Degradation of human calcitonin in human plasma

The degradation in vitro of human calcitonin (HCT) in plasma from normal subjects and patients with disorders of calcium metabolism was studied. As measured by radioimmunoassay, the hormone was stable at 37°C in phosphate buffer for 24 hr but progressively disappeared when incubated in normal human plasma. The loss was temperature and pH dependent, being maximal at 37°C between pH 6.0 and 7.0. Under these conditions ¹²⁵I-HCT appeared to be degraded to at least one labeled fragment that behaved on polyacrylamide gels as if it were smaller than 1000 daltons. The rate of formation of this fragment correlated well with the rate of loss of immunoreactive HCT. Compared to plasma from normal individuals, plasma from patients with hypercalcemia due to causes other than hyperparathyroidism degraded HCT significantly more rapidly. The mean loss of HCT in 5 hr in plasma from nine such patients was 54% ± 17% (± 2 SEM), compared to 22% ± 5% in plasma from 22 healthy volunteers (p < 0.001). Those patients whose plasma most rapidly degraded HCT had milkalkali syndrome, metastatic carcinoma of the colon, metastatic oat cell carcinoma of the lung, and metastatic breast carcinoma. Rates of HCT degradation in plasma from eight hypercalcemic patients with hyperparathyroidism and seventeen normocalcemic patients with malignancy were within the normal range. From these findings we conclude that human plasma contains one or more enzymes that degrade HCT and that the hormone is degraded more rapidly in plasma from some patients with hypercalcemia.     

Divalent cation metabolism: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m² (mean ± 1 standard deviation [SD] p < 0.0001). Although renal function was well preserved, the group with familial hypocalciuric hypercalcemia showed a mean serum magnesium concentration of 2.05 ± 0.17 meq/liter, significantly higher than that in normal subjects (1.74 ± 0.12 meq/liter, p < 0.0001) or than in the group with primary hyperparathyroidism (1.71 ± 0.21 meq/liter, p < 0.0001). In familial hypocalciuric hypercalcemia the degree of hypermagnesemia was directly proportional to the degree of hypercalcemia (R = +0.54, p < 0.01), contrasting with an inverse relation of serum calcium and magnesium concentrations in primary hyperparathyroidism (R = ?0.32, p < 0.02). Urinary excretion of both calcium (calcium:creatinine clearance ratio 0.006 ± 0.004 versus 0.024 ± 0.01, p < 0.0001) and magnesium (magnesium:creatinine clearance ratio 0.031 ± 0.0008 versus 0.047 ± 0.03, p < 0.003) was significantly lower in familial hypocalciuric hypercalcemia than in primary hyperparathyroidism. There was no evidence that abnormal protein binding of cations in serum from those with familial hypocalciuric hypercalcemia accounted for the hypercalcemia and hypermagnesemia or for the disproportionately low urinary excretion of divalent cations by rendering them resistant to glomerular filtration. After fractionation by electrophoresis on cellulose acetate, the major plasma protein components were quantitatively similar in both groups. Furthermore, ionized and ultrafiltrable calcium and ultrafiltrable magnesium showed consistent relations to total calcium and total magnesium concentrations in plasma from both groups. Therefore, in familial hypocalciuric hypercalcemia there are increased serum concentrations of the physiologically active forms of both calcium and magnesium, and the renal handling of the filtered load of these divalent cations differs in familial hypocalciuric hypercalcemia and primary hyperparathyroidism.     

Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin

To study the role of glucagon in human glucose homeostasis, experimental glucagon deficiency was produced by infusing somatostatin (i.v. 250 μg bolus, followed by infusion of 500 μg/hr) in six normal subjects and in two hypophysectomized patients—an insulin-dependent diabetic and a nondiabetic. In normal subjects, somatostatin lowered plasma glucagon from a mean (± SE) basal level of 85 ± 15 to 33 ± 10 pg/ml, p < 0.001. Concurrently, plasma glucose fell from $\text{90 ± 2 to 73 ± 3 mg}\text{100 ml}$, p < 0.001. Serum insulin and growth hormone fell slightly during somatostatin infusion, while plasma free fatty acids rose. In both hypophysectomized patients, somatostatin lowered plasma glucagon and glucose levels. In all subjects, after stopping somatostatin infusions, plasma glucagon and glucose returned promptly to control values, while serum growth hormone did not change. In additional in vitro studies, somatostatin (1 μg/ml) had no effect on muscle glucose uptake. Since it is known that somatostatin has no direct effect on hepatic glucose production, these results suggest that the fall in plasma glucose during somatostatin infusion resulted from inhibition of glucagon secretion, thus providing evidence that this hormone plays a physiologic role in the maintenance of fasting euglycemia in man.     

Fulminating hypercalcemia and markedly increased nephrogenous cyclic AMP in a patient with transitional cell carcinoma of the bladder.

Refractory hypercalcemia developed suddenly in a patient who had undergone a radical cystectomy for an anaplastic transitional cell carcinoma of the bladder. A normal serum parathyroid hormone (PTH) value was obtained by immunoassay while the patient had hypercalcemia and unimpaired renal function. This normal PTH value in the presence of hypercalcemia was consistent with his hypercalcemia being secondary to excessive amounts of circulating PTH. The finding of increased nephrogenous cyclic AMP, however, provided the definitive diagnosis of hyyperparathyroidism. Since autopsy revealed that there was no residual tumor in the bladder area, only evidence of metastatic disease, and since the parathyroid glands were not hyperplastic or adenomatous, we attributed this patient's hypercalcemia to hyperparathyroidism due to the ectopic production of PTH by a metastasis from the transitional cell carcinoma of the bladder.     

Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma

The regulation of parathyroid hormone (PTH) secretion by calcium was studied in normal and abnormal parathyroid tissue from five patients with a parathyroid adenoma. Dispersed cells were prepared from the adenoma and from a portion of a normal parathyroid gland and were incubated for two hours with varying concentrations of calcium. PTH release as a function of the concentration of calcium was determined by radioimmunoassay (C-terminal). Cells from the normal glands showed a lower set-point for calcium (the concentration of calcium causing half of the maximal inhibition of PTH release) than those from the adenomas in four of five cases. Moreover, both set-point and maximal PTH release at low concentrations of calcium were significantly lower in normal glands from patients with an adenoma than in normal glands from patients with normal calcium homeostasis (0.77 ± 0.04 [SEM] versus 0.99 ± 0.03 mM calcium and 3.4 ± 0.43 versus 10.1 ± 0.78 ng/10⁵ cells/hr, respectively). These observations may explain, in part, the transient hypocalcemia frequently seen in patients after removal of a parathyroid adenoma. In addition, they suggest that the set-point for calcium and maximal PTH release in normal parathyroid tissue may be altered by prior exposure to chronic hypercalcemia or other physiologic variables. Finally, the “normal” set-point that we have noted previously in parathyroid tissue from some patients with primary parathyroid hyperplasia may be inappropriately high for the hypercalcemia seen in those cases.     

Plasma alpha-cell glucagon in primary hyperparathyroidism

Plasma glucose, insulin, and alpha-cell glucagon profiles were examined in ten adults with uncomplicated primary hyperparathyroidism before and 8–12 wk after surgical removal of a single parathyroid adenoma. Treatment restored abnormal serum calcium and phosphorus concentrations to a normal range and reduced serum parathyroid hormone levels from 47 ± 4 to 16 ± 4 μ 1 Eq/ml (normal = 0–40). Plasma glucose curves during 100-g oral glucose tolerance, 30 min intravenous glucose (1.5 g/min), or arginine infusions (1.0 g/min) did not differ before and after surgery. However, basal and peak insulin concentrations were higher before treatment during these tests (p < 0.05). Basal glucagon levels were unaffected by hyperparathyroidism (72 ± 7 versus 77 ± 7 pg/ml). Peak 30 min values after arginine provocation were also similar before and after treatment as was maximal suppression of basal glucagon during glucose infusions. Four patients also received 400 g lean beef meals. Glucose and glucagon responses over 240-min periods were nearly identical before and after surgery despite higher insulin levels before treatment.It is concluded that elevated serum parathyroid hormone and plasma insulin concentrations in primary hyperparathyroidism do not relate to abnormalities of plasma alpha-cell glucagon in the basal state or after glucose, arginine, or protein administration.     

