Vitamin D deficiency

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Vitamin D deficiency is characterized by low serum vitamin D levels, although there is significant debate among professional societies over what level constitutes a deficiency. Causes include decreased cutaneous production of vitamin D, insufficient dietary intake, inadequate gastrointestinal absorption, impaired vitamin D metabolism (i.e., decreased activation, increased deactivation), and excessive losses. Patients are typically asymptomatic unless the deficiency is severe, in which case symptoms of complications (e.g., rickets, osteomalacia, hypocalcemia) may develop. Screening for vitamin D deficiency should be performed in individuals with conditions placing them at increased risk (e.g., those causing impaired metabolism or absorption of vitamin D), and may be considered in certain population groups (e.g., individuals with obesity, who are pregnant and/or lactating, or who have darker skin pigmentation). 25-hydroxyvitamin D (25-OHD) is the best diagnostic marker for vitamin D deficiency. Additional diagnostic studies are performed if complications or underlying conditions are suspected. Management involves the administration of vitamin D in addition to treatment of any associated complications and/or underlying conditions. Ensuring adequate daily vitamin D intake, especially in patients at increased risk for vitamin D deficiency, can help prevent associated complications.

Causes of impaired vitamin D synthesis ^[2][3][4]

Inadequate cutaneous synthesis of vitamin D₃

• Inadequate exposure to UV radiation, e.g., due to:
  • Living in sufficiently northern or southern latitudes (typically above or below 33 degrees)
  • Residence in an institution
  • Sunscreen use
  • Skin covering for cultural or religious reasons
• Darker skin pigmentation ^[5]
• Older age ^[3]

The most common cause of vitamin D deficiency is inadequate exposure to UV radiation. ^[2]

Inadequate dietary intake

• Restrictive diets (e.g., vegan diets, avoidance of vitamin-D fortified foods such as dairy products) ^[2]
• Infants: Breast milk is low in vitamin D. ^[6]

Causes of impaired metabolism of vitamin D

• Conditions
  • Liver; disease (e.g., cirrhosis)
  • Chronic kidney disease
  • Hypoparathyroidism ^[2][7]
  • Vitamin D-dependent rickets type 1
  • Granulomatous diseases, lymphoma, and primary hyperparathyroidism ^[2][8]
• Medications: cytochrome P450 modulators, e.g.: ; ^[2][9]
  • Anticonvulsants: phenytoin, carbamazepine, phenobarbital ^[3]
  • Antimicrobials: rifampin, HAART, antifungals ^[10]
  • Glucocorticoids
  • Cholestyramine ^[2][11]

Causes of impaired absorption of vitamin D ^[2][12]

Malabsorptive conditions can cause multiple dietary deficiencies, especially in fat-soluble vitamins (A, D, E, and K). These include:

• Cystic fibrosis
• Chronic pancreatitis
• Inflammatory bowel disease
• Celiac disease
• Bariatric surgery (e.g., Roux-en-Y gastric bypass)
• Radiation colitis

Other causes ^[2]

• Obesity ^[2][3]
• Premature birth ^[11][13]
• Nephrotic syndrome
• Target-organ resistance: vitamin D-dependent rickets type 2 ^[14]

• Mild or moderate vitamin D deficiency
  • Typically asymptomatic ^[4]
  • May lead to osteoporosis and fragility fractures ^[12]
• Severe, chronic vitamin D deficiency may cause: ^[2][4]
  • Clinical features of osteomalacia and/or rickets
  • Symptoms of hypocalcemia

• Screening is recommended for asymptomatic individuals with: ^{[2][15][16][17]}
  • Causes of impaired metabolism of vitamin D
  • Causes of impaired absorption of vitamin D
  • Nephrotic syndrome
  • Malnutrition
• Also consider screening in the following populations: ^[2][18]
  • Individuals with obesity
  • Pregnant and/or lactating women
  • Older adults with a history of falls or nontraumatic fractures
  • Individuals with darker skin pigmentation
• Screen using serum 25-OHD levels; see “Interpretation of serum 25-OHD levels” for further information.

Approach

• Obtain 25-OHD levels in individuals with any of the following: ^[2][3]
  • Indications for screening for vitamin D deficiency
  • Clinical features of osteomalacia and/or rickets
  • Incidental findings of either:
    • Laboratory findings that suggest vitamin D deficiency
    • Radiographic features of osteomalacia and/or rickets
• Consider additional testing if there is concern for:
  • Rickets and/or osteomalacia ^[19]
  • An etiology of vitamin D deficiency that is not inadequate intake/cutaneous production.
  • Malnutrition

Do not routinely test for vitamin D deficiency in patients presenting exclusively with other conditions, e.g., osteoarthritis, chronic pain, fatigue, and/or depression. ^[16]

Interpretation of serum 25-OHD levels ^[4][8][20]

• The Institute of Medicine and Endocrine Society have set different thresholds for vitamin D status and subsequent treatment.
• Individuals age ≥ 65 years and/or conditions associated with adverse outcomes in vitamin D deficiency, consider using the Endocrine Society thresholds.
• For all other individuals, consider using the Institute of Medicine (IOM) thresholds.

