Serum vitamin D and vitamin-D-binding protein levels in children with chronic hepatitis B

ARTICLE HIGHLIGHTS

Research background

Vitamin D is an essential fat-soluble secosteroid hydroxylated by the liver to form the intermediate metabolite {calcidiol, 25-hydroxy vitamin D [25(OH)D]}, which is a reliable indicator for investigating individual vitamin D status. Vitamin D is known to promote absorption of calcium and regulate skeletal function and is a powerful modulator of the immune response. Vitamin-D-binding protein (VDBP) as the major transport protein of vitamin D and its metabolites is mainly synthesized by the liver, and VDBP has many other physiological roles, including regulation of bone development, scavenging actin, and regulation of immune and inflammatory processes. Immune and inflammatory responses are involved in chronic liver injuries and fibrogenesis of chronic hepatitis B (CHB). It has been demonstrated that serum levels of vitamin D and VDBP are associated with the development and progress of CHB. However, few studies have been reported about the relationship of vitamin D and VDBP with hepatitis B virus (HBV) replication and hepatic fibrosis in children with CHB. It is of interest to investigate the clinical significance of serum vitamin D and VDBP levels in children with CHB.

Research motivation

Few studies have been reported about the serum levels of vitamin D and VDBP and their clinical significance in children with CHB. Some studies have revealed that vitamin D can reduce profibrotic factors and collagen expression and that they have immunomodulatory effects on immune cells, including T cells. Patients infected with HBV is pathologically characterized as the functional impairment of T cells. The elimination of HBV in CHB patients largely depends on the cellular immune response mediated by T helper (Th)1 cells. Combination of the active form of vitamin D and vitamin D receptor may inhibit the proliferation of Th1 cells and the release of cytokines, and concurrently activate Th2 cells, thus regulating immune responses. Vitamin D and its metabolites in the circulation are mainly transported by VDBP, which is a multifunctional plasma glycoprotein that can mediate monocyte and neutrophil chemotaxis to inflammatory foci caused by HBV replication. The present study aimed at exploring the clinical significance of serum 25(OH)D and VDBP levels in children with CHB. The results will help to illustrate whether vitamin D and VDBP levels are associated with HBV replication and hepatic fibrosis.

Research objectives

The main objective of this study was to investigate the serum levels of vitamin D and VDBP in children with CHB and analyze the association of vitamin D and VDBP with HBV replication and hepatic fibrosis.

Research methods

We enrolled 204 children with CHB who were admitted to Hunan Children’s Hospital in summer and autumn between 2018 and 2019 and 170 healthy controls. Children with CHB included: 164 hepatitis B e antigen (HBeAg) positive and 40 HBeAg negative; 193 hepatitis B surface antigen (HBsAg) positive and 11 HBsAg negative; 164 with detectable HBV DNA and 40 with undetectable HBV DNA; 131 with HBV genotype B and 23 with HBV genotype C; and 97 with hepatic fibrosis and 27 without hepatic fibrosis. Serum levels of 25(OH)D, VDBP, liver function markers, and other clinical parameters were collected for analysis of the association with vitamin D and VDBP. Mann-Whitney U test, Kruskal-Wallis H test, or t test was used to analyze serum 25(OH)D and VDBP levels in different groups of subjects. Spearman rank correlation test was utilized to analyze the correlation of 25(OH)D and VDBP with other markers. Finally, statistically significant factors for hepatic fibrosis determined by univariate analysis were further analyzed by binary multivariate logistic regression analysis.

Research results

Children with CHB had lower serum 25(OH)D (56.64 ± 17.89 nmoL/L) and VDBP [122.40 (70.74-262.84 μg/L)] levels than healthy controls had (P < 0.001). Serum 25(OH)D and VDBP levels were significantly different among the stages of hepatic fibrosis (P < 0.05). Patients with HBV genotype C, HBsAg, HBeAg, and detectable HBV DNA had lower VDBP levels than patients with HBV genotype B, without HBsAg and HBeAg, and undetectable HBV DNA (P < 0.05). Serum 25(OH)D level was negatively correlated with age and serum total bilirubin level (r = -0.396 and -0.280, respectively, P < 0.001). Serum VDBP level was negatively associated with HBV DNA (log₁₀ IU/mL) (r = -0.272, P < 0.001). Serum 25(OH)D level was not correlated with VDBP level (P > 0.05). Univariate (P < 0.05) and multivariate logistic regression analysis showed that low level of 25(OH)D (odds ratio = 0.951, 95% confidence interval: 0.918-0.985) and high level of HBV DNA (odds ratio = 1.445, 95% confidence interval: 1.163-1.794) were independently associated with hepatic fibrosis (P < 0.01).

Research conclusions

Children with CHB have lower serum levels of 25(OH)D and VDBP. Serum VDBP level is negatively correlated with replication of HBV. Low level of 25(OH)D is independently associated with hepatic fibrosis in CHB children. There is no significant association between serum levels of 25(OH)D and VDBP.

Research perspectives

Previous studies and our data indicate that vitamin D and VDBP are involved in the inflammatory response and immunological regulation in children with CHB. Vitamin D may play an antifibrotic role by reducing stimulation of hepatic stellate cells, profibrotic factors, and collagen expression. VDBP may have a positive effect on alleviating liver injury caused by HBV replication. We speculate that sufficient concentration of vitamin D and VDBP in children with CHB may be beneficial for the progress and prognosis of the disease. The potential value of vitamin D detection in monitoring hepatic fibrosis development and VDBP detection in evaluating the degree of inflammation and liver injury, more detailed mechanism of vitamin D and VDBP on the progression of CHB, and whether VDBP analogs may become a treatment measure for children with CHB warrant further investigation.