Vitamin D—Risk vs Benefit, by Dr. MILDRED S. SEELIG

The important paper by Holmes and Kummerow, in this issue, calls our attention to the need for balancing benefit against risk when providing dietary supplements to all in forms that are not readily recognized. In the case of vitamin D, the prophylactic use of which prevents a former common disease—rickets—recommendation that general widespread supplementation be discontinued or even modified requires careful consideration. Holmes and Kummerow have done this, by putting into focus the evidence that we are consuming far more vitamin D than had been suspected, and that not only the age group most vulnerable to rickets, but those for whom less vitamin D is needed, consume more than antirachitic doses. They provide insight into what the hidden sources of vitamin D are and refer to the unreliability of the assays of activity or toxicity of the different vitamin D precursors, congeners, and breakdown products.

It is well to remember that not all are at equal risk of vitamin D toxicity. Taussig [1] and Beuren [2] called attention to the great variation in the severity of exogenously caused malformation (as in the case of thalidomide) and suggested that the same might be true for the vitamin D-associated abnormalities, their degree depending on the time and magnitude of exposure to excessive intakes. They were referring, principally, to the supravalvular aortic stenosis syndrome (SASS) and related arterial abnormalities, such as those that resulted from the infantile hypercalcemia that occurred in epidemic proportions in Great Britain during the period of oversupplementation of infant formulas and foods [3]. Administration of more than 400 I U of vitamin D—from all sources—was never approved in the United States or Canada, but the disorders that developed in a substantial minority of infants subjected to overdosage are less commonly seen here. This brings us to individual variations in response to vitamin D. Genetic or acquired vitamin D resistance is well recognized. Since the severe manifestations of vitamin D toxicity that are seen in SASS are familial [2], it is plausible that hyperreactivity to vitamin D is genetic. To those with such a metabolic pattern, inadvertent consumption of excess vitamin D is a particular risk. There is still another possibility that should be investigated. Fragmentary animal studies indicate that successive generations, given toxic doses of vitamin D, exhibit increased vulnerability to hypervitaminosis D [4]. We are at least in the third generation of vitamin D supplementation, that from Holmes and Kummerow's evidence, may well be considerably more than necessary. They present a survey of the new developments in our knowledge of the metabolism of vitamin D that have been made possible by the new methodology, which provides the tools to elucidate the mechanisms of altered responsivity.

During the era of eradication of rickets, new pediatric and adult diseases have increased in prevalence. Hutchison [5] observed in 1955 that over the 20 years during which rickets had been eliminated in England, infantile hypercalcemia with and without osteosclerosis, renal tubular acidosis, and fibrocystic disease of the pancreas had emerged as serious diseases of childhood. He noted that antirachitic measures had been associated with the appearance of infantile hypercalcemia. Lightwood [6] reported that the incidence of renal tubular acidosis, as well as that of hypercalcemia, declined when the amount of vitamin D added to infant formula was diminished. Since generalized arteriosclerosis, as well as the mental retardation and valvular damage, is part of the SASS, and juvenile cardiovascular disease has become a serious problem [7], it is possible that excessive vitamin D might contribute to the early roots of arteriosclerosis in a larger segment of our population [8] than those so hyperreactive as to develop the full-blown toxicity. The preliminary clinical evidence of association of only moderately high vitamin D intakes with hypercholesterolemia [9-11] deserves further study.

The wealth of evidence adduced by Holmes and Kummerow that intakes of vitamin D exceed the official recommendations, and far exceed the requirements of many, emphasizes the importance of reopening the question of how best to protect against rickets, without placing others at risk of cardiovascular and renal disease. Practices that result in supplying amounts of vitamin D (directly from supplemented foods for human consumption, or from foods derived from supplemented animals) that can be toxic to a subset of the population require reexamination.

We recognize that this subject is controversial; we welcome letters to the editor and submission of papers presenting other points of view.

MILDRED S. SEELIG. MD, MPH, FACN
Editor

REFERENCES
1. Taussig HB: Possible injury to the cardiovascular system from vitamin D. Ann Intern Med 165:1195-1200,1966.
2. Beuren AJ, Apitz J, Stoermer J, Kaiser B: Vitamin D-hypercalcemic cardiovascular disease. Mschr Kinderheilk 114:457-470, 1966 (Ger).
3. Seelig MS: Vitamin D and cardiovascular, renal, and brain damage in infancy and childhood. Ann NY Acad Sci 147:537-582, 1969.
4. Light RF, Miller GE, Frey CN: Studies on the effects of overdosage of vitamin D. II. J Biol Chem 92:47-52, 1931.
5. Hutchison JH: Some new diseases in paediatrics. Brit Med J 2:339-342, 1955.
6. Lightwood R, Butler N: Decline of renal tubular acidosis: Aetiological implications. Brit Med J 1:855-857, 1963.
7. Seelig MS: Early nutritional roots of cardiovascular disease. In Naito HK (ed): "Nutrition and Heart Disease." New York: SP Medical & Scientific Books, 1982, pp 31-59.
8. Seelig MS: Magnesium deficiency with phosphate and vitamin D excesses: Role in pediatric cardiovascular disease? J Cardiovasc Med 3:637-650. 1978.
9. Dalderup LM, Stockmann VA, Rechsteiner de Vos H, Van der Slikke GJ: Survey on coronary heart disease in relation to diet in physically active farmers. Voeding 26:245-275, 1965.
10. Feenstra L, Wilkens JH: Cholesterol and vitamin D: Ned T Geneesk 109:615-619, 1965 (Dutch).
11. Linden V: Correlations of vitamin D intake to ischemic heart disease, hypercholesterolemia, and renal calcinosis. In Seelig MS (ed): "Mineral. Vitamin D, and Cholesterol Imbalance in Diseases of Infants and Adults." SP Medical & Scientific Books, 1977, pp 23-42.

source: Journal of the American College of Nutrition 2:109-110 (1983), 1983 Alan R. Liss, Inc. www.mgwater.com/