Intraoperative urinary cyclic AMP monitoring in primary hyperparathyroidism.

OBJECTIVE: This study examined the utility of intraoperative urinary cyclic 3'5' adenosine monophosphate (UcAMP), an indicator of parathyroid (PTH) hormone end-organ activity, as a "biochemical frozen section," signaling the real-time resolution of PTH hyperactivity during surgery for primary hyperparathyroidism. SUMMARY BACKGROUND DATA: The unsuccessful initial neck exploration for primary hyperparathyroidism, leaving the patient with persistent hyperfunctioning parathyroid tissue, results in part from the surgeon's inability intraoperatively to correlate a gland's gross appearance and size estimation with physiologic function. Preoperative imaging, intraoperative imaging, and intraoperative histologic/cytologic surveillance have not resolved this dilemma. METHODS: Twenty-seven patients underwent a prospective intraoperative UcAMP monitoring protocol. The patients all had a clinical diagnosis of primary hyperparathyroidism and an average preoperative serum calcium of 12.0 +/- 0.3 mg/dl. UcAMP was assayed intraoperatively using 20-minute nonequilibrium radioimmunoassay providing real-time feedback to the operating team. RESULTS: All patients had an elevated UcAMP confirming PTh hyperactivity at the beginning of the procedure. One patient, subsequently found to have an supernumerary ectopic adenoma, had four normal glands identified intraoperatively, and his intraoperative UcAMP values corroborated persistent hyperparathyroidism, the UcAMP of the remaining 26 patients decreased from 7.0 +/- 1.1 to 2.7 +/- 0.7 nm.dl GF (p < .00005) after complete adenoma excision, and they remain normocalcemic. The protocol provided useful and relevant information to the operating team, and aided in surgical decision-making, in 10 of the 27 cases (37%). CONCLUSION: Intraoperative biochemical surveillance with ucAMP monitoring reliably signals resolution of PTH hyperfunction. It is a useful adjunct to the surgeon's skill, judgment, and experience in parathyroid surgery.     

Intact parathyroid hormone in primary hyperparathyroidism

In 49 patients with primary hyperparathyroidism, intact parathyroid hormone (PTH) was measured with a recently developed immunoradiometric assay, and midregional PTH fragments (sequence 44-68) were measured with an established radioimmunoassay technique. In 47 normal subjects, the concentration of intact PTH ranged from 2.0 to 6.8 pmol/l, and in 49 patients with primary hyperparathyroidism it ranged from 6.4 to 80.0 pmol/l. In contrast, midregional PTH fragments were normal in seven of 49 patients with primary hyperparathyroidism. In five healthy controls and in 12 patients with surgically confirmed primary hyperparathyroidism and serum calcium levels below 3.0 mmol/l, a rapid calcium loading test was performed. In healthy controls, intact PTH was in the low normal to subnormal range within 2.5-5.0 min, and had recovered within 15 min of calcium infusion. In patients with primary hyperparathyroidism, the calcium infusion also led to a 30-50 per cent decrease in intact PTH levels within 5.0-7.5 min after injection, with a slow recovery after 10-15 min. In six of the patients with only slightly elevated basal intact PTH, a suppression to the normal range was observed. In 24 patients (16 patients with a solitary adenoma and eight patients with four-gland hyperplasia) the intact PTH levels were followed intraoperatively during parathyroidectomy, revealing a significantly different rate of decline for single adenomas compared with hyperplasia during the first 15 min after removal of the primary enlarged gland. Intact PTH values remained constantly elevated in one patient with primary hyperparathyroidism and an unsuccessful neck exploration. These results confirm that (a) the measurement of intact PTH in patients with primary hyperparathyroidism is superior to the measurement of midregional fragments; (b) PTH secretion in primary hyperparathyroidism is not totally autonomous; and (c) intraoperative monitoring of intact PTH values could be used to monitor the success of surgery.     

