Explain how vitamin D is formed and metabolized.

Counsel patients, such as pregnant women and nursing mothers, about adequate vitamin D intake.

Discuss sources of vitamin D and at-risk populations.

List benefits of vitamin D, based on recent data.

Describe effects of vitamin D on risk for schizophrenia, multiple sclerosis, and Parkinson’s disease.

Vitamin D Metabolism and Skeletal Health
Vin Tangpricha, MD, PhD, Assistant Professor of Medicine, Emory University School of Medicine, Atlanta, GA

Vitamin D: vitamin D3 —cholecalciferol; produced in skin or obtained through fatty fish consumption; vitamin D2 — ergocalciferol; obtained from irradiated fungi and yeasts; both forms used to fortify foods and supplements

Metabolism of vitamin D: skin—exposure to sunlight breaks β ring of 7-dehydrocholesterol (compound in skin) to form previtamin D; previtamin D undergoes thermally induced isomerization to form vitamin D3 ; vitamin D3 enters circulation bound to vitamin D-binding protein; further irradiation of previtamin D results in inactive vitamin D compounds (eg, lumisterol, tachysterol); liver and kidney—vitamin D circulates to liver and hydroxylated to form 25-hydroxyvitamin D (major circulating form used to determine patient’s vitamin D status); 25-hydroxyvitamin D circulates to kidney and hydroxylated to form 1,25-dihydroxyvitamin D (hormonal form; conversion controlled by parathyroid hormone [PTH]); vitamin D binds to vitamin D receptor (VDR) and enters cell nucleus, then binds to retinoid X receptor (RXR) and goes to vitamin D response elements on DNA; results in increased transcription of genes (for, eg, calcium transport and bone metabolism)

Studies on prevention of osteoporosis and fractures: 1992— >3000 elderly women living in retirement facility randomized to vitamin D (800 IU/day) and calcium; after 18 mo, hip fracture reduced by 43%, bone mineral density (BMD) at hip increased by nearly 5%, nonvertebral fractures reduced by 25%, and BMD at nonvertebral sites increased by 3.7%; positive studies—used vitamin D, 700 to 1100 IU/day; achieved serum levels of 30 ng/mL; adherence high (80%); negative studies— adherence low (30%-60%); serum levels did not reach 30 ng/mL; used 400 to 800 IU/day; study—36 000 postmenopausal women randomized to vitamin D (400 IU/day) and calcium (1000 mg/day); caveats— few women had osteoporosis (3% had T scores <-2.5); low compliance (59%); results—after 9 yr, BMD unchanged (compared to baseline) in women taking vitamin D and calcium, but significantly higher than those taking placebo; no difference in vertebral BMD; with exclusion of women who did not take >80% of medication, risk reduction in hip fracture, 29%

Optimal vitamin D and PTH levels: 30 ng/mL currently suggested optimal level for vitamin D; study randomized women with 3 different vitamin D levels to 50 000 IU once weekly for 8 wk; found PTH levels decreased in group with levels <15 ng/mL and group with levels 16 to 19 ng/mL, but PTH unchanged in group with >20 ng/mL (suggests women with <20 ng/mL had subclinical vitamin D deficiency and subclinical hyperparathyroidism); study found maximum PTH suppression occurs at 31 ng/mL (levels <31 ng/mL resulted in higher PTH levels, indicating subclinical hyperparathyroidism); suggested cutoff based on data, 30 ng/mL

Calcium absorption: vitamin D levels of 30 to 32 ng/mL resulted in maximum calcium absorption; individuals with <30 ng/mL of vitamin D had lower calcium absorption

Comprehensive Look at Benefits of Vitamin D
Michael F. Holick, MD, Professor of Medicine, Physiology, and Biophysics, Boston University Medical Center, Boston, MA

Infants and pregnancy: vitamin D-deficient infants never attain genetically preprogrammed bone density or height; important to be vigilant; study—40 mother-infant pairs; mothers took vitamin D (400 IU/day) in multivitamin and drank 2.3 glasses of milk per day; at time of birth, 76% of mothers and 81% of newborns vitamin D-deficient; higher 25-hydroxyvitamin D levels reduce likelihood for development of preeclampsia in women and need for cesarean delivery; all pregnant women should take 1000 IU/day in addition to prenatal vitamin and drinking 2 glasses of milk per day; 4000 to 6400 IU/ day required to increase concentration in human milk (long-term consequences unknown; “it’s not something we’re recommending”); American Academy of Pediatrics now recommends all infants receive 400 IU/day from birth

Sources of vitamin D: cod liver oil; oily fish (eg, salmon, mackerel, herring); analysis found essentially no vitamin D in farm-raised salmon, compared to wild-caught salmon; exposure to sunlight—during winter (November through February), vitamin D production low in areas north of Atlanta, GA; sunscreen with sun protection factor (SPF) 15 reduces vitamin D production by 95% to 99%; advanced age reduces ability to produce vitamin D; obesity causes vitamin D deficiency (obese patients need 2-3 times more vitamin D than normal-weight patients); depending on time of day, season, and latitude, recommend 5 to 15 min/day (2 times per week) of sun exposure to arms and legs; blacks have lower vitamin D production, due to skin pigmentation (5-10 times sun exposure required to slightly raise blood levels of vitamin D); most blacks in United States vitamin D-deficient