Pancreatic islet cell carcinoma with hypercalcemia. Primary hyperparathyroidism or humoral hypercalcemia of malignancy

A 60-year-old woman presented with hypercalcemia and was found to have metastatic pancreatic islet cell carcinoma. Although clinical features were very suggestive of hyperparathyroidism, her parathyroid hormone levels were not elevated and no abnormal parathyroid tissue was detected by thallium-technetium or computed tomographic scanning techniques. Her hypercalcemia appeared to be due to a humoral factor--distinct from parathyroid hormone--that mimics the action of parathyroid hormone almost exactly. The various tools that may be used to differentiate primary hyperparathyroidism from the humoral hypercalcemia of malignancy are reviewed.     

Hypercalcemia in acute uremia and following citric acid administration: differential effect on parathyroid gland microtubule content.

Hypercalcemia, which occurs 4 hr after bilateral nephrectomy in normal rats, is not seen 4 hr after either bilateral ureterotomy or sham surgery. These results indicate that it is loss of renal mass per se, not the uremic syndrome, which is responsible for the hypercalcemia. Citric acid levels also increase 4 hr after nephrectomy, and a degree of hypercalcemia and hypercitricemia comparable to that which follows nephrectomy can be produced by administration of citric acid to normal rats. In an attempt to evaluate the role of the parathyroid gland in the development of hypercalcemia in these two situations, the microtubule content of parathyroid gland chief cells was determined by ultrastructural sterologic techniques 4 hr after either bilateral nephrectomy or citric acid administration. The results of these measurements indicate that parathyroid gland chief cell microtubule content increases after citric acid administration but not following bilateral nephrectomy. The significance of these results is not clear. However, since a previous study has suggested a correlation between increased microtubule content and increased secretory status in the chief cell, one may speculate that increased microtubule content resulting from citric acid administration may also be associated with increased parathyroid hormone secretion. By this formulation, citric acid-induced hypercalcemia would be secondary to increased parathyroid hormone secretion, but the transient hypercalcemia that occurs after nephrectomy would take place in the absence of an increase in parathyroid hormone secretion. In this latter instance, it is possible that loss of the kidney, a major site of parathyroid hormone removal from plasma, leads to an increase in circulating parathyroid hormone level, and hypercalcemia, in the absence of an increase in hormone secretion rate.     

Renal and systemic magnesium metabolism during chronic continuous PTH infusion in normal subjects

Renal and systemic magnesium metabolism has not been adequately characterized in states of prolonged PTH excess in humans. Whereas acute experimental PTH administration uniformly results in enhanced renal magnesium reabsorption in many species, including humans, numerous clinical reports have documented renal magnesium wasting in human primary hyperparathyroidism. The possibility has been raised, therefore, that secondary consequences of sustained hyperparathyroidism (eg, hypercalcemia, nephrocalcinosis) might override the direct renal effects of PTH. Accordingly, the present studies assessed the effects of chronic (12 days) continuous intravenous (IV) b-(1–34)-PTH infusion in four normal human subjects on plasma, urinary, and intestinal magnesium and calcium homeostasis under metabolic balance conditions. Chronic PTH infusion resulted in a steady-state of hypercalcemia, hypercalciuria, and persistent negative calcium balance, which returned to baseline values in a recovery period. In contrast to plasma calcium concentration, plasma magnesium concentration was not altered by PTH infusion. Significant hypermagnesuria was observed during the period of PTH administration (control, 8.21 ± 0.43 mEq/24 hours; PTH days 7–12, 10.75 ± 0.74 mEq/24 hours, P < 0.05) resulting in an initial, but transient, negative magnesium balance. During days 7–12 of PTH administration, net intestinal magnesium absorption increased sufficiently to result in a return to control magnesium balance. These findings suggest that hypermagnesuria associated with clinical primary hyperparathyroidism results from either direct or indirect effects of PTH excess, per se, and does not require the long-term consequences or complications of the clinical disorder (eg, nephrocalcinosis, renal insufficiency, acidosis).     

