Current practice may over-diagnose vitamin D deficiency

Date: November 20, 2013
Source: Massachusetts General Hospital

Summary:
The current “gold standard” test for measuring vitamin D status may not accurately diagnose vitamin D deficiency in black individuals. A team of researchers has found that genetic differences in a vitamin D carrier protein may explain the discrepancy between the prevalence of diagnosed vitamin D deficiency in black Americans and a lack of the usual symptoms of vitamin deficiency.

The current “gold standard” test for measuring vitamin D status may not accurately diagnose vitamin D deficiency in black individuals. In an article in the Nov. 21 New England Journal of Medicine, a team of researchers report finding that genetic differences in a vitamin D carrier protein referred to as D-binding protein may explain the discrepancy between the prevalence of diagnosed vitamin D deficiency in black Americans — based on measuring the molecule 25-hydroxyvitamin D (25OHD) — and a lack of the usual symptoms of vitamin deficiency.

The essential role of vitamin D in maintaining bone health is well recognized, but while measurement of 25OHD alone consistently classifies from 70 to 90 percent of black Americans as vitamin D deficient, the usual consequences of deficiency — such as low bone density and increased fracture risk — are actually less prevalent among black individuals. That inconsistency led the team led by Ravi Thadhani, MD, MPH, chief of the Division of Nephrology in the Massachusetts General Hospital (MGH) Department of Medicine, to take a closer look at whether current methods accurately determine vitamin D deficiency.

The investigators examined data from more than 2,000 participants in HANDLS (Healthy Aging in Neighborhoods of Diversity Across the Life Span), a larger National Institutes of Health (NIH)-sponsored study, led by Michele K. Evans, MD, co-corresponding author of the current report, and Alan B. Zonderman, PhD, also a co-author. HANDLS is prospective, long-term, epidemiologic study of age-associated health disparities in socioeconomically diverse black and white individuals in the city of Baltimore. Participants — adults ages 30 to 64 — were interviewed and received medical examinations between 2004 and 2009.

For the current study, researchers analyzed levels of 25OHD, levels and genetic variants of D-binding protein, and levels of calcium and parathyroid hormone — another marker of vitamin D deficiency — along with bone density readings in almost 1,200 white and around 900 black participants. The results indicated that black participants had significantly lower levels of both 25OHD and D-binding protein, compared with white participants and also showed that about 80 percent of the difference in D-binding protein levels could be explained by genetic variation. However, bone density and calcium levels were higher in black participants, and while their parathyroid hormone levels also were higher, the difference between black and white participants was slight.

“Black people are frequently treated for vitamin D deficiency, but we may not be measuring the right form of vitamin D to make that diagnosis,” says Thadhani, who is senior and co-corresponding author of the NEJM report. “While our finding that 80 percent of black participants in this study met criteria for vitamin D deficiency is consistent with previous studies, we were surprised to find no evidence of problems with bone health. Most vitamin D in the bloodstream is tightly bound to D-binding protein and is not active. When we determined the concentrations of circulating non-bound vitamin D, which would be available to cells, we found that levels of this form were equivalent between black and white participants, which suggested to us that these black individuals may not be truly deficient.”

He adds, “Although currently there are no commercially available assays that directly measure bioavailable levels of 25OHD, these results suggest that such assays would more accurately identify those with true vitamin D deficiency, allowing us to direct treatment toward those who really need it. Additional studies need to be conducted to establish optimal levels of bioavailable 25ODH across all racial and ethnic groups.” Thadhani is a professor of Medicine at Harvard Medical School.

Evans, who is deputy scientific director and chief of the Health Disparities Research Section at the National Institute on Aging Intramural Research Program (NIA-IRP), notes, “This study confirms the value of addressing clinical questions from a health disparities standpoint that overcomes barriers to inclusion of diverse populations in biomedical research.”

How A Vitamin D Test Misdiagnosed African-Americans

by Richard Knox
November 20, 2013

By the current blood test for vitamin D, most African-Americans are deficient. That can lead to weak bones. So many doctors prescribe supplement pills to bring their levels up.

But the problem is with the test, not the patients, according to a new study. The vast majority of African-Americans have plenty of the form of vitamin D that counts — the type their cells can readily use.

The research resolves a long-standing paradox.

