Transcript Vitamin D - Dr. Tom Archie

Vitamin D
Deficiency, Insufficiency, and
Supplementation
Thomas Archie, MD
St. Luke’s Wood River Family Medicine
Hailey, ID
Overview
 Vitamin D receptors found in gut, bone, brain, breast,
prostate, lymphocytes, placenta, and other tissues
 Routine screening is appropriate
 Safe up to 4000iu/d without monitoring
 Safe up to 10,000iu/d with monitoring
 Supplementation helpful in:
 DM, metabolic syndrome, CAD, depression, autoimmune
diseases, various cancers, HTN, osteoporosis, osteoarthritis,
pain, MS, epilepsy, elderly fall prevention, PCOS, pregnancy &
lactation, periodontal disease, URI and influenza, and
decreasing all-cause mortality
Physiology
 Vitamin D3 (Cholecalciferol)
 Produced in skin with direct sunlight, cod liver oil
 Preferred form of supplementation
 Vitamin D2 (Ergocalciferol)
 Made by irradiating fungi
 Less effective as precursor to 1,25(OH)2-Vit D
Physiology
 Hepatic conversion of Vit D3 to 25-OH-Vit D
(calcidiol)
 Conversion of 25-OH-Vit D to 1,25(OH)2-Vit D
(calcitriol)
 Previously thought exclusively renal
 Requires two factors
 25OH-VitD3-1-alpha-OHase
 Vitamin D Receptor (VDR)
Physiology –
Autocrine Metabolism
 Vitamin D functions as a steroid hormone
 Cells containing 25OH-VitD3-1-alpha-OHase
 Breast, prostate, lung, skin, lymph nodes, colon, pancreas,
adrenal medulla, brain, placenta
 Holllick MF. Am J Clin Nutr. 2004. 79(3):362.
 Zehnder et al. J Clin Endocrin Metab. 2001;86(2)
 Cells containing Nuclear VDR
 Pancreatic islet cells, monocytes, transformed B cells,
activated T cells, neurons, prostate, ovaries, pituitary, aortic
endothelium, placenta, skeletal muscle cells.
 Zittermann A. Br J Nutr. 2003;89(5):552.
 Bischoff HA, et al. Histochem J 2001;33:19.
Calcitriol
 Most biologically active form of Vit D
 Raises GI calcium and phosphorus
absorption
 Induces osteoclast maturation for bone
remodelling
 Promotes calcium deposition in bone and
reduction of PTH
Parathyroid Hormone
 Secondary hyperPTH can be due to
hypovitaminosis D
 25OH-Vit D levels 30-40ng/ml
 Zittermann A. Br J Nutr. 2003;89(5):552.
 Suppression of PTH important
 Low PTH promotes good health
 High PTH associated with increased risk of MI, HTN, stroke
 Kamycheva et al. Eur J Cardiovasc Prev Rehab.
2004;11(1).
 Sato et al. Neurology. 2003;60(4):626.
Calcitriol and Cancer
 Modulates the transcription of several
oncogenes involved with cell differentiation and
proliferation
 C-myc, c-fos, c-sis
 Inverse relationship b/t sun exposure and cancer
mortality
 Grant. Cancer. 2002;94(6):1867.
 Apperly. Cancer Res. 1941;1:191.
Calcitriol and CNS function
 Vit D Modulates neurotransmitter and
neurological function
 Anticonvulsant and antidepressant effect
 Landsdowne et al. Psychopharmacology.
1998;135.
 Christiansen et al. Br Med J.
1974;2(913):258.
Calcitriol
 Reduces inflammation
 Nuclear Vit D receptors in lymphocytes
 Suppresses and may prevent autoimmune
diseases
 Decreases risk of certain cancers
 Seems to reduce severity and frequency of
childhood pneumonia
 Wayse et al. Eur J Clin Nutr. 2004;58(4):563.
Calcium Absorption
 Calcium absorption increases as 25(OH)D
blood levels increase.
 Vit D levels of 34 ng/ml (about 3,000 IU/day) calcium absorption 65% higher than when
levels are 20 ng/ml
 Implies that part of the reason humans need to
take so much extra calcium is because there is
widespread deficiency of vitamin D.
Heaney et al. J Am Coll Nutr. 2003 Apr;22(2):142.
