Yohtaro Furukawa

Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans

SummaryOmeprazole is an inhibitor of gastric H+, K+-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H+-ATPase which is different from the gastric H+, K+-ATPase,in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2 blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.

Heterogeneity of pseudohypoparathyroidism type I from the aspect of urinary excretion of calcium and serum levels of parathyroid hormone

SummaryUrinary excretion of calcium (Ca) was measured in 9 patients with pseudohypoparathyroidism (PHP) type I—3 with Albrights hereditary osteodystrophy (AHO): AHO(+) and 6 without AHO: AHO(−)—and in 13 with idiopathic hypoparathyroidism (IHP), treated with active vitamin D3 (1,25(OH)2D3 or 1αOHD3) to maintain serum Ca levels at 8.4–9.5 mg/dl. Fasting urinary excretion of Ca in PHP was significantly lower than that in IHP. Moreover, fasting urinary excretion of Ca in PHP AHO(+) was lower than that in PHP AHO(−). This difference was also seen in the urine after oral loading of Ca. Urinary excretion, of sodium (Na) was not different between PHP AHP(+) and PHP AHO(−). Serum levels of immunoreactive PTH in PHP AHO(+) were higher than those in PHP AHO(−). The difference in urinary excretion of Ca between PHP AHO(+) and PHP AHO(−) may come from the difference in the circulating levels of PTH.

Sensorineural hearing loss associated with hypoparathyroidism

The hearing loss of 21 patients with hypoparathyroidism was investigated by pure tone audiometry, short increment sensitivity index (SISI) test, Békésy audiometry, speech audiometry, and auditory brain stem response. Sensorineural hearing loss was found in 7 of 21 patients (13 of 42 ears) receiving no treatment for hypoparathyroidism or having chronic hypocalcemia. The high SISI score, presence of recruitment, and prolongation of the wave I (N1) latency suggested that the inner ear is responsible for hearing loss in these cases. Inner ear dysfunction was probably due to the low calcium level in inner ear fluid and/or the direct effect of vitamin D deficiency on the inner ear.

Human PTH(1–34) infusion test in differential diagnosis of various types of hypoparathyroidism: an attempt to establish a standard clinical test

To introduce a simple procedure and reliable diagnostic criteria for parathyroid hormone (PTH) infusion test, 128 patients with either pseudo- (PsH) or idiopathic hypoparathyroidism (IdH) and 25 normocalcemic controls were studied. Incremental responses of urinary cyclic AMP and phosphate to 20 micrograms (67 U) or 30 micrograms (100 U) of human PTH(1-34) were assessed by using simple parameters of urinary excretion rates of the two substances. The results are summarized as follows. (1) PTH dose-cyclic AMP response relation suggests that 100 U of PTH is more appropriate than 67 U as a standard test dose for adults. (2) By presenting the magnitude of cyclic AMP response as either net increase or fold increase during 1 h after 100 U of PTH infusion, we can differentiate PsH type I from others without overlap. (3) Differentiation between PsH and IdH or normocalcemic subjects by phosphaturic response is less clearcut than that made by cyclic AMP response whatever indices and criteria are used. Thus it seems difficult to diagnose PsH type II merely based on the discrepancy between cyclic AMP and phosphaturic responses to exogenous PTH. (4) The test results are essentially similar in the examinations performed before and during vitamin D therapy. However, when the magnitude of phosphaturic response is expressed as net increase during 2 h after PTH, it tends to be enhanced after vitamin D therapy in patients with PsH compared to the response before therapy.

Clinical investigation of olfactory and auditory function in type I pseudohypoparathyroidism: participation of adenylate cyclase system.

Olfactory and auditory function was examined in five patients with type I pseudohypoparathyroidism; in two patients the activity of stimulatory guanine nucleotide-binding protein was examined and found to have low values. The olfactory tests were performed by T & T olfactometer and intravenous injection of thiamine propyl disulphide. The four patients receiving olfactory test showed a disturbance in recognization of the odorants. All five patients had normal hearing at frequencies with the normal range. An adenylate cyclase system is thought to play an important role in olfactory transduction, whereas cochlear function may be unaffected by this system in the normal state.

Response of plasma 1,25-dihydroxyvitamin D in the human PTH(1-34) infusion test: an improved index for the diagnosis of idiopathic hypoparathyroidism and pseudohypoparathyroidism.

SummarySynthetic human parathyroid hormone (1–34) (hPTH(1–34) infusion test has been utilized in the differential diagnosis of hypoparathyroidism by examining the incremental response of urinary phosphate and cyclic adenosine monophosphate (AMP). The response of plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) in parathyroid hormone (PTH) infusion test was studied as a new criterion for the differential diagnosis of idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism (PHP). Fourteen patients with IHP, 4 patients with PHP, and five control subjects were studied. All subjects received an intravenous infusion of 30 μg hPTH(1–34) over 5 minutes. The basal levels of plasma 1,25(OH)2D in patients with IHP and PHP were significantly lower than those in control subjects, but there was no significant difference between the levels in patients with IHP and in patients with PHP. The plasma levels of 1,25(OH)2D increased after the infusion of hPTH(1–34) and reached a peak 6 to 24 hours afterward. The 1,25(OH)2D increase at 24 hours after the infusion (Δ1,25(OH)2D) in control subjects and in patients with IHP were 18.1±3.91 (mean±SEM) and 24.1±2.80 pg/ml, respectively. There was no significant increase in patients with PHP (Δ1,25(OH)2D=4.9±1.97 pg/ml). From these results, the measurement of Δ1,25(OH)2D in hPTH(1–34) infusion test is useful as a criterion for the differential diagnosis of hypoparathyroidism.

