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Vitamin D further down the road

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The possible role of vitamin D in systems beyond bone and mineral metabolism is receiving a lot of attention in the epidemiology literature of late. None of the work is definitive in my opinion, but the data cannot be dismissed out of hand. Clinical conditions receiving most attention are breast and prostate cancer and cardiovascular disease with emphasis on hypertension and congestive heart failure.

As a direct result, requests to labs for measurement of 25-hydroxyvitamin D (25 OHD) have skyrocketed. I have been told, but have not verified, that one of the major testing labs performed 30,000 such assays in January alone! As I have previously mentioned, there is a major flaw with the reporting that does not recognize the ethnic differences in reference intervals for blacks and non-Hispanic whites, with levels being lower in blacks. This is intriguing because of the skeletal advantage of this population, and it is conceivable that this occurs at the expense of disadvantage in other organ systems.

25-hydroxyvitamin D (25 OHD) is the major circulating metabolite of vitamin D with levels about 1,000-fold higher than the most active D metabolite, 1-25 dihydroxyvitamin D (1-25 OHD₂). The binding of 1-25 OHD₂ to the vitamin D receptor is ~100-fold greater than the binding of 25 OHD to the receptor. To date, little attention has been paid to 1-25 OHD₂ levels, but the current issue of Clinical Chemistry provides some interesting observations about an association between circulating 1-25 OHD₂ levels and cardiovascular mortality.

The study involved 510 patients in a cardiology specialty program who were followed for one year after initial 1-25 OHD₂ levels were obtained. Half of the patients were in the end stages of CHF, and approximately 20% (including those with CHF) had diabetes and/or renal failure. 1-25 OHD₂ levels were assessed in quintiles, and those in the lowest quintile were more likely to have CHF, diabetes, hypertension and renal failure. The presence of renal failure is important because 1-25 OHD₂ is synthesized in the kidney such that patients with sufficient circulating 25 OHD would still be deficient in 1-25 OHD₂ if they also had renal failure. Overall, 16% of the patients did not survive one year, and there was a strong association between quintiles of 1-25 OHD₂. A cut-off value of 25 ng/L provided the best discrimination between survivors and non-survivors.

There is no need to begin a stampede of measurements of 1-25 OHD₂! Provided there is good renal function, chronic kidney disease stage 3 or higher, the kidney will maintain the capacity to synthesize this hormone, provided of course there is adequate 25 OHD. Given the 1,000:1 difference in circulating levels of the two metabolites, your patient with normal renal function would have to be dramatically vitamin D deficient to end up with low levels of 1-25 OHD₂. By that time, the patient will likely have clinical symptoms such as myopathy, the serum phosphate will be low, and alkaline phosphatase will be elevated. (Caveat — you also need parathyroid hormone to convert 25 OHD to 1-25 OHD₂.)

Zittermann A. Clin Chem. 2009;55:1163-1170.