Vitamin D levels: deficiency often misdiagnosed; test for 25-hydroxyvitamin D; toxicity occurs at ≥150 ng/mL; studies show PTH levels plateau when vitamin D levels reach 30 to 40 ng/mL; >30 ng/mL shown to maximize intestinal calcium transport; National Osteoporosis Foundation recommends 800 to 1000 IU/day for all adults; speaker recommends 1000 IU/day in addition to multivitamin, 1 to 2 glasses of milk per day, and adequate calcium; preferred range, 30 to 100 ng/ mL

Epidemiology of vitamin D deficiency: unrecognized epidemic in adults >50 yr of age; 42% of young adults; at end of winter, 48% of young white girls in Maine who took multivitamin (vitamin D, 400 IU/day) and 2 glasses of milk per day vitamin D deficient; 52% of Hispanic and black adolescents in Boston; 25% of children in United Arab Emirates and Saudi Arabia have evidence of rickets

Osteomalacia: generalized and isolated bone pain; isolated muscle aches; pain; often misdiagnosed as chronic fatigue syndrome or depression; 40% to 60% dramatically improve with correction of vitamin D deficiency (usually takes ≥3 mo); periosteal bone pain (press with thumb or forefinger on sternum and anterior tibia; if patient winces, osteomalacia likely); higher 25-hydroxyvitamin D levels associated with higher function of lower extremities and higher BMD

Fractures: adequate vitamin D and calcium reduce risk for vertebral and nonvertebral fractures by ≈50%; Women’s Health Initiative—concluded no benefit from calcium and vitamin D, but most women admitted to poor adherence; when compliance good, reduction in hip fracture 29% (statistically significant)

Antiepileptic drugs and bone health: interaction of VDR with 1,25-dihydroxyvitamin D and RXR activates 24-hydroxylase gene, which destroys excess 1,25-dihydroxyvitamin D; steroid and xenobiotic receptor (SXR) binds RXR and glucocorticoid; antiseizure medication activates system and induces 24-hydroxylase to destroy 1,25-dihydroxyvitamin D and 25-hy-droxyvitamin D; patients on most medications more likely to become vitamin D deficient

Treatment of vitamin D deficiency: multivitamin; vitamin D2 (50 000 IU once weekly for 8 wk, then 50 000 IU every 2 wk “forever”); vitamin D2 and D3 appear equally effective; study found ≤10000 IU/day for 6 mo did not lead to intoxication

Cancer: insufficient sun exposure and vitamin D deficiency associated with increased risk for cancer; study data show— residents of New England states more likely to die from cancer than residents of southern states (eg, Georgia, Alabama); residence in higher latitudes associated with higher risk for colorectal, breast, and prostate cancers; projected 50% reduction in developing colorectal cancer with use of 1000 IU/day; women on highest amount of vitamin D had lowest risk for breast cancer; greater lifetime sun exposure reduces likelihood of dying from cancer; young girls exposed to sunlight reduced risk for breast cancer by 69% (young women by 51%; in women >45 yr of age, no benefit); inverse relationship between vitamin D status and risk for deadly cancers (30%-50% reduced risk with level >20 ng/mL); vitamin D-deficient women followed for 8 yr had 253% increased risk for colorectal cancer; retrospective study of women who took calcium (1500 mg/day) and vitamin D (1100 IU/day) found 60% reduction in risk for all cancers; activated vitamin D inhibits cancer cell growth; hypothesis—with sufficient 25-hydroxyvitamin D levels, autocrine function performed in most cells that have 1-hydroxylase to make 1,25-dihydroxyvitamin D for regulation of cell growth and other processes; vitamin D then induces own destruction and never enters circulation; when blood levels >30 ng/mL, 1,25-dihydroxyvitamin D can be made locally; data suggest ≤ 2000 genes directly or indirectly regulated by 1,25-dihydroxyvitamin D

Vitamin D and risk reduction: immune system—inactivated T and B lymphocytes have no VDR, but activated ones do; cytokine production and immunoglobulin synthesis regulated by 1,25-dihydroxyvitamin D; maternal intake of vitamin D during pregnancy reduces risk for wheezing disorder in children by ≤61%; vitamin D protects against tuberculosis, influenza, and upper respiratory infection; arthritis—women who took >400 IU/day reduced risk for rheumatoid arthritis by 44%; significant association between vitamin D deficiency and osteoarthritis; hypertension—raising level of 25-hydroxyvitamin D to >30 ng/mL by UV radiation exposure in tanning beds shown to resolve hypertension; marked reduction in peripheral vascular disease when 25-hydroxyvitamin D at ≈30 ng/mL; heart failure— sufficient vitamin D reduces risk for myocardial infarction (MI) by 50%; men with vitamin D <15 ng/mL have 142% increased risk for MI (72% when level 23-30 ng/mL); level of 28 ng/mL reduces risk for all-cause and cardiovascular mortality; meta-analysis showed that >500 IU/day reduces risk for death by ≤7%; 1000 IU/day recommended; sun exposure—angle of sun’s rays important, eg, early morning sun too oblique and does not stimulate vitamin D synthesis; excessive sun exposure increases risk for nonmelanoma skin cancer; occupational sun exposure decreases risk for malignant melanoma; lifetime sun exposure associated with lower risk for malignant melanoma; “a little sun is good as long as we don’t overdo it”; 10 min/day recommended

