Nephrogenous Cyclic Adenosine Monophosphate Research Articles

THE LOSS OF CIRCADIAN RHYTHM FOR INTACT PARATHYROID HORMONE AND NEPHROGENOUS CYCLIC AMP IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

The measurement of serum intact parathyroid hormone (PTH) (1-84) over a 24-h period has shown the existence of a circadian rhythm in normal males which is absent in patients with primary hyperparathyroidism. The physiological significance of this observation is reflected in the presence of parallel changes in nephrogenous cyclic adenosine monophosphate (N-cAMP) in normals which are also absent in primary hyperparathyroidism. Serum calcium, adjusted for variations in albumin concentrations, showed a transient fall in normal subjects prior to the nocturnal rise in PTH (1-84). A similar transient fall in serum adjusted calcium was observed in the hyperparathyroid patients. Serum phosphate showed a circadian rhythm in normal subjects, and an attenuated rhythm persisted in primary hyperparathyroidism. These data suggest that both ionic factors and higher centres play important roles in the fine control of PTH (1-84) secretion.

Parathyroid Hormone-related Protein and Transforming Growth Factor Activities in an Extract from a Breast Cancer Associated with Humoral Hypercalcemia of Malignancy

The pathogeneses of hypercalcemia and hypophosphatemia which developed in a patient with metastatic invasive ductal breast carcinoma were studied. The patient had low plasma levels of immunoreactive parathyroid hormone (PTH) and 1,25(OH)2D, increased nephrogenous cyclic adenosine monophosphate (cAMP) excretion and low TmPO4/GFR, suggesting the presence of humoral PTH-like activity. The tumor extract showed activities which would stimulate bone resorption in vitro and cAMP generation in the osteogenic cell line, MC3T3 E1, and in the rat kidney cortex. In addition, the extract stimulated epidermal growth factor (EGF)-independent colony formation of the NRK 49F cells in soft agar, and inhibited the binding of EGF to A431 cells, indicating it to have transforming growth factor (TGF)-alpha activity. The extract contained appreciable amounts of immunoreactive PTH-related protein (PTH-rP) but negligible amounts of immunoreactive PTH. Thus, the PTH-like activity for stimulating cAMP generation in the bone and kidney was attributed to PTH-rP. Chromatographic analyses on reverse phase high performance liquid chromatography (HPLC) separated the PTH-rP activity from that of TGF-alpha and the bone resorbing activity in vitro was found only in the fractions of PTH-rP. It was concluded that this breast cancer produced PTH-rP as well as TGF-alpha, and the former was thought to have a major role to play in the humoral hypercalcemia of malignancy observed in this patient.

THE CIRCADIAN RHYTHM OF INTACT PARATHYROID HORMONE (1-84) AND NEPHROGENOUS CYCLIC ADENOSINE MONOPHOSPHATE IN NORMAL MEN

A pronounced circadian rhythm has been demonstrated for intact parathyroid hormone (1-84) in the serum of normal male adults. The broad nocturnal rise of parathyroid hormone (1-84) secretion appears to be of physiological significance, for it is accompanied by a significant rise in nephrogenous cyclic adenosine monophosphate. The rate of return of parathyroid hormone (1-84) to baseline concentrations varies between individuals, an observation which has implications for the optimal time of sampling for the investigation of possible mild hyperparathyroidism.

