Vitamin D Deficiency: Impact on Neuropsychiatric...

Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Vitamin D Deficiency:

Impact on Neuropsychiatric

Disorders

(page 177 in syllabus)

Martha P. Fankhauser, MS Pharm, FASHP, BCPP

Clinical Professor, College of Pharmacy

Pharmacotherapy Specialist, College of Public Health

Clinical Specialist/Pharmacology, Psychology Department

The University of Arizona

Sponsored by the Neuroscience Education Institute

Additionally sponsored by the American Society for the Advancement of Pharmacotherapy

This activity is supported solely by the sponsor, Neuroscience Education Institute.


Faculty Author/ Presenter

Martha P. Fankhauser, MS Pharm, FASHP, BCPP, is a clinical professor at

the College of Pharmacy, a pharmacotherapy specialist at the College of

Public Health, and a clinical specialist/pharmacology in the psychology

department at The University of Arizona in Tucson.

No other financial relationships to disclose.

Individual Disclosure Statement


Learning Objectives

• Identify populations at risk of vitamin D

deficiency

• Identify consequences of vitamin D deficiency


Overview

• Vitamin D physiology

– Sources

– Blood levels of 25(OH)D and 1,25(OH)2D

– Vitamin D receptors (VDR)

• Populations at risk for deficiency

• Replacement therapy and monitoring

• Controversies

– Bone vs body/brain health

– Recommended daily requirements

– Blood levels of 25(OH)D

– Research on prevention and treatment


Pretest Question 1

Which of the following is not associated with

vitamin D deficiency?

1. Malabsorption syndromes

2. Inhibition of CYP enzymes

3. Chronic kidney disease

4. Hyperparathyroidism

5. Obesity (BMI > 30 kg/m2)


Pretest Question 2

Which of the following is not an action of

vitamin D?

1. Vasculoprotection

2. Promotes insulin secretion

3. Reduces inflammation

4. Increases cell proliferation

5. Promotes innate immunity


• Vitamin D is a steroid hormone (pro-hormone)

– Made from cholesterol metabolism in skin (activated in

liver and kidney); classified as a hormone

– 25(OH)D is 90-99% bound to vitamin D binding protein

– 1,25(OH)2D binds to nuclear hormone vitamin D

receptors, where it acts as a molecular switch to signal

target genes

– It is estimated that 2,000 genes are primary targets of

activated vitamin D

• May induce expression of CYP3A4

Vitamin D: The Sunshine Vitamin


Vitamin D and Whole Body Health

• Rickets

• Osteoporosis/osteomalacia

• Periodontal disease

• Cardiovascular disease: hypertension

• Malabsorption: cystic fibrosis, Crohn’s disease

• Cancer: colon, breast, ovarian, prostate cancer

• Rheumatoid arthritis

• Diabetes: types 1 and 2

• Infectious diseases

• SLE

• Allergies

• Mood disorders – Seasonal affective disorder

– Bipolar disorder

– Recurrent unipolar disorder

– Postpartum depression

• Brain development – Autism

– Schizophrenia

• Cognitive disorders – Dementia

• Multiple sclerosis

• Parkinson’s disease

• Muscle weakness and pain

• Fibromyalgia

• Headaches


• 25-hydroxy vitamin D = 25(OH)D – Inactive precursor = calcidiol

– Plasma half-life = 2-3 weeks

– Usually measured to assess vitamin D deficiency or excess

– Reference: 10-100 ng/mL • May be lower in the winter with low sun exposure

• 20-30 ng/mL for bone health and 30-100 ng/mL for whole body health (~ 40-60 ng/mL)

• 1,25-dihydroxy vitamin D = 1,25(OH)2D – Biologically active = calcitriol

– Plasma half-life = 4-6 hrs

– Usually used to evaluate hypercalcemia

– Reference: 15-60 ng/mL

Vitamin D Levels


• 1,25(OH)2D binds to VDRs

– Bone mineral homeostasis (metabolism and calcium/ phosphorus homeostasis)

