Hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets

The treatment of X-linked hypophosphatemia (XLH) consists of phosphate and vitamin D3 derivatives. Transient hypercalciuria and hypercalcemia are well-known signs of vitamin D intoxication. Despite urinary calcium excretion control, the danger of nephrocalcinosis in treated patients has been emphasized. It has recently been suggested that hyperoxaluria might be a causative factor of nephrocalcinosis other than calcium in phosphate-treated XLH patients. We measured urinary oxalate and phosphate excretion in 12 patients with the syndrome of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) receiving only oral phosphates and in 5 XLH patients receiving both oral phosphates and vitamin D. No correlation was found between the dosage of phosphate supplements or urinary phosphate excretion and urinary oxalate excretion, in either group of patients. Nephrocalcinosis, presenting as hyperechogenicity of the medullary pyramids, was found in 2 of the 5 XLH patients and only in 2 HHRH patients who had been treated with excessive doses of vitamin D2 and calcium, prior to the true diagnosis being established. We conclude: (1) hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets; (2) prolonged phosphate treatment alone does not induce nephrocalcinosis in HHRH patients, and (3) we believe that in XLH patients, nephrocalcinosis is essentially due to vitamin D overdosage at some stage, or noncompliance in phosphate intake, leading to repeated undetected hypercalciuric periods.     

The lack of effect of chronic metabolic acidosis on 25-OH-vitamin D metabolism and serum parathyroid hormone in humans

We evaluated the turnover of the plasma 25-OH-vitamin D pool, acid, and mineral balances in paired balance studies of 6 normal subjects during normal acid base conditions and during stable chronic metabolic acidosis induced by NH4Cl. Positive acid balances and negative Ca balances due to hypercalciuria were observed as previously reported. Plasma 25-OH-D pool turnover averaged 6.1+/-0.4 nmol/day during control and did not change during acidosis (6.5 +/- 0.5 nmol/day) nor were any significant increments in net intestinal absorption of Ca, PO4, or Mg, the physiological expression of vitamin D action, observed during acidosis. In 3 other subjects, repetitive measurements of serum iPTH during 7 control days and 24 days of stable NH4Cl acidosis showed no changes. We interpret the data to support the hypothesis that neither PTH nor vitamin D and its metabolites mediates the increase in net bone resorption that must accompany chronic metabolic acidosis.     

Evidence of absorptive hypercalciuria in tuberculosis patients

In patients with granulomatous diseases, disturbances in calcium metabolism have been described. The aim of the study was to evaluate alterations in calcium metabolism in patients with tuberculosis. Forty patients with tuberculosis (TB) were studied in a baseline state (calcium intake 1000 mg/day). Fourteen of these patients were also studied after restrictive calcium diet (400 mg/calcium/day) and after a load of oral calcium of 1000 mg. In all the studies, calcium and phosphorus were measured in serum and urine, and parathyroid hormone (PTH) in plasma. In addition, serum 25OHD and 1,25(OH)2D (calcitriol) levels were measured in the baseline state and after the restrictive diet. In the baseline state, 25OHD levels were lower and urinary calcium higher in TB patients than in the control group. No patients had hypercalcemia, but hypercalciuria was present in 10 patients (25%). The patients with tuberculosis were divided according to the presence or absence of hypercalciuria. In both groups, the 25OHD levels were lower than in controls. Hypercalciuric patients had lower plasma parathyroid hormone levels and higher serum calcitriol levels than the control group and the TB patients without hypercalciuria. Urinary calcium excretion after a calcium load was higher in TB patients with hypercalciuria than in controls. A positive correlation was found between the calcitriol levels and postcalcium load urinary calcium excretion in patients with calcium hyperabsorption. These data indicate that absorptive hypercalciuria is frequently observed in patients with TB and is possible due to inappropriately high serum calcitriol levels.     

Calciotropic hormones and nephrolithiasis

In recurrent calcium stone formers interfering factors or changes in receptor sensitivity may alter the interrelationships among calcium-regulating hormones, and hormonal behavior often does not fit with the theoretical assumptions. The vitamin D system appears to have the most important metabolic and clinical effects. Abnormal up-regulation of the synthesis of calcitriol and the consequent parathyroid hormone (PTH) suppression can induce hypercalciuria. Consequently, the hypocalciuric effect of thiazide would be caused by an enhanced response to PTH and by a reduction in 1,25(OH)2-vit D. A negative role of vitamin D on the skeleton has been observed in the presence of a negative calcium balance. Moreover, vitamin D also plays a role in urine oxalate excretion. PTH seems not to be directly stimulated in hypercalciuria and recurrent calcium nephrolithiasis, and patients with hyperparathyroidism and recurrent calcium nephrolithiasis show a similar degree of bone demineralization, irrespective of the presence of absence of the so-called 'primary hyperparathyroidism.' Calcitonin plays a contributory role in the pathogenesis of recurrent calcium nephrolithiasis that seems to be strictly related to dietary calcium intake. A higher sensitivity of thyroid C cells, particularly in absorptive hypercalciuric patients, could be related to the pathogenesis of hypercalciuria and contribute to its persistence.     

