VITAMIN D DEFICIENCY

26th November 2015 Jeddah Clinic Hospital

History SourcesPhysiology & metabolismDeficiency & resistanceRequirements & TreatmentExtra-skeletal effectsVit. D intoxications Home messages

Leading Points

History1600 1st description of rickets by Whistler & Glisson

1918 Rickets linked with a fat- soluble substancenutrient

1923 Goldblatt & Soames demonstrated that exposure to to sunlight or UV light produced a substance that Is linked to racket.

1936 Identification of Vitamin D by Windaus

Prevalence of Vitamin D Deficiency

U.S. and European elderly: 40 to 100% Postmenopausal women Rx for osteoporosis > 50%. *

Geriatric population : 45/80 (56.2%) **

In Saudi Arabia :30-50 % of general population ***

(* Holick et al. J Clin Endocrinol Metab 2005)

(** VandeGriend et al. J Am Pharm Assoc 2008)

(*** Sedrani SH et al .Nutre. Metabo 1984)

Vitamin D‘Calciferol’ A steroid hormone that primarily acts to increase transcription of vitamin D responsive genes primarily in the gut

These genes mediate increased absorption of calcium and phosphorous

It plays a role in maintaining normal neuromuscular function and immunity

There is some evidence that vitamin D regulates apoptosis, cell proliferation and inflammation as well

Absorption & Metabolism

Affected by fat malabsorption :Pancreatic insufficiencyCFCholestastic liver diseaseCoeliac disease Cohn's disease

Medications That Increase Catabolism of Vitamin D via P450 Enzyme Activity

PhenytoinPhenobarbitalCarbamazepineIsoniazidTheophyllineRifampinGlucocorticoidsHAART

1,25 OH Vitamin D Effects

Calcium absorption in the gut

PTH mediated bone resorption

Bone calcification

Renal calcium and phosphorus excretion

PTH secretion

Non-classical Actions of Vitamin D

Suppress cell growth/proliferationRegulate apoptosisModulate immune responses Susceptibility to infections Susceptibility to autoimmune disorders – MS, T1DM Effects in transplantation immunity

Modulate keratinocyte differentiation and function Key role in psoriasis therapy

Suppress renin-angiotensin systemStimulate insulin secretionControl neuromuscular function and the brain

Dusso AS, et al. Am J Physiol–Renal Physiol 2005;289:F8-F28.

Mechanisms of Vitamin D Deficiency Continued

Impaired availability of vitamin D due to inadequate dietary intake, malabsorptive disorders and obesity (sequestration of vitamin D in body fat)Impaired hydroxylation by the liver due to liver diseaseIncreased hepatic catabolism due to medicationsImpaired renal production of 1,25 –OH vit. D in stage 4 and 5 CKDRenal loss of vit. D and vit. D binding proteins in nephrotic syndrome

PTH EffectsIncreases tubular reabsorption of calcium . Stimulates the kidney to produce 1,25 OH vita. DActivates osteoblasts , which then stimulates the activation of osteoclasts, which dissolve mineralized collagen matrix in the bone, causing osteopenia and osteoporosis and increasing the risk of fracture.Causes phosphaturia. A low Ca-Phos product leads to decreased mineralization of the collagen matrix= rickets in kids and osteomalacia in adults

Consequences of Vitamin D Deficiency

Reduced intestinal absorption of calcium &

phosphorus

Hypophosphatemia precedes hypocalcaemia

Secondary hyperparathyroidism

Bone demineralization

Osteomalacia / rickets

Sources of Vitamin D

Exposure to sunlight

Dietary Sources

Dietary Supplements

Holick M. NEJM 357;3:266-280

Exposure to Sunlight

5-10 minutes of direct exposure to the arms and legs = 3000 IU of vitamin D3

Vitamin D def. common in sunny areas when most of the skin is shielded from the sun (by Hijab)(Saudi Arabia, United Arab Emirates, Turkey, India and Lebanon)

Vitamin D Metabolism

Risk Groups

Elderly:Stores decline with ageWinterHouse-bound or institutionalizedPoor nutritional intake Impaired absorptionCKD

At-Risk Groups

At-Risk GroupsChildrenExclusively breast-fed infantsVariable dietary intake

Vegetarian or fish-free diet

Ethnic background

Women treated for osteoporosis

At-Risk Groups

Hospitalized patients :AgeSun exposure IntakeRenal injuryBurns victims22-42% prevalence in US studies

Clinical Syndromes

OsteomalaciaSoftening of the bone due to impaired mineralization due to low Ca-Phos product.Symptoms include isolated or generalized bone pain, muscular weakness, and weight loss

93% of 150 persons 10 to 65 year old seen in an ED in Minnesota with muscle aches and bone pain were deficient (< 20 ng/ml) in vitamin D and 28% had severe deficiency (< 8 ng/ml) (Plotnikoff, Mayo Clin Proc 2003)