– Hormone secretion, immune function, cellular proliferation and differentiation

– VDRs are found in most tissues and cells in the body

• VDR polymorphisms

– Mutation of VDRs: type 2 vitamin D-dependent rickets (HVDRR) is an autosomal recessive disorder

• Associated with alopecia and the development of rickets within the first two years of life

• Failure of 1,25(OH)2D binding to receptors

Vitamin D Receptors (VDRs)


• A certain amount of shortwave ultraviolet B radiation (290-315 nm) must penetrate the outer skin layer in order to produce vitamin D3

– Arm and leg exposure to sunlight: 3,000 IU vitamin D3

• Depends on time of day, season, latitude

– Problem: darker skin, obesity, using > 30 SPF sunscreen or protective clothing

• Approximately 90% of vitamin D is synthesized in the skin via UV radiation and activated by the kidneys

– 10% comes from foods such as fatty fish and egg yolks without fortified foods or replacement products

Synthesis of Vitamin D3


• Vitamin D2 (ergocalciferol)

– Produced from ergosterol in a variety of plants and yeast by UVR

– Lower levels of 25(OH)D than vitamin D3 (30% effective)

• Vitamin D3 (cholecalciferol)

– Animal/fish sources, supplementation or fortification of dairy

– Produced from 7-dehydrocholesterol in the skin under the influence of UVB radiation (UVR) • Both the intensity of UVR and the level of pigmentation in the skin

regulate the rate of D3 formation

– Stable to heat, light, and storage

– More active than vitamin D2

Vitamin D: D2 vs D3


Life Stage Estimated Average

Requirement (IU/d)

Recommended Dietary

Allowance (IU/d)

Upper Level Intake (IU/d)

Infants 0-6 mos 400 400 1,000

Infants 6-12 mos 400 400 1,500

1-3 yrs 400 600 2,500

4-8 yrs 400 600 3,000

9-13 yrs 400 600 4,000

14-18 yrs 400 600 4,000

19-30 yrs 400 600 4,000

31-50 yrs 400 600 4,000

51-70 yrs 400 600 4,000

71+ yrs 400 800 4,000

14-50 yrs

pregnant/lactating 400 600 4,000

http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/DRI-Values.aspx.

Dietary Reference Intakes for Vitamin D

IOM Report – 11/30/2010


Endocrine Society

Clinical Practice Guidelines

• Vitamin D deficiency is very common in all age groups

• Because few foods contain vitamin D, supplements are recommended

– D3 vs D2

D3 is 87% more potent in raising blood levels of 25(OH)D3

• Serum 25(OH)D should be used for patients at risk for deficiency

– Deficient: < 20 ng/mL

– Insufficient: 21-29 ng/mL

– Sufficient: > 30 ng/mL

Holick MF et al. J Clin Endocrin Metab 2011;96:1911-30;

Heaney RP et al. J Clin Endocrin Metab 2011;96:E447-52.


Endocrine Practice Guidelines

Life Stage Daily Requirement Tolerable Upper Limit

Infants 0-6 mos 400-1,000 IU 2,000 IU

Infants 6-12 mos 400-1,000 IU 2,000 IU

1-3 yrs 600-1,000 IU 4,000 IU

4-8 yrs 600-1,000 IU 4,000 IU

9-13 yrs 600-1,000 IU 4,000 IU

14-18 yrs 600-1,000 IU 4,000 IU

19-30 yrs 1,500-2,000 IU 10,000 IU

31-50 yrs 1,500-2,000 IU 10,000 IU

51-70 yrs 1,500-2,000 IU 10,000 IU

71+ yrs 1,500-2,000 IU 10,000 IU

19-50 yrs

pregnant/lactating 1,000-2,000 IU 10,000 IU

Holick MF et al. J Clin Endocrin Metab 2011;96:1911-30.


