Re: Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort
To the Editor:
We read with great interest the study by Budhathoki et al, BMJ 2018;360:k671 (1), where the authors reported an association between plasma 25-hydroxyvitamin D levels and overall risk of developing cancer. Subgroup analyses showed significant associations especially in i) breast cancer in pre-menopausal women and ii) liver cancer. We believe that at least the latter finding should be interpreted with caution.
Vitamin D is metabolised in the liver into its major circulating form, 25-hydroxyvitamin D, which was evaluated in the abovementioned study (1). The foremost risk factor for developing hepatocellular carcinoma (the most common type of primary liver cancer in adults) is pre-existing cirrhosis, which often is considered a premalignant condition (2), justifying the recommendation of biannual surveillance by means of liver ultrasonography in hepatitis C virus (HCV) infected cirrhotic patients (3). Cirrhosis furthermore augments the risk of developing other malignancies (4).
As liver function declines in more advanced stages of liver fibrosis, especially in decompensated cirrhosis, the ability to metabolise vitamin D into 25-hydroxyvitamin D also is affected, leading to lower concentrations (5).
We previously performed a multicentre therapeutic trial among HCV genotype 2 or 3 infected patients (the NORDynamIC study) (6). A pre-treatment liver biopsy was mandatory and liver fibrosis was evaluated using the Ishak protocol, where fibrosis stage 0 indicates no fibrosis, 1-2 mild fibrosis, 3-4 bridging fibrosis, and 5-6 cirrhosis. In a post-hoc analysis, pre-treatment plasma concentrations of 25-hydroxyvitamin D were determined (Architect 25-hydroxyvitamin D assay, Abbot diagnostics). Cirrhotic patients (i.e. Ishak fibrosis stage 5-6) had significantly lower concentrations as compared to those among non-cirrhotic patients (mean 52 nmol/L ± 18 (SD) (n=43) vs. 60 nmol/L ± 23 (SD) (n=288) respectively, p=0.03 Student’s T-test). When dividing the patients according to quartiles based on 25-hydroxyvitamin D concentrations, as performed in the study by Budhathoki et al, we noted that 16 of 83 (19%) in 0-25th percentile, 11 of 83 (13%) in the 25th-50th percentile, 10 of 83 (12%) in the 50th-75th percentile and 6 of 82 (7%) in the 75th-100th percentile had cirrhosis, and the difference was significant when comparing the 0-25th and 75th-100th percentiles (p=0.04 Fisher’s exact test).
In light of these findings from the NORDynamIC trial, pre-existing cirrhosis should have been accounted for and discussed as a potential underlying confounding factor in the study by Budhathoki et al. Additionally, enhancing vitamin D concentrations without simultaneously attempting to ameliorate advanced stages of liver fibrosis may not lead to decreased risk of developing liver cancer.
1. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-29.
2. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35-50.
3. Lagging M, Wejstal R, Duberg AS, Aleman S, Weiland O, Westin J, et al. Treatment of hepatitis C virus infection for adults and children: updated Swedish consensus guidelines 2017. Infect Dis (Lond). 2018:1-15.
4. Kalaitzakis E, Gunnarsdottir SA, Josefsson A, Bjornsson E. Increased risk for malignant neoplasms among patients with cirrhosis. Clin Gastroenterol Hepatol. 2011;9(2):168-74.
5. Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010;55(9):2624-8.
6. Lagging M, Langeland N, Pedersen C, Farkkila M, Buhl MR, Morch K, et al. Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology. 2008;47(6):1837-45.
Competing interests: No competing interests