Clinical Relevance
 Coronary artery disease
 Hypertension
 Diabetes Type I and
Type 2
 Osteoarthritis
 Depression
 Epilepsy
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Polycystic Ovaries
Musculoskeletal Pain
Autoimmune Disease
Multiple Sclerosis
Cancers
Falls in the Elderly
Pregnancy and Lactation
Laboratory Assessment
 25-OH-Vitamin D level is the appropriate test
 Typical labeled normal range is 8-40ng/ml
 Population based
 Optimal range for best health is 40-65ng/ml
 Based on epidemiologic assessment of normal
levels in tropical humans
 Based on physiologic changes, increases in PTH,
and clinical disease states associated with levels
under 40ng/ml
Heart Disease
 MI risk doubles in pts with 25OHVitD
levels < 34ng/ml
 Scragg et al. Int J Epidemiol. 1990;19(3):559.
 CHF pts have much lower 25OHVitD
levels than controls
 Zitterman et al. J Am Coll Cardiol. 2003;41:105.
 Deaths from CAD more common in
winter
 Scragg. Int J Epidemiol. 1981;10(4):337.
Heart Disease
 1,739 individuals without cardiovascular disease
 Baseline 25-OH-Vitamin D levels were assessed and
participants were followed for a mean of 5.4 years.
 Compared to having a level >15ng/ml
 25-(OH)D < 10 ng/mL - 80% greater risk of having a
cardiovascular incident
 25 (OH)D of 10-15 ng/mL - 53% increased risk
 The authors concluded vitamin D deficiency is
positively correlated with incident cardiovascular
disease.
 Wang TJ, Pencina MJ, Booth Sl, et al. Vitamin D deficiency and
risk of cardiovascular disease. Circulation 2008;117:503-511.
Hypertension
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BP higher in winter
BP higher with increasing latitude
BP higher with darker skin pigmentation
HTN pts given UV light treatments 3 times per
week for 6 weeks had Vit D level increases of
162% and saw mild decreases in BP
 Krause et al. Lancet. 1998;352(9129):709.
 Small doses of Vit D (800iu) for 8 weeks
decreased BP and pulse rate
 Pfeifer et al. J Clin Endocrinol Metab. 2001;86(4):258.
Hypertension
 Studies
 BP is reduced significantly by ultraviolet radiation
comparable to about oral intake of 3,000 IU of
vitamin D a day
 Krause R, Bohring M, Hopfenmhller W, Holick MF,
Sharma AM: Ultraviolet B and blood pressure. Lancet.
1998;352:709-710
 BP not routinely reduced by small amounts of
vitamin D
 Scragg R, Khaw KT, Murphy S: Effect of winter oral
vitamin D3 supplementation on cardiovascular risk
factors in elderly adults. European Journal of Clinical
Nutrition. 1995;49:640-646
Diabetes Type 1
 Study with > 10,000 people
 Supplementation of infants and children with
Vit D 2000iu/day decreased incidence of DM
type 1 by 80%
 Hypponen et al. Lancet. 2001;358(9292):1500.
 Cod liver studies also show significant
reduction of incidence of Type I DM
Diabetes Type 2
 Low Vit D levels assoc with insulin
resistance and Beta-cell dysfunction
 Postprandial glucose and insulin
sensitivity
 Better in healthy adults with highest Vit D
levels
 Chiu. Am J Clin Nutr. 2004;79:820.
Diabetes Type 2
 Metformin improves insulin sensitivity by
13%
 Highest Vit D levels associated with 60%
improvement in insulin sensitivity
 Chiu. Am J Clin Nutr. 2004;79:820.
 Small trial of 10 women with DM Type 2
 Vit D 1332iu per day x 30 days
 21% increase in insulin sensitivity
 Borrisova et al. Int J Clin Pract. 2003;57(4):258.
Upper Respiratory Infection
and Influenza
 Three-year RCT of 208 African-American postmenopausal women
(who are at great risk of vitamin D deficiency)
 Vitamin D 800iu/day for Years 1-2 and 2000iu/day Year 3
 In the three years of the study 34 patients reported cold and flu
symptoms,
 8 in the supplemented group
 26 in the placebo group (p<0.002).
 Participants who got a placebo had a 300% greater risk of having
a cold or flu, and that vitamin D supplementation provided a highly
significant protective effect.
 Aloia JF. Epidemic influenza and vitamin D. Epidemiol Infect
2007;135:1095-1096.
Osteoarthritis
 Framingham data
 Knee OA advanced most quickly in patients
with 25OHVitD < 36ng/ml
 McAlindon et al. Ann Intern Med. 1996;125(5):353.
 Hip OA advanced most quickly in patients
with 25OHVitD < 30 ng/ml
 Lane et al. Arthritis Rheum. 1999;42(5):854.