“The population in the United States with the best bone health happens to be the African-American population,” says Dr. Ravi Thadhani, a professor of medicine at Massachusetts General Hospital and lead author of the study. “But almost 80 percent of these individuals are defined as having vitamin D deficiency. This was perplexing.”

The origin of this paradox is a fascinating tale of genes interacting with geography. More on that later.

To unravel the mystery, Thadhani and his colleagues looked closely at various forms of vitamin D in the blood of 2,085 Baltimore residents, black and white. They focused on a form of the vitamin called 25-hydroxyvitamin D, which makes up most of the vitamin circulating in the blood. It’s the form that the standard test measures.

The 25-hydroxy form is tightly bound to a protein, and as a result, bone cells, immune cells and other tissues that need vitamin D can’t take it up. It has to be converted by the kidneys into a form called 1,25-dihydroxyvitamin D.

For Caucasians, blood levels of 25-hydroxyvitamin D are a pretty good proxy for how much of the bioavailable vitamin they have. But not for blacks.

That’s because blacks have only a quarter to a third as much of the binding protein, Thadhani says. So the blood test for the 25-hydroxy form is misleading. His study finds that because of those lower levels of the protein, blacks still have enough of the bioavailable vitamin, which explains why their bones look strong even though the usual blood tests say they shouldn’t.

“The conclusion from this study is that just because your total levels are low, it doesn’t mean we need to replace vitamin D” using supplements, Thadhani says. The study was published Wednesday in the New England Journal of Medicine.

The reason people of African descent have far less protein-bound vitamin D is probably related to the geographic origins of the human race. Our earliest ancestors lived near the equator in Africa, where sunlight was plentiful and intense year-round.

Vitamin D is synthesized in the skin when sunlight strikes it. When sunlight is deficient, the vitamin has to come from dietary sources such as eggs and fish oil.
For vitamin D supplements, more isn’t necessarily better.

Humans living in sunny climates make plenty of vitamin D on their own. In fact, one reason for the high degree of skin pigmentation in people of African descent is to prevent the synthesis of too much vitamin D, which can be toxic.

Early humans didn’t need to store up reserves of vitamin D, so they didn’t need as much of the binding protein, whose function is to squirrel the vitamin away in a form where it can be used later.

“Everyone who came out of Africa had the ancestral genotype associated with lower vitamin D-binding proteins,” Thadhani says. “When humans moved to areas with less sunlight, a different genotype evolved. The further north they went, the more people needed reserves of vitamin D. So D-binding protein levels went up.”

And that genetic difference in vitamin D-binding proteins is what researchers have finally figured out.

Reducing dietary salt and alcohol, exercising, not smoking and maintaining a healthy weight are other lifestyle tweaks known to help prevent or reduce high blood pressure, doctors say.

Dr. Michael Holick, a leading authority on vitamin D at Boston University Medical School, tells Shots that the new research is prompting him to resurrect blood samples from earlier studies to figure out whether the ill effects of low vitamin D in African-Americans and Caucasians are related to low levels of the bioavailable form or the protein-bound form.

While the effect of vitamin D on bone health is undisputed, Holick says, “there’s a lot of controversy about [the vitamin’s effect on] hypertension, diabetes, cancer and infectious diseases.”

Meanwhile Holick, who wrote an editorial in the journal accompanying Thadhani’s study, intends to keep giving his African-American patients vitamin D supplements when their blood levels of 25-hydroxyvitamin D are low, even though they may not need the pills to maintain strong bones.

“There’s no downside to supplementation, so it’s not a big deal,” Holick says.

But Thadhani says doctors should hold off on prescribing vitamin D until they do other tests to determine whether their African-American patients are really vitamin D deficient. Those tests include blood levels of calcium, bone density tests and parathyroid hormone levels.

There is currently no approved test for the bioavailable 1,25-dihydroxyvitamin D, although Thadhani and his colleagues are working on one and have filed for a patent.

He says he used to take vitamin D supplements “until I realized there are genetic differences, then I stopped. I’ve looked at my bioavailable levels of vitamin D. Now I’m comforted to know that I’m not deficient.”

http://www.npr.org/blogs/health/2013/11/20/246393329/how-a-vitamin-d-test-misdiagnosed-african-americans