Vitamin D Insufficiency/Deficiency

At a Glance

Vitamin D insufficiency/deficiency is common. The National Health and Nutrition Examination Survey (2001-2006) reported that levels of 25-hydoxyvitamin D (25[OH]D) were less than 20 ng/mL in 32% of the population. Screening everyone for vitamin D insufficiency/deficiency is not currently recommended. Indications for screening include:

  • rickets, osteomalacia, or osteoporosis

  • chronic kidney disease

  • hepatic failure

  • malabsorption syndromes

  • hyperparathyroidism

  • antiseizure medications, glucocorticoids, AIDS medications, antifungals, and cholestyramine

  • African-American and Hispanic children and adults

  • pregnant and lactating women

  • older adults with a history of falls

  • older adults with a history of nontraumatic fractures

  • obese children and adults (BMI >30 kg/m2)

  • granuloma-forming disorders

In addition, vitamin D insufficiency/deficiency is common in individuals of all ages with inadequate intake of vitamin D and/or exposure to sunlight. Other groups at risk for vitamin D deficiency include the elderly, institutionalized individuals, exclusively breast fed infants, and individuals of color.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Vitamin D insufficiency/deficiency is assessed by measuring 25[OH]D, not the hormone, 1,25-dihydroxyvitamin D (1,25[OH]2D). 1,25[OH]2D, has a half-life of only 4 hours, compared with 2-3 weeks for 25[OH]D, and circulates at a 1,000-fold lower concentration than 25[OH]D. 1,25[OH]2D is not useful in assessing vitamin D status, since its concentration may be low, normal, or even elevated in vitamin D deficiency. It is one of the most frequently misordered laboratory tests. Measurement of 1,25[OH]2D is rarely indicated, except in a few inherited or acquired disorders of phosphate and 25[OH]D metabolism.

Vitamin D exists as cholecalciferol (D3) and ergocalciferol (D2). D3 is synthesized in skin on exposure to sunlight (UV-B) and absorbed from the diet (primarily oily fish), D3 fortified foods, or D3 supplements. Pharmaceutical preparations and some supplements contain D2 produced by irradiating ergosterol from yeast with UV-B light. Both forms of vitamin D are metabolized to 25[OH]D and biologically active 1.25[OH]2D. Consequently, to assess vitamin D status, vitamin D methods should measure both forms with equimolar potency.

Tests Results indicative of the Disorder 25[OH]D concentrations for separating vitamin D sufficiency, insufficiency, and deficiency are controversial. The Endocrine Society’s recently published Clinical Practice Guidelines define vitamin D sufficiency, insufficiency, and deficiency as 25[OH]D levels of 30-100 ng/mL, 20-29 ng/mL, and less than 20 ng/mL, respectively. These recommendations are based on various lines of evidence, including the reduction of parathyroid hormone levels to a plateau, increased calcium absorption, and reduction of hip fractures when 25[OH]D levels are increased to 30-40 ng/mL or more.

Given the variability between vitamin D methods and measurements, a target of 40 ng/mL was suggested to ensure that individuals achieve true levels is at least 30 ng/mL. In contrast, a committee of the Institute of Medicine defined vitamin D sufficiency, insufficiency, and deficiency as 20-50 ng/mL, 12-20 ng/mL, and less than 12 ng/mL, respectively.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Vitamin D insufficiency/deficiency can occur because of a reduction in the synthesis, ingestion, or absorption of vitamin D, a reduction in the metabolism of vitamin D to 25[OH]D, an increase in the catabolism of 25[OH]D, or an increase in the urinary loss of 25[OH]D.

Vitamin D synthesis in the skin is affected by latitude, season, time of day, use of sunblock, clothing, age, and skin pigmentation. At latitudes above 37 degrees, sunlight is inadequate for synthesis during the winter. Vitamin D synthesis is greatly reduced in the elderly and by skin pigmentation.

Very few foods contain significant amounts of vitamin D. Fatty fish (salmon and mackerel) are good sources of vitamin D. Milk and some bread products, orange juices, cereals, yogurts, cheeses, and margarines are fortified with vitamin D. The Endocrine Society’s Clinical Practice Guidelines recommend a daily requirement of 1,500-2,000 IU with a tolerable upper limit of 10,000 IU for adults at risk for vitamin D deficiency. It may be difficult for the majority of adults to achieve this requirement without supplementation. The dietary reference intakes recommended by the Institute of Medicine are 600-800 IU/d, recommendations that have been criticized by experts in the vitamin D field.

Vitamin D absorption is decreased in malabsorption syndromes, including cystic fibrosis, inflammatory bowel disease, Chron’s disease, bariatric surgery, and radiation enteritis. Medications that may reduce absorption of vitamin D include cholestyramine, orlistat, olestra, and mineral oil.

Cytochrome P450 enzymes are responsible for both the synthesis and catabolism of 25[OH]D in the liver. Many drugs alter the activity of enzymes and may alter 25[OH]D levels. Catabolism of 25[OH]D is increased by a number of drugs, including anticonvulsants, glucocorticoids, and AIDS and antifungals medications. In hepatic diseases, 25[OH]D synthesis is usually adequate until 90% or more of the liver is dysfunctional.

Drugs reported to increase 25[OH]D levels include thaizide diuretics and atorvastatin.

25[OH]D bound to vitamin D binding protein is lost in the urine in nephrotic syndrome.

What Lab Results Are Absolutely Confirmatory?

Serum or plasma 25[OH]D is the test used to confirm vitamin D insufficiency/deficiency. Consequently, methods for vitamin D should be accurate, or at least sufficiently accurate and harmonized, and reproducible.

Methods employed by clinical laboratories include immunoassay (IA) or competitive protein binding assays (CPBA), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS-MS), and high performance liquid chromatography (HPLC) with UV detection. Automated immunoassays using antibodies against 25[OH]D are widely used but not all recognize 25[OH]D3 and 25[OH]D2 equivalently. CBPA use vitamin D binding protein (DBP), the protein transporting vitamin D in blood. LC-MS, particularly LC-MS-MS methods are gaining in popularity especially in large laboratories. LC-MS-MS has the potential to provide the most accurate and reproducible assessment of vitamin D status. A candidate reference measurement procedure was recently published using LC-MS-MS by the National Institute of Standards and Technology.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Tests that may be useful in evaluating patients with vitamin D insufficiency/deficiency are tests used to determine the cause, as well as the effects, of vitamin D insufficiency/deficiency, including calcium, phosphate, albumin, alkaline phosphatase, creatinine, and liver function tests. Parathyroid hormone is useful in diagnosing secondary hyperparathyroidism. The typical reference interval for parathyroid hormone is 10-65 pg/mL. Individuals with vitamin D insufficiency/deficiency were not excluded when these reference intervals were established. The upper limit of normal is considerably lower and typically about 50 pg/mL when individuals with 25[OH]D levels less than 30 ng/mL are excluded. The determination of bone mineral density by dual-energy x-ray absorptiometry is used to diagnosis osteopenia and osteoporosis.