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1.  Immunoreactive Forms of Circulating Parathyroid Hormone in Primary and Ectopic Hyperparathyroidism 
Journal of Clinical Investigation  1974;54(1):175-181.
The immunoreactive forms of parathyroid hormone (iPTH) in the plasma of six patients with primary, adenomatous hyperparathyroidism and six patients with ectopic hyperparathyroidism due to non-parathyroid cancer were compared by using gel filtration on columns of Bio-Gel P-150 and radioimmunoassay of iPTH in eluted fractions after concentration. We found much less (p<0.001) small (mol wt<9,500) COOH-terminal fragments of iPTH in plasma samples from ectopic hyperparathyroid patients (0.52±0.13 ng eq/ml) than in samples from primary hyperparathyroid patients (3.70±1.15 ng eq/ml). The quantity of iPTH eluting with or before native bovine PTH [1-84] was the same in both syndromes (ectopic hyperparathyroidism, 0.82±0.22 ng eq/ml; primary hyperparathyroidism, 0.73±0.09 ng eq/ml), and these values correlated positively with plasma calcium concentration (ectopic hyperparathyroidism, r=0.908; primary hyperparathyroidism, r=0.919). In both syndromes, plasma samples had an iPTH component that eluted well before PTH [1-84] (mol wt 9,500), but this component was present in much larger quantities in three patients with ectopic hyperparathyroidism. We conclude that (a) the decreased quantity of biologically inactive COOH-terminal fragments of iPTH circulating in ectopic hyperparathyroidism accounts for the previously reported relatively lower total serum iPTH values in this syndrome as compared with primary hyperparathyroidism (Riggs et al. 1971. J. Clin. Invest. 50: 2079); (b) there appears to be sufficient iPTH with presumed biologic activity to account for the hypercalcemia in both syndromes; (c) a large PTH component, not previously recognized in plasma, is present in both ectopic and primary hyperparathyroidism and may exist as the predominant immunoreactive form of the hormone in some patients with ectopic hyperparathyroidism.
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PMCID: PMC301537  PMID: 4834887
2.  Hypocalcemia may not be essential for the development of secondary hyperparathyroidism in chronic renal failure. 
Journal of Clinical Investigation  1986;78(4):1097-1102.
Hypocalcemia is the main factor responsible for the genesis of secondary hyperparathyroidism in chronic renal disease. Studies with parathyroid cells obtained from uremic patients indicate that there is a shift in the set point for calcium-regulated hormone (parathyroid hormone [PTH] secretion. Studies were performed in dogs to further clarify this new potential mechanism. Hypocalcemia was prevented in uremic dogs by the administration of a high calcium diet. Initially, ionized calcium was 4.79 +/- 0.09 mg/dl and gradually increased up to 5.30 +/- 0.05 mg/dl. Despite a moderate increase in ionized calcium, immunoreactive PTH (iPTH) increased from 64 +/- 7.7 to 118 +/- 21 pg/ml. Serum 1,25(OH)2D3 decreased from 25.4 +/- 3.8 to 12.2 +/- 3.6 pg/ml. Further studies were performed in two other groups of dogs. One group received 150-200 ng and the second group 75-100 ng of 1,25(OH)2D3 twice daily. The levels of 1,25(OH)2D3 increased from 32.8 +/- 3.5 to a maximum of 69.6 +/- 4.4 pg/ml. In the second group the levels of serum 1,25(OH)2D3 after nephrectomy remained normal during the study. Amino-terminal iPTH did not increase in either of the two groups treated with 1,25(OH)2D3. In summary, the dogs at no time developed hypocalcemia; however, there was an 84% increase in iPTH levels, suggesting that hypocalcemia, per se, may not be the only factor responsible for the genesis of secondary hyperparathyroidism.
PMCID: PMC423770  PMID: 3760186
3.  Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer 
Journal of Clinical Investigation  1971;50(10):2079-2083.
Serum immunoreactive parathyroid hormone (IPTH) was measured by radioimmunoassay in 54 patients with primary hyperparathyroidism and in 18 consecutive patients with ectopic hyperparathyroidism due to nonparathyroid cancer without apparent skeletal metastasis. Although serum calcium concentration was higher in the group with ectopic hyperparathyroidism, serum IPTH was lower (rank sum test, P < 0.001) and was undetectable in eight. A second anti-PTH antiserum also differentiated between IPTH in the two groups, although IPTH was undetectable in only 1 of 14 sera. When IPTH values in serial dilutions were plotted, slopes for the two patients with ectopic hyperparathyroidism who had relatively high IPTH were less (P < 0.001) than slopes for standard hyperparathyroid sera. By using differences in either IPTH rank or slope of the dilutional curve of sera, primary hyperparathyroidism could be excluded as a cause of the hypercalcemia in 16 of the 18 patients with ectopic hyperparathyroidism. The data are interpreted as indicating that PTH-like material in the serum of these patients with ectopic hyperparathyroidism is immunologically different from the PTH in the serum of patients with primary hyperparathyroidism.
PMCID: PMC292141  PMID: 4330004
4.  Serum calcitonin-lowering effect of magnesium in patients with medullary carcinoma of the thyroid. 
Journal of Clinical Investigation  1975;56(6):1615-1621.
