Vitamin D serum level is associated with Child-Pugh score and metabolic enzyme imbalances, but not viral load in chronic hepatitis B patients

Abstract

Vitamin D deficiency is common in patients with chronic liver diseases. However, vitamin D status in persons with chronic hepatitis B virus (HBV) infection is not consistently reported. Specifically, the impact of liver dysfunction on vitamin D status has not been well addressed.We recruited a group of patients (n = 345) with chronic hepatitis B (n = 115), hepatitis B related cirrhosis (n = 115), and age- and gender-matched healthy controls (n = 115). Serum 25-hydroxyvitamin D3 [25(OH)D3], its related metabolic enzymes, intact parathyroid hormone were measured. Calcium, magnesium, and phosphorus were obtained from medical record.Serum 25(OH)D3 levels in chronic hepatitis B patients (7.83 ± 3.47 ng/mL) were significantly lower than that in healthy controls (9.76 ± 4.36 ng/mL, P < 0.001), but significantly higher than that in hepatitis B-related cirrhotic patients (5.21 ± 3.67 ng/mL, P < 0.001). Furthermore, 25(OH)D3 decreased stepwise with higher Child-Pugh classification. However, there were no significant differences in 25(OH)D3 levels between (1) hepatitis B e antigen (HBeAg +) and HBeAg(-) persons, or (2) among persons with different HBV viral load, or (3) between treatment naïve and patients on antiviral therapy. Multiple logistic regression analyses confirmed that higher Child-Pugh score was independently associated with 25(OH)D3 deficiency (<10 ng/mL) with an odds ratio of 1.20 (confidence interval 1.03-1.39, P = 0.016). Levels of cytochrome P450 (CYP) 27A1 were significantly decreased, whereas levels of CYP24A1 were significantly elevated in cirrhotic patients.These results suggest that decreasing vitamin D levels are likely to be a result, rather than a cause, of liver dysfunction and irrespective of HBV viral load. Reduction in 25(OH)D3 levels is possibly due to downregulation of the synthetic hydroxylase CYP27A1 and concurrent upregulation of degrading CYP24A1 in patients with liver cirrhosis.

Figure 1

Flow chart for the selection of chronic hepatitis B, cirrhotic patients and non-HBV controls. Out of a total of 940 chronic hepatitis patients, 230 patients qualified and were matched by age and gender. About 115 controls were selected from 408 healthy subjects without HBV infection, who were also matched by age and gender with chronic hepatitis B and cirrhotic patients.

Figure 2

Vitamin D serum concentration significantly decreased with the deteriorated of liver function. Vitamin D serum concentration of CHB patients significantly higher than non-HBV control but significantly lower than that of cirrhotic patients (A). Vitamin D serum concentrations dropped along with Child–Pugh Class in cirrhotic group (B). One-way ANOVA test were used to do the statistical analysis, P < 0.05 was treated as significant difference. CHB = chronic hepatitis B, HBV = hepatitis B virus, Control = non-HBV infected healthy control, LC = HBV-related cirrhosis.

Figure 3

Viral factors were not associated with serum level of vitamin D. No significant difference of vitamin D serum concentrations between HBeAg (+) and HBeAg (–) chronic hepatitis B patients by independent t test (A). No significantly difference among patients with high, moderate, and low viral groups by one-way ANOVA test. (B). None significantly difference between patients on antiviral therapy using nucleoside analogs and treatment naïve by independent t test (C). In 15 paired patients prior and after antiviral therapy, vitamin D level remains no statistical difference by paired-samples t test (D).

Figure 4

Dysregulation of hydroxylases serum levels relevant to vitamin D metabolism is the possible mechanism of the vitamin D deficiency. Cytochrome P450 cytosomal CYP2R1 for the synthesis of vitamin D, was significantly up regulated (A). In contrast, mitochondrial CYP27A1 the other key synthesizer of vitamin D, was significantly downregulated with the severity of liver dysfunction (B). Degrading CYP24A1 was significantly up regulated (C). One-way ANOVA test was used to do the statistical analysis, P < 0.05 was treated as significant difference. Control = non-HBV–infected healthy control, LC = HBV-related cirrhosis.