> Table of Contents > Vitamin D Deficiency
Vitamin D Deficiency
Marissa Hamrick, MD
Frank J. Domino, MD
Samir Malkani, MD, MRCP—UK
image BASICS
This topic covers the commonly acquired vitamin D deficiency and not type II vitamin D-resistant rickets/type I pseudovitamin D-resistant rickets (both rare autosomal recessive disorders).
DESCRIPTION
  • Vitamin D is both a hormone and a vitamin.
  • Cholecalciferol (D3) is synthesized in the skin by exposure to ultraviolet B (UV-B) radiation.
    Ergocalciferol (D2) and D3 are present in foods.
  • D2 and D3 are hydroxylated in the liver to 25 vitamin D (calcidiol), its major circulating form.
  • Calcidiol is further hydroxylated in the kidney to the active metabolite 1,25 vitamin D (calcitriol).
  • Hypocalcemia stimulates parathyroid hormone (PTH) to be secreted, which prompts the increased conversion of 25 vitamin D to 1,25 vitamin D.
    • 1,25 vitamin D decreases renal calcium and phosphorus excretion, increases intestinal calcium and phosphorus absorption, and increases osteoclast activity. These effects increase serum calcium.
EPIDEMIOLOGY
  • Unclear in general population
  • In the community, a cohort study of asymptomatic adolescents in Boston found 24.1% were deficient, with 4.6% severely deficient.
  • A study of hospitalized patients in Massachusetts found 57% vitamin D-deficient (VDD).
  • Women with history of osteoporosis/osteoporotic fracture have high prevalence of vitamin D deficiency.
  • A cohort study in Arizona found >25% of adults were VDD; highest rates among African Americans and Hispanics
  • A study of about 56,000 individuals across Europe found 13% to have vitamin D deficiency.
Pediatric Considerations
NHANES data found 70% of children did not have sufficient 25-OH vitamin D serum levels (9% deficient and 61% insufficient), which was associated with an increase in BP and decrease in high-density lipoprotein (HDL) cholesterol.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Insufficient dietary intake of vitamin D and/or lack of UV-B exposure (in sunlight) results in low levels of vitamin D.
    • This limits calcium absorption, causing excess PTH to be released.
  • PTH stimulates osteoclast activity, which helps to normalize calcium and phosphorous, but results in osteomalacia.
  • Dietary deficiency
    • Inadequate vitamin D intake
  • Inadequate sunlight exposure
    • Institutionalized/hospitalized patients
  • Chronic illness: liver/kidney disease
  • Malabsorptive states
Genetics
Vitamin D-dependant rickets type 1 occurs due to inactivating mutation of the 1 alpha hydroxylase gene; as a result, calcidiol is autosomal recessive not hydroxylated to calcitriol.
RISK FACTORS
  • Inadequate sun exposure
  • Female
  • Dark skin
  • Immigrant populations
  • Low socioeconomic status
  • Latitudes higher than 38 degrees
  • Elderly
  • Institutionalized
  • Depression
  • Medications (phenobarbital, phenytoin)
  • Gastric bypass surgery
  • Obesity
GENERAL PREVENTION
  • Adequate exposure to sunlight and dietary sources of vitamin D (plants, fish); many foods are fortified with vitamin D2 and D3.
  • Recommended minimum daily requirement from the 2010 Institute of Medicine Report is minimally 600 IU/day for those 1 to 70 years of age and 800 IU/day for those >70 years of age. Up to 4,000 IU/day is safe in healthy adults without risk of toxicity.
  • Higher intake of vitamin D recommended for age >50 years
  • 2005 and 2009: Meta-analysis demonstrated for ages 51 to 70 years, minimally recommended supplementation is 800 IU/day to prevent nonvertebral fractures.
Pediatric Considerations
The American Academy of Pediatrics recommends all breast-fed babies receive 400 IU/day of vitamin D beginning “within the first few days of life.”
Pregnancy Considerations
ACOG recommends data insufficient to screen all pregnancies; only those “at risk” and states it is safe to take 1,000 to 2,000 IU/day during pregnancy (1)[B].
Geriatric Considerations
U.S. Preventive Services Task Force recommends seniors take at least 800 IU/day vitamin D to reduce risk of falls in community-dwelling older adults (2)[A].
COMMONLY ASSOCIATED CONDITIONS
  • Osteomalacia, osteoporosis
  • Premenstrual syndrome
  • Rickets
  • Celiac disease
  • Gastric bypass
  • Chronic renal disease
  • Bacterial vaginosis in pregnant women
  • Hypertension
image DIAGNOSIS
  • Nonspecific musculoskeletal complaints
  • Weak antigravity muscles
  • Fracture with minimal trauma
PHYSICAL EXAM
  • Vague neurologic signs: numbness, proximal myopathy, paresthesias, muscle cramps, laryngospasm
  • Chvostek sign: contraction of the facial muscles by tapping along the facial nerve
  • Trousseau phenomenon: carpal spasms and paraesthesia produced by pressure on nerves and vessels of the upper arm, by inflation of a BP cuff
  • Tetany, seizures
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • 25-OH vitamin D (most sensitive measure of vitamin D status)
  • Vitamin D deficiency
    • <20 ng/mL
  • PTH elevation: not routinely obtained unless severe deficiency
  • Low-normal/low calcium and phosphorous
  • Elevated alkaline phosphatase (in later disease)
  • Plain radiographs: If atypical fracture, radiographs may show osteomalacia (pseudofractures/looser zones) in pelvis, femur, and fibula.
