VIII. REQUIREMENTS 265 



The dosages administered before evidence of intoxication appeared varied 

 tremendously. As little as 400 units daily seemed to have produced fatal 

 pathology in one instance. The shortest length of time over which the vi- 

 tamin had been given before demonstrable calcification Avas produced was 

 14 days. The problem as to whether the toxic effects are due to the vitamin 

 D itself or to contaminating sterols cannot be answered. HoAvever, it has 

 been shown that pure, crystalline vitamin D, or any factor which can cause 

 an increase in the serum ionic calcium can produce toxic s3^mptoms. Al- 

 bright and Reifenstein" ascribed all the manifestations of hypervitaminosis 

 D to an exaggeration of the normal action of the vitamin : (a) to an increase 

 in the absorption of calcium from the gastrointestinal tract, and (b) to an 

 increase in the urinary excretion of phosphorus. 



Clinical symptoms in non-fatal cases are anorexia, nausea, vomiting, 

 diarrhea, polyuria, weakness, lassitude, headache, hyperesthesia, the ap- 

 pearance of areas of brown pigmentation over the skin, and evidence of renal 

 insufficiency. 



There is no agreement as to the mechanism by which the abnormal calci- 

 fication takes place. Some believe that the first step is the appearance of 

 cellular damage followed by calcium deposition. On the basis of experimen- 

 tal data with rats it is believed that abnormal deposition of calcium is the 

 first step. The exact factors which are related to the precipitation of calcium 

 are not known. Abnormal calcification may occur in the presence of a normal 

 total serum clacium. 



Conversely a high serum calcium may be present for a long time without 

 the occurrence of precipitation. It has been found that in rats, following ad- 

 ministration of large doses of calciferol, there was abnormal calcification 

 while the total serum calcium concentration was on the decline rather than 

 while the level was rising. The explanation seems to be that as the serum 

 calcium declined there Avas a rapid release of the part of the total calcium 

 held by the parathyroids and that this fraction Avas too great to be held in 

 solution. It Avould appear, therefore, that a fluctuating- serum calcium is 

 more apt to produce abnormal calcification than a high constant level. Calci- 

 fication is also aided by any factor AA^hich produces some degree of alkalosis, 

 as in continued A'omiting. Reed et al?^ have pointed out that patients AAdth 

 gastrointestinal complaints are more susceptible to the toxic effect of vita- 

 min D. Other factors of importance are the dose of vitamin D ingested, the 

 vehicle, the degree of exposure to sunlight, the amount of dietary calcium 

 ingested, the susceptibility of the individual, the pathologic state for \A'hich 



" F. Albright and E. C. Reifenstein, Parathyroid Gland and Metabolic Bone Dis- 

 ease, p. 95. Williams & Wilkins Co., Baltimore, 1948. 



2» C. I. Reed, I. E. Steck. H. C. Struck, and H. Deutsch, Ann. Internal Med. 10, 951 

 (1937). 