Natural Sources of Vitamin D2 and D3

Sources and Content Typical Vitamin D Content

Salmon, fresh, wild (3.5 oz) 600-1,000 IU (D3)

Salmon, fresh, farmed (3.5 oz) 100-250 IU (D2 or D3)

Salmon, canned (3.5 oz) 300-600 IU (D3)

Sardines, canned (3.5 oz) 300 IU (D3)

Mackerel, canned (3.5 oz) 250 IU (D3)

Tuna, canned (3.6 oz) 230 IU (D3)

Cod liver oil (1 tsp) 400-1,000 IU (D3)

Shitake mushrooms, fresh (3.5 oz) 100 IU (D2)

Shitake mushrooms, sun-dried (3.5 oz) 1,600 IU (D2)

Egg yolk 20 IU (D2 or D3)

Exposure to sunlight, UVB (0.5 MED) 3,000 IU (D3)

Adapted from Zhang, Naughton. Nutr J 2010;9:1-13.


Fortified Foods With Vitamin D3

Sources and Content Typical Vitamin D Content

Fortified butter 50 IU/3.5 oz (D3)

Fortified margarine 430 IU/3.5 oz (D3)

Fortified milk 100 IU/8 oz (D3)

Fortified yogurts 100 IU/8 oz (D3)

Fortified cheeses 100 IU/3 oz (D3)

Fortified orange juice 100 IU/8 oz (D3)

Fortified breakfast cereals 100 IU/serving (D3)

Infant formulas 100 IU/8 oz (D3)

Adapted from Zhang, Naughton. Nutr J 2010;9:1-13.


Sources of Vitamin D

Pharmaceutical Sources Vitamin D Content, IU = 25 mg

Vitamin D2 (ergocalciferol)

50,000 IU/capsule

Drisdol (vitamin D2 liquid)

8,000 IU/cc

Supplements

Multivitamin (D2 or D3)

400; 500; 1,000 IU

Calcium + Vitamin D3 400 IU

Vitamin D3

400, 800, 1,000; 2,000; 5,000;

10,000; 50,000 IU


• Diminished cutaneous synthesis

– Season, latitude, time of day

– Darker skin, sunscreen, lack of sun exposure

– Obesity

• Impaired availability of vitamin D

– Inadequate intake (oily fish, fortified foods, supplements)

– Lack of fat in the diet for gut absorption

– Malabsorption disorders

– Lipase inhibitor (orlistat)

– Reduced cholesterol levels

• Cholestyramine, lipid-lowering agents

Causes of Vitamin D Deficiency



• Obesity with storage of vitamin D in fat

• Impaired liver hydroxylation to produce 25(OH)D

• Increased hepatic catabolism of 25(OH)D

– Carbamazepine, phenobarbital, phenytoin, rifampin,

HIV medications

• Impaired renal production of 1,25(OH)2D



• Abnormal binding proteins

• Abnormal receptor binding

• Genetic variant

– Cholesterol synthesis

– Hydroxylation of vitamin D

– Vitamin D transport

Wang TJ et al. Lancet 2010;376:180-8.


• Darker skin: African-American and Hispanic

• Winter months/lack of sunlight (UV radiation)

• Lack of fortified foods or supplements

• Elderly

• Infants and children

• Pregnant or lactating women

• Hospitalized/institutionalized patients

• Chronic renal and/or liver disease

• Gastrointestinal diseases, malabsorption, or gastric bypass

• Obesity (BMI > 30 kg/m2)

• Low cholesterol levels for synthesis

• Drugs that affect vitamin D metabolism or absorption (e.g., anticonvulsants, glucocorticoids, antifungal drugs, HIV medications, cholestyramine)

Risk of Vitamin D Deficiency

Zhang, Naughton. Nutr J 2010:9:1-13.


Jablonski NG, Caplin G. J Hum Evolution 2000;39:57-106.