Low calcium diet in hypercalciuric calcium nephrolithiasis: first do no harm

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading.     

Effect of growth hormone on urine calcium and serum vitamin D metabolites in renal failure

Growth hormone (GH) causes a modest increase in urine calcium excretion in normal adults, but uremic rats given both GH and calcitriol developed hypercalciuria. Ten short prepubertal children with renal insufficiency treated with recombinant human GH (rhGH) had urine calcium to creatinine (Ca/Cr) ratios and serum vitamin D metabolite concentrations monitored prospectively for up to 24 months. Six were also treated with calcitriol and two with other vitamin D preparations. Mean urine Ca/Cr ratios or mean serum concentrations of 1,25-dihydroxy vitamin D, 24,25-dihydroxy vitamin D, and 25-hydroxy vitamin D did not change significantly during treatment with rhGH. The risk for rhGH-induced hypercalciuria is small in children with renal insufficiency, even when treated concomitantly with a vitamin D preparation.     

Bronchogenic cyst: an unusual cause of lump in the neck

This article describes a patient in whom disseminated infection with coccidioidomycosis was associated with hypercalcemia. The patient had a low level of 1,25-dihydroxyvitamin D and a suppressed parathyroid hormone value, an indication that the hypercalcemia was not mediated by vitamin D or parathyroid hormone. The episode resolved readily with administration of pamidronate, an outcome suggesting that this is effective treatment of hypercalcemia of this origin. On follow-up of the patient while he was receiving antifungal therapy for Coccidioides immitis, calcium values remained normal.     

Monitoring furosemide in racehorses participating in an EIPH program

We report a rare case of temporary and severe hypercalcemia: the patient, a 69-year-old woman, was admitted to Osaka City University Hospital on July 25, 1992, for severe hypercalcemia. The laboratory data on admission revealed severe hypercalcemia (14.9 mg/dl) and renal dysfunction with increased serum creatinine level (2.9 mg/dl). The urinary excretion of pyridinoline and deoxypyridinoline was increased, and serum levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D were decreased. The data suggested that increased bone resorption was a probable main factor in the development of the hypercalcemia. The development of hypercalcemia seemed to be of acute onset because of (1) her severe symptoms caused by hypercalcemia and (2) impaired renal function which was improved after normalization of serum calcium level. Combination therapy with saline infusion and furosemide was administered, and there was a gradual decrease and subsequent normalization of serum calcium level along with serum creatinine. Even 8 months after discontinuation of the therapy for hypercalcemia, the serum calcium level remained within the normal range. The measured values of serum factors which are suspected to have a hypercalcemic effect, such as PTH, parathyroid hormone-related peptide and the cytokines (interleukin-1 alpha, interleukin-1 beta, interleukin-2, interleukin-6 and tumor necrosis factor-alpha) were all within the normal range. In summary, the hypercalcemia in this patient was regarded to be a type of disequilibrium hypercalcemia due to a combination of increased bone resorption and decreased renal capacity to excrete calcium. Furthermore, since it was temporary and did not recur even in the absence of treatment, the hypercalcemia was concluded to have developed due to an imbalance in calcium regulation rather than as a result of organic disease.     

Expression of fmrfamide gene neuropeptides is partly different in the embryonic nervous system of the pond snail, Lymnaea stagnalis L

The prevalence of hypercalcemia in patients with untreated tuberculosis (TB) varies widely between countries. Since the vitamin D status and calcium intake are important determinants of hypercalcemia in TB, these two factors were compared among four populations (U.K., Hong Kong, Malaysia, Thailand) with a low prevalence (<3%) and two populations (Sweden, Australia) with a high prevalence (>25%). In the three Asian countries, the circulating vitamin D levels are abundant, but the calcium intakes are low. Subjects from the U.K. have the lowest circulating vitamin D level of all, although their calcium intake is high. In Sweden and Australia, both the circulating vitamin D levels and calcium intakes are high. Since serum 1,25(OH)2D concentration will only be raised if its substance for extrarenal conversion, 25(OH)D, is plentiful and the effect of a given serum 1,25 (OH)2D concentration on serum calcium is determined by the calcium intake, it is postulated that the regional variation in the prevalence of hypercalcemia in TB may be due to differences in the circulating vitamin D levels and calcium intakes in these populations.     