  • Osteoporosis screen
    • Women ≥65 years with no risk factors
    • Women ≥60 years at risk: body weight <70 kg (best predictor)
    • Less evidence: smoking, low body mass index, family history, decreased activity, alcohol or caffeine use
    • African American women have higher bone density than Caucasians.
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image TREATMENT
  • Treatment goals remain unclear, but current “normal” 25-OH vitamin D levels are based on suppression of PTH.
  • Obesity: Treatment of VDD in obesity, especially those who are obese and depressed, improves depressive symptoms and may improve weight loss (4)[B].
Geriatric Considerations
In senior citizens, serum 25-OH vitamin D of 20 ng/mL resulted in improved physical performance scores; recent data suggests supplementation may not improve fracture risk and remains unclear about a true benefit.
MEDICATION
  • Vitamin D sufficient (25-OH vitamin D ≥20 ng/mL)
    • Vitamin D 800 to 4,000 IU/day D2/D3 (6)[A]
    • D3 (animal derived) may be slightly more effective than D2 (plant derived), but clinical significance is uncertain.
    • Calcium supplementation: Unclear benefit and may increase some CHD risk in patients. No supplementation currently required (see below).
  • Vitamin D deficiency (25-OH vitamin D <20 ng/mL)
    • D2 50,000 IU/week for 8 to 12 weeks, followed by 800 to 2,000 IU/day of vitamin D3 (6)[A]
  • Calcium: meta-analysis data support
    • Dietary intake of ˜700 mg/day leads to best outcomes; higher doses did NOT decrease risk of osteoporotic fractures.
    • Dietary calcium may be more beneficial than calcium supplementation.
    • Supplementary calcium associated with an increased risk of MI, especially in women (7)[A], but this data remains controversial (8)[C].
ISSUES FOR REFERRAL
Endocrinology if no response to treatment
ADDITIONAL THERAPIES
Aggressive calcium in ICU patients with ionized calcium <3.2 mg/dL or if symptomatic (tetany, seizures, QT prolongation, bradycardia, or hypotension, or ventilated patient with decreased diaphragmatic function)
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Symptoms of severe hypocalcemia or
  • Malabsorption syndromes
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Follow-up of abnormal 25-OH vitamin D not required
DIET
  • Cod liver oil is most potent source of vitamin D and has ˜1,300 IU vitamin D/tablet/tablespoon.
  • Fatty fish (tuna, salmon)
  • Fortified milk (100 IU/8 oz), cereal, and foods
PROGNOSIS
  • Systematic review of 63 observational studies found adequate 25-OH vitamin D levels correlate with lower rates of colon, breast, and prostate cancer.
  • Cohort study found that vitamin D deficiency is correlated with increased risk of all-cause mortality.
REFERENCES
1. ACOG Committee on Obstetric Practice. ACOG Committee Opinion no. 495: vitamin D: screening and supplementation during pregnancy. Obstet Gynecol. 2011;118(1):197-198.
2. Moyer VA; U.S. Preventive Services Task Force. Prevention of falls in community-dwelling older adults: U.S. Preventive Task Force recommendation statement. Ann Intern Med. 2012;157(3):197-204.
3. Correia LC, Sodré F, Garcia G, et al. Relationship of severe deficiency of vitamin D to cardiovascular mortality during acute coronary syndromes. Am J Cardiol. 2013;111(3):324-327.
4. Vimaleswaran KS, Berry DJ, Lu C, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383.
5. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2011;(7): CD007470.
6. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7): 1911-1930.
7. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
8. Chrysant SG, Chrysant GS. Controversy regarding the association of high calcium intake and increased risk for cardiovascular disease. J Clin Hypertens (Greenwich). 2014;16(8):545-550.
9. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014; 348:g1903.
Codes
&NA;
ICD10
  • E55.9 Vitamin D deficiency, unspecified
  • M83.8 Other adult osteomalacia
Clinical Pearls
&NA;
  • Risk factors for VDD: senior citizen, renal disease, GI (malabsorption) disorders, liver dysfunction, immigration from tropical to colder climates, darkskinned/veiled individuals, housebound patients, perimenopause
  • Diagnosis: 25-OH vitamin D (most sensitive measure of vitamin D status)
  • Vitamin D deficiency: <20 ng/mL
  • Up to 4,000 IU/day is safe in healthy adults without risk of toxicity.
  • 2005 and 2009: Meta-analysis demonstrated for ages 51 to 70 years minimally recommended supplementation is 800 IU/day to prevent nonvertebral fractures.
  • The American Academy of Pediatrics recommends all breast-fed babies receive 400 IU/day of vitamin D beginning within a few days of birth.