The effect of magnesium chloride or magnesium sulfate infusion on circulating levels of immunoreactive calcitonin (iCT) was evaluated on nine occasions in three patients with metastatic medullary carcinoma of the thyroid. One patient was normocalcemic and had normal circulating levels of immunoreactive parathyroid hormone (iPTH), one patient was hypocalcemic and had surgical hypoparathyroidism, and one patient had mild to moderate hypercalcemia associated with bone metastases. The basal serum iPTH levels were undetectable in the latter two patients. In every instance magnesium administration produced a rapid and striking fall in circulating iCT and usually a detectable fall in serum calcium. During the hypermagnesemic state, serum iPTH fell from normal to undetectable in the patient with normal parathyroid function, while serum iPTH levels remained undetectable in the hypoparathyroid patient and in the patient with hypercalcemia associated with bone metastases. The results of these studies indicate that: (a) contrary to what has been reported in normal experimental animals, magnesium administration lowers circulating iCT in human subjects with thyroid medullary carcinoma and (b) the calcium-lowering effect produced by magnesium in patients with medullary carcinoma may, in part at least, be due to a redistribution of body calcium that is not mediated by the actions of either parathyroid hormone or clacitonin.
PMCID: PMC333141  PMID: 1202087
5.  Etiology of Hyperparathyroidism and Bone Disease during Chronic Hemodialysis. III. EVALUATION OF PARATHYROID SUPPRESSIBILITY 
Journal of Clinical Investigation  1973;52(1):173-180.
Parathyroid function was assessed by calcium infusions (4-8 h) in 16 patients with chronic renal insufficiency being treated by long-term hemodialysis. The concentrations of two immunoreactive species of parathyroid hormone in plasma (iPTH-9, mol wt 9500; iPTH-7, mol wt 7000) were estimated by radioimmunoassays utilizing two relatively specific antisera. Control values of the smaller species, iPTH-7, were uniformly high, whereas values of iPTH-9 were normal in 12 of 19 studies. Response of iPTH-7 to calcium infusions was variable, with significant decreases occurring only five times in 27 infusions. Concentrations of iPTH-9, however, decreased during every calcium infusion. In contrast to these acute responses, five of six patients studied during periods of dialysis against both low (< 6 mg/100 ml) and high (7-8 mg/100 ml) calcium concentrations in the dialyzate showed a decrease in values of iPTH-7 during the period of dialysis against the higher calcium concentration. It is concluded that plasma concentrations of iPTH-9 reflect primarily the moment-to-moment secretory status of the parathyroid glands, while concentrations of iPTH-7 reflect more closely chronic parathyroid functional status. It is further concluded that the failure of iPTH-7 to decrease during induced hypercalcemia should not be equated with autonomy of parathyroid gland function.
PMCID: PMC302239  PMID: 4734166
6.  Acute metabolic acidosis enhances circulating parathyroid hormone, which contributes to the renal response against acidosis in the rat. 
Journal of Clinical Investigation  1990;86(2):430-443.
Acute PTH administration enhances final urine acidification in the rat. HCl was infused during 3 h in rats to determine the parathyroid and renal responses to acute metabolic acidosis. Serum immunoreactive PTH (iPTH) concentration significantly increased and nephrogenous adenosine 3H,5H-cyclic monophosphate tended to increase during HCl loading in intact and adrenalectomized (ADX) rats despite significant increments in plasma ionized calcium. Strong linear relationships existed between serum iPTH concentration and arterial bicarbonate or proton concentration (P less than 0.0001). Serum iPth concentration and NcAMP remained stable in intact time-control rats and decreased in CaCl2-infused, nonacidotic animals. Urinary acidification was markedly reduced in parathyroidectomized (PTX) as compared with intact rats during both basal and acidosis states; human PTH-(1-34) infusion in PTX rats restored in a dose-dependent manner the ability of the kidney to acidify the urine and excrete net acid. Acidosis-induced increase in urinary net acid excretion was observed in intact, PTX, and ADX, but not in ADX-thyroparathyroidectomized rats. We conclude that (a) acute metabolic acidosis enhances circulating PTH activity, and (b) PTH markedly contributes to the renal response against acute metabolic acidosis by enhancing urinary acidification.
PMCID: PMC296745  PMID: 2166755
7.  Metabolism in immunoreactive parathyroid hormone in the dog. The role of the kidney and the effects of chronic renal disease. 
The role of the kidney in the metabolism of parathyroid hormone (PTH) was examined in the dog. Studies were performed in awake normal and uremic dogs after administration of bovine parathyroid hormone (b-PTH) or synthetic amino terminal tetratricontapeptide of b-PTH (syn b-PTH 1-34). The renal clearance of immunoreactive PTH was determined from the product of renal plasma flow and the percent extraction of PTH immunoreactivity by the kidney. Blood levels of circulating immunoreactive PTH were determined by radioimmunoassay. The normal dog kidney extracted 20 plus or minus 1% of the immunoreactive b-PTH delivered to it, and renal clearance (RC) of immunoreactivity was 60 ml/min. When RC was compared to an estimate of total metabolic clearance (MCR) of immunoreactivity, it accounted for 61% of the total. Both MCR and RC were markedly decreased in dogs with chronic renal disease. However, the percent extraction of immunoreactive PTH was unchanged in chronic renal disease, and the observed decrease in RC was due to changes in renal plasma flow. The largest portion of the reduction in total MCR was accounted for by the decrease in RC, and there was no compensation for the decrease in RC by extrarenal sites of PTH metabolism.