Type I collagen and procollagen fragments in patients with metabolic bone diseases

The purpose of the present study was to evaluate the serum levels of two new markers, and to compare their clinical usefulness with two conventional markers. Healthy women and patients with aberrant bone metabolism were evaluated for serum or urine levels of different bone markers. We measured serum levels of the pyridinoline cross-linked telopeptide domain of type I collagen (S-ICTP) and carboxy-terminal propeptide of type I procollagen (S-PICP) as markers of bone resorption and formation, respectively. These levels were compared to the concentrations of serum bone gamma-carboxyglutamic acid protein (S-BGP) and total urinary pyridinium cross-links (U-PYD). The control group included 222 premenopausal and postmenopausal women, and the disease groups consisted of 61 individuals with malignancy-associated hypercalcemia, Graves' thyrotoxicosis or primary hyperparathyroidism. Both S-PICP and S-BGP reflected higher bone turnover in postmenopausal than premenopausal women. All patient groups had significantly higher S-ICTP and U-PYD than the controls. Increased S-PICP was seen in malignancy-associated hypercalcemia and Graves' thyrotoxicosis, but not in primary hyperparathyroidism, while higher S-BGP was seen in Graves' thyrotoxicosis and primary hyperparathyroidism, but not in malignancy-associated hypercalcemia. Discrepancy between S-PICP and S-BGP in malignancy-associated hypercalcemia and primary hyperparathyroidism was noted. S-ICTP and U-PYD had higher sensitivity and specificity in discriminating patients from controls. We conclude that S-ICTP is superior to U-PYD as an index of bone resorption in aberrant bone metabolism. S-PICP may also be a useful bone turnover marker but discrepancies between it and S-BGP in malignancy-associated hypercalcemia and primary hyperparathyroidism need further investigation.     

Medical management and complications of X-linked hypophosphatemic vitamin D resistant rickets

To improve the growth failure, bowed legs, and biochemical and radiological abnormalities in patients with X-linked hypophosphatemic vitamin D resistant rickets (XLH), combined therapy of phosphate and calcitriol is the best therapeutic approach at present. However, the complications involving combined therapy, such as hypercalcemia, nephrocalcinosis and hyperparathyroidism, are not fully solved. To achieve better control, new therapeutic approaches have been reported recently, for example, growth hormone (GH) or new vitamin D analogs. GH improved linear growth, decreased phosphate reabsorption and increased 1-alpha-hydroxylase activity. Furthermore, 24R,25-dihydroxyvitamin D3 (24,25) improved the bone lesions in hypophosphatemic (Hyp) mice, and also in XLH, without the adverse effects such as hypercalcemia or hypercalciuria compared with 1,25-dihydroxyvitamin D3. These new approaches should be considered for the treatment of patients with XLH.     

Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3 and two analogues

The hormonally active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] stimulates biological responses related to calcium homeostasis, cell differentiation, and immunomodulation in many target cells, including leukemic cells. Most of these responses are dependent upon 1 alpha,25(OH)2D3 interaction with a nuclear receptor protein. Structural analogues of 1 alpha,25(OH)2D3 might allow for separation of biological function, avoiding adverse calcemic effects. This report quantitates intestinal calcium absorption, bone calcium resorption, induction of intestinal and renal calcium-binding protein (CaBP), and occupancy of the intestinal and renal nuclear 1 alpha,25(OH)2D3 receptor in vitamin D-deficient chicks after a single dose of 1 alpha,25(OH)2D3, 1 alpha,25-dihydroxyvitamin-16-ene-23-yne-D3 (analogue V), or 22-[m-(dimethylhydroxymethyl)phenyl]-23,24,25,26,27- pentanor-1 alpha-hydroxy-vitamin D3 (analogue EV). The interaction of these compounds with chick intestinal nuclear 1 alpha,25(OH)2D3 receptor and chick plasma vitamin D-binding protein was determined in vitro; analogues V and EV bound 68% and 62% [1 alpha,25(OH)2D3 receptor] and 8% and 13% (vitamin D-binding protein), respectively, as well as 1 alpha,25(OH)2D3 (100%). 1 alpha,25(OH)2D3 doses (0.075-1.2 nmol) generated responses in intestinal calcium absorption, bone calcium resorption, intestinal CaBP, and renal CaBP. When analogue V (1.2-300 nmol) was administered, increases in bone calcium resorption and renal CaBP were noted. However, a significant response in intestinal calcium absorption and intestinal CaBP appeared only after a 300-nmol dose. Unoccupied nuclear 1 alpha,25(OH)2D3 receptor in the intestine and kidney was determined in vivo after doses of 1 alpha,25(OH)2D3, analogue V, or analogue EV. Doses (0.25-6.0 nmol) of 1 alpha,25(OH)2D3 and analogue EV reduced unoccupied receptor to 24% and 59% (intestine) and to 13% and 41% (kidney), respectively. Analogue V (6.0-600 nmol) decreased unoccupied receptor in the kidney. In the intestine analogue V (300-600 nmol) reduced unoccupied receptor only to 75%. These results confirm that some vitamin D analogues can generate selective biological responses and different levels of target organ receptor occupancy.     