Relation between parathyroid hormone and adrenocorticotropic hormone in primary hyperparathyroidism

Parathyroid hormone is concerned with urolithiasis, and regulated by serum ionized calcium concentration. We thought that parathyroid hormone might also be regulated by a hormone. 1 mg of ACTH injection was given intramuscularly to 6 patients with primary hyperparathyroidism, 6 patients with urolithiasis, and 5 control subjects. Serum calcium significantly increased 2 h after ACTH injection in primary hyperparathyroidism. However in the other two groups, an increase of serum calcium was not observed. Parathyroid hormone increased after ACTH injection in most subjects of all three groups. Calcium concentration in a culture medium of parathyroidectomy increased in 4 cases, and the parathyroid hormone concentration in the culture medium increased in 3 cases after ACTH addition. From these data, we believe that ACTH directly influences the parathyroid glands, and that calcium is released from the parathyroid cells. Therefore, the decrease in calcium concentration in the parathyroid cells activates the excretion of parathyroid hormone. The fact that serum parathyroid hormone increases in most subjects in all groups supports our hypothesis, namely that ACTH acts directly on the parathyroid gland.     

Interaction between parathyroid hormone and catecholamines on renal cortical cyclic AMP.

Parathyroid hormone (PTH) and catecholamines (CA) increased cAMP levels in isolated tubules of rat renal cortex. A rise in cAMP could be detected 10 sec after the addition of agonists, and it reached the peak in 30-60 sec and then decreased despite the presence of active agonists. Direct relationships exist between theophylline concentrations and cAMP levels in response to agonists. Three- to fivefold rises in cAMP levels were observed with a maximal dose of PTH compared with that of CA, and there was no additive effect. Both PTH and CA stimulated renal gluconeogenesis; when added together with each maximal dose, no additive effect was observed. These results suggest the important role of phosphodiesterase to control tubular cAMP in response to hormonal stimuli, and there is a tubule cell group responding to both PTH and CA.     

Immunoheterogeneity of parathyroid hormone pre- and postoperatively in primary hyperparathyroidism

Zusammenfassung Bei primärem Hyperparathyreoidismus (pHPT) kann, wie man weiß, eine Freisetzung eher von intaktem PTH (i-PTH) als von Fragmenten mit end-ständigen Carboxylgruppen erfolgen. Wir untersuchten, ob die Freisetzung von PTH-Fragmenten mit terminalen Aminogruppen (N-PTH) sich ebenfalls ändert. Es wurden die Serumspiegel von i-PTH und N-PTH unter folgenden Bedingungen bestimmt: (1) bei 6 pHPT-Patienten (a) ohne Kalziumgabe, (b) nach oraler Kalziumgabe vor und unmittelbar nach Operation und (2) bei 7 gesunden Personen. Bei ersteren waren präoperativ beide Spiegel — i-PTH und N-PTH — erhöht, die i-PTH-Spiegel etwas stärker. Daher war das Verhältnis N-PTH/i-PTH im Vergleich zu gesunden Personen vermindert (p<0,05). Postoperativ war am 1. Tag das Serum-i-PTH stärker vermindert als das N-PTH, wodurch das N-PTH/i-PTH-Verhältnis gegenüber Gesunden zunahm (p<0,05); am 5. Tag normalisierte sich dieses Verhältnis. Präoperativ verbesserte sich die Supprimierung von i-PTH-Kalzium bei den Patienten, während die Supprimierung von N-PTH-Kalzium normal blieb, was seinen Ausdruck fand in einem unveränderten N-PTH/i-PTH-Verhältnis während der oralen Kalziumeinnahme. Im Gegensatz dazu vergrößerte sich das N-PTH/i-PTH-Verhältnis in normaler Weise während der Kalziumeinnahme am 5. Tag postoperativ (p<0,05). Schlußfolgerungen: (1) Bei pHPT ändert sich die zirkulierende PTH-Immunheterogenität mit einer vorzugsweisen Freisetzung von i-PTH im Vergleich zu N-PTH, und diese Veränderung normalisiert sich nach Operation. (2) Die Sekretion von i-PTH und N-PTH zeigt unterschiedliche Sensitivität gegenüber einer Inhibierung durch Kalzium.