• One billion people worldwide have vitamin D deficiency

– Lowers life expectancy and may increase mortality rates

• Mostly attributable to people getting less sun exposure because of climate, lifestyle, and concerns about skin cancer

• 1997 Dietary Reference Intake values for vitamin D were established to prevent rickets and osteomalacia

• 2010 Institute of Medicine (IOM) Report increased recommended daily intakes for bone health

– Current studies suggest we need high serum levels of 25(OH)D to prevent chronic diseases (40-60 ng/mL)

Worldwide Issue

Holick MF. Curr Drug Targets 2011;12:4-18; Garland CF et al. Anticancer Res

2011;31:607-12; Grant WB. Eur J Clin Nutr 2011;DOI:10.1038/ejcn.2011.68;

Ross AC et al. J Clin Endocrin Metab 2011;96:53-8.

Copyright © 2011 Neuroscience Education Institute. All rights reserved. Ginde AA et al. Arch Intern Med 2009;169:626-32.

Mean Serum 25-hydroxyvitamin D (25[OH]D) Levels in the Third National Health and Nutrition Examination Survey (NHANES III)

(1988-1994) and in NHANES 2001-2004, Stratified by Demographic Characteristics


Indications for 25(OH)D Levels

• Rickets

• Osteomalacia/osteoporosis

• Chronic kidney disease

• Hepatic failure

• Malabsorption syndrome – Cystic fibrosis

– Inflammatory bowel disease

– Crohn’s disease

– Bariatric surgery

– Radiation enteritis

• Hyperparathyroidism

• Some lymphomas

• African-American/Hispanic

• Pregnant/lactating women

• Older adults with hx of falls or nontraumatic fractures

• Obesity (BMI > 30 kg/m2)

• Granuloma-forming disorders – Sarcoidosis

– Tuberculosis

– Histoplasmosis

– Coccidiomycosis

– Berylliosis

• Medications – Antiseizure, glucocorticoids, HIV

medications, antifungals, cholestyramine

Holick et al. J Clin Endocrinol Metab 2011;96(7):1911-30.


Serum Levels (ng/mL) Health Status

< 10 (< 25 nmoL/L)

Associated with vitamin D deficiency and rickets in

infants and young children

10-20 (25-50 nmoL/L)

Generally considered inadequate for bone and

overall health in healthy adults

20-30 (50-75 nmoL/L)

Generally considered adequate for bone health:

IOM recommended 20-30 ng/mL

< 30-32 (< 75-80 nmoL/L)

Insufficiency for overall health

32-100 (80-250 nmoL/L)

Proposed as desirable for overall health and

disease prevention: 40-60 ng/mL target levels

> 200 (> 500 nmoL/L)

Considered potentially toxic, leading to

hypercalcemia, hypercalciuria, nephrolithiasis,

hyperphosphatemia, soft tissue calcification

25-hydroxyvitamin D3 (25[OH]D)


Vitamin D Toxicity

• Extremely rare

• Doses > 50,000 IU/d raises 25(OH)D more

than 150 ng/mL

– Associated with hypercalcemia and

hyperphosphatemia

– High calcium doses increase risk

• Doses of 10,000 IU/d D3 for up to 5 months

does not cause toxicity

Zhang, Naughton. Nutr J 2010;9:1-13.


• Inhibits parathyroid hormone secretion

• Promotes insulin secretion

• Neuroimmunomodulator

– Promotes innate immunity (activates T cells)

– Inhibits adaptive immune response

– Inhibits cell proliferation

– Reduces inflammation

– Promotes wound healing

• Neuroprotective function

Actions of Vitamin D

Nimitphong H, Holick MF. Curr Opin Clin Nutr Metab Care 2011;14:7-14.


http://images.google.com/imgres?imgurl=http://ownurlife.files.wordpress.com/2009/04/rickets23.jpg&imgrefurl=http://ownurlife.wordpress.com/2009/05/07/minimum-wage-for-nutrition/&usg=__atcTF2awaj6Cmevra3QhT_R7fS8=&h=426&w=300&sz=11&hl=en&start=4&um=1&itbs=1&tbnid=EZtmFRUAOF1b0M:&tbnh=126&tbnw=89&prev=/images?q=rickets&hl=en&rlz=1T4DMUS_enUS297US298&sa=N&um=1


Skeletal/Muscular Vitamin D Deficiency

• Rickets → bone deformity

• Osteomalacia → bone/muscle pain

• Osteopenia → osteoporosis

• Bone fractures/falls – Calcium + vitamin D = ↓ falls in elderly

• Periodontal disease → tooth loss

• Muscle weakness/aches/pain – Often misdiagnosed as fibromyalgia or chronic

fatigue syndrome

Holick MF. Curr Drug Targets 2011;12:4-18;

Nimitphong H, Holick MF. Curr Opin Clin Nutr Metab Care 2011;14:7-14.


