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Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia.

ABSTRACT: To investigate the mechanism of 25 hydroxyvitamin D (25(OH)D) deficiency in children with biliary atresia (BA) and its effect on liver fibrosis. The serum vitamin D and 25(OH)D, and expression of 25 hydroxylase (CYP2R1 and CYP27A1) in the liver of BA patients were detected and compared with those in the control group. We investigated the effect of differential expression of CYP2R1 in hepatocytes on the expression of genes related to liver fibrosis in primary hepatic stellate cells (HSCs) of BA and animal models of cholestasis. The ratio of 25(OH)D/vitamin D in the BA group was significantly lower than that in the control group. The mRNA and protein expression of CYP2R1 and CYP27A1 in liver tissue of the BA group was significantly lower than that in the control group. Exogenous active vitamin D (calcitriol) inhibited the proliferation and migration of primary HSCs isolated from BA patients, and reduced the expression of fibrosis-related genes in vitro. Downregulation of expression of CYP2R1 in hepatocytes increased expression of transforming growth factor (TGF)-β1, collagen (Col)-1α1 and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased the expression of matrix metalloproteinase (MMP)-2 in cocultured primary HSCs of BA. Upregulation of expression of CYP2R1 in mice with bile duct ligation significantly increased the level of 25(OH)D, decreased the expression of TGF-β1, Col-1α1 and TIMP-1, and increased the expression of MMP-2. Children with BA have impaired vitamin D activation due to CYP2R1 deficiency. The dysactivation of vitamin D can promote the proliferation and activation of HSCs and participate in the development of hepatic fibrosis in BA.

SUBMITTER: Sun S

PROVIDER: S-EPMC8494743 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We investigated noninvasive follow-up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin <20 µmol/L after PE (n = 39), Metavir fibrosis stage was evaluated at PE and in follow-up protocol liver biopsies (n = 83). PH was defined as endoscopically confirmed esophageal varices or thrombocytopenia associated with splenomegaly. The accuracy of liver biochemistry and stiffness in detecting liver fibrosis and PH was analyzed by the area under the receiving operating characteristic curve (AUROC) and multiple regression models. During a median native liver survival of 8.3 years (interquartile range 2.5-10.8 years), cirrhosis (Metavir F4) had developed in 51% of patients and PH in 54% of patients. Cirrhosis was equally common in all age tertiles of 1.2-2.1 years (n = 10/27), 3.9-5.8 years (n = 12/28), and 9.0-14 years (n = 12/28). In the two oldest age tertiles, histologic liver fibrosis had progressed further in patients with PH than without PH (P < 0.001). PH was accurately predicted by the aspartate aminotransferase-to-platelet ratio index (APRI) (cutoff, 0.70; AUROC, 0.92), bile acids (cutoff, 49 µmol/L; AUROC, 0.91), and liver stiffness (cutoff, 16.9 kPa; AUROC, 0.89; P < 0.001 each) across all age tertiles. Liver stiffness was the most accurate predictor of cirrhosis overall (AUROC, 0.82; P < 0.001), whereas bilirubin was >11 µmol/L in the youngest tertile (AUROC, 0.91; P < 0.001), bile acids was >80 µmol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.

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Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia.

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