Expression of stanniocalcin in zona glomerulosa and medulla of normal human adrenal glands, and some adrenal tumors and cell lines

Stanniocalcin (STC) is a calcium (Ca)‐regulating hormone that was originally discovered in the fish Stannius body, which is a unique endocrine organ. Hypercalcemia increases STC secretion, which inhibits Ca uptake by the gills and normalizes serum Ca level. In this study we investigated the STC expression in human normal and abnormal adrenal cells. Immunohistochemistry using monoclonal antibody against STC revealed specific staining in zona glomerulosa and medulla of normal human adrenal glands. STC was also detected in human adrenal tumors, such as pheochromocytoma, differentiated neuroblastoma, and aldosterone‐producing adenoma, and cultured adrenal tumor cells (rat pheochromocytoma PC‐12 cells and human neuroblastoma NB‐1 cells). However, undifferentiated human adrenal neuroblastoma was negative for STC staining. Reverse transcription polymerase chain reaction demonstrated STC mRNA expression in cultured PC‐12 cells and NB‐1 cells. Following several studies indicating that zona glomerulosa cells of adrenal glands express neuroendocrine properties, STC expression in normal and abnormal adrenal cells provides additional evidence to support the neuroendocrine differentiation of these cells. In conclusion, STC may be useful as a new cell marker of adrenal glands under physiological and pathological conditions.

Effects of parathyroid hormone on urinary excretion of N-acetyl-β-D-glucosaminidase in idiopathic hypoparathyroidism and pseudohypoparathyroidism

SummaryN-acetyl-β-D-glucosaminidase(NAG) is a lysosomal enzyme predominantly located in renal proximal tubules. In idiopathic hypoparathyroidism(IHP), 100 Units of human PTH(1–34) increased urinary excretion of NAG from 0.029±0.027 to 0.173±0.035 U/1GF (p<0.05) in two patients before treatment and from 0.025±0.004 to 0.189±0.092U/1GF (p<0.02) in four patients during treatment with active vitamin D3 (1,25(OH)2D3 or 1αOHD3). In pseudohypoparathyroidism(PHP), PTH did not significantly increase the urinary excretion of NAG in one patient with before treatment (0.048 to 0.025 U/1GF) and four patients during treatment with active vitamin D3 (0.018±0.008 to 0.036±0.015 U/1GF). Increase in urinary excretion of NAG after injection of PTH may be a new indicator of renal effect of PTH.

Sigmoidal Curve Shift in Idiopathic Hypoparathyroidism and Pseudohypoparathyroidism

Abstract. The sigmoidal curves plotting serum parathyroid hormone (PTH) against serum Ca in primary hyperparathyroidism and secondary hyperparathyroidism due to renal failure deviate to the right. We previously found the leftward curve shift in PTH-deficient hypoparathyroidism. In the present study, we investigated the curve shift in pseudohypoparathyroidism (PHP) with secondary hyperparathyroidism due to target organ resistance to PTH. In renal failure the sigmoidal curves move to the left after vitamin D3 treatment. We also examined the effect of vitamin D3 on the curve shift in pseudohypoparathyroidism (PHP) and idiopathic hypoparathyroidism (IHP). Before vitamin D3 treatment, the sigmoidal curve deviated to the left in both types of hypoparathyroidism. After vitamin D3 treatment it moved to the right. These results indicate that vitamin D3 and/or extracellular Ca modify the relationship between PTH and Ca dynamics even in hypoparathyroid disorders with decreased or increased maximum serum PTH. Following vitamin D3 treatment, the point plotting baseline serum PTH against baseline serum Ca moved to the right at first in accordance with the rightward shift of the sigmoidal curve and then the point moved downward in PHP or downward in IHP. These changes suggest that vitamin D3 resets PTH secretion at a higher extracellular Ca level at first and then suppresses it in a time-dependent manner. 1,25(OH)2D3 and/or extracellular Ca may be the determinant factors of the sigmoidal curve shift in hypoparathyroid disorders. Mechanisms other than the Ca sensing system error may contribute to the curve shift.

The effect of endogenous parathyroid hormone, exogenous calcitonin, and dibutyryl cyclic AMP on urinary excretion of N-acetyl-β-D-glucosaminidase

Urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) transiently increases after PTH(1–34) infusion in idiopathic hypoparathyroidism (IHP) but this response is impaired in pseudohypoparathyroidism (PHP) type I. We investigated the effects of endogenous PTH, exogenous calcitonin (CT), and dibutyryl cAMP (DBcAMP) on urinary excretion of NAG. Urinary NAG excretion in 14 patients with primary hyperparathyroidism (1oHPT) was more than in normal subjects (P<0.001) and decreased after parathyroidectomy (P<0.01). Urinary NAG excretion increased after the infusion of 1.5 MRC/kg of eel CT in eight normal subjects (P<0.001), two patients with IHP, and a patient with PHP type Ib but not in a patient with PHP type Ia. The increases of urinary NAG excretion by CT and by PTH(1–34) were positively correlated with the increases of urinary cAMP excretion (r=0.752; P<0.001 and r=0.534; P<0.002, respectively). Urinary NAG excretion increased after DBcAMP infusion in five normal subjects (P<0.01), two patients with IHP, and two with PHP type I. The increase of urinary NAG by 6.0 mg/kg of DBcAMP was more than by 2.5 mg/kg of DBcAMP in normal subjects (P<0.01). The increase of urinary NAG by 2.5 mg/kg of DBcAMP in PHP type I was comparable with that by 6.0 mg/kg in normal subjects, suggesting a hyperresponsiveness to DBcAMP in PHP type I. Urinary excretion of NAG is a useful indicator of renal tubular responsiveness to PTH and CT. Cyclic AMP-dependent mechanism is probably involved in PTH and CT-induced increase in urinary excretion of NAG.