Ronald L. Horst

Biochemical evaluation of patients with cancer-associated hypercalcemia. Evidence for humoral and nonhumoral groups.

In 50 consecutive patients with cancer-associated hypercalcemia, we measured nephrogenous cyclic AMP, tubular phosphorus threshold, fasting calcium excretion, plasma 1,25-dihydroxyvitamin D, and immunoreactive parathyroid hormone as determined by four region-specific antiserums. Nephrogenous cyclic AMP excretion was elevated in 41 patients and suppressed in nine (means, 5.85 vs. 0.51 nmol per 100 ml of glomerular filtrate). There was no overlap between these groups. When compared with 15 patients with primary hyperparathyroidism, the group with increased cyclic AMP excretion had similar reductions in tubular phosphorus threshold; higher fasting calcium excretion (means, 0.66 vs. 0.25 mg per 100 ml of glomerular filtrate, P < 0.01); marked reductions in 1,25-dihydroxyvitamin D (means, 20 vs. 83 pg per milliliter, P < 0.001); and lower levels of immunoreactive parathyroid hormone in all four assays. The data suggest that elevated excretion of nephrogenous cyclic AMP may be a useful marker of humorally mediated cancer-associated hypercalcemia, that this type of hypercalcemia is common, that the humoral factor responsible for this syndrome is not native 1-84 parathyroid hormone, and that the various subtypes of cancer-associated hypercalcemia are biochemically distinguishable from primary hyperparathyroidism.

Hypercalcemia in an Anephric Patient with Sarcoidosis: Evidence for Extrarenal Generation of 1,25-Dihydroxyvitamin D

HYPERCALCEMIA can occur in up to 10 per cent of patients with sarcoidosis.1 , 2 During the active phase of the disease, increased absorption of calcium from the intestine leads to hypercalciuria an...

The Importance of Circulating 1,25-Dihydroxyvitamin D in the Pathogenesis of Hypercalciuria and Renal-Stone Formation in Primary Hyperparathyroidism

Fifty patients with primary hyperparathyroidism were studied with an oral calcium-tolerance test, measurements of plasma levels of vitamin D metabolites, and determination of calcium excretion on both a low-normal (400 mg) and high-normal (1000 mg) calcium intake. There were strong positive correlations between plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) and both the calciuric response to the calcium-tolerance test (r = +0.75, P less than 0.001) and calcium excretion on the 1000-mg calcium diet (r = +0.65, P less than 0.001). The patients were classified into two subpopulations: 30 patients showed hyperabsorption with the calcium-tolerance test, striking hypercalciuria, marked elevations in plasma 1,25(OH)2D, and a high incidence (19 of 30 patients) of renal stones; 20 patients had a normal response to the tolerance test, normocalciuria, normal or high-normal plasma 1,25(OH)2D, and a low incidence of stones (three of 20 patients). The findings emphasize the importance of circulating 1,25(OH)2D in the pathogenesis of hypercalciuria and stone formation in primary hyperparathyroidism.

Hepatic Abnormalities Associated with Aluminum Loading in Piglets

Cholestasis is a common complication of total parenteral nutrition (TPN) in infants. A contributing factor to the hepatic dysfunction may be a contaminant of the TPN solution, such as aluminum, that accumulates in liver and may act as a hepatotoxin. To study the hepatic effects of aluminum, growing piglets were given daily intravenous injections of aluminum, 1.5 mg/kg, for 50 days; pair-fed controls were given heparinized saline. At sacrifice, liver and serum were obtained. Liver was analyzed for histopathology and for aluminum content and localization. The hepatocyte lysosomes of the experimental group showed aluminum peaks by x-ray microanalysis, whereas the control group did not. No differences in ultrastructure were noted between the two groups when examined by electron microscopy. Mean serum total bile acid levels (27.8 +/- 15.9 SD vs 6.3 +/- 1.5 mumol/liter, p less than 0.05), mean alkaline phosphatase (309 +/- 108 vs 180 +/- 27 IU/liter, p = NS), and mean hepatic copper content (24.8 +/- 4.5 vs 14.4 +/- micrograms/g dry weight, p less than 0.01), were elevated in the aluminum-loaded piglets, indicating that cholestasis may have been produced. Also, a small but significant reduction in serum levels of 25 hydroxy-vitamin D was found in the aluminum-loaded piglets, suggesting that vitamin D hydroxylation may be impaired. Inasmuch as lysosomal contents are excreted into the bile, aluminum accumulation in lysosomes may alter lysosomal function and possibly affect bile flow or content.

