J.-C. Souberbielle

The role of hypovitaminosis D as a possible risk factor for multiple sclerosis is reviewed. First, it is emphasized that hypovitaminosis D could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. Secondly, the classical physiological notions about vitamin D have recently been challenged and the main new findings are summarized. This vitamin could have an important immunological role involving a number of organs and pathologies, including autoimmune diseases and multiple sclerosis. Furthermore, human requirements for this vitamin are much higher than previously thought, and in medium- or high-latitude countries, they might not be met in the majority of the general population due to a lack of sunshine and an increasingly urbanized lifestyle. Thereafter, the different types of studies that have helped to implicate hypovitaminosis D as a risk factor for multiple sclerosis are reviewed. In experimental autoimmune encephalomyelitis, vitamin D has been shown to play a significant immunological role. Diverse epidemiological studies suggest that a direct chain of causality exists in the general population between latitude, exposure to the sun, vitamin D status and the risk of multiple sclerosis. New epidemiological analyses from France support the existence of this chain of links. Recently reported immunological findings in patients with multiple sclerosis have consistently shown that vitamin D significantly influences regulatory T lymphocyte cells, whose role is well known in the pathogenesis of the disease. Lastly, in a number of studies on serum levels of vitamin D in multiple sclerosis, an insufficiency was observed in the great majority of patients, including at the earliest stages of the disease. The questionable specificity and significance of such results is detailed here. Based on a final global analysis of the cumulative significance of these different types of findings, it would appear likely that hypovitaminosis D is one of the risk factors for multiple sclerosis.

CONTEXT: Loss-of-function mutations of CYP24A1 (which encodes the 25-OH-D3-24-hydroxylase) have recently been reported to cause hypercalcemia. OBJECTIVES: The aims of this study were: 1) to evaluate the frequency of CYP24A1 mutations in patients with medical history of hypercalcemia; 2) to show the clinical utility of a simultaneous assay of serum 25-hydroxyvitamin D3 (25-OH-D3) and 24,25-dihydroxyvitamin D3 (24,25-[OH]2D3) by liquid chromatography tandem mass spectrometry (LC-MS/MS); and 3) to investigate biochemical parameters in heterozygous gene carriers with CYP24A1 mutations. PATIENTS AND METHODS: We screened for CYP24A1 mutations in 72 patients with serum calcium levels > 2.6 mmol/L and PTH levels < 20 pg/mL and recruited 24 relatives after genetic counseling for subsequent investigations. Vitamin D metabolite concentrations were assessed in a subset of patients by LC-MS/MS and results expressed as a ratio (R) of 25-OH-D3:24,25-(OH)2D3. RESULTS: Twenty-five patients with hypercalcemia (35%) harbored CYP24A1 variations. Twenty (28%) had biallelic variations, mostly found in subjects with nephrocalcinosis or renal stones (19/20). Five patients, all neonates, were heterozygous, without renal disease. We describe 15 new variations leading to loss-of-function according to pathogenicity prediction programs, and we functionally characterized 5 of them in vitro. A dramatic increase of R, usually >80, was found in patients harboring biallelic mutations providing evidence in vivo for the loss of CYP24A1 activity. In contrast, R value remains <25 in patients without CYP24A1 mutations. Subjects carrying one mutant allele, hypercalcemic individuals, as well as gene-carrier relatives, had a detectable 24,25-(OH)2D3 level and R < 25, indicating normal 24-hydroxylase activity. CONCLUSION: CYP24A1 biallelic mutations are frequently found in patients presenting with hypercalcemia, low PTH, and renal disease. We confirm the accuracy and effectiveness of a novel blood test estimating the ratio between relevant vitamin D metabolites as a useful screening tool for CYP24A1 mutations. Haploinsufficiency is not associated with CYP24A1 deficiency.

BACKGROUND: There is growing evidence of the usefulness of vitamin D supplementation in dialysis patients who are most often vitamin D deficient. Due to the long half-life of vitamin D, there is much interest in administering it intermittently for long-term adherence. However, there are no data to indicate which dosage would be most efficient. Objective. The aim was to assess the long-term efficiency and safety of a monthly oral dose of cholecalciferol (100 000 IU) in vitamin D-deficient haemodialysis (HD) patients. METHODS: HD patients with a serum 25-hydroxyvitamin D (25(OH)D) level <75 nmol/L were enrolled in a 15-month prospective study. The exclusion criteria were as follows: use of any vitamin D derivatives, prescription of cinacalcet and bisphosphonates, uncontrolled hypercalcaemia (>2.55 mmol/L), hyperphosphataemia (>2 mmol/L) and severe secondary hyperparathyroidism (SHPT; serum PTH >600 pg/mL). Biological data were recorded in the following months: M-3, M0, M1, M3, M9 and M15. We aimed to maintain stable levels of the phosphate binder and oral and dialysate calcium during the course of the study. RESULTS: Of the 250 patients screened, 161 were enrolled, and the results from 107 were recorded at the end of the study. Of these 107 patients, 56% were males, and the average age of the patient group was 66.4 +/- 15 years. Diabetics accounted for 36% of the total patients. The dialysis schedule ranged from 3 x 5 to 3 x 8 h, with a mean dialysate calcium concentration of 1.48 +/- 0.6 mmol/L. After 15 months, the mean serum 25(OH)D level increased from 32 +/- 13 to 105.8 +/- 27 nmol/L (P < 0.001) and plateaued after M3. Of the patients, 91% had a level higher than the target level (>75 nmol/L), while none had levels >200 nmol/L. The serum calcitriol (1,25(OH)(2)D) level increased from 13.7 +/- 14 to 45 +/- 13 pmol/L (P < 0.001) and plateaued after M9. The levels of serum PTH (median 295-190 pg/mL, P < 0.001), bone alkaline phosphatase (20.5 +/- 9-17.1 +/- 7 microg/L, P < 0.05) and beta-cross-laps (2.5 +/- 1-2.07 +/- 0.8 microg/L, P < 0.05) decreased significantly. No significant changes were observed in the values of the following: calcaemia, phosphataemia, blood pressure, serum albumin, haemoglobin and C-reactive protein. CONCLUSIONS: Long-term monthly administration of oral cholecalciferol (100 000 IU) was a safe, effective, inexpensive and simple method for correcting vitamin D deficiency in almost 90% of the HD patients in this study and led to optimal compliance. The most evident consequences were a slight decrease in the levels of PTH and bone markers and an increase in the level of serum 1,25(OH)(2)D.