Ectopic hyperparathyroidism (pseudohyperparathyroidism) in esophageal malignancy: Report of a case and a review of the literature

Described here is a patient with esophageal carcinoma who had hypercalcemia, an elevated serum level of parathyroid hormone and normal parathyroid glands. A review of the literature reveals that a total of 25 other patients with ectopic hyperparathyroidism in esophageal malignancy have been described, four of whom had documented elevations of serum parathyroid hormone levels. Esophageal neoplasms should be added to the list of tumors associated with ectopic secretion of parathyroid hormone.     

A CARBOXY-TERMINAL SPECIFIC ASSAY FOR HUMAN PARATHYROID HORMONE

An homologous carboxy-terminal specific immunoradiometric assay for human parathyroid hormone (PTH) has been developed which uses an antiserum raised in a goat against intact human PTH. This assay has been applied to the measurement of circulating PTH in man; the reference preparation was a 53–84 fragment prepared from native human parathyroid hormone. PTH was detectable in all the normal subjects studied (range 0·1–0·79 ng/ml) and elevated concentrations were found in a group of patients with primary hyperparathyroidism (range 0·82–25·5 ng/ml). Carboxy-terminal hormone concentrations were particularly raised in uraemic subjects (range 1–02–52–5 ng/ml) but some patients with vitamin D deficient osteomalacia had concentrations within the normal range (0·5–2·4 ng/ml). All patients with pseudohypoparathyroidism had elevated concentrations (range 1·0–2·8 ng/ml) and in patients with idiopathic or surgical hypoparathyroidism the concentration ranged from undetectable to 0·4 ng/ml. These results have been compared with those obtained using an amino-terminal specific assay. In normal subjects carboxy-terminal immuno-reactive hormone concentrations were, on average, three times higher than those measured in the amino-terminal assay (C:N ratio 3·28). In patients with secondary hyperparathyroidism this ratio was dependent on renal function and the plasma calcium concentration. The disappearance of endogenous carboxy-and amino-terminal PTH from the circulation of a patient with primary hyperparathyroidism was studied. Amino-terminal reactive PTH disappeared much more rapidly (t½= 1·5 min) than carboxy-terminal hormone (t½= 2·75 h). It is hoped that the carboxy-terminal specific assay described here will be of value in the further study of the secretion and metabolism of PTH.     

Effects of hydrochlorothiazide and dietary sodium restriction on calcium metabolism in corticosteroid treated patients

The effect of treatment with hydrochlorothiazide (HCT) and dietary sodium restriction on calcium economy in glucocorticoid-treated patients was investigated. Fractional ⁴⁷Ca intestinal absorption (FCaA) and fractional urinary calcium excretion (FCaEx) were measured in six normal individuals and in ten patients receiving glucocorticoids for chronic obstructive pulmonary disease before and after 60 days of treatment with a 50 mEq sodium diet and HCT 50 mg twice daily.FCaA was significantly decreased in glucocorticoid-treated patients (27.5 ± 4.3%) when compared to normal individuals (41.8 ± 2.8%, p < 0.005). A significant increase in FCaA to 38.9 ± 4.8%, (p < .05) was seen in glucocorticoid-treated patients after treatment with HCT and dietary sodium restriction. Baseline FCaEx was higher in glucocorticoid-treated patients than in the normal subjects. A significant decrease in FCaEx after dietary sodium restriction and thiazide administration occurred in both normal (0.99 ± 0.28% before vs. 0.69 ± 0.30% after; p < .025) and glucocorticoid-treated patients (1.46 ± 0.19% before vs. 0.73 ± 0.13% after; p < 0.025).These data suggest that dietary sodium restriction and HCT therapy may improve total body calcium economy in glucocorticoid-treated patients by increasing intestinal calcium absorption and decreasing urinary calcium excretion.     

