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Breaking down a recent mortality study

Posted on: August 29, 2013   by  John Cannell, MD


Another paper has reported a U or J shaped curve for total mortality and baseline 25(OH)D levels. This study is from the Office of Dietary Supplements of the National Institutes of Health. Dr. Christopher Sempos and colleagues did a tremendous amount of work in collecting and analyzing the data.

Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA, Looker AC, Schleicher RL, Cao G, Burt V, Kramer H, Bailey RL, Dwyer JT, Zhang X, Gahche J, Coates PM, Picciano MF.  Is There a Reverse J-Shaped Association Between 25-Hydroxyvitamin D and All-Cause Mortality? Results from the U.S. Nationally Representative NHANES. J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9.

I have responded to these types of studies before.

Nature knows best: A response to the Dror study. Posted on May 17, 2013 by John Cannell, MD

This is at least the sixth study using the same study design. First, a single baseline 25(OH)D level is obtained, this time from 15,000 individuals in an NHANES III cohort of the general population. Then those patients are followed to see if baseline 25 (OH)D levels are associated with mortality. In all these studies, as the authors point out: “The shape of this association appears to be asymmetric and in a reverse J-shape, with a clear upturn in the risk of death from all causes at low concentrations of 25(OH)D and possibly a shallow increase in the risk of death with higher serum 25(OH)D levels.”

In other words, low levels are clearly associated with a much higher risk of mortality, but high levels may or may not be associated with a slightly higher risk of death.

Of note, >99% of the population is in the range where the association is inverse to level. The upward blip occurs in the most extreme 1% of the population. A common explanation for this 1% blip is that these people suffer from diseases and thus are supplementing with alternative and complementary medicine in attempt to combat their disease.

Also, as I have said before, I believe this association is confounding by subclinical vitamin A toxicity. Please see this recent letter to the Food and Nutrition Board, signed by 18 nutrition experts including Professors Walter Willett, Edward Giovannucci, JoAnn Manson, and Carlos Camargo from Harvard, Professor Hector DeLuca from the University of Wisconsin, Professor Michael Holick from Boston University, Professor William Blaner from Columbia and other notable vitamin D and vitamin A experts. The letter clearly explains the confounding that is probably occurring in such studies. As we said:

“Future vitamin D and mortality studies should correct for retinol intake.”

I will not repeat what is in the letter. We did hear back from Doctor Suzanne Murphy, the chair of the standing Food and Nutrition Board. Without putting words in her mouth, she said they would like to review vitamin A for subclinical toxicity, but the FNB does not have funding to do so. We also heard from the European Food Safety Authority, who said they would review vitamin A in 2014 for evidence of subclinical vitamin A toxicity.

Also, as I have said before, I think it highly unlikely that humans would have evolved with an average 25(OH)D level of 46 ng/ml (115 nmol/L) if such levels were dangerous.

Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA.Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012 Nov 14;108(9):1557-61.

Natural selection simply does not work that way.

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