Monitoring calcium intake in osteoporosis by assay of nephrogenous cyclic AMP

We studied the relationship between urinary and nephrogenous cyclic adenosine monophosphate (CAMP) and intake of calcium in patients with clinical osteoporosis. Serum and urinary Ca, alkaline phosphatase, and CAMP were measured by standard techniques. Lumbar mineral density was assessed by dual photon absorptiometry. Mean (+/- SD) urinary and nephrogenous CAMP was 4.6 +/- 1.4 mumol/g creatinine (0.52 +/- 0.16 mumol/mmol creatinine) and 15 +/- 8.0 nmol/L GF in patients using an extra gram of Ca carbonate daily and 6.5 +/- 2.6 mumol/g creatinine and 32 +/- 18 nmol/L GF in patients consuming dietary Ca (p less than 0.05). Serum Ca was increased (p less than 0.05) in the supplemented group (9.8 +/- 0.4 vs 9.3 +/- 0.6 mg/dL [2.4 +/- 0.099 vs 2.32 +/- 0.14 mmol/L]) but urinary Ca and serum alkaline phosphatase were similar. Bone mineral density was the same in both (0.88 +/- 0.19 vs 0.87 +/- 0.08 g/cm2). We concluded that CAMP is greater in patients with no supplemental Ca in the diet. This test may be useful to assess patient compliance and biological availability of dietary or supplemental Ca.

Monitoring calcium intake in osteoporosis by assay of nephrogenous cyclic AMP

We studied the relationship between urinary and nephrogenous cyclic adenosine monophosphate (CAMP) and intake of calcium in patients with clinical osteoporosis. Serum and urinary Ca, alkaline phosphatase, and CAMP were measured by standard techniques. Lumbar mineral density was assessed by dual photon absorptiometry. Mean (+/- SD) urinary and nephrogenous CAMP was 4.6 +/- 1.4 mumol/g creatinine (0.52 +/- 0.16 mumol/mmol creatinine) and 15 +/- 8.0 nmol/L GF in patients using an extra gram of Ca carbonate daily and 6.5 +/- 2.6 mumol/g creatinine and 32 +/- 18 nmol/L GF in patients consuming dietary Ca (p less than 0.05). Serum Ca was increased (p less than 0.05) in the supplemented group (9.8 +/- 0.4 vs 9.3 +/- 0.6 mg/dL [2.4 +/- 0.099 vs 2.32 +/- 0.14 mmol/L]) but urinary Ca and serum alkaline phosphatase were similar. Bone mineral density was the same in both (0.88 +/- 0.19 vs 0.87 +/- 0.08 g/cm2). We concluded that CAMP is greater in patients with no supplemental Ca in the diet. This test may be useful to assess patient compliance and biological availability of dietary or supplemental Ca.

Clinical evaluation of calcium metabolism in adult T-cell leukemia/lymphoma

• To clarify the mechanism of development of hypercalcemia in adult T-cell leukemia/lymphoma (ATLL), ten patients with a serum creatlnlne level less than 177 μmol/L (2 mg/dL) were examined. Although hypercalcemia was seen in only four (40%) of these patients, four of six normocalcemic patients showed hypercalciuria (&gt;5 mmol/d [&gt;200 mg/24 h]). All hypercalcemic patients exhibited high nephrogenous cyclic adenosine monophosphate (NcAMP) levels in the face of low-normal immunoreactive parathyroid hormone and reduced serum 1,25-dihydroxyvitamin D [1,25(OH)₂D] concentration. Half of the hypercalciuric patients with normocalcemia also showed high NcAMP and reduced serum 1,25(OH)₂D levels. Furthermore, the changes in NcAMP and serum 1,25(OH)₂D concentration closely paralleled the development of hypercalcemia and hypercalciuria in two patients. These results are reminiscent of the syndrome of humoral hypercalcemia of malignancy and suggest that derangements in calcium metabolism develop by a similar mechanism in patients with ATLL. The present data also indicate the importance of the measurement of urinary calcium excretion for early detection and prevention of fatal hypercalcemia in patients with ATLL. (<i>Arch Intern Med</i>1988;148:921-925)