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Immunoheterogeneity of parathyroid hormone pre- and postoperatively in primary hyperparathyroidism

In primary hyperparathyroidism (pHPT), a preferential release of intact PTH (i-PTH) versus carboxyl-terminal PTH fragments is known to occur. We studied whether the release of amino-terminal PTH fragments (N-PTH) is also changed. Serum levels of i-PTH and N-PTH were determined under basal conditions and following oral intake of calcium in six patients with pHPT before and immediately after surgery and in seven healthy subjects. In the patients, baseline levels of both i-PTH and N-PTH were increased preoperatively. The increase was larger in i-PTH compared to N-PTH. Therefore, the N/i ratio was reduced compared to healthy subjects (P<0.05). On the first postoperative day, serum i-PTH decreased to a larger extent than N-PTH, which increased the N/i ratio above that in healthy subjects (P< 0.05). On the 5th postoperative day, the N/i ratio was normalized. Preoperatively, the suppressibility of i-PTH calcium was impaired in the patients (P<0.05), whereas the suppressibility of N-PTH was normal, resulting in unchanged N/i ratio during the oral calcium load. In contrast, the N/i ratio increased normally during the calcium load at day 5 postoperatively (P<0.05). We therefore conclude that: (1) in pHPT, circulating PTH immunoheterogeneity is altered with a preferential release of intact PTH compared to N-terminal PTH fragments and this alteration is normalized after surgery, (2) the secretion of intact PTH and N-terminal PTH shows different sensitivity to inhibition by calcium.

     

Urinary excretion of cyclic AMP in hyperparathyroidism.

The urinary excretion of adenosine 3', 5'-monophosphate (cAMP) was investigated in 15 subjects with primary hyperparathyroidism prior to parathyroidectomy and in 13 of them also after the operation. In comparison with healthy control subjects the cAMP excretion was raised in 8 of the patients pre-operatively and after operation all values had become normal. The discriminatory value of the cAMP analyses seemed to be increased by relating the cAMP values to the urinary excretion of calcium. With the applied methods determination of urinary cAMP was superior to a radioimmunoassay of parathyroid hormone in recognizing patients with primary hyperparathyroidism. In normal subjects it appeared that the cAMP excretion expressed per gram creatinine was somewhat higher in women than in men.     

Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism.

BACKGROUND. This study investigates 410 persons (median age, 67 years) who underwent parathyroid operation for sporadic primary hyperparathyroidism 6 to 32 years (mean, 14.2 years) before 1991. METHODS. Patient records and operative specimens were scrutinized, the patients answered a questionnaire, and fasting serum samples were analyzed for calcium, albumin, creatinine, and intact parathyroid hormone (PTH) values. RESULTS. After primary parathyroid operations were performed with a conservative surgical approach, persistent and recurrent hypercalcemia were noticed in 3.7% and 1.7% of patients, respectively, whereas 4.7% of patients required vitamin D substitution or had essentially mild hypocalcemia. The PTH values were generally increased in patients with postoperative hyperparathyroidism, low in those with vitamin D substitution, and normal to elevated in the patients with hypocalcemia and in those with postoperative normocalcemia. The mean serum creatinine concentration was just below the upper reference range and correlated strongly with serum PTH value. No significant differences in serum PTH values were present between the normocalcemic patients and matched control patients after operation (n = 107), but the patients who underwent operation exhibited greater variation in the PTH concentration. CONCLUSIONS. The results substantiate the efficacy of parathyroid operation in sporadic primary hyperparathyroidism. Biochemical derangements compatible with secondary hyperparathyroidism may evolve during long-term follow-up and contribute to decreases in serum calcium values and increases in serum PTH values of these patients.     

Dissociation of renal cyclic AMP and phosphate responses to parathyroid hormone in uremia