Calcium-regulated parathyroid hormone release in primary hyperparathyroidism: studies in vitro with dispersed parathyroid cells.

Dispersed parathyroid cells were prepared from three normal human parathyroid glands as well as from pathologic parathyroid tissue of 30 patients with primary hyperparathyroidism (17 with adenoma, 12 with primary hyperplasia and one with carcinoma). Immunoreactive parathyroid hormone (PTH) release from cells of normal glands showed a “set-point” (the calcium concentration half-maximally inhibiting PTH release) of 1.0 mM, similar to that of normal bovine and canine parathyroid cells. Cells from parathyroid tissue of one patient each with multiple endocrine neoplasia type I (MEN I) and unclassified familial hyperparathyroidism, and from eight of 12 glands from patients with sporadic hyperplasia had “setpoints” of 1.0 to 1.1 mM. By contrast, only two of 17 cell preparations from adenomas had “set-points” of < 1.2 mM. Hormone secretion from cells of eight of 17 adenomas, four of 12 sporadic hyperplastic glands and a gland from a single patient with multiple endocrine neoplasia type II (MEN II) had “set-points” of 1.2 to 1.5 mM. PTH release from dispersed cells from the remaining seven adenomas, one sporadic hyperplastic gland and metastatic parathyroid carcinoma in a single patient showed relatively poor suppressibility (12 to 43 per cent) by 3.0 mM calcium.The present results and previous data from this laboratory in 20 additional patients with primary hyperparathyroidism suggest heterogeneous responsiveness to calcium in this disorder. In some cases (most primary hyperplasia and occasional adenomas), calcium-regulated PTH release is relatively normal. In others (most adenomas and some sporadic primary hyperplasia), maximal suppressibility of secretion is normal but with an elevated “set-point.” In the remaining adenomas, in rare primary hyperplasia and in the single carcinoma in this series, relative autonomy was observed. The relationship of these various secretory patterns to the pathophysiology of primary hyperparathyroidism is discussed.     

STUDIES OF CIRCULATING PARATHYROID HORMONE IN MAN USING A HOMOLOGOUS AMINO-TERMINAL SPECIFIC IMMUNORADIOMETRIC ASSAY

Circulating immunoreactive parathyroid hormone (PTH) was measured by a homologous, amino-terminal, specific, immunoradiometric assay in man. In forty-two healthy subjects the concentrations ranged between < 40 pg/ml and 120 pg/ml. No hormone could be detected in the sera of eleven patients with hypoparathyroidism, but the concentrations were clearly elevated in six patients with pseudohypoparathyroidism (range 190–1120 pg/ml). In thirty-five patients with primary hyperparathyroidism the mean (±SEM) concentration was 283·4±42·4 pg/ml (range 100–1350 pg/ml). A significant positive correlation was demonstrated between immunoassayable hormone and serum calcium concentrations in these patients. In nine patients PTH concentrations were measured before and after parathyroidectomy. In all of them they were elevated pre-operatively but fell to the normal range after parathyroidectomy. The disappearance of exogenously administered synthetic human PTH (1–34) from the circulation of two normal subjects was rapid with an apparent plasma half-disappearance time (t½) between 2 and 3 min; the metabolic clearance rate was 12·9 and 9·0 ml. kg^-1, min^-1 respectively. Similarly, the disappearance of endogenous, amino-terminal, immunoreactive PTH from the circulation of two patients with primary hyperparathyroidism after parathyroidectomy was rapid; the apparent t½ was approximately 3 min. Homologous amino-terminal specific immunoassays for PTH can thus be useful for the study of both the acute, and chronic, changes of circulating hormone in man and represent an improvement over heterologous unselected assay systems.     

