Aside from hypercalcemia, risks of acute or chronic vitamin D doses above the level deemed safe by the Institute of Medicine are perhaps real, but they’re difficult to measure at present, says Christopher Burnett, M.D.
Detroit - Aside from hypercalcemia, risks of acute or chronic vitamin D doses above the level deemed safe by the Institute of Medicine are perhaps real, but they’re difficult to measure at present, says Christopher Burnett, M.D.
"Is there such a thing as too much vitamin D? Yes, in acute high doses. If this were the only part of the story, it would be very simple," says Dr. Burnett, senior staff physician, department of dermatology, Henry Ford Health System, Detroit. "There might also be a risk with long-term high doses. The question becomes, ‘How much is too much?’"
IOM and intake levels
The IOM's 2010 report on vitamin D defines tolerable upper intake level as "the highest average daily intake likely to cause no risk of adverse health effects for nearly all persons in the general population," Dr. Burnett says. Data regarding the health impact of chronic high vitamin D doses are lacking, however, and available reports in this regard often conflict, he explains.
"Many experts believe the IOM was somewhat conservative with its recommendations, particularly the upper intake recommendations. It's important to remember that these are guidelines - a public-health document, and that current data are limited," Dr. Burnett says, adding that these factors may explain why the guidelines appear somewhat conservative.
The report's safe upper limits range from 1,000 IU daily for children up to 6 months old to 4,000 IU for adults and children more than 9 years old (www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx).
In contrast, IOM dietary reference intake (DRI) levels range from 400 IU for children less than 1 year old to 600 IU for people ages 1 to 70 years, and 800 IU for people above 70 years old. As such, "There's a large safety margin between recommended daily intake and the upper limits,” Dr. Burnett says.
Conversely, the report defines serum levels below 20 ng/mL as vitamin D insufficient. "The category at risk of excess is defined as greater than 125 nmol/L or 50 ng/mL," he says. For patients whose vitamin D dose or serum level is too high, hypervitaminosis D can present as acute intoxication or chronic excess. The former can lead to hypercalcemia, Dr. Burnett explains.
"Early vitamin D intoxication can present with very nonspecific symptoms such as weight loss and arrhythmias. As it progresses, however, it will lead to soft tissue and vascular calcification, eventually leading to renal and cardiac failure, which are the most common causes of death from vitamin D intoxication,” he says.
As for identifying precisely the levels at which the risk of hypervitaminosis D begins to escalate, "Unfortunately, we're lacking well-controlled studies, and there's wide variability in the literature,” Dr. Burnett says. “From most of the studies, it appears that the toxicity threshold may be anywhere between 10,000 and 40,000 IU per day - very high doses, taken consistently. These correspond with serum vitamin D levels of 400 to 500 nmol/L or 160 to 200 ng/mL. Therefore, the risk is low for the average person, especially if people adhere to recommended dosages."
According to the IOM, doses less than 10,000 units daily create a low risk of acute vitamin D intoxication. "As you increase above 10,000 IU, the risk increases, but where the risk begins to escalate significantly is not well-defined,” he says.
By the same token, risks associated with chronic excess vitamin D doses have been described graphically as a U-shaped curve, Dr. Burnett says. Experts debate the meaning and validity of this curve.
Although Dr. Burnett says he believes the topic requires more study, "It's a signal that's emerged in the literature that we should not ignore. The idea is that there are certain conditions - particularly bone health, but possibly others as well - in which low vitamin D levels increase the risk. And some studies have suggested that with increasing vitamin D levels, risk is only decreased up to a point" that corresponds with optimal vitamin D levels. Beyond the optimal range, risks of a particular disease start rising again, he says.
Various studies also have shown a similar relationship between vitamin D and all-cause mortality, says Dr. Burnett. In one such study, "Researchers found not exactly a U-shape, but a reverse J-shape that depicts risk beginning to rise at serum vitamin D levels above 20 ng/mL (Jia X, Aucott LS, McNeill G. Br J Nutr. 2007;98(3):593-599. Epub 2007 Apr 19). This is not a statistically significant result, but an interesting trend that we see across multiple studies (Visser M, Deeg DJ, Puts MT, et al. Am J Clin Nutr. 2006;84(3):616-622)."
