Circulating Thrombospondin-2 as a Novel Fibrosis Biomarker of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes

Diabetes Care. 2021 Sep;44(9):2089-2097. doi: 10.2337/dc21-0131. Epub 2021 Jun 28.


Objective: Preclinical studies have suggested that thrombospondin-2 (TSP2) is implicated in liver fibrosis. However, the clinical relevance of TSP2 in nonalcoholic fatty liver disease (NAFLD) remains undefined. Here, we investigated the cross-sectional and longitudinal associations of circulating TSP2 levels with advanced fibrosis (F3 or greater [≥FE] fibrosis) in NAFLD.

Research design and methods: Serum TSP2 levels were measured in 820 patients with type 2 diabetes and NAFLD. All participants received vibration-controlled transient elastography (VCTE) at baseline to evaluate their hepatic steatosis and fibrosis using controlled attenuation parameter (CAP) and liver stiffness (LS) measurements, respectively. Among those without advanced fibrosis at baseline, reassessment VCTE was performed to determine whether ≥F3 fibrosis had developed over time. Multivariable logistic regression analysis was used to evaluate the cross-sectional and longitudinal associations of serum TSP2 level with ≥F3 fibrosis.

Results: Baseline serum TSP2 level was independently associated with the presence of ≥F3 fibrosis (odds ratio [OR] 5.13, P < 0.001). The inclusion of serum TSP2 level significantly improved the identification of ≥F3 fibrosis by clinical risk factors. Over a median follow-up of 1.5 years, 8.8% developed ≥F3 fibrosis. Baseline serum TSP2 level was significantly associated with incident ≥F3 fibrosis (OR 2.82, P = 0.005), independent of other significant clinical risk factors of fibrosis progression, including BMI, platelet count, and CAP at baseline.

Conclusions: Circulating TSP2 level was associated with both the presence and the development of advanced fibrosis and might be a potentially useful prognostic biomarker for the development and progression of liver fibrosis in patients with type 2 diabetes and NAFLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / pathology
  • Fibrosis
  • Humans
  • Liver / pathology
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / pathology
  • Non-alcoholic Fatty Liver Disease* / complications
  • Non-alcoholic Fatty Liver Disease* / diagnostic imaging
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Thrombospondins


  • Biomarkers
  • Thrombospondins
  • thrombospondin 2

Associated data

  • figshare/10.2337/figshare.14673267