Depression
 Seasonal Affective Disorder
 Single dose 100,000 iu Vit D superior to light
therapy for one month
 Gloth et al. J Nutr Health Aging. 1999;3(1):5.
 Vit D 400-800iu per day associated with
improved mood within 5 days
 Landsdowne et al. Psychopharmacology.
1998;135.
Mental Illness Comorbidities
 Mental Illness and Vitamin D deficiency
share similar comorbidities
 Cardiac mortality, DM type I and II,
osteoporosis, MS, rheumatoid arthritis, HTN
Epilepsy
 Seizures can be first sign of Vit D def
 Johnson, Willis. Med J Aust. 2003;178(9):467.
 Hypovitaminosis D decreases Seizure
threshold
 Several anticonvulsants
 Interfere with renal calcitriol formation
 Induce hepatic clearance of calcitriol
 May cause iatrogenic seizures via iatrogenic
hypovitaminosis D
 Ali et al. Ann Pharmacother. 2004;38(6):1002.
Epilepsy
 Placebo controlled pilot study
 4000-16000iu/day of Vit D2
 Decrease in seizure frequency
 Christiansen et al. Br Med J. 1974;2(913):258.
Polycystic Ovary Syndrome
 Small study of 13 PCOS pts
 9 of 13 w/ Vit D deficiency
 Ca 1500mg/day + Vit D2 50,000iu/week
 9 of 9 pts with normalization of menses
and/or fertility within 3 months
 Thys-Jacobs S. Steroids. 1999;64(6):430.
Pain
 Study with 150 pts with persistent, nonspecific
musculoskeletal pain at Mayo clinic
 93% had Vit D deficiency
 Plotnikoff, Quigley. Mayo Clin Proc. 2003;78(12):1463.
 Children w/ limb pain improved in 3 months
 Low Back Pain
 83% of 299 LBP pts had Vit D def
 5000-10,000iu/day
 Decrease in pain medication in nearly 100% after 3 months
 Al Faraj, Al Mutairi. Spine 2003;28(2):177.
Autoimmune Disease
 Vitamin D insufficiency in:
 50% of pts w/ fibromyalgia + SLE
 Huisman et al. J Rheumatol. 2001;28(11):2535.
 58% Japanese F’s with Graves Disease
 Yamashita et al. Endocr J. 2001;48(1):63.
 73% Austrian pts w/ Ankylosing Spondilitis
 Falkenbach et al. Wien Klin Wochenschr.
2001;113(9):328
 Rhematoid Arthtritis
 Cantorna.Proc Soc Exp Biol Med. 2000;223(3):230
Multiple Sclerosis
 48% of MS pts are Vit D deficient
 Mahon. J Neuroimmunol. 2003;134(1-2):128.
 MS rare near equator
 Zittermann A. Br J of Nutr. 2003;89:552-572
 5,000iu/d plus Ca 1000mg and Mag
600mg decreased the relapse rate in MS
patients – no side effects
 Goldberg P. Medical Hypothesis. 1986;21:193-200
Inflammation
 Vit D injections averaging 547iu/day x 2-5
years – 23% decrease in CRP
 Timms et al. QJM. 2002;95:787.
 25(OH)Vit D level should be checked in any
patient with any inflammatory condition
 Michael Hollick, PhD, MD Professor of Medicine,
Dermatology, Physiology and BioPhysics, Director of the
General Clinical Research Center and Director of the Bone
Health Care Clinic at Boston University Medical Center
 Vit D supp in pts w/ prolonged clinical illness
saw decreases in IL-6 and CRP
 Van den Berghe et al. J Clin Endocrinol Metab.
2003;88(10):4623.
Cancer
 Vitamin D levels inversely correlated to colon
cancer mortality (but not to all cancer mortality)
 Freedman et al. J Natl Cancer Inst. 2007. 99(21):1563.
 47,800 men over 14 years –
10 ng/ml rise in Vitamin D level of associated w/
 17% reduction in cancer incidence
 29% reduction in all cancer mortality
 45% reduction in GI cancer mortality
 Giovanucchi et al. J Natl Cancer Inst. 2006. 98(7):428.
Cancer
 Long-term study of 50,000 men at Harvard
School of Public Health suggests vitamin D
may reduce the risk of all cancers by at least
30 percent.
 Giovannucci. J Natl Cancer Inst. 2006 Apr 5:98(7):428.