Ultrastructural evaluation of the interaction of glucocorticoids and vitamin D on bone cells in thyroparathyroidectomized rats

To determine the direct effects of cortisol on bone, rats were thyroparathyroidectomized (T(X)PT(X)), fed a low-calcium diet, and given high (50 mg/kg) or low (8 mg/kg) pharmacologic levels of cortisol with or without excess vitamin D3 (15,000 IU). Rats given vitamin D had osteoblasts and osteocytes interpreted ultrastructurally to be actively engaged in matrix synthesis, mineralization of matrix, and in calcium mobilization. Osteoclasts were numerous on metaphyseal trabeculae and in vascular channels of cortical bone. In T(X)PT(X) rats not given vitamin D, osteoblasts and osteocytes were interpreted to have reduced metabolic activity with minimal evidence of participation in bone formation or resorption. Cortisol at both dose levels failed to alter the electron microscopic appearance of osteoblasts, osteocytes, and osteoclasts with or without vitamin D. Bone turnover indicated by urinary hydroxyproline excretion was unaffected by cortisol treatment. These findings suggest that glucocorticoids have little direct action on bone cells and that their effects on calcium metabolism are probably mediated by an interference in intestinal calcium transport and by secondary hyperparathyroidism.     

Markers of bone remodeling in the elderly subject: effects of vitamin D insufficiency and its correction

The elderly subject is prone to both vitamin B insufficiency and calcium insufficiency due to a low calcium intake and calcium malabsorption. These two alterations may lead to secondary hyperparathyroidism, and thus to increased bone loss. We investigated 72 elderly subjects (16 men and 56 women) with vitamin D insufficiency and 25 healthy elderly women with normal vitamin D status, with respect to their indices of calcium metabolism and of bone remodeling: serum total alkaline phosphates (phosphatases), bone AP (BAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), urine hydroxyproline (HYP), and the 3-OH-pyridinium derivatives pyridinoline (PYD) and deoxypyridinoline (DPD), which are new markers of bone resorption. We then studied the modifications of these markers in the patients with vitamin D insufficiency at 3 months and 6 months after onset of a daily vitamin D and calcium supplementation. When compared with elderly subjects with normal vitamin D status, patients with vitamin D insufficiency had increased intact parathyroid hormone (iPTH) levels (60.1 +/- 10.2 vs 30.2 +/- 4.5, p < 0.001) and a high bone turnover as reflected by increased values of most serum and urine markers of bone remodeling. PYD and DPD levels were significantly correlated with all indices of bone turnover, unlike HYP, which showed no correlation with bone formation markers (AP, BAP, and BGP). A daily supplement of 800 IU vitamin D3 and 1 g of elemental calcium increased 25(OH)D levels and induced a dramatic decrease of iPTH levels; at 3 and 6 months, the mean iPTH level decreased by 50% (p < 0.0001), reaching the mean value of healthy vitamin D sufficient elderly women. All markers of bone turnover, except TRAP, decreased significantly at 3 and 6 months. The PYD/DPD ratio increased significantly at 3 and 6 months. The decrease of bone markers was more marked in patients with more severe hyperparathyroidism, the greatest variations being obtained with BAP (45%, p = 0.006) and DPD (43%, p = 0.036) levels. Most markers of bone remodeling are increased in elderly subjects with vitamin D insufficiently and vary with its correction. However, BAP and DPD are the most sensitive indicators of increased bone turnover due to secondary hyperparathyroidism.     