Summary Various investigators have shown that chronic uremia is associated with a normal or exaggerated phosphaturic response to parathyroid hormone (PTH). To explore the relationship between progressive uremia, renal tubular cyclic AMP (cAMP), and inorganic phosphate (Pi) response to PTH and acidosis, in vivo and in vitro experiments were designed in rats with experimental uremia of 4–6 weeks’ duration. Both uremic and pair-fed control rats were treated with 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) and/or chronic NH₄Cl feeding. Urinary Pi and cAMP and plasma immunoreactive PTH (iPTH) were measured as well as PTH- and NaF-stimulated cAMP from isolated renal tubules. Excretion of cAMP decreased by 30% in uremic as compared to control rats despite a 3-fold rise in Pi excretion. Acidosis superimposed on uremia did not further decrease cAMP excretion, nor did it significantly alter the elevated Pi excretion. 1,25(OH)₂D₃ treatment of uremic rats further lowered cAMP excretion although Pi excretion rose, hypercalcemia occurred, and plasma iPTH fell. In nonuremic control rats, 1,25(OH)₂D₃ treatment led to hypercalcemia, a progressive decrease in cAMP, and increase in Pi excretion. Isolated renal tubules from uremic or acidotic uremic rats revealed a 50% reduction in both PTH- and NaF-stimulated cAMP generation compared to control rat renal tubules. This observation was unchanged by 1,25(OH)₂D₃ treatment. Renal tubules of 1,25(OH)₂D₃-treated control rats demonstrated a decreased cAMP production in response to both PTH and NaF which was inversely related to the calcium content of the renal tubules. Renal tubular calcium levels of uremic rats, initially 3-fold elevated, also increased during 1,25(OH)₂D₃ treatment. These results are consistent with the hypothesis that progressive uremia results in a dissociation between PTH, urinary cAMP, and Pi excretion which cannot be explained by either metabolic acidosis or 1,25(OH)₂D₃ deficiency.     

Inhibition of human platelet aggregation by parathyroid hormone. Is cyclic AMP implicated?

Parathyroid hormone (PTH) is a polypeptide which in different in vitro systems raises intracellular cyclic AMP (cAMP) levels via adenyl cyclase activation and stimulates Ca2+ transport across cell membranes. We tested whether, on the basis of this mechanism, PTH would inhibit human platelet aggregation. The latter was tested in vitro by a photometric technique. Platelet aggregation induced by the calcium ionophore A 23187 was inhibited by PTH at concentrations (0.5-3 USP U/ml) similar to those effective in other in vitro systems. Higher concentrations of PTH were required to prevent aggregation initiated by adenosine-5'-diphosphate, arachidonic acid, or platelet-aggregating factor. The terminal synthetic fragment 1-34 b PTH was ineffective against all aggregation stimuli. The antiaggregating effect of PTH was potentiated by verapamil and theophylline and was additive to that of PGI2. However, PTH did not appear to increase platelet cAMP levels and was not counteracted by an inhibitor of platelet adenyl cyclase. It is therefore unlikely that PTH inhibits platelet aggregation through an adenyl cyclase stimulated increase of cAMP. Since PTH levels are markedly increased in uremic plasma, it might contribute to the defective platelet function and the bleeding tendency frequently occurring in uremic patients.     

Intraoperative monitoring of intact parathyroid hormone during surgery for primary hyperparathyroidism

The aim of the present study was to evaluate a new immunometric assay for intraoperative parathyroid hormone monitoring. The test was applied in 70 patients who underwent surgery for primary hyperthyroidism (pHPT) between 6/1999 and 6/2001. Among these patients, 61 showed a solitary adenoma, eight a hyperplasia and one a double adenoma. Intraoperative iPTH samples were taken at the beginning of the operation and 5, 10 and 15 min after removal of the parathyroid gland. Criterion for a successful operation were a decrease of iPTH levels of more than 50 % within 5 min and of more than 60 % within 15 min after parathyroidectomy. Following the removal of a solitary adenoma, iPTH levels decreased by 63 % (+/- 13 %) after 5 min and by 76 % (+/- 10 %) after 15 min respectively. In case of hyperplasia, a significant decrease of iPTH levels was not observed until a subtotal parathyroidectomy had been carried out. In the present study there were 2 false negative and one false positive results corresponding with a sensitivity of 97 % and a specificity of 89 % for prediction of a solitary adenoma. In our opinion, intraoperative iPTH monitoring using this new assay allows the safe distinction between adenoma and multiglandular disease. It represents a valuable adjunct to surgical skill as it permits minimally invasive operations for solitary adenomas, and in case of recurrent surgery helps to detect the region of interest by selective venous sampling for parathyroid hormone.     