PMCID: PMC436553  PMID: 1141439
8.  The Renal Handling of Parathyroid Hormone 
Journal of Clinical Investigation  1977;60(4):808-814.
The mechanisms of uptake of parathyroid hormone (PTH) by the kidney was studied in anesthetized dogs before and after ureteral ligation. During constant infusion of bovine PTH (b-PTH 1-84), the renal arteriovenous (A-V) difference for immunoreactive PTH (i-PTH) was 22±2%. After ureteral ligation and no change in renal plasma flow, A-V i-PTH fell to 15±1% (P < 0.01), indicating continued and significant uptake of i-PTH at peritubular sites and a lesser role of glomerular filtration (GF) in the renal uptake of i-PTH. Since, under normal conditions, minimal i-PTH appears in the final urine, the contribution of GF and subsequent tubular reabsorption was further examined in isolated perfused dog kidneys before and after inhibition of tubular reabsorption by potassium cyanide. Urinary i-PTH per 100 ml GF rose from 8±4 ng/min (control) to 170±45 ng/min after potassium cyanide. Thus, i-PTH is normally filtered and reabsorbed by the tubular cells. The physiological role of these two mechanisms of renal PTH uptake was examined by giving single injections of b-PTH 1-84 or synthetic b-PTH 1-34 in the presence of established ureteral ligation. After injection of b-PTH 1-84, renal A-V i-PTH was 20% only while biologically active intact PTH was present (15-20 min). No peritubular uptake of carboxyl terminal PTH fragments was demonstrable. In contrast, after injection of synthetic b-PTH 1-34, renal extraction of N-terminal i-PTH after ureteral ligation (which was 13.4±0.6% vs. 19.6±0.9% in controls) continued for as long as i-PTH persisted in the circulation. These studies indicate that both GF and peritubular uptake are important mechanisms for renal PTH uptake. Renal uptake of carboxyl terminal fragments of PTH is dependent exclusively upon GF and tubular reabsorption, whereas peritubular uptake can only be demonstrated for biologically active b-PTH 1-84 and synthetic b-PTH 1-34.
PMCID: PMC372428  PMID: 893678
9.  Proximal tubule reabsorption after hyperoncotic albumin infusion. Role of parathyroid hormone and dissociation from plasma volume. 
Journal of Clinical Investigation  1974;53(2):501-507.
Preferential expansion of the plasma volume by infusion of salt-poor hyperoncotic albumin solution decreases sodium reabsorption by the proximal tubule. The present micropuncture studies test the thesis that albumin infusion depresses proximal reabsorption by an effect unrelated to expansion of the plasma volume, perhaps due to an effect of parathyroid hormone (PTH) on proximal sodium reabsorption. Infusion of salt-poor hyperoncotic albumin significantly decreased plasma ionized calcium, increased immunoreactive PTH (iPTH) in plasma, decreased sodium reabsorption by the proximal tubule, and increased phosphate clearance. In contrast, infusions of albumin, in which the ionized calcium was restored to normal plasma levels, had no significant effect on ionized calcium, iPTH, proximal reabsorption, or phosphate clearance in intact dogs. Similarly, in parathyroidectomized animals given a constant replacement infusion of PTH, albumin infusion had no significant effect on proximal reabsorption or phosphate clearance. Plasma volume was markedly expanded following albumin infusion in all groups of dogs. These findings (a) indicate that PTH plays a significant role in the decrease in sodium reabsorption by the renal proximal tubule after salt-poor hyperoncotic albumin infusion, and (b) dissociate preferential expansion of the plasma volume from decreases in sodium reabsorption by the proximal tubule.
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PMCID: PMC301492  PMID: 11344563
10.  High-intensity focussed ultrasound (HIFU) treatment in uraemic secondary hyperparathyroidism 
Background.
The recently developed non-invasive high-intensity focussed ultrasound (HIFU) technique for the destruction of parathyroid adenomas could also be of interest for the treatment of secondary hyperparathyroidism (SHP) in patients with chronic kidney disease (CKD). We conducted a pilot study using this method.
Methods.
Five chronic haemodialysis patients with severe SHP underwent one to three HIFU treatments, respectively. They had at least one or two enlarged parathyroid glands, which were accessible to this technique.
Results.
In Patients 1-I and 5-V, serum intact parathyroid hormone (iPTH) could be successfully reduced in the long run. In Patient 3-N, serum iPTH decreased dramatically down to the normal range but increased again subsequently. In Patients 2-E and 4-D, transient reductions in serum iPTH were also obtained but HIFU failed to correct SHP during follow-up. Serum total calcium and phosphorus decreased in four among the five patients, either transiently or permanently. Serum total alkaline phosphatases were reduced in four of five patients. Side effects included local oedema, transient impairment of vocal cord mobility and bitonal voice.
Conclusions.
HIFU treatment may be of help in controlling SHP in selected patients with CKD. Further experience is clearly needed.
doi:10.1093/ndt/gfr590
PMCID: PMC3276310  PMID: 22015443
chronic kidney disease; high-intensity focussed ultrasound; parathyroid ablation; secondary hyperparathyroidism
11.  Immunoheterogeneity of Parathyroid Hormone in Venous Effluent Serum from Hyperfunctioning Parathyroid Glands 
Journal of Clinical Investigation  1977;60(6):1367-1375.
