II. Physiology: General

  1. See Serum Calcium for Calcium Metabolism
  2. Vitamin D2 (Ergocalciferol) and D3 (Cholecalciferol) are fat soluble
  3. Although termed a Vitamin, it is actually a steroid Hormone
    1. Vitamin D acts at both cellular receptors as well as nuclear receptors (directly affecting DNA Transcription)
  4. Sources
    1. Vitamin D is synthesized in skin after exposed to sun (ultraviolet light)
    2. Also may be ingested and absorbed from Small Intestine
  5. Vitamin D circulates in blood as Calcifediol (Calcidiol, 25-hydroxyvitamin D3)
  6. Active form is Calcitriol (1,25 Hydroxycholecalciferol)
    1. Promotes renal and gastrointestinal Calcium absorption, and calcification of bone
    2. In excess, Vitamin D triggers Calcium absorption from bone

III. Physiology: Synthesis

  1. See Serum Calcium for Calcium Metabolism
  2. Images
    1. calciumHomeostasis.png
  3. Step 1a: Start with 7-Dehydrocholesterol (Cholesterol precursor)
    1. Skin exposure to sunlight or other ultraviolet light (290-315 nm of UV-B radiation)
    2. This pathway represents 90% of Vitamin D synthesis in humans
    3. Sun Exposure resulting in light pink skin (1 minimal erythema dose) = 20,000 IU (500 mcg) Oral Vitamin D
  4. Step 1b: Start with Dietary Vitamin D2 or D3
    1. Proceed to step 2 (bypasses sunlight-mediated synthesis pathway)
    2. Typically represents only 10% of Vitamin D source (unless specifically supplemented)
  5. Step 2: Cholecalciferol (Vitamin D3)
    1. Metabolized in liver by Vitamin D3-25 hydroxylase to 25-HYdroxycholecalciferol
  6. Step 3: Calcidiol (25-hydroxycholecalciferol, or 25-hydroxyvitamin D3)
    1. Metabolized in Kidney by 25-OH-D3-1a hydroxylase to 1, 25 Hydroxycholecalciferol (Calcitriol)
    2. Triggered by Parathyroid Hormone
  7. Step 4: Calcitriol (1, 25 Hydroxycholecalciferol)
    1. Calcitriol is the active form of Vitamin D)

IV. Pathophysiology

  1. Vitamin D Excess
    1. Hypercalcemia
    2. Ureteral Stones
  2. Vitamin D Deficiency
    1. Risk Factors
      1. Homebound elderly
      2. Inhabitants of Northern States
    2. Vitamin D Deficiency related conditions
      1. Children: Rickets
      2. Adults: Osteomalacia, Osteoporosis

V. Indications: Vitamin D Supplementation or Replacement

VI. Contraindications: Vitamin D Supplementation

  1. Granulomatous disease (e.g. Tuberculosis, Sarcoidosis)
  2. Metastatic bone disease
  3. Williams Syndrome

VII. Preparations: Dietary and Supplement Sources

  1. Fish (Vitamin D3, most in fatty fish)
    1. Salmon (450 IU per 3 oz)
    2. Sardines
    3. Fish oils
    4. Tuna (150 IU per 3 oz)
  2. Egg yolk (40 IU or 1 mcg)
  3. Butter
  4. Liver and other organ meats
  5. Vitamin D Fortified Milk (USA) contains 100 IU (2.5 mcg) per cup
  6. Fortified Orange Juice contains 80 to 120 IU (2 to 3 mcg) per cup
  7. Multi-Vitamin Contains 400 IU (10 mcg) Vitamin D per tablet

VIII. Signs: Vitamin D Deficiency

  1. See Vitamin D Deficiency
  2. Osteomalacia
  3. Muscular hypotonia

IX. Signs: Vitamin D Toxicity (related to Hypercalcemia)

  1. Headache
  2. Metallic Taste
  3. Vascular calcinosis or nephrocalcinosis
  4. Pancreatitis
  5. Nausea or Vomiting

X. Dosing (higher than current RDA)

  1. Children and Adolescents: 400 IU (10 mcg) per day
  2. Adults Age 18-50 years: 400-800 IU (10-20 mcg) per day
  3. Adults Age >50 years or Osteoporosis (higher levels are controversial)
    1. Southern regions: 800 IU (20 mcg) per day
    2. Northern climates: 1000-2000 IU (25-50 mcg) per day may be required
  4. Expect a 0.4 ng/ml increase for every 40 IU (1 mcg) daily of Vitamin D
    1. Expect 4 ng/ml increase from 400 IU (10 mcg) daily
    2. Expect 40 ng/ml increase from 4000 IU (100 mcg) daily
  5. Vitamin D is fat soluble and is best absorbed with fat in the meal