Successful palliation of hypercalcemia secondary to metastatic parathyroid cancer: an unusual indication for hepatic resection

Primary carcinoma of the parathyroid gland is a rare disease. It is often diagnosed after recurrence of hyperparathyroidism following resection for presumed adenomatous disease. Local and distant recurrence is high and aggressive resection is advocated. Patients with parathyroid cancer are frequently plagued by severe hypercalcemia, which is often refractory to medical therapy. Herein we describe the case of a patient with metastatic parathyroid cancer localized to the liver. The patient was treated with a palliative hepatic resection for the management of persistent and refractory hypercalcemia. Intraoperative parathyroid hormone levels were utilized as an adjunct to determine successful metastatectomy. Our case highlights the importance of an aggressive approach to patients with metastatic parathyroid cancer, as well as the utility of intraoperative parathyroid hormone levels to confirm successful extirpation of disease.     

Severe hypercalcemia as an initial presenting manifestation of hepatocellular carcinoma.

An 80-year-old white woman who presented with fatigue, weakness, weight loss, constipation and polydipsia is reported. The patient was given a diagnosis of severe hypercalcemia and was subsequently found to have clinical, roentgenographic and pathological evidence of hepatocellular carcinoma. Further studies revealed a low parathyroid hormone level, excluding the possibility of primary hyperparathyroidism, and a negative bone survey, precluding metastatic bone disease. The patient's hypercalcemia was believed to emanate from the humoral secretion of a parathyroid hormone-related peptide, which was found to be elevated, and was abated with conservative management while her cancer was being treated with chemotherapy. The details of this rarely documented presentation, which can easily be mistaken for hepatic encephalopathy, are provided.     

Parathyroid carcinoma: clinical and pathologic features in 43 patients.

Parathyroid carcinoma accounts for 0.5 to 5% of all cases of hyperparathyroidism. We reviewed the clinical, surgical, and pathologic features observed in all patients with parathyroid carcinoma evaluated at the Mayo Clinic from 1920 through 1991. Forty-three patients (22 women, 21 men; mean age, 54 yrs, range 29-72) were identified, including 2 with familial hyperparathyroidism. Information on initial presentation was available in 40 patients: 15 (38%) presented with polydipsia or polyuria, 11 (27%) with myalgias or arthralgias, 7 (17%) with weight loss, and 4 (10%) with nephrolithiasis; 3 patients (7%) were asymptomatic at presentation. Of 31 patients in whom the initial neck examination was recorded, 14 (45%) had a palpable neck mass. The mean serum calcium and serum phosphorus levels were 14.6 mg/dl and 2.3 mg/dl, respectively. Parathyroid hormone levels were elevated in 21 of 21 patients (mean elevation, 10.2 times upper limit of normal). Complications included nephrolithiasis in 14 of 25 patients (56%), bone disease in 20 of 22 patients (91%) and both in 8 of 15 patients (53%). All patients underwent primary surgical resection of parathyroid carcinoma. Twenty-six of 43 patients (60%) required a second operation with 18 patients requiring multiple re-explorations. At the second operation, residual tumor was found in the neck (68%), mediastinum (16%), or both (12%). Six patients received radiation therapy to the neck (5 patients) or bones (1 patient) for recurrent or metastatic disease. Of these, 1 patient appeared cured of parathyroid carcinoma by radiation therapy 11 years after documented tumor invasion of his trachea. Repeated excision of tumor recurrences was an effective means of controlling hypercalcemia in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypertension and hyperparathyroidism: Inverse relation of serum phosphate level and blood pressure