The immunoreactive parathyroid hormone (iPTH) in the plasma of hyperparathyroid man consists largely of carboxyl (COOH)-terminal fragments of the hormone. Although these fragments have been thought to arise principally or solely from peripheral metabolism of intact human PTH {hPTH(1-84)} secreted from the parathyroid gland, there is disagreement about the source of iPTH fragments in vivo.
To reexamine this question, we fractionated peripheral and thyroid or parathyroid venous effluent sera from four patients with primary hyperparathyroidism using a high-resolution gel filtration system (Bio-Gel P-150 columns run by reverse flow). The column effluents were analyzed using two PTH radioimmunoassays, one directed toward the amino(NH2)-terminal region of the molecule, the other toward the COOH-terminal region.
In all four thyroid or parathyroid venous effluent sera studied, iPTH was 9-180 times higher than in peripheral serum from the same patient; after fractionation, hPTH(1-84) accounted for only a portion of the total iPTH (35-55% with the assay directed toward the COOH-terminal region of hPTH, >90% with the NH2-terminal directed assay.) The remaining iPTH eluted from Bio-Gel P-150 after hPTH(1-84) as NH2-or COOH-terminal hPTH fragments. These results suggest that parathyroid tumors secrete large quantities of hPTH fragments. Based on estimates of their molar concentrations in serum, tumor-secreted COOH-terminal hPTH fragments could account for most of these peptides in peripheral serum if their survival times were, as estimated by several other workers, 5-10 times that of hPTH(1-84).
We conclude that, in contrast to published information, secretory products of hyperfunctioning parathyroid tissue are probably a major source of serum PTH immunoheterogeneity.
PMCID: PMC372494  PMID: 915003
12.  Epinephrine is a Hypophosphatemic Hormone in Man. PHYSIOLOGICAL EFFECTS OF CIRCULATING EPINEPHRINE ON PLASMA CALCIUM, MAGNESIUM, PHOSPHORUS, PARATHYROID HORMONE, AND CALCITONIN 
Journal of Clinical Investigation  1983;71(3):572-578.
The physiologic effects of epinephrine on mineral metabolism are not known. In six healthy men, insulin-induced hypoglycemia, a potent stimulus to endogenous epinephrine secretion, resulted in a decrement of 0.9±0.1 mg/dl (mean±SE, P < 0.001) in serum inorganic phosphorus and smaller increments in magnesium and total and ionized calcium. Plasma immunoreactive parathyroid hormone (iPTH) decreased and plasma immunoreactive calcitonin (iCT) increased appropriately with the increments in calcium and magnesium. We wished to determine to what extent these changes in mineral metabolism might be attributable to epinephrine. Therefore, in the same protocol, we infused the hormone over 60 min in these six men, in doses that resulted in steady-state plasma epinephrine concentrations ranging from 52 to 945 pg/ml (levels that span the physiologic range), for a total of 25 studies. Serum ionized calcium, iPTH, and iCT concentrations were unaltered by these physiologic elevations of plasma epinephrine. However, epinephrine resulted in dose-dependent decrements in serum inorganic phosphorus of 0.6±0.1 mg/dl (P < 0.005) for the highest epinephrine infusion rate. The plasma epinephrine concentration threshold for this hypophosphatemic effect was ∼50-100 pg/ml. Thus, the sensitivity of the hypophosphatemic response to epinephrine is comparable to that of the cardiac chronotropic, systolic pressor, and lipolytic responses to epinephrine, and considerably greater than that of the diastolic depressor, glycogenolytic, glycolytic, and ketogenic responses to the hormone in human beings. In view of its rapidity, the hypophosphatemic effect of epinephrine is probably the result of a net shift of phosphate from the extracellular compartment to intracellular compartments. We suggest that it is a direct effect of epinephrine, in that it is not mediated by changes in availability of the primary regulatory hormones PTH and CT, although indirect effects mediated by changes in other hormones, such as insulin, cannot be excluded. The hypophosphatemic response is also not attributable to increments in plasma calcium. These data indicate that epinephrine in physiologic concentrations is a hypophosphatemic hormone in man.
PMCID: PMC436905  PMID: 6402521
13.  Radioimmunoassay of human parathyroid hormone in serum 
A new radioimmunoassay for human parathyroid hormone (PTH) in serum, which can measure the hormone present in 94% of the normal sera tested, is described. It is based on the ability of human PTH to compete with 131I-labeled bovine PTH for binding to an antiserum directed against porcine PTH. This antiserum distinguishes between human PTH extracted from parathyroid adenomata and that present in hyperparathyroid sera. Evidence is given to suggest that this is due to immunochemical changes in the hormone extracted from adenomata and not to immunochemical heterogeneity of the hormone present in serum.