• Cancer – Colon, breast, ovarian, pancreatic, lymphoma, prostate(?)

– Melanoma

• Cardiovascular – Hypertension

• Autoimmune/immune – Multiple sclerosis, type 1 diabetes, rheumatoid arthritis,

autoimmune thyroid disease, Crohn’s disease, asthma

– Interstitial lung disease: systemic lupus, scleroderma, Sjögren’s syndrome

– Infections: HIV, tuberculosis, viral infections, UTIs

– Allergic reactions: allergies, hives

• Dermatological (psoriasis, acne)

Nonskeletal Vitamin D Deficiency


• Neurodevelopment

– Neurocognitive development, attention deficit

disorder, autism spectrum disorder

• Mood

– Depression, seasonal affective disorder, bipolar

disorder, PMS, postpartum depression

• Psychosis

– Schizophrenia

Vitamin D Deficiency in the Brain

Nimitphong H, Holick MF. Curr Opin Clin Nutr Metab Care 2011;14:7-14;

Holick MF. Curr Drug Targets 2011;12:4-18; Zhang, Naughton. Nutr J 2010:9:1-13.


Vitamin D Deficiency in the Brain

• Parkinson’s disease

• Alzheimer’s disease/dementia

• Multiple sclerosis

• Migraines/headaches

• Seizures

• Strokes

• Blindness/macular degeneration

Nimitphong H, Holick MF. Curr Opin Clin Nutr Metab Care 2011;14:7-14; Holick MF. Curr Drug Targets 2011;12:4-18.


Most American Children Are Not Getting

Enough Vitamin D

• Lack of synthesis of vitamin D from sun

exposure and use of sunscreen in summer

months

– Caucasians may make enough with adequate

outdoor UVB exposures if they do not use sunscreen

• Importance of vitamin D supplements and

fortified foods

– US Food and Drug Administration

Godar DE et al. Environ Health Perspect 2011;Epub ahead of print;DOI:10.1289/ehp.1003195.


• Vitamin D deficiency is present in 40-80% of pregnant women

• 70% of children in US are deficient in vitamin D

• Early deficiency may increase the risk of many chronic diseases – Osteomalacia, rickets, multiple sclerosis, heart

disease, type 1 diabetes, asthma, cancer, and mental illness

Vitamin D and Perinatal Health

Brannon PM, Picciano MF. Annu Rev Nutr 2011;31:89-115;

Kaludjerovic J, Vieth R. J Midwifery Women’s Health 2010;55(6):550-60;

Kumar J et al. Pediatrics 2009;124:e362-70.


• Recent IOM recommendation for vitamin D3 supplementation during pregnancy and breastfeeding is low (600 IU/day) – Recommendations of up to 4,000 IU/day without

sun exposure or risk factors

– A daily dose of 400 IU D3 raises 25(OH)D by 2.8-4.8 ng/mL

• Estimates of vitamin D deficiency in pregnant women are between 5-50%, with African-American women at a much higher risk – Supplements may improve fetal growth and infant

weight

Vitamin D and Pregnancy

Vieth R et al. Am J Clin Nutr 2007;85:649-50; Holmes VA et al. Br J Nutr 2009;102(6):876-81.


Vitamin D and Neurodevelopment

• Brain development in utero depends on mother’s

vitamin D levels

– Sun exposure, dietary intake, or supplements

• Brain development after birth depends on sun

exposure and vitamin D dietary intake or

supplements

– Increased risk of food and environmental allergies and

asthma

Sharief et al. J Allergy Clin Immunol 2011;DOI:10.1016/j.jaci.2011.01.017;

Arnedo-Pena A et al. Int J Biometerol 2010;53(3):423;DOI:10.1007/s00484-010-0353-x.


