Serum Thrombospondin-2 Levels Are Closely Associated With the Severity of Metabolic Syndrome and Metabolic Associated Fatty Liver Disease

Abstract

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.

Serum thrombospondin‐2 level changes with liver stiffness improvement in patients with type 2 diabetes

“…7 In morbidly obese individuals, serum TSP2 levels significantly increased with worsening glucose tolerance and the presence of more components of metabolic syndrome. 8 In T2D patients, higher TSP2 levels were significantly associated with higher BMI, WC, HbA1c, as well as higher CAP and LS measurements on VCTE. 1 In this study, we demonstrated a modest but significant reduction in serum TSP2 levels from baseline in patients treated with dapagliflozin who also experienced HbA1c reduction, weight loss and improvements in hepatic steatosis and fibrosis.…”

“…[5][6][7] Circulating TSP2 was recently identified as a potential novel biomarker of hepatic fibrosis. 1,[8][9][10] In morbidly obese individuals, higher circulating TSP2 levels were associated with increasing severity of hepatic steatosis, inflammation and fibrosis. 1,8 In T2D patients with coexisting NAFLD, baseline circulating TSP2 level was associated with the presence and the development of advanced hepatic fibrosis.…”

“…1,[8][9][10] In morbidly obese individuals, higher circulating TSP2 levels were associated with increasing severity of hepatic steatosis, inflammation and fibrosis. 1,8 In T2D patients with coexisting NAFLD, baseline circulating TSP2 level was associated with the presence and the development of advanced hepatic fibrosis. 1 While all these studies investigated the prognostic importance of circulating TSP2 level measured at baseline, it is also important to evaluate if circulating TSP2 level changes with improvements in hepatic fibrosis, to provide further support for its potential clinical use as a biomarker of hepatic fibrosis.…”

“…Thrombospondin‐2 (TSP2) is a matricellular protein that modulates several important biological functions including extracellular matrix (ECM) assembly, tissue remodelling, angiogenesis and wound healing 5–7 . Circulating TSP2 was recently identified as a potential novel biomarker of hepatic fibrosis 1,8–10 . In morbidly obese individuals, higher circulating TSP2 levels were associated with increasing severity of hepatic steatosis, inflammation and fibrosis 1,8 .…”

Thrombospondin 2 is a key determinant of fibrogenesis in non‐alcoholic fatty liver disease

“…15,16 These results were supported by a large investigation of NAFLD patients with diabetes mellitus or metabolic-associated fatty liver disease. 17,18 Furthermore, a correlation between the degree of fibrosis and inflammation and serum TSP2 levels was observed not only in NAFLD, but also in hepatitis C virus-infected patients. 19,20 Despite these advances, however, the specific liver cell populations responsible for THBS2/TSP2 expression in NAFLD, the underlying mechanisms governing expression dynamics, and the precise role of THBS2/TSP2 in the pathogenesis of NAFLD remain largely unknown.…”