 Decreased sunlight assoc with increased
cancer mortality
 Breast, colon, cancer, prostate, bladder, esophagus,
kidney, lung, pancreas, rectum, stomach, uterus,
non-Hodgkin’s Lymphoma
 Grant. Cancer. 2002;94(6):1867.
Falls in the Elderly
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Vit D receptors in skeletal muscle
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Bischoff HA, et al. Histochem J 2001;33:19.
Vit D deficiency reported to affect predominantly the
weight-bearing antigravity muscles of the lower limb,
which are necessary for postural balance and walking
Glerup H et al. Calcif Tissue Int 2000;66:419.
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Significant correlation between serum 25(OH)D3
concentration and the occurrence of falls in elderly
reported in literature.
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Mowé M et al. J Am Geriatr Soc 1999;47:220
Stein MS et al. J Am Geriatr Soc 1999;47:1195
Falls in the Elderly
 STOP/IT (Sites Testing Osteoporosis Prevention and Intervention
Treatments) trial
 489 women randomly assigned to receive estrogen, calcitriol, both
estrogen and calcitriol, or a placebo for 3 years.
 The increase in bone density was twice as large with estrogen as
with calcitriol.
 The subjects w/ calcitriol had fewer fractures from falls than did
the group who took estrogen (odds ratio: 0.78 and 0.94,
respectively).
 Improvement in lower extremity muscle strength and balance with
vitamin D supplementation thought to explain the reduced number
of fall-related fractures.
 Dawson-Hughes et al. N Engl J Med 1997;337:670
Pregnancy
 Vit D2 100,000 iu/day throughout pregnancy
associated with no fetal abnormalities
 Current recommendation of 200-400iu per day
inadequate
 Hollis & Wagner recommend up to 4000iu
 Pre-eclamsia and SGA babies associated with
Vit D deficiency
 Halhali et al. J Clin Endocrin & Met 2000. 85(5), 18281833 .
Lactation
 Breast-feeding mothers need 4,000 units
of vitamin D a day in order to maintain
adequate infant Vit D status.
 2,000 iu/day was not effective.
 Wagner CL, et al. Pediatr Res 2003.
 Hollis et al. Am J Clin Nutr 2004;80(suppl):1752S–
8S.
 Basile et al. Breastfeeding Medicine. March 1,
2006, 1(1): 27-35
Lactation
 25-OH-D content of maternal milk responsible
for vitamin D concentrations of serum of
exclusively breast-fed infants
 Cancela et al. J Endocrinol. 1986 Jul;110(1):43-50.
 Hypovitaminosis D common in summer in
exclusively breast-feeding infants and their
mothers
 Dawodu et al. J Pediatr. 2003 Feb;142(2):169
 Breastfed infants should be given Vit D 1000iu
 Increase this to 2000iu in family hx of DM type 1
Periodontal Disease
 Periodontal attachment loss inversely
associated with 25-OH-Vitamin D levels
in adults > 50yrs old
 Dietrich Am J Clin Nutr. 2004 Jul;80(1):108-13.
Medical Inpatients
 290 medical inpatients in Boston
screened
 57% with Vitamin D < 15ng/ml
 Thomas et al. N Engl J Med 1998;338(12):777-83
 Separate Finish study
 40-70% medical patients deficient
Lake Almanor Clinic
 T Archie - unpublished case series of over 90
patients with range of diagnoses (40 deg
latitude)
 25OHVitD levels checked Sept 04-Jan 07
 HTN, chronic kidney disease, osteoarthritis,
depression, SAD, musculoskeletal pain,
autoimmune disease, CHF, DM, overweight, CVA,
elevated CRP, healthy pregnancy, screening
 All but 5 patients had levels below 40ng/ml
 95% incidence among this group
 Common to see level 12-25ng/ml
Longevity
 Meta-analysis of 18 RCTs – 57,311 patients
 Range of 300-2000iu/day
 Highest intake – 7% reduction in all-cause
mortality
 “Based on the total body of evidence of health
conditions associated with vitamin D deficiency,
abetted with the results from this metaanalysis, a more proactive attitude to identify,
prevent and treat vitamin D deficiency should
be part of standard medical care.”
 Giovannuchi. Arch Intern Med. 2007;167:1709-1710.
Toxicity
 No credible evidence of toxicity at Vit D
levels <150ng/ml
 No evidence for toxicity at doses of
10,000iu/d indefinitely
 Vieth R. Am J Clin Nutr. 1999;69
 Indicator of direct Vit D toxicity
 Elevated serum calcium - AND  25OHVitD > 90ng/ml
 Berkow. Merck Manual. 1987:928.