Physiologic data supporting the validity and specificity of the assay are presented. Induced episodes of hypercalcemia and hypocalcemia resulted in appropriate responses in serum immunoreactive PTH (IPTH) in normal subjects and in patients with Paget's disease of bone. In normals, there was a progressive increase in serum IPTH in the late afternoon and evening, suggesting a diurnal secretory rhythm. A negative correlation was found between the serum calcium and serum IPTH over the normal range of serum calcium values; a positive correlation was found between these variables in patients with primary hyperparathyroidism. There was apparent overlap between serum IPTH values in normal subjects and patients with primary hyperparathyroidism, but formal discriminate analysis of values for serum calcium and IPTH demonstrated separation of these two groups, without overlap.
PMCID: PMC291890  PMID: 5543877
14.  Correlates of parathyroid hormone concentration in hemodialysis patients 
Nephrology Dialysis Transplantation  2013;28(6):1516-1525.
Background
The implications of chemical hyperparathyroidism on bone and mineral metabolism measures in maintenance hemodialysis (MHD) are not well known. We hypothesized that a higher serum intact parathyroid hormone (iPTH) level is associated with the higher likelihood of hyperphosphatemia, hyperphosphatasemia [high serum alkaline phosphatase (ALP) levels] and hypercalcemia.
Methods
Over an 8-year period (July 2001–June 2009), we identified 106 760 MHD patients with iPTH and calcium (Ca), phosphorous (P) and ALP data from a large dialysis clinic. Logistic regression models were examined to assess the association between serum iPTH increments and the likelihood of hyperphosphatemia (P ≥5.5 mg/dL), hypercalcemia (Ca ≥10.2 mg/dL) and hyperphosphatasemia (ALP ≥120 U/L).
Results
Patients were 61 ± 16 years old and included 45% women, 59% diabetics and 33% Blacks. Compared with an iPTH level of 100 to <200 pg/mL, patients with an iPTH level of 600–700, 700 to <800 and ≥800 pg/mL had 122% (OR: 2.22, 95% CI: 2.04–2.41), 153% (OR: 2.53, 95% CI: 2.29–2.80) and 243% (OR: 3.43, 95% CI: 3.22–3.66) higher risk of hyperphosphatemia, respectively, and had 109% (OR: 2.09, 95% CI: 1.93–2.26), 130% (OR: 2.30, 95% CI: 2.10–2.52) and 376% (OR: 4.76, 95% CI: 4.50–5.04) higher risk of hyperphosphatasemia, respectively. Compared with an iPTH level of 100 to <200 pg/mL, both the low iPTH (<100 pg/mL, OR: 2.45, 95% CI: 2.27–2.64) and the high iPTH (≥800 pg/mL: OR: 2.13, 95% CI: 1.95–2.33) levels were associated with hypercalcemia.
Conclusions
Higher levels of iPTH are incremental correlates of hyperphosphatemia and hyperphosphatasemia, whereas both very low and high PTH levels are linked to hypercalcemia. If these associations are causal, correction of hyperparathyroidism may have overarching implications on bone and mineral disorders in MHD patients.
doi:10.1093/ndt/gfs598
PMCID: PMC3685307  PMID: 23348879
hemodialysis; serum alkaline phosphatase; serum calcium; serum intact parathyroid hormone; serum phosphorous
15.  Parathyroid Function in Primary Osteoporosis 
Journal of Clinical Investigation  1973;52(1):181-184.
Two major species of serum immunoreactive parathyroid hormone (iPTH) were measured in 47 untreated patients with primary osteoporosis by using two highly specific radioimmunoassays. Mean iPTH was normal with one antiserum but was lower than normal (P < 0.001) with the other, iPTH values did not correlate with biochemical parameters or with the proportion of bone-resorbing surfaces in iliac crest bone biopsy specimens. These data suggest that the increased bone resorption is not due to increased parathyroid function in most osteoporotic patients. However, seven of our patients (15%) appear to represent a separate population because they had increased values with one or the other of the antisera.
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PMCID: PMC302240  PMID: 4734167
16.  Limited role for intraoperative intact PTH measurement in parathyroid surgery. 
Primary hyperparathyroidism may be cured surgically by complete excision of abnormal parathyroid tissue. Reoperation for persistent hypercalcaemia due to residual abnormal parathyroid tissue may be associated with a high complication rate. It is possible to assay intact parathormone (iPTH) intraoperatively and as iPTH has a relatively short half-life, its measurement intraoperatively may be used to predict successful parathyroidectomy. We have studied intraoperative iPTH levels in a consecutive series of 33 patients undergoing surgery for primary hyperparathyroidism. We found that iPTH levels fell significantly (P < 0.05) from a median pre-excision level of 122 pg/ml to a median level of 36 pg/ml 20 min after excision. However, in 3/31 successful parathyroidectomies, the intraoperative iPTH levels either remained unchanged or had risen. Reliance on intraoperative iPTH levels in these patients may have resulted in unnecessary re-exploration. We conclude that intraoperative iPTH measurement has limited usefulness as a predictor of successful parathyroidectomy for primary hyperparathyroidism.
PMCID: PMC2502514  PMID: 7717640
17.  Efficacy and safety of oral doxercalciferol in the management of secondary hyperparathyroidism in chronic kidney disease stage 4 
Indian Journal of Nephrology  2013;23(4):271-275.