However, Dr. Burnett says, "There's more to the story." A recent comprehensive review of 14 studies that analyzed vitamin D relative to all-cause mortality showed that "there are also several studies which show a nonlinear decrease in risk as circulating 25(OH)D increases, with optimal concentrations being around 75 to 87.5 nmol/L (Zittermann A, Iodice S, Pilz S, et al. Am J Clin Nutr. 2012;95(1):91-100. Epub 2011 Dec 14)," he says.
In particular, Dr. Burnett says that three studies evaluated vitamin D supplementation at daily doses between 400 and 880 IU daily, and one study involved about 1,100 IU. At these doses, "Researchers found no significant effects. But they noted a possible nonsignificant trend of increased risk at serum levels between 75 and 120 nmol/L,” he explains.
As for risks of pancreatic cancer relative to vitamin D, "One pooled analysis that included about 2,200 patients showed that patients with serum 25(OH)D levels greater than 100 nmol/L faced twice the risk versus patients with levels between 50 and 75 nmol/L (Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Am J Epidemiol. 2010;172(1):81-93. Epub 2010 Jun 18),” Dr. Burnett says. He says, however, that because other studies contradict these results, "It's not a settled issue."
Regarding cardiovascular disease, a 1,739-patient study with a mean follow-up of 5.4 years showed that risks increased in subjects with vitamin D deficiency (defined here as less than 37.5 nmol/L). Raising serum vitamin D level to 75 nmol/L decreased this risk, "But that effect tapered off,” Dr. Burnett says. “There was no further risk reduction once patients got above this level," and a nonsignificant trend toward possible increased risk of cardiovascular disease above this level (Wang TJ, Pencina MJ, Booth SL, et al. Circulation. 2008;117(4):503-511. Epub 2008 Jan 7).
Somewhat similarly, a 132,000-patient study showed that at serum levels above 249 nmol/L (100 ng/mL), subjects faced a 2.5 times higher risk of atrial fibrillation versus patients with normal vitamin D levels (Smith MB, Bunch TJ. Presented at: American Heart Association Annual Meeting. Nov. 12-16, 2011. Orlando, Fla.). "This is a very high serum level, so the implications are unclear for the average person" who doesn't have such high levels, Dr. Burnett says.
Regarding asthma and atopic dermatitis (AD), Dr. Burnett says, "There are scant data regarding possible harm from vitamin D. One larger cohort study showed that vitamin D supplementation in infancy may be associated with increased risk of adult atopy and allergic rhinitis (Hyppönen E, Sovio U, Wjst M, et al. Ann N Y Acad Sci. 2004;1037:84-95)." Another study found that infants who were given vitamin D doses higher than 13.1 mcg daily were more likely to develop AD (Bäck O, Blomquist HK, Hernell O, Stenberg B. Acta Derm Venereol. 2009;89(1):28-32).
As for falls and fractures, one recent study randomized 2,256 patients over age 72 to receive various vitamin D doses including a single annual dose of 500,000 IU of vitamin D for three to five years. "Investigators found that those patients who got that dose had 15 percent more falls and 26 percent more fractures,” Dr. Burnett says. “The highest risk occurred in the three-month period that followed that dose (Sanders KM, Stuart AL, Williamson EJ, et al. JAMA. 2010;303(18):1815-1822. Erratum in: JAMA. 2010;303(23):2357). It's a somewhat unexpected result" that other studies have not corroborated.
Overall, Dr. Burnett concludes that despite a relative paucity of data at present, the U-shaped curve indicating potential rising risk of various diseases and mortality at elevated vitamin D doses "should give us pause. Perhaps there can be too much of a good thing. This idea certainly warrants further research."
Disclosures: Dr. Burnett reports no relevant financial interests.