Toxicity
 Toxicity rare and requires long-term
administration of at least 40,000iu/day in
infants (or 100,000iu/d in adults) for several
months
 Berkow. Merck Manual. 1987:928.
 Toxicity sx’s appear with level >125ng/ml
 Anorexia, nausea, vomiting, weakness,
nervousness, pruritis, polyuria, polydipsia, renal
impairment, soft tissue calcifications
 Holick. Am J Clin Nutr. 2001;73(2):288.
Toxicity
 Caution in Sarcoidosis
 Macrophages in sarcoid patients have
considerably increased rates of conversion
of 25OHVitamin D to 1,25(OH)2Vitamin D.
Supplementing
 Physiologic requirement 3000-5000iu/day
 Vitamin D deficiency
 <20ng/ml (some authors believe this should be
<30ng/ml – and some labs have cut off at 32ng/ml)
 Vitamin D insufficiency
 <40ng/ml
 PTH levels increase at 30-40ng/ml
 Elderly men and women shown to have increasing
PTH levels at Vit D levels <45ng/ml
Supplementing
 Optimal goal is 40-65ng/ml
 Humans living near the equator have mean serum
25(OH)D levels of more than 40 ng/ml
 Solar input equivalent to about 4,000 IU of vitamin D
a day
 Linhares et al. Am J Clin Nutr. 1984:39(4):625-630
 American lifeguards, working in swimsuits, have
even higher 25(OH)D levels (64 ng/ml), in spite of
temperate latitudes.
 Holmes R, Kummerow F. J Amer Coll Nutr. 1983;2:173.
Supplementing
 All patients at higher latitudes (above 35
degrees) should be screened
 High latitude and high prevalence of Vit D deficiency
in local small case series (95% incidence)
 42% health adolescents Vit D def
 Gordon et al. Arch Pediatr Adolesc Med.
2004;158(6):531.
 62% morbidly obese pts Vit D def
 Buffington et al. Obes Surg. 1993;3:421.
 High risk of avoiding supplementation
 Low risk of supplementing
Supplementing
 28 Adults given 4000iu/d x 5 months
 Levels averaged 40ng/ml
 Vieth. Am J Clin Nutr 2001.73(2):288.
 67 men given higher doses x 20 weeks
 5000iu/d – avg 25OHVitD level 60ng/ml
 10,000iu/d – average level 90ng/ml
 No toxicity seen
 Heany et al. Am J Clin Nutr. 2004;79(3):362.
Supplementing in Obesity
 Double the Vitamin D dosage in the
patient with obesity
 Excessive adipose tissue absorbs
Vitamin D and decreases bioavailability
by 57%
 Wortsman et al. Am J Clin Nutrition, 2000: 72 (3),
690-693
Supplementing
 Replacement
 4000-10,000iu per day for 5-9 months
 Baseline supplementation
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Infants 1000iu/day
Children 2000iu/day
Adults 2000iu - 4000iu/day
Pregnancy and Lactation 4000iu/day
Supplementation
 Serum levels plateau after 3-4 months of
daily supplementation
 Heaney. Am J Clin Nutr. 2003;77(1):204.
 Therefore, be prepared to increase
supplementation if necessary.
Supplementation
 Cod Liver Oil (concern is Vit A toxicity
depending on dose)
 Vitamin D3 (cholecalciferol)
 Highest single dose available 5000iu per softgel
(Pure Encapsulations). 1000iu – Life Extension
Source
 Preferred source
 Capsule can be opened into milk for infants
 Vitamin D2 (ergocalciferol)
 Available as 50,000iu given every 1-2 weeks
 Less effective for conversion to calcitriol
Monitoring
 25-OH-Vit D levels and serum calcium
 Re-check every 2-4 months when
starting with levels below 35ng/ml.
 Re-check every 1-2 months when levels
over 35ng/ml until levels plateau.
 Consider continuing age-appropriate
supplementing with infrequent monitoring
Repeating the Overview
 Vitamin D receptors found in gut, bone, brain,
breast, prostate, lymphocytes, placenta, and
other tissues
 Routine screening is appropriate at Lat >35deg
 Safe up to 4000iu/d without monitoring
 Safe up to 10,000iu/d with monitoring
 Supplementation helpful in:
 DM, metabolic syndrome, CAD, depression, autoimmune
diseases, various cancers, HTN, osteoporosis,
osteoarthritis, pain, MS, epilepsy, elderly fall prevention,
PCOS, pregnancy & lactation, periodontal dz, URI/flu
prevention, all-cause mortality