Pathogenesis of metabolic dysfunction-associated steatotic liver disease and donor liver damage

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than a quarter of adults worldwide. MASLD is associated with severe medical burdens and leads to further reduction of the donor pool for liver transplantation. However, there is a lack of systematic evaluation of the pathogenesis of MASLD development and MASLD graft damage. As a multisystem disorder, the pathogenesis of MASLD is closely related to genetics, metabolic and endocrine disorders, imbalanced intestinal flora, abnormal hepatocyte homeostasis, and hepatic inflammation. Mutations or single nucleotide polymorphisms and epigenetic modifications in multiple genes increase a person's susceptibility to developing MASLD. Lipid accumulation is a central pathogenic driver, and intestinal microbiota and endocrine disorders can exacerbate steatosis and inflammation. These issues cause endoplasmic reticulum stress in hepatocytes, leading to apoptosis and promoting the recruitment and activation of immune cells. Ultimately, hepatic stellate cells are activated, resulting in liver fibrosis. These molecular and pathological changes are important causes of why a MASLD donor liver is likely to suffer ischemia-reperfusion injury and cold ischemic injury. Lipid deposition, microcirculation disturbance, and inflammation in the MASLD donor liver exacerbates ischemia-reperfusion-related damage. During transplantation, cold ischemia time should be minimized, and machine perfusion implemented and treatments for MASLD used after transplantation to protect the graft. This systematic review describes the pathogenesis of MASLD and the mechanism of MASLD donor liver damage to potentially increase the use of MASLD donor livers and provide strategies to preserve organ function.