K6 - VitaminDTArchie.ppt

Vitamin DDeficiency, Insufficiency, and SupplementationThomas Archie, MDSt. Lukes Wood River Family MedicineHailey, ID

OverviewVitamin D receptors found in gut, bone, brain, breast, prostate, lymphocytes, placenta, and other tissuesRoutine screening is appropriateSafe up to 4000iu/d without monitoringSafe up to 10,000iu/d with monitoringSupplementation 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

PhysiologyVitamin D3 (Cholecalciferol)Produced in skin with direct sunlight, cod liver oilPreferred form of supplementationVitamin D2 (Ergocalciferol)Made by irradiating fungiLess effective as precursor to 1,25(OH)2-Vit D

PhysiologyHepatic 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 renalRequires two factors25OH-VitD3-1-alpha-OHaseVitamin D Receptor (VDR)

Physiology Autocrine MetabolismVitamin D functions as a steroid hormoneCells containing 25OH-VitD3-1-alpha-OHaseBreast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, brain, placentaHolllick MF. Am J Clin Nutr. 2004. 79(3):362.Zehnder et al. J Clin Endocrin Metab. 2001;86(2)Cells containing Nuclear VDRPancreatic 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.

CalcitriolMost biologically active form of Vit DRaises GI calcium and phosphorus absorptionInduces osteoclast maturation for bone remodellingPromotes calcium deposition in bone and reduction of PTH

Parathyroid HormoneSecondary hyperPTH can be due to hypovitaminosis D 25OH-Vit D levels 30-40ng/mlZittermann A. Br J Nutr. 2003;89(5):552.Suppression of PTH importantLow PTH promotes good healthHigh PTH associated with increased risk of MI, HTN, strokeKamycheva et al. Eur J Cardiovasc Prev Rehab. 2004;11(1).Sato et al. Neurology. 2003;60(4):626.

Calcitriol and CancerModulates the transcription of several oncogenes involved with cell differentiation and proliferationC-myc, c-fos, c-sisInverse relationship b/t sun exposure and cancer mortalityGrant. Cancer. 2002;94(6):1867.Apperly. Cancer Res. 1941;1:191.

Calcitriol and CNS functionVit D Modulates neurotransmitter and neurological functionAnticonvulsant and antidepressant effectLandsdowne et al. Psychopharmacology. 1998;135.Christiansen et al. Br Med J. 1974;2(913):258.

CalcitriolReduces inflammationNuclear Vit D receptors in lymphocytesSuppresses and may prevent autoimmune diseasesDecreases risk of certain cancersSeems to reduce severity and frequency of childhood pneumoniaWayse et al. Eur J Clin Nutr. 2004;58(4):563.

Calcium AbsorptionCalcium 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/mlImplies 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 RelevanceCoronary artery diseaseHypertensionDiabetes Type I and Type 2OsteoarthritisDepressionEpilepsy

Polycystic OvariesMusculoskeletal PainAutoimmune DiseaseMultiple SclerosisCancersFalls in the ElderlyPregnancy and Lactation

Laboratory Assessment25-OH-Vitamin D level is the appropriate testTypical labeled normal range is 8-40ng/mlPopulation basedOptimal range for best health is 40-65ng/mlBased on epidemiologic assessment of normal levels in tropical humansBased on physiologic changes, increases in PTH, and clinical disease states associated with levels under 40ng/ml

Heart DiseaseMI risk doubles in pts with 25OHVitD levels < 34ng/mlScragg et al. Int J Epidemiol. 1990;19(3):559.CHF pts have much lower 25OHVitD levels than controlsZitterman et al. J Am Coll Cardiol. 2003;41:105.Deaths from CAD more common in winterScragg. Int J Epidemiol. 1981;10(4):337.

Heart Disease1,739 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 incident25 (OH)D of 10-15 ng/mL - 53% increased riskThe 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.

HypertensionBP higher in winterBP higher with increasing latitudeBP higher with darker skin pigmentationHTN pts given UV light treatments 3 times per week for 6 weeks had Vit D level increases of 162% and saw mild decreases in BPKrause et al. Lancet. 1998;352(9129):709.Small doses of Vit D (800iu) for 8 weeks decreased BP and pulse ratePfeifer et al. J Clin Endocrinol Metab. 2001;86(4):258.

