Acute effects. Vitamin D deficiency produces a range of clinical effects.a-c One well-documented consequence of vitamin D deficiency is osteomalacia—bone demineralization—which produces characteristic bone deformity and growth retardation in children.d,e In adults, osteomalacia may manifest as diffuse pain bone discomfort and muscle aches that may resemble fibromyalgia or arthritis.f Because vitamin D receptors are present in skeletal muscle, deficiency also may lead to proximal muscle weakness; an increased risk of falls; global bone discomfort, often elicited with pressure over the sternum or tibia; and low back pain in older women.c,f
Long-term effects. A large epidemiologic study found that adults with 25-hydroxyvitamin D (25[OH]D) levels <21 ng/mL had an increased risk of hypertension, diabetes, obesity, and dyslipidemia.g Cardiovascular mortality was higher in individuals with 25(OH)D levels <10 ng/mL compared with those with >40 ng/mL.h Adolescents in the National Health and Nutrition Examination Survey-III with serum 25(OH)D levels <15 ng/mL were more likely to have elevated blood glucose levels than those with >26 ng/mL.i Other epidemiologic data have demonstrated associations of vitamin D deficiency with multiple sclerosis, seasonal allergies, asthma, and various infectious diseases.j,k
Because vitamin D is known to promote cellular differentiation and inhibit cellular proliferation, its role in cancer has been studied extensively. A recent meta-analysis of case-control studies found that the odds of colon cancer were reduced by >40% for each 20 ng/mL increase in serum 25(OH)D levels.l Another meta-analysis reported a lower risk of breast cancer among women in the highest quartile of 25(OH)D values compared with the lowest quartile.m
References
- Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353-373.
- Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73-78.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
- Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(4):1080S-1086S.
- Bordelon P, Ghetu MV, Langan RC. Recognition and management of vitamin D deficiency. Am Fam Physician. 2009;80(8):841-846.
- Hicks GE, Shardell M, Miller RR, et al. Associations between vitamin D status and pain in older adults: the Invecchiare in Chianti study. J Am Geriatr Soc. 2008;56(5):785-791.
- Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167(11):1159-1165.
- Ginde AA, Scragg R, Schwartz RS, et al. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc. 2009;57(9):1595-1603.
- Reis JP, von Mühlen D, Miller ER 3rd, et al. Vitamin D status and cardiometabolic risk factors in the United States adolescent population. Pediatrics. 2009;124(3):e371-379.
- Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86(1):50-60.
- Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
- Yin L, Grandi N, Raum E, et al. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther. 2009;30(2):113-125.
- Chen P, Hu P, Xie D, et al. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat. 2010;121(2):469-477.
Vitamin D’s role in the brain
Vitamin D’s role in psychiatric illnesses is suggested by region-specific expression of vitamin D receptors (VDR) in the cingulate cortex, thalamus, cerebellum, amygdala, and hippocampus.12 Most of these regions also express 1α-hydroxylase enzymes capable of metabolizing 25(OH)D to 1,25(OH)2D3, which suggests that vitamin D may have an autocrine or paracrine function in brain.13
Vitamin D regulates expression of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, norepinephrine, and epinephrine.14 Vitamin D also promotes survival of monoaminergic neurons through upregulation of glial cell line-derived neurotrophic factor, which supports survival of midbrain dopaminergic neurons and confers resistance to neurotoxins that deplete dopaminergic neurons in Parkinson’s disease.15 Vitamin D also promotes neuronal survival by inhibiting oxidative pathways in the brain through inhibition of inducible nitric oxide synthase (reducing free radical formation)16 and upregulation of γ-glutamyl transpeptidase (increasing antioxidant production).17 Vitamin D may play a neuroprotective role through regulation of calcium channels. In vitro studies have shown that vitamin D downregulates expression of L-type calcium channels, conferring protection against excitatory neurotoxins in cultured neurons.18 Proteomic analysis of brain tissue in a rat model of developmental vitamin D revealed dysregulation of 36 brain proteins involved in many biologic pathways involved in calcium homeostasis, synaptic plasticity, and neurotransmission.19 Taken together, these findings suggest vitamin D has a neurosteroid-like role in the CNS.