Do not use 1,25(OH)₂D levels to diagnose Vitamin D deficiency. 1,25(OH)₂D is often normal or elevated in vitamin D deficiency as a result of elevated PTH levels. ^[12][22]

A serum 25-OHD level of < 20 ng/mL usually requires treatment; some patients may benefit from treatment at < 30 ng/mL. ^[2][3]

Additional studies ^[4][11][12]

• Request the following laboratory studies in suspected osteomalacia/rickets; common laboratory findings in vitamin D deficiency include:
  • ↑ PTH (secondary hyperparathyroidism) ^[4][12]
  • ↑ ALP especially bone-specific ALP
  • ↓ 24-hour urinary calcium (without concurrent use of thiazide)
  • ↓ Phosphorous
  • ↓ Calcium (total and ionized) ^[4][12]
• If an alternative etiology is suspected (not decreased intake/cutaneous production): Obtain diagnostic studies as indicated, e.g., liver chemistries, renal function tests.
• Malnutrition: Consider evaluating for additional micronutrient deficiencies, e.g., iron deficiency, folate deficiency. ^[23]

Imaging is not routinely performed during the workup for vitamin D deficiency. If it is performed, it may show radiographic features of osteomalacia and/or rickets (e.g., Looser zones).

In the initial stages of vitamin D deficiency, serum levels of PTH, ALP, phosphorus, and calcium may be within normal range. ^[12]

Initial management ^[2]

• Treat any underlying etiology of vitamin D deficiency.
• Administer treatment doses of vitamin D.
  • Most patients: cholecalciferol or ergocalciferol ^[2][8][17]
  • Patients with obesity, malabsorption, or medication that affects vitamin D metabolism: high-dose cholecalciferol or ergocalciferol ^[2][8]
  • Patients with impaired 1α-hydroxylation or glucocorticoid excess may require an activated form of vitamin D (e.g., calcitriol ). ^[4][8]
• Ensure adequate calcium intake throughout treatment. ^[4][24]
• Patients with rickets and/or osteomalacia may require additional treatment (see “Treatment for osteomalacia and/or rickets”).

Individuals with obesity or malabsorption syndromes, or who take medications that affect vitamin D metabolism, typically need higher doses of vitamin D and calcium (e.g., 2–3 times the normal treatment doses). ^[2][8]

Monitoring and follow-up ^[2]

• Determine the treatment goal based on individual patient characteristics. ^[2][4]
  • Adults > 65 years and/or conditions associated with adverse outcomes in vitamin D deficiency: ≥ 30 ng/mL
  • All other adults: ≥ 20 ng/mL may be sufficient.
• The following groups require monitoring during treatment: ^[2]
  • Patients with extrarenal production of 1,25(OH)₂D (e.g., with granulomatous diseases, lymphoma)
    • Patients are at risk for hypercalcemia.
    • Monitor serum 25-OHD and calcium levels regularly; aim for a serum 25-OHD level of 20–30 ng/mL. ^[2]
  • Patients with primary hyperparathyroidism: Monitor calcium levels regularly during treatment.
• Recheck 25-OHD levels at the end of treatment for all patients.
  • Target goal reached: Switch to daily maintenance doses of vitamin D (see “Prevention of vitamin D deficiency”). ^[2]
  • Target goal not reached
    • Consider possible causes. ^[12]
    • Adjust dose as needed and recheck levels until normalization.
    • If no further improvement, refer to endocrinology.

Patients with extrarenal production of 1,25(OH)₂D or primary hyperparathyroidism are at risk for hypercalcemia and require monitoring during vitamin D repletion. ^[2]

Common complications

• Electrolyte and metabolic abnormalities: See “Common laboratory findings in vitamin D deficiency.” ^[4][12]
• Bone changes
  • Osteoporosis and/or fragility fractures ^[12]
  • Osteomalacia and/or rickets ^[2][4]

Conditions associated with adverse outcomes in vitamin D deficiency ^[8]

To prevent complications, patients with the following conditions may benefit from maintaining a higher vitamin D level (≥ 30 ng/mL).

• Primary hyperparathyroidism
• Hypoparathyroidism
• Osteoporosis
• Chronic kidney disease
• Multiple sclerosis
• Prediabetes
• Diabetes
• Malignancy
• Risk factors for severe COVID-19

We list the most important complications. The selection is not exhaustive.

• Vitamin D deficiency prevention relies on adequate dietary intake of vitamin D, as recommended sunscreen for skin cancer prevention prevents vitamin D from being synthesized in the skin. ^[2]
• Intake may be in the form of foods and/or supplements (usually both). ^[8]
• Foods high in vitamin D include: ^[3]
  • Fatty fish (salmon, sardines, mackerel, tuna)
  • Fish liver oil
  • Egg yolks
  • Vitamin-D fortified foods (e.g., milk, cereals, orange juice, yogurt)
• Supplements are usually in the form of cholecalciferol or ergocalciferol. ^[2][25]

Adults with ongoing risk factors for vitamin D deficiency may require 2–3 times the recommended daily intake (i.e., 1500–2000 IU/day). ^[2][28]

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