I recently came across several papers published in The Veterinary Record in the 1960s documenting the efficacy and risks of injecting cows with a mega-dose of vitamin D just before calving to prevent “milk fever,” which isn’t a fever at all, but is a mix of clinical symptoms including weakness, loss of appetite, and in the extreme case heart failure. It results from low blood levels of calcium, which sometimes occur in the first few days of lactation, before the cow can adequately adjust its calcium balance to meet the new demands for this mineral. It may be a relatively recent disease resulting from the excessive demand for lactation placed on modern dairy cows. In this post, I will review these papers, which provide evidence that thyroid hormone and vitamin A protect against the harmful effects of the vitamin D injections.
In 1963, JB Tutt published an uncontrolled study showing that nine out of ten cows that had previously developed milk fever remained free of clinical symptoms when injected with ten million IU of vitamin D just prior to calving (Vet Rec. 1963;75:469-70). Tutt did not report the weight of the cows, but we should keep in mind that the body weight of cows can run ten or more times the weight of a typical human, so this dose is very high but not as extreme as it sounds, and its human equivalent is probably close to a single dose of one million IU.
JM Payne soon responded (Vet Rec. 1963;75:848-9) by publishing the results of his own department’s study wherein this dose of vitamin D was not without harm. In this study, the investigators injected cows with either 2.5 million IU, 10 million IU, or 40 million IU. The highest dose produced symptoms of vitamin D toxicity such as excessive urination and loss of appetite, but the cows recovered within seven days. Apart from this, all cows appeared healthy until they were slaughtered seven months later.
Post-mortem examination revealed the cows that received 10 million and 40 million IU were not so healthy after all. Untreated cows and cows given 2.5 million IU appeared normal in these examinations, but those receiving higher doses of vitamin D had extensive lesions in the heart, the aorta and other arteries, and the kidneys. These included pitting and corrugation of the walls of the arteries, widespread calcification, and blood clots at the bifurcations in the arteries and in the heart. The medulla and the tubules of the kidneys were also calcified, with large stones lodged in the renal pelvices, which are the funnel-shaped cavities through which urine exits the kidney into the ureter.
A few years later, Payne published a second report with R Manston showing that vitamin A and thyroid hormone both protect against these effects (Vet Rec. 1967;81:215-6). As in the experiment previously mentioned, while the cows given 40 million IU experienced clinical signs of toxicity including loss of appetite, excessive urination, and even death, those given 10 million IU were free of symptoms. Despite this, 83 percent of them developed extensive calcification of the cardiovascular system and kidneys.
If the cows were also given 100 milligrams of thyroxine (the “T4” form of thyroid hormone) or 5 million IU of vitamin A, the occurrence of these lesions dropped to zero.
Payne’s group also injected cows with 5 million or 7.5 million IU of vitamin D. Two-thirds of them suffered from pathological calcification. Untreated cows and those receiving 2.5 million IU vitamin D did not, but this low dose of vitamin D did nothing to prevent low blood levels of calcium. It was safe, but not effective.
The authors included in the same report several later experiments they conducted using diets that contained less calcium, more phosphorus, and slightly more magnesium. In these experiments, the dose of vitamin D required to produce pathological calcification increased to 20 million IU. Thyroid hormone still proved effective at preventing the calcification, although the investigators did not report additional experiments with vitamin A at this dose of vitamin D. When they experimentally manipulated the mineral content of the diet and the timing of the injections, they found that either increasing magnesium and phosphorus or dividing the dose of vitamin D into several injections could reduce, but not eliminate, the incidence of pathological calcification.
Even though the only treatments that reliably and completely eliminated the pathological calcification were the co-administration of either vitamin A or thyroxine, Payne and Manston concluded that “there seemed to be little point in pursuing this line of work if a ‘natural’ factor was already available awaiting discovery,” by which they meant manipulating the mineral intake of the cows.
As I wrote about in my recent article, “Nutritional Adjuncts to the Fat-Soluble Vitamins,” thyroid hormone directly regulates the expression of matrix Gla protein (MGP), a vitamin K-dependent protein that protects against soft tissue calcification. Normal levels of thyroid hormone also protect rats from blood vessel calcification that would otherwise occur spontaneously in the absence of this hormone. These studies in cows show that greater-than-normal levels of thyroid hormone also protect against soft tissue calcification induced by vitamin D.
In order for MGP to fulfill its protective function, vitamin K must activate the protein by adding carbon dioxide to it. The fact that normal levels of thyroid hormone protect rats from blood vessel calcification suggests that normal levels of this hormone increase the production of MGP in its active form, since inactive MGP would not be protective. The study in question, however, did not measure this directly.
If, as I have hypothesized, vitamin D toxicity leads to soft tissue calcification at least in part because it results in the production of defective vitamin K-dependent proteins, it seems unlikely that thyroid hormone could prove protective simply by increasing the production of MGP. Toxic doses of vitamin D increase the production of MGP between six-fold (cartilage) and 100-fold (lung), depending on the tissue. Research from Tufts University confirmed a critical part of my hypothesis, that calcitriol, the active form of vitamin D, increases the production of MGP in kidney beyond the capacity for vitamin K and its associated enzyme and cofactors to activate it, leading to the production of defective MGP.
If thyroid hormone does nothing more than increase the production of MGP, then extra thyroid hormone should aggravate this situation, yet it is protective. This suggests to me that thyroid hormone also either increases the production of the vitamin K-dependent activation enzyme, increases the production of the enzyme that recycles vitamin K, or that it increases the ability of vitamin K and its associated enzyme to activate the protein by increasing the supply of carbon dioxide.
That vitamin A is protective in cows is consistent with results from mice, rats, turkeys, and chickens, as well a study comparing cod liver oil to vitamin D2 in humans, as I have discussed elsewhere.
Unfortunately, Payne’s group did not report blood levels of calcium, but the fact that the vitamin D was used to improve low blood levels of calcium would seem to suggest that the cows did not have clinical hypercalcemia. If so, this would contradict the common claim that vitamin D must cause hypercalcemia in order to cause soft tissue calcification, but it would be consistent with studies in chickens and hyperparathyroidectomized rats showing that vitamin D causes soft tissue calcification even in the absence of hypercalcemia.
Perhaps the most remarkable point we can take from this study is that the therapeutic dose overlaps with the toxic dose when vitamin D is given alone. While 2.5 million IU was safe, it did not effectively prevent hypocalcemia. Effective doses were toxic.
Such overlap may also be present in human populations, as suggested by a major clinical trial published in 2006 showing that 400 IU of vitamin D and 1000 milligrams of calcium had no effect on the risk of fracture but increased the risk of kidney stones by 17 percent. The population was elderly, and perhaps following recommendations to avoid intakes of vitamin A above the RDA because of research suggesting that vitamin A can aggravate the risk of fracture. The trial, of course, was unable to tease apart the effect of calcium from the effect of vitamin D, but the fact that renal calcification appears to be the most sensitive sign of vitamin D toxicity should give us pause.
If the critical point is the dose of vitamin D, it makes no sense that the therapeutic and toxic windows overlap. If the point is that vitamin D must cooperate with other nutrients, such as vitamin A, and metabolic factors, such as thyroid hormone, such an overlap in the absence of these synergistic partners makes perfect sense.
Read more about the author, Chris Masterjohn, PhD, here.