XI. Dosing: Supplementation in Infants and Children under age 2 years

  1. Indications
    1. See Vitamin D Deficiency for risk factors
    2. Breastfed Infants
    3. Children and adolescents consuming <1 Liter (34 oz) Vitamin D Fortified milk daily
  2. Supplements with daily dose of 1 drop (equivalent to 400 IU or 10 mcg) for age under 2 years
    1. Carlson Baby D Drops
  3. Supplements with daily dose of 1 ml (equivalent to 400 IU or 10 mcg) for age under 2 years
    1. Enfamil Poly-Vi-Sol Multivitamin Supplement drops
    2. Enfamil Poly-Vi-Sol Vitamins A, C and D with Iron
    3. Sunlight Vitamins Just D Infant Vitamin Drops
    4. Twinlab Infant Care Multivitamin Drops with DHA
  4. References
    1. Casey (2010) Am Fam Physician 81(6): 745-50 [PubMed]

XII. Dosing: Children with Vitamin D Deficiency (Rickets)

  1. Ergocalciferol (D2, Calciferol)
    1. Dose: 25-125 mcg (1-5000 IU) PO/IM for 6-12 weeks
  2. Cholecalciferol (D3, 40,000 IU/mg)
    1. Option 1: 125-250 mcg (5-10,000 IU) PO for 3 months
    2. Option 2: 15,000 mcg (600,000 IU) divided qid x1 day
  3. Dihydrotachysterol (DHT, 120,000 IU/mg)
    1. Option 1: 500 mcg (0.5 mg) for single dose or
    2. Option 2: 13-50 mcg PO per day until resolved
  4. References
    1. Khatib (2005) Consultant Pediatrician 4:33-9 [PubMed]

XIII. Dosing: Adults with Vitamin D Deficiency

  1. Mild (Serum 25-hydroxyvitamin D 8-15 ng/ml)
    1. Calcium 1200 to 1500 mg orally daily
    2. Vitamin D
      1. Option 1: Vitamin D 50,000 IU PO weekly for 8 weeks (repeat another course if Vitamin D <30 ng/ml)
      2. Option 2: Vitamin D 1000 IU daily per every 10 ng/ml shortfall in addition to maintenance for 6 weeks
        1. Example: Vitamin D 10 ng/ml
          1. Take 2000 IU (50 mcg) replacement in addition to 1000 IU (25 mcg) maintenance daily
      3. Option 3: Vitamin D 20-25 IU/kg IV daily (Parenteral for hospitalized patients)
      4. Maintenance after acute replacement: Vitamin D 800-1000 IU (20-25 mcg) PO daily
  2. Severe (Serum 25-hydroxyvitamin D <8 ng/ml)
    1. Vitamin D 50,000 IU (1250 mcg) orally daily for 1-3 weeks
    2. Then maintain as mild deficiency doses above
  3. Monitoring Vitamin D level at 6-8 weeks after starting therapy
    1. Goal 25-Hydroxyvitamin D >30-40 ng/ml
    2. Storage of Vitamin D does not start until 40 ng/ml

XIV. Efficacy: Vitamin D in Osteoporosis Prevention

  1. Dutch Study of 348 women over age 70 years
    1. Given Vitamin D 400 IU (10 mcg) or Placebo
    2. Vitamin D Group had greater BMD at 2 years
      1. Greater femoral neck Bone Mineral Density
      2. Placebo group had decreased Bone Mineral Density
    3. No change in femoral trachanter or distal radius BMD
    4. Ooms (1995) J Clin Endocrinol Metab 80:1052-8 [PubMed]
  2. Vitamin D does not reduce Fracture risk in adults over age 50 years (even in Vitamin D Deficiency)
    1. LeBoff (2022) N Engl J Med 387(4): 299-309 [PubMed]

XV. Efficacy: Conditions for which Vitamin D has no proven benefit

  1. Cardiovascular disease primary prevention (no proven benefit)
    1. Manson (2019) N Engl J Med 380(1): 33-44 [PubMed]
  2. Cancer primary prevention (no proven benefit)
    1. Manson (2019) N Engl J Med 380(1): 33-44 [PubMed]

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