HypertensionStudiesBP 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 1Study 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 2Low Vit D levels assoc with insulin resistance and Beta-cell dysfunctionPostprandial glucose and insulin sensitivityBetter in healthy adults with highest Vit D levelsChiu. Am J Clin Nutr. 2004;79:820.

Diabetes Type 2Metformin improves insulin sensitivity by 13%Highest Vit D levels associated with 60% improvement in insulin sensitivityChiu. Am J Clin Nutr. 2004;79:820.Small trial of 10 women with DM Type 2Vit D 1332iu per day x 30 days21% increase in insulin sensitivityBorrisova et al. Int J Clin Pract. 2003;57(4):258.

OsteoarthritisFramingham dataKnee OA advanced most quickly in patients with 25OHVitD < 36ng/mlMcAlindon et al. Ann Intern Med. 1996;125(5):353.Hip OA advanced most quickly in patients with 25OHVitD < 30 ng/mlLane et al. Arthritis Rheum. 1999;42(5):854.

DepressionSeasonal Affective DisorderSingle dose 100,000 iu Vit D superior to light therapy for one monthGloth et al. J Nutr Health Aging. 1999;3(1):5.Vit D 400-800iu per day associated with improved mood within 5 daysLandsdowne et al. Psychopharmacology. 1998;135.

Mental Illness ComorbiditiesMental Illness and Vitamin D deficiency share similar comorbiditiesCardiac mortality, DM type I and II, osteoporosis, MS, rheumatoid arthritis, HTN

EpilepsySeizures can be first sign of Vit D defJohnson, Willis. Med J Aust. 2003;178(9):467.Hypovitaminosis D decreases Seizure thresholdSeveral anticonvulsants Interfere with renal calcitriol formationInduce hepatic clearance of calcitriolMay cause iatrogenic seizures via iatrogenic hypovitaminosis DAli et al. Ann Pharmacother. 2004;38(6):1002.

EpilepsyPlacebo controlled pilot study4000-16000iu/day of Vit D2Decrease in seizure frequencyChristiansen et al. Br Med J. 1974;2(913):258.

Polycystic Ovary SyndromeSmall study of 13 PCOS pts9 of 13 w/ Vit D deficiencyCa 1500mg/day + Vit D2 50,000iu/week9 of 9 pts with normalization of menses and/or fertility within 3 monthsThys-Jacobs S. Steroids. 1999;64(6):430.

PainStudy with 150 pts with persistent, nonspecific musculoskeletal pain at Mayo clinic93% had Vit D deficiencyPlotnikoff, Quigley. Mayo Clin Proc. 2003;78(12):1463.Children w/ limb pain improved in 3 monthsLow Back Pain83% of 299 LBP pts had Vit D def5000-10,000iu/day Decrease in pain medication in nearly 100% after 3 monthsAl Faraj, Al Mutairi. Spine 2003;28(2):177.

Autoimmune Disease

Vitamin D insufficiency in:50% of pts w/ fibromyalgia + SLEHuisman et al. J Rheumatol. 2001;28(11):2535.58% Japanese Fs with Graves DiseaseYamashita et al. Endocr J. 2001;48(1):63.73% Austrian pts w/ Ankylosing SpondilitisFalkenbach et al. Wien Klin Wochenschr. 2001;113(9):328Rhematoid ArthtritisCantorna.Proc Soc Exp Biol Med. 2000;223(3):230

Multiple Sclerosis48% of MS pts are Vit D deficientMahon. J Neuroimmunol. 2003;134(1-2):128.MS rare near equatorZittermann 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 effectsGoldberg P. Medical Hypothesis. 1986;21:193-200

InflammationVit D injections averaging 547iu/day x 2-5 years 23% decrease in CRPTimms et al. QJM. 2002;95:787.25(OH)Vit D level should be checked in any patient with any inflammatory conditionMichael 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 CRPVan den Berghe et al. J Clin Endocrinol Metab. 2003;88(10):4623.

CancerVitamin 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 incidence29% reduction in all cancer mortality45% reduction in GI cancer mortalityGiovanucchi et al. J Natl Cancer Inst. 2006. 98(7):428.

CancerLong-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-Hodgkins LymphomaGrant. Cancer. 2002;94(6):1867.

Falls in the ElderlyVit D receptors in skeletal muscleBischoff 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.

