly, thrombin generation was observed in patients with NAFLD/nonalcoholic steatohepatitis8). Heparin cofactor II (HCII) and antithrombin inhibit thrombin activity by binding to dermatan sulfate, and HCII has been shown to be an independent risk factor for anti-atherosclerosis9).
MAFLD was previously known as NAFLD/nonalcoholic steatohepatitis (NASH). DM: diabetes mellitus; ASCVD: atherosclerotic cardiovascular disease; FIB-4: hepatic fibrosis including fibrosis-4; NFS: NAFLD fibrosis score; APRI: aspartate aminotransferase-to-platelet ratio index; PAR2: protease activated receptor 2.
In the current issue, Hara et al.10) reported that plasma HCII activity was inversely associated with hepatic fibrosis indices, including fibrosis-4 (FIB4) index, NAFLD fibrosis score (NFS), aspartate aminotransferase-to-platelet ratio index (APRI), and the prevalence of advanced hepatic fibrosis in patients with T2DM. The results suggest that HCII can serve as a novel biomarker for assessment of anti-liver fibrosis in patients with T2DM. They also suggested that HCII is negatively involved in the pathogenesis of NAFLD via inactivation of the thrombin–protease activated receptors (PARs) axis. These results are interesting. However, several issues need to be discussed and clarified before suggesting a coagulation-and-MAFLD/NAFLD interaction in people with T2DM.
Future studies are required to clarify 1) whether a coagulation-and-MAFLD/NAFLD interaction can be observed in people without T2DM, 2) how plasma HCII activity can be regulated in patients with or without T2DM, and 3) how the coagulation-and-MAFLD/NAFLD interaction is associated with the onset of ASCVD.
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