The metabolic effects of excess noradrenaline secretion from a pheochromocytoma

We report a 14-year-old boy with severe hypertension who was cured by surgical removal of a pheochromocytoma. The tumor was shown biochemically and morphologically to secrete predominantly noradrenaline. The metabolic effects noted in this patient were raised free fatty acid levels and depressed insulin levels, hyperreninemia, hypercalcemia, and hypercalciuria with normal parathyroid function. All these abnormalities returned to normal after removal of the tumor. It is suggested that these effects were mediated via beta-adrenergic stimulation of the excess noradrenaline.     

The tale of parathyroid function in idiopathic hypercalciuria

At the origin, idiopathic hypercalciuria has been described as a syndrome consisting of normocalcemia, low plasma phosphate levels and abnormally high urinary calcium excretion. The cause of this syndrome was subject to many investigations throughout the years. Two main pathophysiologic hypotheses have been proposed: a) primary intestinal hyperabsorption of calcium, leading to depression of parathyroid hormone (PTH) secretion ("absorptive" hypercalciuria); and b) primary renal tubular leak of calcium which stimulates PTH secretion (secondary hyperparathyroidism). Most of the published studies indicate that intestinal hyperabsorption of calcium with subsequent relative hypoparathyroidism is the primary event causing idiopathic hypercalciuria, and that this occurs as a consequence of increased production of 1,25(OH)2-vitamin D3 (calcitriol). Fasting hypercalciuria, originally taken as evidence for a "renal leak" of calcium, appears to be, at least in part, the consequence of relative hypoparathyroidism.     

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease

Glucocorticoids (GC) are widely used for anti-inflammatory and immunosuppressive therapy. Thirty to 50% of GC-treated patients develop osteoporosis. Potential mechanisms of GC-induced osteoporosis (GC-OP) include abnormalities in calcium balance, vitamin D metabolism, parathyroid hormone release and activity, prostaglandin E2 and cytokine synthesis, interference with c-fos and p-53 expression in osteoblasts, and hypogonadism. Early diagnosis and detection of patients at risk are accomplished with rapid, safe and non-invasive bone density measurements. Preventive measures include maintaining a positive calcium balance, vitamin D supplementation (if indicated) and treatment of hypogonadism. The shortest duration and the smallest doses possible of GC for a particular condition are advisable. For high-risk patients and those with established GC-OP calcitonin or bisphosphonate therapy is recommended.     

Influence of exogenous porcine growth hormone on vitamin D metabolism and calcium and phosphorus absorption in intact pigs

The influence of growth hormone (GH) on vitamin D metabolism and calcium and phosphorus absorption in vivo is not clear. We, therefore, measured calcium and phosphorus balance, plasma 1,25-dihydroxyvitamin D (1,25(OH)2D), and intestinal vitamin D-dependent calcium-binding protein (CaBP 9k) in intact growing pigs given exogenous GH. Six 10-week-old pigs were given two daily subcutaneous injections of 50 micrograms porcine GH/kg body weight for 2 months; six control pigs were given vehicle. They were all fed a diet containing 1.1% Ca, 0.6% P, and 1000 IU vitamin D3/kg. Apparent Ca and P absorption and retention were measured in a 10-day balance trial at the end of the 2 months. The plasma levels of Ca, P, 1,25(OH)2D, IGF-I, and GH were determined, and the duodenal and jejunal mucosal CaBP 9k content was measured at slaughter. The plasma Ca and P of GH-treated pigs were unchanged, but all aspects of mineral metabolism, including the plasma 1,25(OH)2D concentration (40%), Ca absorption and retention (70%), P absorption (33%) and retention (45%), and jejunal CaBP 9k (40%), were stimulated, in addition to an increase in the circulating IGF-I concentration.     

The functional status of the parathyroid in adult spasmophilia patients estimated by plasma parathormone assay

In 25 cases of spasmophilia the parathyroid function was assessed by complete exploration of the P-Ca metabolism and radioimmunoassay (RIA) of parathormone (PTH). Concomitantly the bone mineralization status was assessed by induced hypercalciuria tests and administration of 30 mg vitamin D2. RIA of PTH revealed increased values in 50% of the cases. The values fall within the range of secondary hyperparathyroidism, but this percentage varies with the values of the parathyroid function obtained by P-Ca metabolism explorations. The increased PTH values do no correlate with the level of plasma total calcium, ionic calcium, and magnesemia. Nor do they correlate with the bone mineralization disorders or the duration of the disease and the age of the patients.