• Increases nerve growth factor in the brain

– Nootropic or brain-enhancing

• Vitamin D receptors appear in a wide variety of

brain tissue early in brain development

• Estrogen and testosterone have different effects

on vitamin D metabolism

– Estradiol has enhancing effects on vitamin D metabolism, whereas testosterone does not

– Higher rates of autism, ADHD, and Tourette syndrome in boys



• Prepregnancy to first 24 months of a child’s life

has profound effects on human health

• Higher fish consumption during pregnancy has

been associated with better infant cognition:

vitamin D and omega-3 fatty acids

• Lower maternal seafood consumption has been

associated with increased risk of lower verbal IQ,

poor outcomes for social behaviors, fine motor

skills, communication, and social development



• Government recommendations for infants, children,

pregnant women, and young adults are too low

without sun exposure

• Prenatal vitamins and infant drops contain 400 IU of

vitamin D3 and may be inadequate for infant

development

• Sun protection during pregnancy and for children

increases the risk of vitamin D deficiency

• Children and adolescents who do not drink vitamin D

fortified milk or eat oily fish may be vitamin D deficient without supplementation



• Infant formula is fortified with vitamin D3

• Human milk varies with sun exposure and

D3 intake

• Breast milk contains the 25-hydroxycholecalciferol form of

vitamin D (less active)

• The liver in infants is not that functional for the first

hydroxylation of cholecalciferol

• Requires up to 4,000 units/day of vitamin D3

supplementation in mother to achieve healthy levels

in infants

• Breastfed babies should be supplemented with

vitamin D3 immediately after birth

Infant Formula vs Breast Milk

Brannon PM, Picciano MF. Annu Rev Nutr 2011;31:89-115;

Abrams SA. Annu Rev Nutr 2011;31:285-97.


• Premature labor and preeclampsia

• Increased risk of low birth weight

• Rickets, weaker bones, fractures

• Defects in tooth enamel, dental caries

• Hypocalcemic seizures or tetany

• Type I diabetes

• Asthma

• Allergies

• Viral bronchitis and pneumonia in first year of life

• Anemia with low hemoglobin

• Multiple sclerosis in adulthood

• Neurodevelopmental disorders

Vitamin D: Pregnancy/Infancy

Brannon PM, Picciano MF. Annu Rev Nutr 2011;31:89-115.


Signs of Vitamin D Deficiency

• Gastrointestinal: malabsorption, GERD

• Autoimmune: allergies, asthma, type 1 diabetes

• Bone/muscular: dental caries, bone fractures, osteomalacia, osteoporosis, muscular pain or sprains

• Neuropsychiatric:

– Developmental disorders

– Attention deficit disorder

– Mood disorders: depression, bipolar disorder

– Psychotic disorders: schizophrenia

– Headaches


• Increased rates of autism in blacks (or dark-skinned

individuals who immigrated to the north) vs whites

• Increased rates of autism in northern latitudes

• Increased rates of autism births in the winter,

especially in March, when vitamin D levels are low

– Storage of vitamin D may be lowest in March after a

long winter with little sunlight exposure

• Children conceived in winter have increased risk of

being diagnosed with autism (December – March)

Autism Spectrum Disorders

Cannell JJ. Med Hypotheses 2008;70:750-9.


Mood Disorders: Depression

• Association between low vitamin D levels and depression:

– Bertone-Johnson et al. Am J Clin Nutr. 2011.

DOI:10.3945/ajcn.111.017384.

• Reduction in depressive symptoms for over 800 IU D3 in

postmenopausal women

– Ganji V et al. Int Arch Med. 2010;3(29):1-8.

– Hoogendijk WJG et al. Arch Gen Psychiatry. 2008;65(5):508-12.