Significant correlation between serum 25(OH)D3 concentration and the occurrence of falls in elderly reported in literature.Mow M et al. J Am Geriatr Soc 1999;47:220 Stein MS et al. J Am Geriatr Soc 1999;47:1195

Falls in the ElderlySTOP/IT (Sites Testing Osteoporosis Prevention and Intervention Treatments) trial489 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

PregnancyVit D2 100,000 iu/day throughout pregnancy associated with no fetal abnormalitiesCurrent recommendation of 200-400iu per day inadequateHollis & Wagner recommend up to 4000iuPre-eclamsia and SGA babies associated with Vit D deficiencyHalhali et al. J Clin Endocrin & Met 2000. 85(5), 1828-1833 .

LactationBreast-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):1752S8S.Basile et al. Breastfeeding Medicine. March 1, 2006, 1(1): 27-35

Lactation25-OH-D content of maternal milk responsible for vitamin D concentrations of serum of exclusively breast-fed infantsCancela 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 1000iuIncrease this to 2000iu in family hx of DM type 1

Periodontal DiseasePeriodontal 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 Inpatients290 medical inpatients in Boston screened57% with Vitamin D < 15ng/mlThomas et al. N Engl J Med 1998;338(12):777-83Separate Finish study 40-70% medical patients deficient

Lake Almanor ClinicT Archie - unpublished case series of over 90 patients with range of diagnoses (40 deg latitude)25OHVitD levels checked Sept 04-Jan 07HTN, 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 groupCommon to see level 12-25ng/ml

LongevityMeta-analysis of 18 RCTs 57,311 patientsRange of 300-2000iu/dayHighest intake 7% reduction in all-cause mortalityBased on the total body of evidence of health conditions associated with vitamin D deficiency, abetted with the results from this meta-analysis, 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.

ToxicityNo credible evidence of toxicity at Vit D levels 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 monthsBerkow. Merck Manual. 1987:928.Toxicity sxs appear with level >125ng/mlAnorexia, nausea, vomiting, weakness, nervousness, pruritis, polyuria, polydipsia, renal impairment, soft tissue calcificationsHolick. Am J Clin Nutr. 2001;73(2):288.

ToxicityCaution in SarcoidosisMacrophages in sarcoid patients have considerably increased rates of conversion of 25OHVitamin D to 1,25(OH)2Vitamin D.

SupplementingOptimal goal is 40-65ng/mlHumans living near the equator have mean serum 25(OH)D levels of more than 40 ng/mlSolar input equivalent to about 4,000 IU of vitamin D a day Linhares et al. Am J Clin Nutr. 1984:39(4):625-630American 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.

SupplementingAll patients at higher latitudes (above 35 degrees) should be screenedHigh latitude and high prevalence of Vit D deficiency in local small case series (95% incidence)42% health adolescents Vit D defGordon et al. Arch Pediatr Adolesc Med. 2004;158(6):531.62% morbidly obese pts Vit D defBuffington et al. Obes Surg. 1993;3:421.High risk of avoiding supplementationLow risk of supplementing

Supplementing28 Adults given 4000iu/d x 5 monthsLevels averaged 40ng/mlVieth. Am J Clin Nutr 2001.73(2):288.67 men given higher doses x 20 weeks5000iu/d avg 25OHVitD level 60ng/ml10,000iu/d average level 90ng/mlNo toxicity seenHeany et al. Am J Clin Nutr. 2004;79(3):362.

Supplementing in ObesityDouble the Vitamin D dosage in the patient with obesityExcessive adipose tissue absorbs Vitamin D and decreases bioavailability by 57%Wortsman et al. Am J Clin Nutrition, 2000: 72 (3), 690-693

SupplementingReplacement4000-10,000iu per day for 5-9 monthsBaseline supplementationInfants 1000iu/day Children 2000iu/day Adults 2000iu - 4000iu/dayPregnancy and Lactation 4000iu/day

SupplementationSerum levels plateau after 3-4 months of daily supplementationHeaney. Am J Clin Nutr. 2003;77(1):204.

Therefore, be prepared to increase supplementation if necessary.

SupplementationCod 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 SourcePreferred sourceCapsule can be opened into milk for infantsVitamin D2 (ergocalciferol)Available as 50,000iu given every 1-2 weeksLess effective for conversion to calcitriol

Monitoring25-OH-Vit D levels and serum calciumRe-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 OverviewVitamin D receptors found in gut, bone, brain, breast, prostate, lymphocytes, placenta, and other tissuesRoutine screening is appropriate at Lat >35degSafe up to 4000iu/d without monitoringSafe up to 10,000iu/d with monitoringSupplementation 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

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