Vitamin D: how much is enough, too much, or too little?

Remember cholesterol testing in the late 1980s and early 1990s? The first new cholesterol lowering medications, statin inhibitors, were introduced, and people concerned about years of eating the wrong foods and not exercising wanted to know if the new treatments were right for them. They flocked to health fairs at shopping malls, clinics, and public buildings, and stood in long lines to obtain their cholesterol numbers. Today, there is increasing interest in vitamin D, as more health care professionals and consumers learn about the rising prevalence of vitamin D deficiency and the potential health risks associated with it. Many people know that vitamin D is necessary to help the body absorb calcium; however, many don’t know that insufficient levels of this important vitamin may lead to other health problems. Healthcare professionals, including laboratorians, need to be up to date on the issue, and on the latest assays that have been developed in response to growing professional and public awareness of vitamin D deficiency.

The general term vitamin D refers to two different vitamins. Vitamin D2 (ergocalciferol) is synthesized by plants, and Vitamin D3 (cholecalciferol) is synthesized in the skin when it is exposed to the sun’s ultraviolet rays.¹ Vitamin D is also found in some fish, mushrooms and egg yolks. In the United States, foods such as milk and other dairy products, orange juice, and cereals are fortified with vitamin D.²

Mounting data show that vitamin D deficiencies are on the rise in the United States and around the world. According to the International Osteoporosis Foundation, vitamin D insufficiency is a worldwide health issue, and the percentage of the world population that has low vitamin D status is high, with some countries exceeding 75 percent.³ It is well known that Americans, Canadians, Europeans, and other population groups living in the Northern Hemisphere do not get enough vitamin D from the sun.⁴

Low vitamin D levels have several causes:²

• Sun avoidance: Many fair-skinned individuals concerned about skin cancer avoid sun exposure and use sunscreen faithfully when outdoors. Sunscreen absorbs UV radiation and use of an SPF 15 sunscreen reduces vitamin D production by up to 99 percent.
• Melanin: Individuals with dark skin often do not produce enough vitamin D from sun exposure. Melanin in the skin absorbs UV radiation and reduces vitamin D synthesis.
• Liver or kidney problems: Vitamin D undergoes two hydroxylation steps to become the active or bioavailable form of vitamin D. One step occurs in the liver and one in the kidney. Reduced liver or kidney function increases risk for deficiency.
• Malabsorption: People with Crohn’s disease, cystic fibrosis, celiac disease or other digestive disorders are unable to absorb vitamin D through food digestion.
• Vegetarian diet: Since most dietary sources of vitamin D are animal-based products, individuals following a plant-based diet may not get enough of the vitamin every day.
• Obesity: Those with a Body Mass Index (BMI) above 30 often have low vitamin D levels because vitamin D is sequestered in fat and is not available for use.

Ironically, it is sometimes the most health-conscious consumers who discover they have a vitamin D deficiency. Being careful about sun exposure limits the major source of vitamin D. Good dietary habits, such as avoiding animal-based food products, could cause shortfalls in daily intake of the vitamin. So people who wisely follow guidelines to prevent cardiovascular disease and skin cancer may unintentionally lower their vitamin D levels.

Health risks for vitamin D deficiency

Low concentrations of vitamin D cause secondary hyperparathyroidism (high levels of parathyroid hormone or PTH) and diseases related to impaired bone metabolism. When PTH is abnormally high, calcium is lost from bones and bone mineral density is decreased.⁵

Bone pain and muscle weakness are symptoms of possible vitamin D deficiency. In children, the decreased mineralization leads to skeletal deformities associated with a disorder known as rickets. Affected children have trouble standing and walking. In adults, decreased mineralization leads to osteomalacia, which causes muscle weaknesses and can lead to an increased risk of falls and fractures in the elderly.⁵

Determination of vitamin D concentration is important for patients with osteoporosis, chronic kidney disease, or malabsorption, or patients taking medication that may impair bone health.

There is increasing evidence that vitamin D deficiency may increase risk for some cancers, cardiovascular problems, autoimmune disorders, and infectious diseases. However, there is disagreement among experts regarding the benefits of vitamin D beyond its traditional role in promoting calcium and phosphorus absorption to maintain healthy bones. Additional studies, including randomized controlled trials, are needed to sort out how vitamin D impacts these other disease states.⁵

Published recommendations

In late 2010, the Institute of Medicine (IOM) of the National Academy of Sciences issued a report on the dietary intake requirements for vitamin D and calcium.⁶ The report addressed three main issues: (1) what health outcomes are impacted by vitamin D and calcium; (2) how much vitamin D and calcium are needed for an average adult to stay healthy; and (3) how much is too much.