This study was carried out to evaluate the efficacy and safety of doxercalciferol as therapy for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 4 in a prospective clinical trial. A total of 35 CKD-4 patients who had a baseline parathyroid hormone (iPTH) >150 pg/mL and had not received any vitamin D analog in the preceding 8 weeks were followed up at intervals of 6 weeks for 18 weeks on oral therapy with doxercalciferol. The starting dose was 1.5 μg/day, and the dose was increased in steps of 1 μg/day if iPTH did not decrease by at least 30% on the subsequent visit. Doxercalciferol was stopped temporarily if low iPTH (<70 pg/mL), hypercalcemia (>10.7 mg/dL), or severe hyperphosphatemia (>8.0 mg/dL) occurred, and was restarted at a lower dose on reversal of these abnormalities. Calcium acetate was the only phosphate binder used. Mean iPTH decreased by 35.4 ± 4.4% from 381.7 ± 31.3 pg/mL to 237.9 ± 25.7 pg/mL (P < 0.001). The proportion of patients who achieved 30% and 50% suppression of iPTH levels was 83% and 72%, respectively. Mean serum calcium, phosphorus, and calcium-phosphorus product values did not differ significantly from the baseline values. Four, two, and nine patients developed hypercalcemia, severe hyperphosphatemia, and high CaxP (>55), respectively. Almost all patients recovered to an acceptable level within 2 weeks of stopping doxercalciferol and adjusting the phosphate binder dose. In all, 21 patients required temporary stoppage of therapy. Most of them were restarted on therapy at a reduced dose during the study. It can, therefore, be concluded that doxercalciferol is effective in controlling SHPT in CKD-4 patients with an acceptable risk of hyperphosphatemia and hypercalcemia.
doi:10.4103/0971-4065.114492
PMCID: PMC3741971  PMID: 23960343
Chronic kidney disease; doxercalciferol; parathyroid hormone; pre-dialysis; secondary hyperparathyroidism; vitamin D
18.  Acute Parathyroid Hormone Response to Epinephrine In Vivo 
Journal of Clinical Investigation  1973;52(10):2434-2440.
The acute effects of epinephrine, norepinephrine, and isoproterenol on the plasma immunoreactive parathyroid hormone (iPTH) response were studied in 13 550-600 kg cows. Catecholamines were infused for 7.0 min. During epinephrine infusions at 0.08 μmol/min iPTH increased from 0.48±0.12 (mean±SE, ng/ml) to 1.09±0.18 ng/ml (P < 0.02). Small increases in plasma free fatty acids and glucose could be detected with 0.08 μmol/min epinephrine; the iPTH response to epinephrine was as sensitive as the free fatty acid and glucose responses and possibly of physiological importance. Plasma calcium (total and ionized) and magnesium did not change.
The responses were more pronounced at 0.8 μmol/min epinephrine with a mean iPTH increase from 0.49±0.16 ng/ml to 1.74±0.35 ng/ml (P < 0.01). Small decreases in plasma calcium occurred at 0.8 μmol/min epinephrine, but the plasma magnesium remained unchanged. However, when the plasma calcium was lowered with ethylene glycol bis(β-aminoethyl ether)-N, N′-tetraacetic acid (EGTA), a much more pronounced lowering of the plasma calcium was required to produce comparable increases of the plasma iPTH concentrations than when epinephrine was infused. It appears that epinephrine has a direct effect on the release of iPTH from the parathyroid glands.
Simultaneous infusions of calcium and epinephrine suppressed the stimulation by epinephrine. This points towards a common mechanism of the regulation of parathyroid hormone secretion caused by decreases in the extracellular calcium concentration and/or alterations in the distribution of calcium within parathyroid cells following the administration of epinephrine.
The iPTH response to epinephrine was suppressed in the presence of propranolol. Isoproterenol was less active in raising iPTH than epinephrine, and norepinephrine was the least active. The stimulation by isoproterenol and the suppression by propranolol suggest beta adrenergic receptor sites within the parathyroid glands.
PMCID: PMC302502  PMID: 4729041
19.  Effect of treatment with cimetidine for one year on gastrin cell and parietal cell function and sensitivity to cimetidine in patients with duodenal or gastric ulcers. 
Postgraduate Medical Journal  1980;56(660):698-701.
Twenty-two duodenal and 16 gastric ulcer patients were treated with 400 mg cimetidine twice daily for one year after their ulcers had healed. No change in gastric acid secretion was observed before and after treatment in 20 duodenal and 13 gastric ulcer patients. Similarly, the inhibitory effect of 200 mg cimetidine on gastric acid secretion was unaltered in 11 duodenal and 6 gastric ulcer patients studied and cimetidine blood concentration were unchanged in 9 duodenal and 4 gastric ulcer patients after one year. In 7 duodenal and 6 gastric ulcer patients the serum gastrin response to a standard test meal before and after treatment was identical.
PMCID: PMC2426032  PMID: 7220403
20.  Calcium Metabolism in Newborn Infants THE INTERRELATIONSHIP OF PARATHYROID FUNCTION AND CALCIUM, MAGNESIUM, AND PHOSPHORUS METABOLISM IN NORMAL, “SICK,” AND HYPOCALCEMIC NEWBORNS 
Journal of Clinical Investigation  1974;54(2):287-296.
Serum immunoreactive parathyroid hormone (iPTH) and plasma total calcium, ionized calcium, magnesium, and phosphorus levels were determined during the first 9 days of life in 137 normal term infants, 55 “sick” infants, and 43 hypocalcemic (Ca <7.5 mg/100 ml; Ca++<4.0 mg/100 ml) infants.
