Biomedical subjects
Publications and source records attributed to R Arie.
Familial hypocalciuric hypercalcemia (FHH) is often considered in the differential diagnosis of hyperparathyroidism, but is rarely diagnosed. So far, FHH has not been documented in Israel. This report presents preliminary evidence for the occurrence of FHH in Israel.
OBJECTIVE: Previous studies have suggested that alpha-D3 therapy can cause deterioration in renal function. We have, therefore, examined the long-term effect of 1 alpha-hydroxyvitamin D3 (alpha-D3) administration upon renal function in hypoparathyroid patients. DESIGN: This is a prospective long-term follow-up study of alpha-D3 administration on hypoparathyroid patients at a mean daily dose of 1 microgram (range 0.5-2.5 micrograms) during a total of 2040 patient-months. PATIENTS: Seventeen unselected patients (14 females and 3 males), two with primary and 15 with post-surgical hypoparathyroidism. RESULTS: The significant effect of alpha-D3 on serum and urinary calcium was achieved during the first week of treatment and remained stable at the same range during the close follow-up of 2040 patient-months. No significant change was observed in the serum creatinine during the whole follow-up period. During follow-up, five women developed hypercalciuria and one patient developed hypercalcaemia that disappeared when the dose of the drug was reduced or discontinued. CONCLUSIONS: From our study we concluded that alpha-D3 is a safe and effective drug in the long-term therapy of hypoparathyroid patients.
Sensorineural hearing impairment is a lesser known feature of hypoparathyroidism. The hearing of 20 patients with idiopathic hypoparathyroidism was investigated by pure-tone audiometry. Bilateral sensorineural hearing loss was found in three (15%). Sensorineural hearing loss is considered to be associated with a prolonged low calcium level in the inner ear fluid and is a possible complication of hypoparathyroidism.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a new autosomal form of hypophosphatemic rickets, recently described. This disease is characterized, and differs from other forms of hereditary hypophosphatemic rickets and/or osteomalacia by increased serum levels of 1,25-dihydroxyvitamin D, hypercalciuria and complete remission of the disease on phosphate therapy alone. However, only another probable Israeli kindred, and seemingly a few sporadic cases from Europe, North America and Japan have been reported in the literature. We describe here a new kindred of Jewish Yemenite origin (unrelated to other Israeli families) with typical HHRH. Two additional members of this family suffer from a milder asymptomatic form of the disease, which presents as absorptive hypercalciuria without signs or symptoms of bone disease. It seems to us that HHRH is underdiagnosed, due to its similarity to other hypophosphatemic syndromes in clinical, radiological and most biochemical parameters. Therefore, it is recommended that urinary calcium excretion and serum 1,25-dihydroxyvitamin D concentrations be measured in every patient with hypophosphatemic rickets/and or osteomalacia before the initiation of any therapy. The correct diagnosis of HHRN is of immense therapeutic implications. Phosphate therapy alone could cause a complete remission in HHRH, while the addition of active vitamin D metabolites, as is recommended in hypophosphatemic vitamin D resistant rickets, could cause deterioration in the patient's condition.
A search for possible lithogenous factors was under-taken in a group of 42 lichen planus (LP) patients (15 with urolithiasis and 27 without). Normal mean values of calcium, phosphorus, uric acid and creatinine were found in the serum and in the 24-hour urine collection. However, 9 patients (21%) manifested laboratory deviations consisting of hyperuricemia, hyperuricosuria or hypercalciuria, or combinations of the three. The prevalence of hyperuricemia among LP patients was greater than in matched controls and vis-à-vis the recorded prevalence of hyperuricemia in the general population and in other calcium stone formers. These findings may suggest involvement of metabolic defects in LP.
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Among 59 closely related members of one Bedouin tribe, we identified 9 who had the characteristic features of hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We found "idiopathic" hypercalciuria in 21 of the 50 asymptomatic members. The biochemical abnormalities observed in these 21 subjects were qualitatively similar to those in the 9 with HHRH, but were quantitatively milder. The urinary calcium concentration was 0.43 +/- 0.14 mg per milligram of creatinine (mean +/- SD) in the patients with HHRH, 0.34 +/- 0.07 in the subjects with idiopathic hypercalciuria, and 0.14 +/- 0.05 in normal subjects from the same tribe. Tubular reabsorption of phosphorus and serum phosphorus concentrations were 3.0 and 4.3 SD units below the age-related mean, respectively, in HHRH, and 1.1 SD units below the normal mean for both variables in idiopathic hypercalciuria. Mean serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) were 303 pg per milliliter in HHRH and 145 pg per milliliter in idiopathic hypercalciuria (upper normal limit, 110). We conclude that the subjects with hypercalciuria and the patients with HHRH shared a hereditary renal phosphate leak that led to hypophosphatemia, elevated serum concentrations of 1,25-(OH)2D, increased intestinal calcium absorption, and hypercalciuria. The magnitude of the hypophosphatemia, which regulates 1,25-(OH)2D levels, appears to determine which subjects will have hypercalciuria alone and which will also have bone disease.