– Jorde R et al. J Intern Med. 2008;264:599-609.

– Murphy PK et al. J Am Psychiatr Nurs Assoc. 2011;16(3):170-7.

– Penckofer S et al. Issues Ment Health Nurs. 2010;31:385-93.

– Shipowick CD et al. Appl Nurs Res. 2009;22:221-5.

– Stewart R, Hirani V. Psychosom Med. 2010;72:608-12.

– Wilkins C et al. Am J Geriatr Psychiatry. 2006;14:1032-40.


Mood Disorders: Depression

• Equivocal results

– May HT et al. Am Heart J. 2010;159:1037-43.

– Nanri A et al. Eur J Clin Nutr. 2009;63:1444-7.

– Pan A et al. J Affective Disord. 2009;118:240-3.

– Zhao G et al. Br J Nutr. 2010;20:1-7.

• No benefit of high doses (500,000 IU D3/yr

for 3-5 yrs) in women 70 yrs and older

– Sanders KM et al. Br J Psych. 2011;198:357-64.


• Children (N=67) with severe mental health disorders, including psychosis, had twice the rate of vitamin D deficiency as mentally healthy children

– < 20 ng/ml 25(OH)D = deficiency

• 21% (1 out of 5)

– < 30 ng/mL 25(OH)D = insufficiency

• 61% (2 out of 3)

– “The prevalence of vitamin D deficiency (43%) was most common in children with psychotic disorders compared to other mental health disorders.”

Vitamin D and Mental Disorders

Zhang M et al. Presented at: 164th Annual Meeting of the American Psychiatric Association;

NR01-67; May 2011; Honolulu, HI.


Schizophrenia

• Decreased Risk

– Increased sun exposure

– Vitamin D supplementation during first year of

life (for males only)

• Increased Risk

– Black skin

– Winter births (December − March)

– Low levels of 25(OH)D

Kaludjerovic J, Vieth R. J Midwifery Women’s Health 2010;55(6):550-60; McGrath J.

Schizophr Res 1999;40:173-7; McGrath J et al. Schizophr Res 2004;67:237-45;

Nimitphong H, Holick MF. Curr Opin Clin Nutr Metab Care 2011;14:7-14;

Schneider B et al. J Neural Transm 2000;107:839-42.


• Vitamin D has vasculoprotective roles in the brain

• Vitamin D deficiency is associated with cognitive impairment in elderly women, all-cause dementia, Alzheimer’s disease, stroke (with and without dementia symptoms), and cerebrovascular disease

– Vitamin D supplements may improve or maintain cognition

– Important role in brain function and development

Cognition

Annweiler C et al. Neurology 2010;74:27-32; Buell JS et al. Neurology 2010:74:18-26;

Ginde A et al. J Am Geriatr Soc 2009;57:1595-603; Kalueff A et al. CNS Neurol Disord Drug Targets

2006;5:363-71; Miller JW. Neurology 2010;74:13-5; Oudshoorn C et al. Geriatr Cogn Disord

2008;25:539-43; Przybelski R, Binkley N. Arch Biochem Biophys 2007;460:202-5; Slinin Y et al.

Neurology 2010;74:33-41; Wilkins C et al. Am J Geriatr Psychiatry 2006;14:1032-40.


• African-Americans are about twice as likely to have Alzheimer's disease than whites, and Hispanics are about 1.5 times more likely than whites to develop the disease

• No known genetic factor for these differences

• High blood pressure and diabetes are more prevalent in the African-American and Hispanic communities

• No mention of darker skin color or possible link with vitamin D deficiency

Alzheimer’s Disease: 2010 Report

http://www.alz.org/documents_custom/report_alzfactsfigures2010.pdf.


• Vitamin D insufficiency (lower 25(OH)D levels <

30 ng/mL) reported in patients with PD

compared to controls

– Lower sun exposure and decreased activity outside

• More severely affected PD patients had a higher

prevalence of 25(OH)D deficiency than less

severely affected patients with a shorter disease

duration

Parkinson’s Disease

Evatt ML et al. Arch Neurol 2008;64(10):1348-52; Evatt ML et al. Arch Neurol

2011;68(3):314-9; Newmark HL, Newmark J. Mov Disord 2007;22(4):461-8;

Sato Y et al. Neurology 1997;49(5):1273-8.