In the cord blood, elevated levels of plasma Ca++ and Ca were observed, while levels of serum iPTH were either undetectable or low. In normal newborns during the first 48 h of life there was a decrease in plasma Ca and Ca++, while the serum iPTH level in most samples remained undetectable or low; after 48 h there were parallel increases in plasma Ca and Ca++ and serum iPTH levels. Plasma Mg and P levels increased progressively after birth in normal infants.
In the sick infants, plasma Ca, Ca++ and P levels were significantly lower than in the normal newborns, while no significant differences were found in the plasma Mg levels. The general pattern of serum iPTH levels in the sick infants was similar to that observed in the normal group, though there was a tendency for the increase in serum iPTH to occur earlier and for the iPTH levels to be higher in the sick infants.
In the hypocalcemic infants, plasma Mg levels were consistently lower than in the normal infants after 24 h of age, while no significant differences were found in the plasma P levels. Hyperphosphatemia was uncommon and did not appear to be a contributing factor in the pathogenesis of hypocalcemia in most infants. Most of the hypocalcemic infants, including those older than 48 h, had inappropriately low serum iPTH levels.
Evidence obtained from these studies indicates that parathyroid secretion is normally low in the early new born period and impaired parathyroid function, characterized by undetectable or low serum iPTH, is present in most infants with neonatal hypocalcemia. Additional unknown factors appear to contribute to the lowering of plasma Ca in the neonatal period. The net effect of unknown plasma hypocalcemic factor(s) on the one hand and parathyroid activity on the other may account for differences in plasma Ca levels observed between normal, sick, and hypocalcemic infants. Depressed plasma Mg is frequently present in hypocalcemic infants. To what degree the hypomagnesemia reflects parathyroid insufficiency or the converse, to what degree parathyroid insufficiency and hypocalcemia are secondary to hypomagnesemia, is uncertain.
PMCID: PMC301556  PMID: 4858778
21.  Association of Secondary Hyperparathyroidism with Hemoglobin Level in Patients with Chronic Kidney Disease 
Purpose:
Secondary hyperparathyroidism (SHPT) is one of the less recognized reasons of anemia in chronic kidney disease (CKD). In this study, we evaluated the role of SHPT as a cause of anemia and correlation of intact parathyroid hormone (iPTH) and hemoglobin (Hb) level in hemodialysis (HD) patients.
Methods:
This cross-sectional study was carried out in 63 individuals admitted in HD unit of the institute. Serum samples were collected and urea, creatinine, Hb, ferritin and iPTH levels were measured. Statistical analysis was carried out using the SPSS software (IBM, NY, USA).
Results:
Mean ± standard deviation for serum urea, creatinine, Hb, ferritin and intact PTH were 177 ± 15.52, 15.16 ± 2.28 mg/dl, 7.03 ± 2.26 g/dl, 654.7 ± 563.4 ng/ml, 539.18 ± 493.59 pg/ml respectively. A reverse correlation was found between intact PTH and Hb level.
Conclusions:
A variety of postulated pathophysiological mechanisms linking SHPT and anemia in CKD are discussed. An efficient control of parathyroid hormone hypersecretion may be required to achieve a better management of anemia in HD patients.
doi:10.4103/0974-2727.115935
PMCID: PMC3758707  PMID: 24014970
Anemia; chronic kidney disease; ferritin; hemoglobin; intact parathyroid hormone; secondary hyperparathyroidism
22.  Failed Switching off in the MIBI-Parathyroid Scintigraphy in a Dialyzed Patient with Secondary Hyperparathyroidism Responsive to Cinacalcet Therapy 
The aims of your case report is to show the predictivity of 99mTc-sestamibi (MIBI) scintigraphy and doppler ultrasound imaging on secondary hyperparathyroidism (SHPT) in a patient responsive to calcimimetic treatment. Moreover, it has been reported that calcimimetic has great potential in reducing the volume of the parathyroid gland. On the other hand, the MIBI scintigraphy is considered a crucial diagnostic procedure to monitor the response to therapy in terms of turnover and cellular metabolism; whereas, ultrasound to monitor the volume variation in response to treatment. It is described the case of a 73-year-old man on hemodialysis from 1995 for ESRD. Within 2 years the patient gradually developed SHPT with progressively increased iPTH up to 1,000 ρg/ml. The ultrasound, highlighted the presence of two parathyroid hyperplasia, confirmed by scintigraphy, showing focal increase uptake of sestamibi in the same anatomical areas. As a result of the patient's refusal to perform a parathyroidectomy, cinacalcet, was administered (65 mg overage daily dose). After a year of treatment, there was a striking decrease of iPTH (from 1300 to 57 ρg/ml, −95%); but, on the contrary to expectations, this positive metabolic outcome, was not followed by parathyroid changes in ultrasound and scintigraphic findings.
doi:10.1155/2010/206801
PMCID: PMC2905699  PMID: 20652073
23.  Role of parathyroid hormone in the glucose intolerance of chronic renal failure. 
Journal of Clinical Investigation  1985;75(3):1037-1044.