The IOM report concluded that vitamin D is essential for bone health but stated the evidence is inconclusive with regard to its benefits for preventing cardiovascular disease, diabetes, cancer, and other conditions. IOM also concluded that a majority of adults receive adequate amounts of vitamin D, and there is emerging evidence that too much of the nutrient could be harmful to the kidneys. However, the organization did recommend that most adults get 600 international units (IU) of vitamin D daily instead of the previously recommended 400 IU/day and that higher doses of 800 IU/day are better for anyone age 70 and older.

In July 2011, a task force of The Endocrine Society published a clinical practice guideline for vitamin D deficiency in the Journal of Clinical Endocrinology and Metabolism.⁵ The guidelines were developed to help clinicians evaluate, treat, and prevent vitamin D deficiency, especially for patients with high risk factors. The task force report recommends screening for vitamin D deficiency for at-risk patients but stops short of calling for general population screening. The guidelines align with the IOM recommendations on the Recommended Daily Amount (RDA) for vitamin D. However, the task force suggests that individuals should maintain serum vitamin D levels of at least 30 ng/mL and acknowledges that some individuals need more than the RDA to achieve those levels. The guidelines also recommend testing with an assay that measures levels of circulating 25-hydroxyvitamin D or 25(OH) D, which is regarded as the most accurate way to measure vitamin D levels.

Vitamin D testing

Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are the forms of vitamin D that we ingest in our food or in supplements. However, these are not the forms of vitamin D that are measured in laboratory assays, nor are they the active, bioavailable form of the vitamin. Vitamin D (either D2 or D3) undergoes two hydroxylation steps to become an active molecule. The first step occurs in the liver, where vitamin D is converted to 25-hydroxyvitamin D (25 (OH) D). This is the form of vitamin D that is measured by most vitamin D assays.

The second hydroxylation occurs in the kidney, where 25 (OH) D is converted into 1,25-dihydroxyvitamin D (1,25 (OH)₂ D). This form of the vitamin binds to the vitamin D receptors and acts on many different cell types.¹ 25-(OH) D is the body’s repository of vitamin D. It is stable in blood and is established as the appropriate measurable indicator of vitamin D status.⁷ In the laboratory, 25 (OH) D can be measured by using either chromatographic methods, such as HPLC or LC-MS/MS, or immunoassays. Chromatographic methods have the advantage of being able to report separate concentrations for 25 (OH) D2 and 25 (OH) D3. However, they are labor-intensive. Immunoassays provide a total 25 (OH) D result (vitamin D2 plus vitamin D3) and, with automation, have high throughput and convenience.⁸

In recent years, immunoassays have become a primary laboratory method for vitamin D testing, and they provide laboratories with a viable alternative to sending the vitamin D samples to reference labs. With the recent introductions of new, automated vitamin D tests, large and small laboratories can better manage their increasing vitamin D testing volumes and provide rapid and highly accurate test results to physicians. The new assays are designed for quantitative determination of 25-hydroxy vitamin D in human serum and plasma to aid in the assessment of vitamin D sufficiency. Abbott’s ARCHITECT® automated 25-OH Vitamin D assay was cleared by the FDA in November 2011.

As more evidence is published about vitamin D, increasing numbers of patients will be asking their doctors about it. Demand for this test will continue to rise as doctors and patients better understand the role vitamin D plays in overall health.

Beth A. Schodin, PhD, is manager of global scientific affairs at Abbott Diagnostics.

References

1. Holick MF. Vitamin D requirements for humans of all ages: new increased requirements for women and men 50 years and older. Osteoporos Int. 1998;Suppl 8:S24-S29.
2. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
3. Dawson-Hughes B, Mithal A, Conjour J-P, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21:1151-1154.
4. Mithal A, Wahl DA, Bonjour J-P, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807-1820.
5. 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;96:1911-1930.
6. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-58.
7. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(suppl):1678S-1688S.
8. de la Hunty A, Wallace AM, Gibson S, Viljakainen H, Lamberg-Allardt C, Ashwell M. UK food standards agency workshop consensus report: the choice of method for measuring 25-hydroxyvitamin D to estimate vitamin D for the UK National Diet and Nutrition Survey. Br J Nutr. 2010;104:612-619.