Serum Bioavailable, Rather Than Total, 25‐hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival

Abstract

BaCKgRoUND aND aIMS:Free and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. appRoaCH aND ReSUltS: We included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum-free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable-adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. CoNClUSIoNS:Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis. (Hepatology 2020;0:1-14).

Vitamin D and Clinical Cancer Outcomes: A Review of Meta‐Analyses

“…( 71 ) As evidence of importance, a large, prospective cohort study reported that higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in patients with hepatocellular carcinoma. ( 72 ) Further, in a recent RCT of patients with digestive tract cancer, vitamin D supplementation improved 5‐year relapse‐free survival in those with low bioavailable 25OHD, but not in those with high bioavailable 25OHD ( 71 ) or in those with low total 25OHD (<20 ng/mL). ( 73 ) These studies suggest that for some cancer types, free and bioavailable 25OHD may better assess true vitamin D status (and deficiency) than total 25OHD in future trials.…”

Effect of Vitamin D Deficiency on Liver Cancer Risk: A Systematic Review and Meta-Analysis

“…Nevertheless, the evidence of the association of vitamin D with liver cancer risk remains controversial. Fang et al, (2019) shown that 25(OH)D levels were associated with risk of liver cancer in the population-based HCC cohort in China. Therefore, our meta-analysis aimed to explore the correct relationship between vitamin D and liver cancer risk.…”

“…The five cohort studies (Wong et al, 2015;Sanjeev et al, 2018;Finkelmeier et al, 2014;Buonomo et al, 2019;Fang et al, 2019) consisting of 9,347 incident cases, and 6 case-control studies (Wang et al, 2013;Nghiem et al, 2016;Hammad et al, 2013;Veronika et al, 2014;Schaalan et al, 2012;Gabriel et al, 2018) consisting 1723 cases and 1825 controls were included. Among these, 4 studies were conducted in the Europe (Finkelmeier et al, 2014;Buonomo et al, 2019;Veronika et al, 2014;Gabriel et al, 2018), 2 in the Egypt (Hammad et al, 2013;Schaalan et al, 2012), 5 in Asia (Wang et al, 2013;Wong et al, 2015;Sanjeev et al, 2018;Fang et al, 2019;Nghiem et al, 2016). The included studies, basic characteristics of enrolled patients, and surgical techniques are presented in Table 1.…”

Effect of Vitamin D Supplementation on Survival of Digestive Tract Cancer Patients with Low Bioavailable 25-Hydroxyvitamin D Levels: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

“…To our knowledge, this is the first report showing that vitamin D supplementation may improve the survival of patients with low bioavailable 25(OH)D levels in patients with digestive tract cancer. Other studies have shown that high bioavailable levels, but neither free nor total 25(OH)D levels, are positively associated with survival time of patients with hepatocellular carcinoma [10] and with colorectal cancer [11], although both studies were observational. Those results are considered consistent with the results of this study.…”

“…Because DBP has a 1000-fold stronger affinity for 25(OH)D than albumin, cancer cells cannot easily take up DBP-bound 25(OH)D, but they can easily take up bioavailable 25(OH)D [9]. In a prospective cohort study of 1031 patients with hepatocellular carcinoma, higher bioavailable levels, but not total or free 25OHD levels, were associated with improved survival [10]. We thus hypothesized that bioavailable 25(OH)D might be a more appropriate marker of vitamin D insufficiency than total 25(OH)D levels, and that vitamin D supplementation may improve the survival of patients with low bioavailable levels of 25(OH)D.…”