We studied a new hereditary syndrome of hypophosphatemic rickets and hypercalciuria in six affected members of one kindred. In all patients, the manifestations of disease began in early childhood. The characteristic features are rickets, short stature, increased renal phosphate clearance (the ratio between the maximal tubular reabsorption rate for phosphorus and the glomerular filtration rate [TmP/GFR] is 2 to 4 S.D. below the age-related mean), hypercalciuria (8.6 mg of urinary calcium per kilogram of body weight per 24 hours vs. the upper normal value of 4.0), normal serum calcium levels, increased gastrointestinal absorption of calcium and phosphorus, an elevated serum concentration of 1,25-dihydroxyvitamin D (390 +/- 99 pg per milliliter vs. the upper normal value of 110), and suppressed parathyroid function (an immunoreactive parathyroid hormone level of 0.33 +/- 0.1 ng per milliliter and a cyclic AMP level of 1.39 +/- 0.12 nmol per deciliter of glomerular filtrate vs. the lower normal values of 0.3 and 1.5, respectively). Long-term phosphate supplementation as the sole therapy resulted in reversal of all clinical and biochemical abnormalities except the decreased TmP/GFR. We propose that the pivotal defect in this syndrome is a renal phosphate leak resulting in hypophosphatemia with an appropriate elevation of 1,25-dihydroxyvitamin D levels, which causes increased calcium absorption, parathyroid suppression, and hypercalciuria. This syndrome may represent one end of a spectrum of hereditary absorptive hypercalciuria. Our observations support the importance of phosphate as a mediator in controlling 1,25-dihydroxyvitamin D production in human beings.
Extensive metabolic studies were performed in a 14-year-old boy suffering from the rare clinical entity known as childhood idiopathic hypercalciuria associated with dwarfism, renal tubular abnormalities and bone lesions. The salient features were: hyperphosphaturia with hypophosphatemia, hypercalciuria with normocalcemia, elevated serum 1,25-dihydroxycholecalciferol[1,25(OH)2D3] levels, marked intestinal hyperabsorption of calcium and phosphorus, with low serum parathyroid hormone (PTH) and urinary adenosine 3':5'-cyclic monophosphate (c-AMP). Bone biopsy confirmed the clinical and radiological diagnosis of rickets. It appears that the following pathophysiological sequence is operating: primary renal phosphate leak with hypophosphatemia, increased 1,25(OH)2D3 synthesis, enhanced intestinal calcium absorption which in turn inhibits release of PTH and c-AMP. Hypercalciuria is seen to be secondary to both avid intestinal calcium absorption and depressed PTH activity, and rickets the result of phosphate depletion. Treatment with oral phosphorus only resulted in an acceleration of growth rate, cure of rickets, and return of urinary calcium excretion to normal values.
A severely thyrotoxic patient was found to have hypocalcaemia and tetany, which cleared when she became euthyroid. Cessation of treatment with propranolol and propylthiouracil resulted in a recurrence of the thyrotoxicosis and the reappearance of hypocalcaemia. Reinstitution of treatment resulted in a second remission of the thyrotoxicosis and correction of the hypocalcaemia. It is suggested that in this patient, the thyrotoxicosis was the cause of hypocalcaemia. The various pathogenetic mechanisms are discussed.
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A 62-year-old man was admitted to hospital 10 times over 12 years because of pyrexia of unknown origin. Hypothalamic hypopituitarism was diagnosed by dynamic tests including clomiphene, LRH, TRH and chlorpromazine stimulation. Lack of ACTH was demonstrated by long and short tetracosactrin tests. The aetiology of the disorder was believed to be previous encephalitis. Following substitution therapy with adrenal and gonadal steroids there were no further episodes of fever.
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A double-blind study was done on the plasma from 59 hospitalized patients to determine whether a diminished lymphocytic cortisol metabolism-enhancing effect among cancer patients could be used to distinguish them from persons with noncancerous diseases. Known concentrations of human lymphocytes from healthy donors were incubated with cortisol in media containing 50% phosphate-buffered saline (PBS) and 50% of one of the following additives: 1) homologous plasma (HP), 2) plasma from the patient being tested, or 3) additional PBS. Plasma in which the metabolism-enhancing effect was less than 70% of that obtained with HP was considered to be that of a cancer patient. Among the 19 patients known to have cancer, there were only two false-negative results, whereas among the 40 patients diagnosed as having noncancerous diseases, there were six false-positive results. Thus the test findings and the pathologic diagnosis were obviously correlated in approximately 90% of the patients.
The influence of a) tissue culture medium (RPMI), b) homologous plasma (HP), and c) fetal calf serum (FCS) on lymphocytic cortisol metabolism was compared to that of phosphate buffered saline alone. RPMI was found to enhance the conversion rate 1.71 times, whereas HP and FCS enhanced it about 3.2 times. Raising the temperature of the HP and FCS to 100 degrees C before incubation reduced the enhancing effect to the level of that obtained with RPMI.
A study was made in order to see whether human thrombocytes are capable to metabolize cortisol. Known concentrations of thrombocytes were incubated with 1.23H-cortisol and the products isolated and identified by t.l.c., paper chromatography, and derivations. Two metabolites were found to be produced by thrombocytes: 20beta-hydroxycortisol and tetrahydrocortisol. The enzymatic nature of the reactions was proved by (1) heat treatment (2) finding out NADPH to be a specific cofactor and (3) the dependence of the activity on the number of thrombocytes in suspensions.
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