Contemporary surgical treatment of primary hyperparathyroidism without intraoperative parathyroid hormone measurement

Introduction

Primary hyperparathyroidism (pHPT) is usually the result of a single adenoma that can often be accurately located preoperatively and excised by a focused operation. Intraoperative parathyroid hormone (IOPTH) measurement is used occasionally to detect additional abnormal glands. However, it remains controversial as to whether IOPTH monitoring is necessary. This study presents the results of a large series of focused parathyroidectomy without IOPTH measurement.

Methods

Data from 2003 to 2014 were collected on 180 consecutive patients who underwent surgical treatment for pHPT by a single surgeon. Preoperative ultrasonography and sestamibi imaging was performed routinely, with computed tomography (CT) and/or selective venous sampling in selected cases. The preferred procedure for single gland disease was a focused lateral approach guided by on-table surgeon performed ultrasonography. Frozen section was used selectively and surgical cure was defined as normocalcaemia at the six-month follow-up appointment.

Results

Focused surgery was undertaken in 146 patients (81%) and 97% of these cases had concordant results with two imaging modalities. In all cases, an abnormal gland was discovered at the predetermined site. Of the 146 patients, 132 underwent a focused lateral approach (11 of which were converted to a collar incision), 10 required a collar incision and 4 underwent a mini-sternotomy. At 6 months following surgery, 142 patients were normocalcaemic (97% primary cure rate). Three of the four treatment failures had subsequent surgery and are now biochemically cured. There were no complications or cases of persistent hypocalcaemia.

Conclusions

This study provides further evidence that in the presence of concordant preoperative imaging, IOPTH measurement can be safely omitted when performing focused parathyroidectomy for most cases of pHPT.     

The role of parathyroid hormone measurements after surgery for primary hyperparathyroidism

BACKGROUND: During parathyroidectomy for primary hyperparathyroidism (pHPT), intraoperative parathyroid hormone (IOPTH) levels are used to confirm removal of all hyperfunctioning parathyroid tissue. The phenomenon of elevated parathyroid hormone (PTH) levels with normocalcemia after curative parathyroidectomy, seen in up to 40% of patients, continues to be an unexpected and unexplained finding. We therefore investigated whether postoperative PTH levels are as reliable as IOPTH levels in predicting cure after surgery for pHPT. METHODS: We reviewed our prospective database of consecutive patients undergoing surgery for pHPT between December 1999 and November 2004. Curative parathyroidectomy was defined as normocalcemia 6 months or longer postoperatively. RESULTS: A total of 328 patients who underwent 330 operations for pHPT had IOPTH measurements and serum follow-up calcium levels at 6 months or longer. Surgery was curative in 315 (95.5%) operations. IOPTH levels correctly predicted operative success in 98.2% (positive predictive value [PPV]. Postoperatively, the PPV of a normal PTH level at 1 week, 3 months, and 6 months was 97.1%, 97.3%, and 96.5%, respectively. Of all patients with an elevated postoperative PTH level at 1 week, 3 months, or 6 months, only 13.7%, 14.3%, and 14%, respectively, were not cured. CONCLUSIONS: Normal postoperative PTH levels reliably predict operative success. However, they do not improve upon results predicted by IOPTH levels. Elevated postoperative PTH levels do not predict operative failure in most patients. We propose that PTH measurements after surgery for pHPT may be misleading, costly, and not indicated in normocalcemic patients.     

Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism

BACKGROUND: Most commercial intact parathyroid hormone (intact PTH) assays cross-react with non-(1-84) PTH (likely 7-84 PTH). Using a whole-molecule PTH (whole PTH) assay that specifically measured only 1-84 PTH, we compared the kinetics of whole PTH and intact PTH after parathyroidectomy in patients with primary hyperparathyroidism (HPT) and secondary HPT. METHODS: This study comprised 74 patients with primary HPT caused by a single adenoma and 18 patients with secondary HPT who underwent parathyroidectomy. Blood samples were drawn after anesthesia, just before excision of a single adenoma in primary HPT, and just before excision of the last parathyroid gland in secondary HPT, and at 5, 10, and 15 minutes after excision. The 7-84 PTH level was calculated by subtracting the whole PTH value from the intact PTH value. RESULTS: There was a difference between the percentage of 7-84 PTH/intact PTH in plasma samples from patients with primary HPT and secondary HPT (28%+/-12% vs 35%+/-9%; P<.05). Plasma whole PTH decreased more rapidly than intact PTH after parathyroidectomy in patients in both the primary HPT (P<.0001) and secondary HPT groups (P<.0001). Decline of intact PTH was slower in patients with secondary HPT than in patients with primary HPT; however, there was no significant difference in the decline of whole PTH between the 2 groups. CONCLUSIONS: The quick intact PTH assay is not used frequently during surgery in patients with secondary HPT; however, our results suggest that a quick whole PTH assay may be a more useful adjunct to parathyroidectomy in both secondary HPT and primary HPT.     