OsteomalaciaAfter closure of epiphyseal platesImpaired mineralizationFracturesLab testsLow calcium & phosphateHigh ALP

X-raysDiffuse bone lucencies

Vitamin D and Fracture Risk

Among 3270 elderly French women given 1200 mg calcium and 800 IU of vit D3 daily for 3 years, the risk of hip fracture and nonvertebral fracture decreased by 43% and 32% respectively (Chapuy, NEJM 1992)In 389 subjects over 65 years old, 700 IU of vit D3 and 500 mg per day of calcium decreased nonvertebral fracture by 58% compared to placebo. (Dawson-Hughes, NEJM 1997)

Vitamin D and Falls

Deficiency causes muscle weakness because skeletal muscle has a vit. D receptor and may require vitamin D for maximal function.

A meta-analysis of 5 RCT state that increased vit. D intake reduced the risk of falls by 22%. RCT, residents receiving 800 IU of vit. D3 per day plus calcium had a 72% reduction in the risk of falls compared with placebo.

(Broe, J Am Geriatr Soc, 2007)(Bischoff-Ferrari, Am J Clin Nutr 2006)

Vit. D and Fracture Risk

A meta-analysis of 7 RCT’s evaluating fracture risk in pts given 400 IU of vit D3 per day revealed little benefit.

In studies using 700-800 IU of, the RR of hip fracture and non-vertebral fracture were reduced by 26% and 23% respectively compared to calcium and placebo.

(Bischoff-Ferrari, Am J Clin Nutr 2006)

Role of Vit. D in CVDFramingham Offspring Study1739 subjects (mean 59 yr, 55% F, all C)No prior CVDMean 25-OH-D 19.7 ng/mL

28% with 25-OH-D <15 ng/mL 9% with 25-OH-D <10 ng/mL

5.4 yr follow-up120 developed first CV event

Wang TJ, et al. Circulation 2008;117:503-511.

Evidence for Role of Vitamin D in CVD

Health Professionals Follow-up Study Prospective trial nested case control 18,225 M age 40-75 (mean 63.8 yr) 94% C No known CVD, baseline 25-OH-D 24.5 vs. 23 ng/mL 10 yr follow-up 454 with nonfatal MI or fatal CHD

Giovannucci E, et al. Arch Intern Med 2008;168(11):1174-1180.

Compared with 25-OH-D >30 ng/mL

<15ng/mL

15-22.5ng/mL

22.6-29.9ng/mL

RR of MI after adjustment*

2.09(1.24-3.54)

1.43(0.96-2.13)

1.60(1.10-2.32)

*FHx MI, BMI, EtOH, activity, DM, HTN, ethnicity, region, marine -3 intake, LDL, HDL, TG

Vitamin D and Hypertension148 F age 75 yr with 25-OH-D level <50 nmol/L received calcium 600 mg plus 400 IU D3 BID vs. calcium 600 mg alone BID over 8 weeks

Pfeifer M, et al. J Clin Endocrinol Metab 2001;86:1633-37.

Initial FinalCa only Vit. D + Ca Ca only Vit. D + Ca

25-OH-D (nmol/L)

24.6 25.7 44.4(17.8 ng/mL)

64.8(25.9 ng/mL)

PTH (pmol/L) 6.1 6.1 5.3 4.6

SBP (mmHg) 140.6 144.1 134.9 131.0DBP (mmHg) 82.6 84.7 75.7 77.5

HR (mmHg) 74.1 75.4 73.9 71.3

Vitamin D and Hypertension

In a study of hypertensive patients who were exposed to ultraviolet B radiation three times per week for 3 months, 25 OH vitamin D levels increased by approximately 180% and both SBP and DBP were reduced by 6 mm Hg. (Krause, Lancet 1998)

Proposed mechanism: The 1,25 OH vitamin D produced in the kidney enters the circulation and down regulates renin production in the kidney

Studies Needed of Interactions Between Vitamin D and CVD

Prospective studies to prove that vitamin D deficiency results in increased CVD eventsWell-designed studies to determine mechanisms for increased riskProspective studies to prove that adequate vitamin D replacement decreases CVD eventsStudies to determine optimal formulation, dosing, target levels

Deficiency & ResistanceImpaired availability of Vit D Lack of sun exposure, can be seasonal