1,25(OH)2D3 is not the only D metabolite involved in the pathogenesis of osteomalacia☆

Three patients are described in whom there was no simple correlation between plasma 1,25(OH)2D3 concentration and the occurrence of osteomalacia. One patient had severe osteomalacia with high plasma 1,25(OH)2D3 and normal mineral ion product; the second had a normal mineral ion product and no evidence of osteomalacia even though plasma 1,25(OH)2D3 was undetectable; and the third had osteomalacia, low plasma 1,25(OH)2D3 and a reduced mineral ion product. In considering these data in the light of presently available information, it is concluded that osteomalacia can occur as a consequence of a lack of a vitamin D metabolite other than 1,25(OH)2D3, or a consequence of a reduced mineral ion product, but not as a consequence of 1,25(OH)2D3 lack if the mineral ion product is normally maintained and other D metabolites are present. However, a deficiency of 1,25(OH)2D3 normally leads to a reduction in the mineral ion product hence 1,25(OH)2D3 deficiency may play a role in the development of certain forms of osteomalacia.

Renal osteodystrophy in children undergoing continuous ambulatory peritoneal dialysis.

Summary: This paper describes a retrospective evaluation of the course of renal bone disease in 14 children undergoing treatment with continuous ambulatory peritoneal dialysis (CAPD) for an average of 11.9 ± 1.5 months (mean ± SE). The patients were divided in two groups according to the changes in serum alkaline phosphatase activity during the period of observation: five patients had alkaline phosphatase activity that decreased or was relatively stable (group I), and nine patients exhibited a rising serum alkaline phosphatase activity (group II). Serial radiological examinations showed adequate control of renal osteodystrophy in the patients of group I, whereas the patients of group II had no improvement or worsening of their bone disease. Group I had higher serum calcium and lower parathyroid hormone levels than group II at the end of period of observation despite similar dosage of vitamin D metabolite. The progression of bone disease was not related to the duration of CAPD or type of previous treatment for end stage renal disease.The observation that the radiological manifestations of secondary hyperparathyroidism were prevented in patients whose serum calcium levels were frequently above 2.62 mmol/liter (group I) while serum calcium levels between 2.25 and 2.50 mmol/liter in group II patients failed to lead to regression of secondary hyperparathyroidism is consistent with the existence of altered “setpoint” regulation of the parathyroid gland in children undergoing CAPD.

Serum levels of 1,25-dihydroxyvitamin D in children receiving parenteral nutrition with reduced aluminum content.

Both adults and children receiving total parenteral nutrition (TPN) have been found to have low serum levels of 1,25(OH)2-vitamin D [1,25(OH)2D]. Many of these were subsequently found to have inadvertently received large quantities of aluminum in the TPN solution. Since aluminum administration to dogs is associated with a fall in serum 1,25(OH)2D levels, the present study was designed to prospectively follow serum levels of this sterol while patients received a TPN solution low in aluminum. Nine children received a TPN solution comparable to that previously administered to children who demonstrated low serum levels of 1,25(OH)2D, except for a moderately reduced phosphorus and markedly reduced aluminum content. Serum was obtained during the first and fourth weeks of TPN treatment and analyzed for 1,25(OH)2D, 25-hydroxyvitamin D [25(OH)D], immuno-reactive parathyroid hormone (iPTH), calcium, and phosphorus. Results revealed normal or high serum levels of 1,25(OH)2D and normal levels of iPTH, calcium, phosphorus, and 25(OH)D. Thus, low aluminum-containing TPN does not produce a fall in serum 1,25(OH)2D, providing evidence that aluminum may have been a factor in causing the reduced serum 1,25(OH)2D in those children previously receiving TPN.

The Pathophysiological Basis of Hypercalciuria in Primary Hyperparathyroidism

When initially described in the mid-1920’s, primary hyperparathyroidism (l°HPT) was regarded as a rare and severe disorder of bone. Shortly thereafter, Albright and colleagues recognized a different clinical presentation of l°HPT in patients with renal stones who lacked evidence of overt bone disease1. It subsequently became clear that renal stones are a far more frequent complication of l°HPT than overt osteitis, being the presenting complaint in approximately 50% of patients2. Further, it was recognized that patients presenting with stones rarely display evidence of clinical bone involvement and that patients presenting with clinical bone disease only rarely gave a history of renal stones (nephrocalcinosis was variably observed in a minority of patients with both presentations). Thus, early investigators were impressed by reasonably distinctive “bone” and “stone” presentations of the disorder and offered several hypotheses in attempt to explain their observations. These included Albright’s “dietary calcium” hypothesis1. Dent’s “dual hormone” hypothesis3, and the general proposal that clinical bone involvement developed as a function of the duration of the disease. Although Albright’s general tenets concerning external calcium balance were later supported by the observation of negative balance in patients with overt bone disease and zero or even positive balance in patients with stone disease4. All three hypotheses were subsequently either disproven or could not be supported by the accumulated evidence2. Thus, the clinical “spectrum” of the disorder remained enigmatic well through the 1960’s.

Correction: Symposium Article on Calcium-Regulating Hormones

Excerpt To the editor: In the excellent review of the Seventh International Conference on Calcium-Regulating Hormones (1), our observations on the metabolic bone diseases associated with total pare...