Noninvasive parathyroid imaging in primary hyperparathyroidism

Several studies suggested that preoperative localization of abnormal parathyroid (PT) glands may be useful in reducing operative time facilitating parathyroidectomy, especially in patients with ectopic PT glands. At present, noninvasive techniques used to evaluate patients with primary HPT include (1) 99mTc-sestamibi scintigraphy, (2) high-resolution neck ultrasonography, (3) CT scanning, and (4) magnetic resonance imaging (MRI). The sensitivity and positive predictive value of each technique range from 70% to 90%, and a combination of two of more tests may significantly improve the results. In the minimally-invasive era both radioguided and video-assisted parathyroidectomy require an accurate preoperative localization of the abnormal PT glands, and PT imaging should be obtained before surgery in all patients with primary hyperparathyroidism, with the aim of reducing operative time and hospital stay.     

Reelevation of parathyroid hormone level after parathyroidectomy in patients with primary hyperparathyroidism: importance of decreased renal parathyroid hormone sensitivity

BACKGROUND: We hypothesized that impaired peripheral sensitivity to parathyroid hormone (PTH) may play a role in reelevation of PTH after successful operation for primary hyperparathyroidism (pHPT). METHODS: Factors affecting reelevation of PTH were determined in 90 patients who underwent parathyroidectomy for pHPT. PTH/nephrogenous cyclic adenosine monophosphate ratio, as an index of renal resistance to PTH, was examined in relation to factors shown to influence reelevation of PTH. RESULTS: Serum PTH levels were elevated above the upper limit of normal in 23 patients (26%) at 1 week and in 39 patients (43%) at 1 month after parathyroidectomy. These 39 normocalcemic patients with elevated serum PTH at 1 month after parathyroidectomy had a higher preoperative serum level of PTH and lower serum phosphate and 25-hydroxyvitamin D (25OHD) concentrations than those with normal PTH (n = 59). Elevated PTH and low 25OHD were shown by multivariate analysis to be significant predictors of reelevation of PTH. Renal resistance to PTH was higher in patients with vitamin D deficiency or renal insufficiency than in patients with normal serum vitamin D concentrations or normal renal function, and it increased according to increases in levels of PTH. CONCLUSIONS: The mechanism of PTH reelevation in patients with pHPT after successful parathyroidectomy appears to be renal resistance to PTH.     

Experience with the radioimmunoassay for parathyroid hormone in the diagnosis of primary hyperparathyroidism

Our results with radioimmunoassay studies for parathyroid hormone performed during the last 6 years are compared retrospectively to results of the laboratory tests customarily secured when hyperparathyroidism is suspected. The results obtained in patients with known primary hyperparathyroidism and in patients with unconfirmed but presumptive hyperparathyroidism are compared to the results obtained from a group of normal controls. Despite the fact that certain discrepant results were noted in the earlier assay techniques the over-all results and, in particular, those of more recent years have been highly sensitive and reproducible corroboratives of the existence of primary hyperparathyroidism. About two-thirds of the patients with primary hyperparathyroidism will present to the urologist. All patients with calcium-containing stones should have at least 3 determinations of the serum calcium in screening for primary hyperparathyroidism. The radioimmunoassay for parathyroid hormone provides the most reliable confirmation. The patient with calculous disease, elevation of the immunoreactive parathyroid hormone level and hypercalcemia is virtually certain to have primary hyperparathyroidism.