Fat malabsorptive states

Impaired liver hydroxylation to 25-OHD

Impaired renal hydroxylation to 1,25-OHD

End-organ insensitivity to Vit D metabolites Hereditary Vit D resistant rickets

Glucocorticoids – inhibit intestinal Vit D dependent calcium

absorption

Vitamin D and DiabetesIn 10,366 children in Finland given 2000 IU of vitamin D3 per day during their first year of life and then followed for 31 years, the risk of type 1 DM was reduced by 80%. In subset analysis, among children with vitamin D deficiency, the risk was increased by 200%. (Hyponen, Lancet 2001)Combined daily intake of 1200 mg of calcium and 800 IU of vitamin D lowered the risk of type 2 diabetes by 33 % compared to daily intake of less than 600 mg calcium and less than 400 IU of vitamin D. (Pittas, Diabetes Care 2006)Proposed mechanism: The 1,25 OH vitamin D produced in the kidney enters the circulation and stimulates insulin secretion in the islet cells of the pancreas

Vitamin D Deficiency and All Cause MortalityRetrospective analysis of 13,331 adults 20 years or older from NHANES III testing association of low 25 OH vitamin D and all cause, cancer and cardiovascular mortalityMedian follow up was 8.7 years, during which there were 1806 deaths, including 777 from CVDIn multivariate models (adjusted for baseline demographics and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25 OH vitamin D <17.8 ng/ml) was associated with a 26% increased rate of all cause mortality, (95% CI, 1.08-1.46. Cancer and CVD mortality was not statistically significant.Conclusion: Lowest quartile of 25 OH vitamin D (<17.8 ng/ml) is independently associated with all cause mortality in the general population. (Melamed, Arch Intern Med, 2008)

Ginde et al, Arch Intern Med 2009

Association Between 25- OH Vitamin D and URI

Retrospective analysis of 18,883 subjects 12 and older from NHANES III The median serum 25 OH vit D was 29 ng/mL. Recent URI was reported by 24% with 25 OH vit D < 10 ng/mL, by 20% with levels of 10 to < 30 ng/mL and 17% with levels of >30 ng/mL (p<0.001).The association between 25 OH vit D and URI higher in those with asthma (OR 5.67) and COPD (OR 2.26)Conclusion: Serum 25 OH vit D levels are inversely associated with recent URI.

Vit. D Deficiency and Other Conditions

Linked to increased incidence of :Schizophrenia

Depression

Reactive Airway Disease

Associated Clinical Conditions

Bone Density and Fractures Risk of osteoporosis may be reduced with

adequate intake of vitamin D and calcium. Studies support the concept that vitamin D at

doses between 700 and 800 IU/d with calcium supplementation effectively increase hip bone density and reduced fracture risk, whereas lower vitamin D doses may have less effect.

Role in Cancer Prevention Low intake of vitamin D and calcium has been

associated with an increased risk of non-Hodgkin lymphomas, colon, ovarian, breast, prostate, and other cancers.

The anti-cancer activity of vitamin D a nuclear transcription factor that regulates cell

growth, differentiation, & apoptosis, central to the development of cancer

Vitamin D is not currently recommended for reducing cancer risk

Associated Clinical Conditions

Associated Clinical Conditions

Autoimmune Disease Vitamin D supplementation is associated with a lower risk of

autoimmune diseases. In a Finnish birth cohort study of 10,821 children,

supplementation with vitamin D at 2000 IU/d reduced the risk of type 1 diabetes by approximately 78%, whereas children who were at risk for rickets had a 3-fold higher risk for type 1 diabetes.

In a case-control study of 7 million US military personnel, high circulating levels of vitamin D were associated with a lower risk of multiple sclerosis.

Similar associations have also been described for vitamin D levels and rheumatoid arthritis.

Vitamin D and Cancer

Vit. D level below 20 ng/ml is associated with a 30-50% increased risk of incident of : Colon, prostate and breast cancer, Along with higher mortality from these cancers

The mechanism?? High doe for cancer ttt

Low mortality with normal level.

Role in Cardiovascular Diseases Vit. D deficiency activates the renin-angiotensin-

aldosterone system and can predispose to hypertension and left ventricular hypertrophy.

increase in PTH, which increases insulin resistance secondary to down regulation of insulin receptors and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk.

Associated Clinical Conditions

Vitamin D deficiency early in pregnancy is associated with a five-fold increased risk of preeclampsia.

Role in All Cause Mortality

Researchers concluded that having low levels (<17.8 ng/mL) was independently associated with an increase in all-cause mortality in the general population.

Role in Reproductive Health

Associated Clinical Conditions

Muscle Weakness and Falls Proximal muscle weakness Chronic muscle aches Myopathy Increase in falls Dailly 700 and 800 IU/d in a vitamin D-deficient elderly

population can significantly reduce the incidence of falls.