In a retrospective study of 120 patients with surgically proved primary hyperparathyroidism, 71 patients who were normotensive and 49 patients (41 percent) who were either hypertensive at the time of parathyroidectomy or had a history of hypertension were compared. The mean serum calcium levels in the normotensive and hypertensive patients were very similar (11.6 ± 0.1 [SEM] mg/dl, and 11.8 ± 0.1), ruling against the hypothesis that hypercalcemia per se is the dominant cause of the hypertension of hyperparathyroidism. The mean serum creatinine levels in the two groups were also very similar (1.02 ± 0.05 and 1.09 ± 0.05 mg/dl), indicating that the hypertension of hyperparathyroidism is not the consequence of advanced renal parenchymal damage. The hypertensive patients did not have a significantly higher prevalence of urolithiasis. A review of the data in this and related studies leads to the conclusion that the hypertension of hyperparathyroidism is heterogeneous in origin. The mean serum phosphate level in the hypertensive patients was significantly lower than that in the normotensive patients (2.20 ±0.06 mg/dl versus 2.69 ± 0.09 mg/dl, p < 0.02), which may be due to a decrease in renal tubular phosphate reabsorption secondary to hypertension.     

Hypercalcemia with low-normal serum intact PTH: a novel presentation of primary hyperparathyroidism

The diagnosis of primary hyperparathyroidism has rested on the finding of hypercalcemia coupled with an elevated serum parathyroid hormone (PTH) level. Over 300 consecutive patients with primary hyperparathyroidism have had elevated or high-normal serum PTH levels using a specific immunoradiometric assay. Here we present a patient who proved to have surgically documented primary hyperparathyroidism in whom PTH levels were completely normal in all assays used. In the immunoradiometric assay, his normal result was unprecedentedly low (17 to 28 pg/mL; normal, 10 to 60 pg/mL) for this condition, and in a range consistent with non-PTH-dependent hypercalcemia or familial hypocalciuric hypercalcemia. This rare biochemical presentation of primary hyperparathyroidism should be considered in the differential diagnosis of hypercalcemia.     

Effects of thyroid hormone on plasma adenosine 3',5'-monophosphate production in man.

Thyroid hormone may nonspecifically modulate cAMP production and end-organ responsiveness to diverse hormonal stimuli. This hypothesis was tested in 18 hyperthyroid, 16 euthyroid, and 8 hypothyroid human subjects by measurement of cAMP in plasma and urine both in the basal state and following stimulation by epinephrine, parathyroid hormone, and glucagon—hormones known to act through cAMP. Supine fasting plasma cAMP (PcAMP) concentrations (mean ± SEM) were minimally elevated in the hyperthyroid patients (23.5 ± 1.3 nM, p < 0.001) when compared with the euthyroid (17.1 ± 0.6 nM) or hypothyroid (20.5 ± 1.7 nM) groups. Infusion of propranolol over 45 min failed to lower basal PcAMP concentrations in 5 hyperthyroid subjects. Epinephrine infusions (0.05 μg/kg/min) caused an exaggerated peak PcAMP response (58.7 ± 5.7 nM) in 5 hyperthyroid patients and a diminished response (27.3 ± 3.2 nM) in 5 hypothyroid patients when compared with 5 euthyroid subjects (42.3 ± 2.6 nM, p < 0.05). Administration of parathyroid hormone, 200 units intravenously, also caused significant differences in urinary cAMP excretion (μmole/hr) in the hyperthyroid (11.37 ± 0.96, p < 0.005) and hypothyroid patients (2.4 ± 0.58, p < 0.001) when compared to the euthyroid group (6.59 ± 0.74). Glucagon (1 mg intravenously) caused an enhanced peak PcAMP response in the hyperthyroid patients (514 ± 34 nM) compared with the euthyroid (240 ± 29 nM) or hypothyroid (223 ± 28 nM) groups (p < 0.005). The PcAMP disappearance half-time following the peak response to glucagon was similar in all three groups, indicating that plasma sampling is probably a valid indicator of cAMP production. These studies demonstrate that thyroid hormone may modulate the response of multiple hormonal effects mediated by cAMP. The findings suggest a further cellular mode of action of thyroid hormone which may account for a number of the metabolic disturbances observed in patients with thyroid disease.