Vitamin D and Neurologic Disorders
Marian L. Evatt, MD, Assistant Professor of Neurology, Emory University, School of Medicine, and Assistant Chief of Neurology, Movement Disorders Program, Wesley Woods Geriatric Hospital, Inc, Atlanta

Introduction: vitamin D critical for all stages of nervous system development; vitamin D deficiency may contribute to neuro-psychiatric problems, autoimmune diseases, seizures and epilepsy, and neurodegenerative diseases; neurotrophic support critical to central nervous system (CNS); nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) regulated by vitamin D, and bind to specific protein kinase receptors to promote cell survival and differentiation of neurons; glial-derived neurotrophic factor (GDNF) regulated by vitamin D and important for survival of dopaminergic neurons; vitamin D fat- soluble and crosses blood-brain barrier; activating enzyme that converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D widespread in peripheral and CNS; activating enzyme and vitamin D receptor found in substantia nigra (highest concentration; center for dopaminergic circuits within brain), hippocampus, and hypothalamus

Regulation of target genes by vitamin D: neurotrophin expression (may affect differentiation and survival of dopaminergic and other neurons); synaptogenesis (formation of connections between brain and peripheral nerve cells); synaptic plasticity (important in memory formation); neurotransmitter synthesis; generation of toxic free radicals; maintenance of calcium signaling and homeostasis

Seizures: hypercalcemic seizures secondary to rickets in infants; older anticonvulsant agents may increase metabolism of vitamin D, leading to iatrogenic vitamin D deficiency, with loss of seizure control; study of patients with intractable epilepsy found 30% reduction in frequency of seizures with vitamin D (4000 or 16000 IU/day); animal models— 1,25-dihydroxyvitamin D increases seizure threshold for rat hippocampal cells; after exposure to toxins, latency to seizures shorter in mice lacking vitamin D receptor (knock-out mice), compared to wild-type mice; through its receptor, vitamin D down-regulates interleukin-6 (IL-6; proconvulsant) and up-regulates GDNF and NT-3 (anticonvulsant neurotrophic factors); vitamin D stimulates expression of calcium-binding proteins known to exert antiepileptic effects

Schizophrenia: associated with increased activation of dopa-mine (hyperactive); however, in some areas of brain, dopamine may be hypoactive; risk for schizophrenia increased in those born in winter or spring months; mothers with low vitamin D have children at increased risk; risk diminished in infants supplemented with vitamin D during first year of life; vitamin D deficiency may increase risk

Multiple sclerosis (MS): caused by autoimmune demyelination of nervous system; geographic distribution—lower prevalence in areas closer to equator; risk increases towards more northerly and southerly latitudes; risk associated with area of residence up to age 15 to 16 yr; studies found residents and those who performed outdoor work in high sunlight areas had markedly decreased odds of developing MS (in case-controlled studies, findings “a mixed bag; in general, tendency towards decreased odds ratio”); longitudinal studies found statistically significant (60%) risk reduction with vitamin D (400 IU/day); dietary intake and higher serum levels of 25-hydroxyvitamin D correlate with reduced risk for MS; 1980s study of 16 patients with MS treated with combination of minerals and vitamin D saw fewer exacerbations than expected (9 exacerbations, 22 expected; open-label study [“hard to make many conclusions”]); study using 6-mo supplementation with 25 µg of vitamin D saw increase in serum 25-hydroxyvitamin D and “good” cytokines, and decrease in “bad” cytokines; study of 12 patients treated with 1000 µg/day for 28 wk saw decreased number of lesions on brain imaging studies; role of vitamin D in pathogenesis and treatment of MS

Parkinson’s disease: characterized by tremors, gait disorder, and rigidity in muscle tone; nonmotor symptoms (eg, depres sion, anxiety, cognitive problems, fatigue) recently recognized as more common and more disabling symptoms; pathogenesis—multifactorial; mitochondrial dysfunction; may be affected by certain toxins; inflammation; patients may be more susceptible to oxidative stress and inappropriate apoptosis; long-term inadequate vitamin D intake hypothesized to contribute to pathogenesis; geographic distribution—similar to that of MS; prevalence rate in northern states, 1.6 to 1.3 per 100000 (1.0-1.1 per 100000 in southern states); in animal models, pretreatment with active vitamin D may reduce toxicity of Parkinson’s disease; vitamin D transcription necessary for inducing GDNF (critical for support of dopaminergic neurons); analysis of database from speaker’s facility found prevalence of vitamin D deficiency in patients with Parkinson’s disease higher than in healthy controls