Idiopathic hypercalcemia

Hydroxyindoles (Dalgliesh), I, 194 Hypercalcemia, Idiopathic, of Infancy (Forfar and Tompsett), 2, 168 Immunoelectrophoresis Methods, Interpretation, Results (Wunderly), 4, 206... 

Acute adrenal insufficiency Pheochromocytoma Familial hypocalciuric hypercalcemia Idiopathic hypercalcemia of infancy Vitamin overdose Vitamin D Vitamin A... 

Malabsorption syndrome Steatorrhea Tropical sprue Idiopathic hypercalcemia... 

Idiopathic Hypercalcemia of Infancy John O. Forfar and S. L. Tompsett... 

An alternative to thiazides is allopurinol. Some studies indicate that hyperuricosuria is associated with idiopathic hypercalcemia and that a small nidus of urate crystals could lead to the calcium oxalate stone formation characteristic of idiopathic hypercalcemia. Allopurinol, 300 mg daily, may reduce stone formation by reducing uric acid excretion. 

Idiopathic hypercalcemia of infancy was first described as such by Lightwood in 1952 (L3). In the same year Fanconi and Girardet (F2) and Schlesinger et al. (SI) described two children in whom hypercalcemia was first recognized at the age of approximately 20 months but who had exhibited symptoms at a much earlier age. In both of these children the hypercalcemia was associated with mental retardation, cranial abnormalities, and cardiac murmurs. 

Is idiopathic hypercalcemia of infancy a new disease or is it one whose anonymity has for long been cloaked under terms such as marasmus To this question no categorical answer can be given. In the earlier literature cases were reported which, from a clinical point of view, might well have been idiopathic hypercalcemia of infancy. Usually, however, the biochemical data essential for conclusive diagnosis have been absent. 

Broadly speaking, idiopathic hypercalcemia has been divided into two types, the so-called mild type typified by the cases described by Lightwood in 1952 and the so-called severe type typified by the cases de-... 

In the majority of cases of idiopathic hypercalcemia of infancy the course is a self-limiting one. The disease on the one hand may clear up fully after a few weeks on the other hand it may drag on for months with intermittent remissions and exacerbations. In some cases the infant suffers from a comparatively trivial transient illness. In others, and fortunately a minority, he may be critically ill and suffer permanent sequelae. In a group of 45 cases reported in the literature (B5, C3, D3, F7, L6, Ml, M3, S2) there were six deaths, but of course the real death rate will be only a fraction of this because many milder cases will not have been reported or will not have been recognized. 

The evidence that is available regarding the morbid anatomy of idiopathic hypercalcemia of infancy is naturally derived from severer cases which have proved fatal (D3, L6, Rl, S2). In these, pathological changes are found predominantly in the skeleton, kidneys, and cardiovascular system, but other systems may be involved to a lesser degree. 

The renal lesions which have been described in idiopathic hypercalcemia are not specific. Similar changes have been observed in hyperchloremic renal acidosis of infancy (B7, D7), in various other diseases of infancy and in hypervitaminosis D. It is interesting to note that a recent re-examination of the histological sections of Thatcher s cases of a quarter of a century ago showed that the changes there were essentially the same as those occurring in idiopathic hypercalcemia of infancy (Rl). 

The increase in serum calcium above the normal range would appear to have been the initial stimulus to the study of this condition. Values up to 18.7 mg/100 ml have been reported (S2), although the usual range of maximum levels is from 12.5 to 15 mg/100 ml. There is, however, good evidence that in the disease entity which we call idiopathic hypercalcemia the serum calcium can be lower than 12.5 mg/100 ml. The disease has been reported in the presence of levels of 11.2 mg/100 ml and 12.0 mg/100 ml (F7, L6). Recovery from idiopathic hypercalcemia is accompanied by a return to within the normal range. It is probably true to say that an elevated serum calcium may be regarded as a diagnostic aid, and it is, of course, implied in the title of the condition. 

Fyfe (F10) has investigated plasma vitamin A levels. He observed that the fasting levels in infants with idiopathic hypercalcemia were higher than in the normal and that after a large oral dose of vitamin A,... 

Harrison (H5) has reported that serum citrate is increased above the normal range in hypervitaminosis D. Winberg and Zetterstrom (Wl) found it to be low in an 11-month-old infant suffering from vitamin D intoxication. Forfar et al. (F7) have reported that during the active phase of idiopathic hypercalcemia, serum citrate levels are low. 

In idiopathic hypercalcemia hypophosphaturia has been found (F7, M3), but hyperphosphaturia has also been reported (S6). 

Forfar et al. (F7) have examined urinary citrate excretion in one case of idiopathic hypercalcemia. During the active phase of the condition, citrate excretion was 9.5 and 10.6 mg/day rising to 96 mg/day during the recovery phase. The latter represents a low normal value. It would appear that in this particular case, a hypocitruria existed during the active phase of the condition. 

Balance studies involve the measurement of both the intake of a substance and the excretion (urine and feces). The interpretation of some published studies is therefore difficult since the intake has been calculated merely from tables. A reliable balance study should include a chemical analysis of a comparable aliquot of the intake. The vomiting which is a feature of idiopathic hypercalcemia of infancy may also make accurate balance studies very difficult technically. 

Forfar et al. (F7) have reported the calcium balance in 3 active cases of idiopathic hypercalcemia. The mean calcium intake was 1.02g/day and the mean retention was 49% or 0.45g/day. Morgan et al. (M3) observed retentions of 53 % and 54 % in two cases, the actual daily retentions being 0.46g/day and (on a low calcium intake) 0.31 g/day. These results suggest that there may be some increased calcium retention in idiopathic hypercalcemia. As there is at the same time hypercalcuria without evidence of loss of calcium from bones, the most likely explanation is that there is increased alimentary absorption of calcium. 

There thus appears to be an increased retention of phosphorus in idiopathic hypercalcemia. 

A low-calcium diet lowers the serum calcium level in idiopathic hypercalcemia of infancy (B5, F4, F7, Ml, R4, S8). It results in a marked reduction in calcium retention and can convert a strongly positive calcium balance to a less positive or even negative one (F7, Ml). 

Forfar et al. (F7) examined the effect of cortisone (25mg/day) in one case of idiopathic hypercalcemia. Cortisone was administered on four occasions. On each occasion the serum calcium fell, rising again after the cortisone was withdrawn. Similar results have been obtained by other workers (C3, F3, S9). 

Morgan et al. (M3) examined the effect of the administration of EDTA in idiopathic hypercalcemia. Given orally, a dosage of up to 3 g daily resulted in a fall in the serum calcium level. Given subcutaneously in a dosage of 1 g daily, there was a fall in calcium retention in a balance study, a retention of 51 % being converted to a retention of 28 % on similar dietary intakes of calcium. There was an increase in the urinary excretion of calcium. 

Awareness of the existence of idiopathic hypercalcemia of infancy is probably the most important factor in early diagnosis. Thereafter, in the majority of cases, a knowledge of the clinical and biochemical features of the disease makes diagnosis fairly easy. 

As the blood urea nitrogen is usually raised in idiopathic hypercalcemia, its estimation is important in diagnosis. 

The various etiological theories which have been advanced in respect of idiopathic hypercalcemia are given in Table 2. 

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