Evidence has accumulated suggesting that the state of secondary hyperparathyroidism and the elevated blood levels of parathyroid hormone (PTH) in uremia participate in the genesis of many uremic manifestations. The present study examined the role of PTH in glucose intolerance of chronic renal failure (CRF). Intravenous glucose tolerance tests (IVGTT) and euglycemic and hyperglycemic clamp studies were performed in dogs with CRF with (NPX) and without parathyroid glands (NPX-PTX). There were no significant differences among the plasma concentrations of electrolytes, degree of CRF, and its duration. The serum levels of PTH were elevated in NPX and undetectable in NPX-PTX. The NPX dogs displayed glucose intolerance after CRF and blood glucose concentrations during IVGTT were significantly (P less than 0.01) higher than corresponding values before CRF. In contrast, blood glucose levels after IVGTT in NPX-PTX before and after CRF were not different. K-g rate fell after CRF from 2.86 +/- 0.48 to 1.23 +/- 0.18%/min (P less than 0.01) in NPX but remained unchanged in NPX-PTX (from 2.41 +/- 0.43 to 2.86 +/- 0.86%/min) dogs. Blood insulin levels after IVGTT in NPX-PTX were more than twice higher than in NPX animals (P less than 0.01) and for any given level of blood glucose concentration, the insulin levels were higher in NPX-PTX than NPX dogs. Clamp studies showed that the total amount of glucose utilized was significantly lower (P less than 0.025) in NPX (6.64 +/- 1.13 mg/kg X min) than in NPX-PTX (10.74 +/- 1.1 mg/kg X min) dogs. The early, late, and total insulin responses were significantly (P less than 0.025) greater in the NPX-PTX than NPX animals. The values for the total response were 143 +/- 28 vs. 71 +/- 10 microU/ml, P less than 0.01. There was no significant difference in the ratio of glucose metabolized to the total insulin response, a measure of tissue sensitivity to insulin, between the two groups. The glucose metabolized to total insulin response ratio in NPX (5.12 +/- 0.76 mg/kg X min per microU/ml) and NPX-PTX (5.18 +/- 0.57 mg/kg X min per microU/ml) dogs was not different but significantly (P less than 0.01) lower than in normal animals (9.98 +/- 1.26 mg/kg X min per microU/ml). The metabolic clearance rate of insulin was significantly (P less than 0.02) reduced in both NPX (12.1 +/- 0.7 ml/kg X min) and NPX-PTX (12.1 +/- 0.9 ml/kg X min) dogs, as compared with normal animals (17.4 +/- 1.8 ml/kg X min). The basal hepatic glucose production was similar in both groups of animals and nor different from normal dogs; both the time course and the magnitude of suppression of hepatic glucose production by insulin were similar in both in groups. There were no differences in the binding affinity, binding sites concentration, and binding capacity of monocytes to insulin among NPX, NPX-PTX, and normal dogs. The data show that (a) glucose intolerance does not develop with CRF in the absence of PTH, (b) PTH does not affect metabolic clearance of insulin or tissue resistance to insulin in CRF, and (c) the normalization of metabolism in CRF in the absence of PTH is due to increased insulin secretion. The results indicate that excess PTH in CRF interferes with the ability of the beta-cells to augment insulin secretion appropriately in response to the insulin-resistant state.
Images
PMCID: PMC423657  PMID: 3884663
24.  Effect of long-term cimetidine on gastric acid secretion, serum gastrin, and gastric emptying. 
Gut  1979;20(5):404-407.
Gastric acid secretion, gastric emptying, fasting serum gastrin and the serum gastrin response to a meal were measured in duodenal ulcer patients before, and at least five days after completing prolonged treatment with cimetidine (1 or 2 g/day for four or eight weeks followed by 600 mg twice daily for six months). Fasting serum gastrin and the gastrin response were also measured during treatment. Compared with pretreatment values, fasting serum gastrin concentrations were raised both during and five to 31 days after stopping treatment (P less than or equal to 0.02). The integrated gastrin response and the rate of gastric emptying of the solid component of the meal were increased during treatment (P less than 0.001 and P less than 0.002 respectively) but returned to pretreatment levels after stopping therapy. No significant changes were observed in the basal or maximal acid outputs or the rate of emptying of the liquid component of the meal. The results imply that the hypergastrinaemia associated with long-term cimetidine therapy does not result in increased gastric acid secretion.
PMCID: PMC1412435  PMID: 468071
25.  Effect of cimetidine treatment in the prevention of gastric ulcer relapse: a one year double blind multicentre study. 
Gut  1983;24(9):853-856.
One hundred and forty six gastric ulcer patients were given open treatment using 1 g cimetidine daily to heal their ulcers. Of 130 who completed the acute treatment period of eight weeks, 112 (86%) had healed ulcers. Of these 112 patients with healed ulcers, 108 entered a one year double blind study to compare the effect of cimetidine maintenance therapy (400 mg at night) with placebo. Of the 84 patients available for assessment at the end of one year, 86% in the cimetidine treated group were in remission compared with 45% in the placebo treated group (chi 2 = 15.03; p less than 0.001). There were similar losses from non-compliance and drop out in both groups. The incidence of untoward effects and significant drug related laboratory abnormalities was low. The results indicate that cimetidine heals nearly 90% of acute gastric ulcers within eight weeks and that subsequent low dose maintenance treatment at night offers a considerable benefit over placebo therapy.
PMCID: PMC1420086  PMID: 6350116

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