Context Metabolic associated fatty liver disease (MAFLD) is the hepatic manifestation of obesity-related metabolic syndrome (MetS). Non-invasive biomarkers for monitoring the progression and severity of these metabolic comorbidities are needed. Objectives To investigate the associations of serum thrombospondin-2 (TSP2) with MetS and MAFLD severity, and the potential diagnostic value of serum TSP2 for identifying at-risk metabolic associated steatohepatitis (at-risk MASH). Methods Blood samples, clinical data, and liver biopsies were collected from consecutively recruited 252 individuals with morbid obesity receiving bariatric surgery. Histopathology of liver biopsies were examined in a blinded fashion by three independent pathologists. Serum TSP2 levels were measured by ELISA. Results Serum TSP2 levels were significantly elevated in MetS (1.58 (1.07-2.20) ng/mL) compared with non-MetS (1.28 (0.84-1.73) ng/mL; P=0.006) in obese patients and positively correlated with increasing number of the MetS components, fasting glucose, HbA1c, fasting insulin, C-peptide, HOMA-IR after adjustment of conventional confounders. Serum TSP2 levels differentiated MASH (1.74 (1.32-3.09) ng/mL) from the other non-MASH less severe groups normal liver (1.41 (1.04-1.63) ng/mL), simple steatosis (1.45 (0.89-1.92) ng/mL) and borderline MASH (1.30 (0.99-2.17) ng/mL) (P<0.05). Elevated serum TSP2 was positively associated with the severity of hepatic steatosis, inflammation, fibrosis, and abnormal liver function independent of age, sex and adiposity. Furthermore, high serum TSP2 identified at-risk MASH with AUC of 0.84 (95%CI 0.70-0.98). Conclusions Serum TSP2 is closely associated with severity and progression of MetS and MAFLD, and is a promising noninvasive biomarker for differentiating MASH from benign steatosis and identifying at-risk MASH patients among individuals with obesity.

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