Work up

Assessment

Screening

Vitamin D BasicsUnits

ng/mL vs. nmol/L 2.5 nmol/L = 1 ng/mL

Rule of thumbFor every 100 IU D3 ingested, blood level of 25-

OH-D increases by 1 ng/mL

Who Should Be Screened ?Elderly

Home bound or institutionalized patients

Patients with known or suspected malabsorption

Patients with osteoporosis or osteopenia

CKD and chronic liver disease patients

Patients with nonspecific musculoskeletal pain

On medications that induce P-450 enzyme activity

Obese and pregnant women

Investigations

Diagnosis

Vitamin D MeasurementsInterpretation Level (nmol/l) Action

Deficiency < 25 Replace Vit D

Loading dose followed by maintenance

Insufficient 25-50 Consider replacement if:• Glucocorticoids• Osteopenia/osteoporosis• 2° HPTH• Hypocalcaemia• CKD

Maintenance dose

Replete >50 No need for replacement or continue dose

Toxic >150 Check calciumStop treatment

Preventive MeasuresSensible sun exposure ( 5-30) minutes of

exposure of arms and legs between 10 am and 3

pm twice a week is often adequate.

50,000 IU of vitamin D2 every 1-4 weeks

1000 IU of vitamin D3 per day

100,000 IU of vitamin D3 once every 3 months

Variations of sun exposure

Reduced skin synthesis: Sunscreen use (reduces vitamin D3 synthesis by 99%)

Skin pigmentation

Patients with skin grafts for burns

Aging (reduction of 7 dehydrocholesterol reduces

vitamin D3 synthesis by 75% in a 70 year old)

Season, latitude and time of day

Treatment of Vitamin D Deficiency50, 000 IU capsule of vitamin D2 (erogocalciferol) once per week for eight weeks, repeat for another 8 weeks if 25 OH vitamin D is < 30 ng/ml

50, 000 IU capsule of vitamin D2 (erogocalciferol) once per week for eight weeks, then 50,000 IU of vitamin D2 every 2 to 4 weeks thereafter for maintenance.

If malabsorption syndrome, 50,000 IU of vitamin D2 every day or qod + the use of a tanning bed for 30-50% of the time recommended for tanning until deficiency corrected, then maintenance therapy

If stage 4 or 5 CKD, 0.25-1.0 ug of 1,25 dihydroxyvitamin D3 (calcitriol) bid

Vitamin D preparations

Current recommended of vitamin D levelsVitamin D level Health Status

>20-25 ng/ml Currently considered to be sufficient in otherwise healthy people

>30 ng/ml New recommendations based on new studies suggesting improved health outcomes at higher levels

Current vitamin D intake recommendationsAge Daily Intake

Under 50 600 IU50-70 and pregnant 600IU

Over 71 800 IU

Current vitamin D intake recommendations

Institute of Medicine, December 2010

D3 ≠ D2 ≠ 1,25-di(OH)-D3

*From 7-dehydrocholesterol **From ergosterol

Name D name Details

*Cholecalciferol D 3 Animal origin and from sun exposure not active

** Ergocalciferol D2 Plant origin , only 1/3 as active as D3

Calcitriol 1,25-di(OH)-D3 is converted in the kidney and other tissues - biologically active

“Vitamin D”

Vitamin D SupplementationDeficiency (<25 nmol/l or 10 mcg/l)

Oral Therapy1st line agent:

D3 800 iu capsules x4/d D3 3200 iu daily for 8-12 weeks. 2nd line:

D3 20,000 units / week for 8-12 weeks.Injection therapy Ergocalciferol(D2) 300,000 (or 600,000) iu single

dose by intramuscular injection Every 3 months .

Combined calcium & Vit. D supplements

unnecessary in primary vitamin D deficiencyLess palatable ? affects compliance

Dual replacement if severe deficiency accompanied by hypocalcaemia leading to secondary hyperparathyroidism

Appropriate for the management of osteoporosis and in the frail elderly.

Monitoringafte1 month Bone and renal profile

After 3 monthsBone and renal profile, vitamin D, and plasma parathyroid hormone.

Once vitamin D replacement is optimised no further measurement of vitamin D is necessary.

Vitamin D Intoxication

Common symptoms: Anorexia, nausea and vomiting.

Polyuria, polydipsia, weakness and pruritus

Lab abnormalities: AKI, hypocalcaemia .

Hyperphosphatemia

Treatment: Stop vitamin D, low calcium diet

Acidify the urine and steroids

Take Home PointsVit. D deficiency is so common

25 OH vitamin D is a predictor of bone health

Vit. D is . potentially an independent predictor of risk of

CVD,HTN, cancer,DM, all cause mortality, and URI

At least 800 IU of vitamin D3 per day

Sensible sun exposure is a great way to maintain

vitamin D sufficiency

Take Home Points

• A strong evidence to support vit. D deficiency screening

• Supplementation IS NESSARY in elderly individuals.

• Controversy remains as to whether new vitamin D goals

• New recommendations regarding vitamin D testing and

supplementation are likely in the coming years.