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Vitamin D

Vitamin D is the hormone that enhances intestinal absorption of calcium and insures healthy bone formation. The best way to obtain vitamin D is through direct exposure of the skin to sunlight, because ultraviolet B rays stimulate the skin to synthesize vitamin D3.

Some people do not have adequate exposure to sunlight and are at higher risk of developing vitamin D deficiency. Examples include individuals who:

  • Live in latitudes >35o from the equator
  • Live in heavily polluted cities
  • Belong to cultures that require clothing that covers their entire body
  • Are institutionalized or homebound
  • Have dark skin
  • Apply sunscreen compulsively
  • Are elderly (decreased skin synthesis)
  • Are obese (vitamin accumulates in fat)

 

Individuals living under these conditions can only receive adequate vitamin D by ingesting vitamin D rich foods or supplements. Individuals ingesting a balanced diet obtain 200 to 300 IU of vitamin D per day. In 2010, The Institute of Medicine recommended a daily intake of 600 IU for children and adults less than 70 years and 800 IU for adults older than 70 years.

The Endocrine Society recommends a higher daily intake of 1500 to 2000 IU daily. In the United States, most vitamin D supplements contain vitamin D3 while prescriptions consist of vitamin D2.  Daily intake of 1000 IU of vitamin D increases 25-OHD level by 6-10 ng/mL. The prescription of 50,000 IU per month increases 25-OHD by 2 ng/mL.

Vitamin D is inert and must be converted to its active form. The liver metabolizes it to 25-hydroxyvitamin D (25-OHD), which is the major storage and circulating form of the hormone. The kidney converts 25-OHD to 1,25-dihydroxyvitamin D (1,25-OHD) under the regulation of parathyroid hormone. Therefore, normal vitamin D metabolism is dependent on sunlight exposure, intestinal absorption, and liver and kidney function. Vitamin D malabsorption may be associated with several GI disorders including Crohn disease, celiac disease, and pancreatic insufficiency. 

As vitamin D levels fall, the initial compensatory mechanism is increased PTH secretion, which stimulates the kidneys to increase phosphate excretion and decrease the calcium excretion. Blood calcium levels remain normal until the very late stages of vitamin D deficiency. Alkaline phosphatase is usually elevated in response to the effect of PTH on calcium absorption from bone. The combination of a normal serum calcium, low phosphate, and elevated alkaline phosphatase is suggestive of disturbed vitamin D metabolism. If creatinine and BUN are also increased, the problem probably lies with the renal production of 1,25-OHD. If liver function tests are abnormal or serum albumin is low, the problem may be a low 25-OHD level due to liver disease or malnutrition. 

 When 1,25-OHD levels are low, either due to deficient vitamin D stores or renal disease, the parathyroid glands release more PTH to try to synthesize more 1,25-OHD. Since this cannot happen, increased PTH promotes calcium absorption from skeletal bone, which may result in severe bone disease. Children develop rickets, while adults develop osteomalacia. Osteomalacia may present as a diffuse, dull, aching pain affecting many areas of the body including ribs and sternum. Vitamin D deficiency is a major risk factor for bone loss, weakness and fracture in the elderly. 

Some patients taking long-term antiepileptic drug therapy develop a syndrome of low plasma 25-OHD, intestinal malabsorption of calcium, slight decrease in plasma calcium, secondary hyperparathyroidism and cortical osteopenia. In one study of inpatients on a medical ward, the most common disorders associated with vitamin D deficiency were anticonvulsant therapy, renal dialysis, nephrotic syndrome, and winter season.  Cirrhosis, malabsorption and glucocorticoid therapy were also contributory factors (NEJM 1998; 338:777). 

Both 25-OHD and 1,25-OHD can be measured to assess vitamin D status. 25-OHD is the preferred test for patients with normal renal function. Measurement of 1,25-OHD should be restricted to patients with renal disease.  The reference range for 25-OHD is:

 

25-OHD ng/mL

Interpretation

<12

Deficient

12 – 30

Insufficient

>30

Adequate

>80

Toxicity possible

 

Individuals with intense sun exposure have a mean 25- hydroxyvitamin D level of 36 ng/mL and a range of 20 to 70 ng/mL. In 2010, the Institute of Medicine endorsed a 25-OHD concentration of 20 ng/mL as being adequate to prevent rickets and osteomalacia. In the United States, 30 to 35% of individuals have vitamin D levels below 20 ng/mL. However, 21% of individuals with 25-OHD levels between 20 and 30 ng/mL have increased osteoid volume. Most experts believe that the optimal concentration of 25-OHD is at least 30 ng/mL because this is the threshold for elevation of parathyroid hormone (JAMA 292:1416-18, Sep 22/29, 2004). The American Association of Clinical Endocrinology recommends that physicians target a 25-OHD concentration between 30 and 50 ng/mL.

A decade ago, physicians ordered vitamin D levels to assess bone health. Recent epidemiological studies have suggested that vitamin D deficiency may play an important role in the pathogenesis of cardiovascular disease, diabetes, cancer, multiple sclerosis, rheumatoid arthritis, asthma, periodontal disease and depression (J Am Coll Cardiol 2008;52:1949-56). All tissues possess vitamin D receptors and 25-hydroxylase enzyme. Accordingly, demand for 25(OH) vitamin D testing has skyrocketed. A laboratory in Kansas City, MO, received orders for 1710 vitamin D levels in 2007, 11,331 in 2008 and 26,024 in 2009.

The Third National Health and Nutrition Examination Survey (NHANES III) reported the prevalence of vitamin D deficiency in the United States to be between 25% and 75% of adults (Bone 2002;30:771-7).  The following table demonstrates the distribution of 25-OHD results in Kansas City in 2009.

 

25-OHD

Number

Percent

<25 ng/mL

6469

25%

<30 ng/mL

10,221

39%

>80 ng/mL

175

0.6%

 

Using a cutoff of 30 ng/mL, 39% of Kansas Citians, who were tested, were vitamin D insufficient, while less than 1% of people had levels above the upper limit of the normal range. The highest observed value was 327ng/mL. 

The cost of performing vitamin D testing in 2009 exceeded $550,000. Given the high incidence of vitamin D insufficiency and the low risk of adverse effects from vitamin D supplementation, a more practical clinical strategy might be to simply recommend vitamin D supplementation without ordering testing.

 

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