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

Abstract

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.

Correlation between T-Lymphocyte Subsets, Regulatory T Cells, and Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver

“…In addition, we found that Th17/Treg was positively correlated with AST, ALT, PCIII, CIV, LN, HA, MDA, and inflammatory factors, and negatively correlated with SOD and GSH-PX by the Pearson correlation coefficient, indicating that elevated Th17/Treg would promote liver injury, hepatic fibrosis, inflammation, and OS. It is well known that hepatic fibrosis appears after almost all chronic liver injuries and is a dynamic process in which various cells such as hepatic parenchymal cells, hepatic stellate cells, hepatic sinusoidal endothelial cells, and a series of cytokine interactions involved jointly mediate the process of hepatic fibrosis, which is a necessary stage of progression to cirrhosis and a common pathological process in many chronic liver diseases [ 23 , 24 ]. Thus, we believe that due to the imbalance of Th17/Treg, hepatocytes can undergo degeneration and necrosis under the long-term inflammatory infiltration and oxidative reaction of lipids, forming a large amount of extracellular matrix (such as noncollagenous glycoproteins and proteoglycans), remaining collagen components, and accumulating in large amounts, which eventually cause fibrosis.…”

Non‐alcoholic fatty liver disease and type 2 diabetes: An update

“…In contrast, our group recently showed that among 682 type 2 diabetes patients from hospital clinics, 8.8% developed AF (defined as LS ≥9.6 kPa) over a median follow‐up period of 1.5 years. Those who were obese, with low platelet count and high hepatic steatosis on VCTE at baseline were at increased risk of incident AF 78 . Therefore, it is recommended that patients with fibrosis at baseline should be monitored at least annually, whereas those without can be monitored every 2–3 years, provided there is no worsening of concomitant metabolic risk factors.…”

“…There have also been suggestions on the direct use of VCTE in fibrosis risk stratification among type 2 diabetes patients 74 . Several recent studies worldwide using VCTE assessments alone have reported a high prevalence of moderate‐to‐advanced liver fibrosis in type 2 diabetes patients, ranging from 15% to 27% 75 , 76 , 77 , 78 . However, VCTE is not widely available in healthcare institutions, and even if it is, given the large volume of type 2 diabetes patients with NAFLD, it is still a challenge to provide timely assessments to all patients with type 2 diabetes in both primary and secondary care sectors.…”

Thrombospondin 2 Promotes IL-6 Production in Osteoarthritis Synovial Fibroblasts via the PI3K/AKT/NF-κB Pathway

“…TSP2 was proposed as prognosis marker in liver fibrosis, 47,48 non-alcoholic fatty liver disease, 49 and different cancers. [50][51][52][53] This study demonstrates that TSP2 is an important player in OA pathogenesis, with a positive correlation observed between TSP2 expression and synovial tissue inflammation, suggesting TSP2 could been developed as novel osteoarthritis marker.…”