• Possible association between the amount of sunlight that children are exposed to and whether or not they will develop MS as adults

• Most cases of this degenerative neural disorder are in the temperate regions of the world, where the sunlight is rarely intense

• Children growing up in tropical and subtropical regions rarely develop MS regardless of where their ancestors came from

Multiple Sclerosis

Correale J et al. Brain 2009;132:1146-60; Kaludjerovic J, Vieth R. J Midwifery Women’s

Health 2010;55(6):550-60; Munger KL et al. JAMA 2006;23:2832-8;

Munger KL et al. Neurology 2004;62:60-5; Nimitphong H, Holick MF. Curr Opin Clin Nutr

Metab Care 2011;14:7-14; Smolders J et al. J Neuroimmunology 2008;194:7-17.


Multiple Sclerosis

• Decreased Risk – Increased sun exposure during early life

– UV exposure and 25(OH)D inversely associated with MS relapse

– Fall births

– White skin lowers prevalence of MS disability

– Consumption of fish 3-4 times a week

– Intake of vitamin D is inversely associated with MS risk

• Increased Risk – Darker-skinned immigrants in higher latitudes

– Spring births

– Low fish intake and high meat/dairy products intake

Kaludjerovic J, Vieth R. J Midwifery Women’s Health 2010;55(6):550-60;

Lucas RM et al. Neurology 2011;76(6):540;DOI:10.1212/WNL.0b013e31820af93d.


• Chronic, late-onset disease due to degeneration of the macula

– Leading cause of irreversible vision loss in developed countries

– Affects approximately 8.5 million Americans aged 40 yrs and older

– No cure for the condition

• Vitamin D may protect against age-related macular degeneration (AMD)

– Reduces inflammation

Macular Degeneration

Millen AE et al. Arch Opthalmol 2011:129(4):481-9;

Parekh N et al. Arch Opthalmol 2007;135:661-9.


Potential Benefits of Vitamin D

• Skeletal

– Improved bone density and fewer fractures and falls

• Nonskeletal

– Lowered mortality rate – elderly women in institutions

– Reduced risk of cancer

– Reduced risk of multiple sclerosis

– Reduced risk of allergy and asthma

– Reduced risk of infections

– Reduced risk of renal disease

– Reduced musculoskeletal pain

– Reduced risk of mental illness

Thacher TD, Clarke BL. Mayo Clin Proc 2011;86(1):50-60;

Bjelakovic G et al. Cochrane Collaboration 2011;7:1-186.


Summary

• Vitamin D deficiency is very common and a

potentially serious problem

• Requires population-based screening of serum

25(OH)D levels

– High-risk and critically ill patients

– Serum levels 30-100 ng/mL (~ 40-60 ng/mL)

• Supplements should be titrated to achieve serum

levels

– Vitamin D2 vs D3

– Daily vs weekly vs monthly dosing

– Monitor upper limits closely: > 10,000 IU/d D3 or > 100

ng/mL 25(OH)D


Research Questions

• Serum 25 (OH)D levels: what is the best for bone vs whole body health?

• Is there a safe level of sun exposure that provides sufficient vitamin D levels but does not increase the risk of skin cancer?

• Does high doses of calcium plus vitamin D cause toxicities (e.g., hypercalcemia, kidney stones)?

• Does vitamin D induce CYP3A4 enzymes and increase the metabolism of CYP3A4 substrates?

• Studies needed for preventative and treatment effects of vitamin D on mortality, cardiac disease, cancer, diabetes, autoimmune disorders, infections, and neuropsychiatric disorders

Brannon PM et al. Am J Clin Nutr 2008;88(Suppl):483S-90S;

Lindh JD et al. Drug Metab Dispos 2011;39:933-7.

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