Cedars-Sinai Medical Center

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A BI-WEEKLY PUBLICATION FROM THE CEDARS-SINAI CHIEF OF STAFF May 25, 2012 Issue | Archived Issues

What vitamin D test to order?

During the past decade, there has been an explosion in the number of articles written about vitamin D and its importance in the maintenance of normal bone and muscle function. Vitamin D deficiency has been associated with osteopenia, osteoporosis, bone pain, as well as muscle weakness and aches and increased risk of falls. Although a cause-and-effect relationship has not been established, low blood levels of vitamin D have also been associated with an increased risk of cardiovascular disease, autoimmune diseases, some cancers and depression. The two sources of vitamin D are sunlight and nutrition. When skin is exposed to ultraviolet light, vitamin D3 (cholecalciferol) is synthesized. Nutritional sources of vitamin D3 include fatty fish such as salmon, mackerel and herring fish liver oils and egg yolks. Vitamin D2 (ergocalciferol) is present in yeast and plants. For many of us, dietary and sunlight sources of vitamin D are inadequate to provide sufficient quantities of vitamin D to maintain optimal health.

Click here to read about test changes in the Core Laboratory.

Vitamin D made in the skin or ingested in the diet is converted to 25-hydroxy vitamin D [25(OH)D] in the liver and to 1,25 dihydroxy-vitamin D [1,25(OH)2D (calcitrol)] in the kidney. 1,25(OH)2D is the most active metabolite of vitamin D and is responsible for increasing calcium and phosphorus absorption from the intestine, promotion of bone osteoid mineralization, stimulation of proximal tubular phosphate reabsorption and maintenance of calcium reabsorption by the kidneys and decreasing parathyroid hormone synthesis and secretion. Vitamin D deficiency is found in individuals who use sunscreen, hats and long sleeve shirts, people who are housebound, and individuals with gastrointestinal problems such as Crohn’s disease and post-bariatric surgery which cause malabsorption of lipids. Hispanic and African Americans are also at higher risk than caucasians, because of the effect of skin pigmentation from melanin. Vitamin D toxicity is rare and generally found in individuals consuming more than 10,000 IU per day of exogenous vitamin D.

25(OH)D is the main circulating form of vitamin D with a half-life of two to three weeks. Serum quantities are measured in ng/ml.In contrast, 1,25(OH)2D has a half-life of about four hours and serum concentrations are measured in pg/ml, which is a thousand times less than 25(OH)D. Most importantly, however, serum concentration of 1,25(OH)2D are often normal or elevated in the presence of vitamin D deficiency. Therefore, 1,25(OH)2D should not be used to asses vitamin D levels and the only appropriate marker to assess vitamin D status is 25(OH)D.

Although a number of publications have debated the actual cutoff values for diagnosing vitamin D deficiency, data supports levels of 25(OH)D less than 20 ng/ml to be considered a deficiency, between 21-29 ng/ml vitamin D insufficiency, and levels greater than 30 ng/ml vitamin D sufficiency. Serum concentrations of greater than 150 ng/ml are indicative of vitamin D intoxication.

Low levels of 1,25(OH)2D may be seen in severe vitamin D deficiency, renal osteodystrophy or renal failure. However, 25(OH)D remains the appropriate test and will detect the deficiency. Low 1,25(OH)2D levels also may be seen in the setting of pseudohyperparathyroidism and hypoparathyroidism, where measurement of parathyroid hormone along with serum calcium is better tests. High levels of1,25(OH)2D are found with 1,25(OH)2D intoxication and hyperparathyroidism.

When should 1,25(OH)2D levels be ordered?

There are very few indications for measurements of 1,25(OH)2D levels. These include:

  • Hypercalcemia with a low parathyroid hormone. The initial test to evaluate hypercalcemia should be a measurement of parathyroid hormone. If it is elevated in the presence of elevated serum calcium, the diagnosis of hyperparathyroidism is made. If the parathyroid hormone level is suppressed, the elevated calcium may be due to production of parathyroid hormone-related protein from a tumor, local production of osteolytic factors from metastatic disease to the bone, or the production of 1,25(OH)2D from granulomatous diseases, some lymphomas and rare leukemias.
  • Tumor induced osteomalacia (oncogenic osteomalacia) (rare) is associated with a very low phosphate and low 1,25(OH)2D level.
  • Hereditary phosphate-losing disorders are also rare and may be associated with abnormalities in 1,25(OH)2D.
  • Renal insufficiency is associated with both low serum 25(OH)D and low serum 1,25(OH)2D concentrations, with high normal or elevated serum phosphate and low serum calcium. Again, 25(OH)D is the appropriate test to evaluate vitamin D status with kidney disease.
  • The very rare vitamin D-dependent rickets type 1, also known as pseudo-vitamin D deficient rickets, is associated with a combination of normal or low serum 25(OH)D and low 1,25(OH)2D with a low serum phosphorus.

Analysis of vitamin D ordering patterns at Cedars-Sinai

A review of 176 patients who had 1,25(OH)2D levels ordered over a three-month period showed that 3.4 percent had an indication for the measurements (hypercalcemia with a suppressed parathyroid hormone) and an additional 3.4 percent had marginal indications, primarily related to renal disease.Thus, at the most 6.8 percent of the 1,25(OH)2D levels ordered could be justified.

Recommendations

Screening for vitamin D deficiency should be carried out with measurements of serum 25(OH)D levels only. 1,25(OH)2D will be removed from the ordering panels on CS-Link™, but can be ordered specifically at the request of the attending physician.

Article prepared by: Holli M. Mason, MD, associate director, Transfusion Medicine, medical director, Core Laboratory; Hossein Sadrzadeh, PhD, scientific director, Core Laboratory; and Glenn D. Braunstein, MD, vice president, Clinical Innovation.