Clinical Evaluation of Calcium Metabolism in Adult T-Cell Leukemia/Lymphoma

To clarify the mechanism of development of hypercalcemia in adult T-cell leukemia/lymphoma (ATLL), ten patients with a serum creatinine level less than 177 mumol/L (2 mg/dL) were examined. Although hypercalcemia was seen in only four (40%) of these patients, four of six normocalcemic patients showed hypercalciuria (greater than 5 mmol/d [greater than 200 mg/24 h]). All hypercalcemic patients exhibited high nephrogenous cyclic adenosine monophosphate (NcAMP) levels in the face of low-normal immunoreactive parathyroid hormone and reduced serum 1,25-dihydroxyvitamin D [1,25(OH)2D] concentration. Half of the hypercalciuric patients with normocalcemia also showed high NcAMP and reduced serum 1,25(OH)2D levels. Furthermore, the changes in NcAMP and serum 1,25(OH)2D concentration closely paralleled the development of hypercalcemia and hypercalciuria in two patients. These results are reminiscent of the syndrome of humoral hypercalcemia of malignancy and suggest that derangements in calcium metabolism develop by a similar mechanism in patients with ATLL. The present data also indicate the importance of the measurement of urinary calcium excretion for early detection and prevention of fatal hypercalcemia in patients with ATLL.

Bone Disease in Alcohol Abuse

We evaluated bone disease in eight white men between the ages of 49 and 61 years who had been abusing alcohol for at least 10 years. The mean density of vertebral cancellous bone was 58% of normal, whereas the mean density of appendicular cortical bone was 90% of normal. Marked reduction in active bone resorption and bone formation was seen without evidence of osteomalacia. Serum levels of calcium and magnesium were in the lower range of normal; serum levels of phosphorus, calcifediol, and calcitriol were normal; and serum levels of parathyroid hormone and nephrogenous cyclic adenosine monophosphate were in the higher range of normal. These data suggest that bone disease in these subjects is not due to inhibition of parathyroid hormone secretion or function, or abnormal vitamin D metabolism, but to an inhibition of bone remodeling by a mechanism independent of the calciotropic hormones.

Nephrogenous cyclic AMP and plasma parathyroid hormone in hypercalcaemia: the influence of renal function.

Immunoreactive parathyroid hormone (PTH) levels and nephrogenous cyclic adenosine monophosphate (cAMP) have been reported to be useful parameters in the diagnosis of hyperparathyroidism. Measurements in hyperparathyroid patients usually give values above the normal range when PTH is measured with a carboxyterminal radioimmunoassay and when nephrogenous cAMP is related to glomerular filtration rate. We tested these two parameters in two groups of hypercalcaemic patients (twelve cases of primary hyperparathyroidism and fourteen cases of hypercalcaemia of non-parathyroid origin) and in two groups of normocalcaemic subjects (twenty-one young healthy volunteers and fourteen elderly subjects without parathyroid disease). Slight impairment of renal function caused elevated values of immunoreactive parathyroid hormone in a carboxyterminal radioimmunoassay and also of nephrogenous cAMP when related to glomerular filtration rate. We found that elevated nephrogenous cAMP without parathyroid disease could be attributed to renal insufficiency and to the mode of expression generally used for the nephrogenous cAMP.

Paraneoplastic Hypercalcemia Associated with Bladder Carcinoma: Report of 2 Cases

Hypercalcemia associated with bladder carcinoma is rare. We report on 2 patients with hypercalcemia and bladder tumor without bone metastases. In both patients serum calcium returned to normal after removal of the tumor. Serum immunoreactive parathyroid hormone levels were normal in both patients. In 1 case a high gradient of immunoreactive parathyroid hormone across the tumor was demonstrated but the secretion of nephrogenous cyclic adenosine monophosphate was normal. Urinary excretion of prostaglandins also was normal in this case. These data show that hypercalcemia was caused by the tumoral production of some humoral factor different from parathyroid hormone.

The Pathogenesis of Idiopathic Hypercalciuria: Evidence for Parathyroid Hyperfunction

We studied the effect of calcium deprivation and loading in 17 healthy subjects and 76 patients with renal calculi. Five had primary hyperparathyroidism with an elevated plasma ionised calcium and detectable plasma parathyroid hormone. Forty-nine had idiopathic hypercalciuria, defined by a urine calcium greater than 7 mmol/day on a free diet. Twenty-two were normocalciuric. Fasting plasma calcium, corrected for albumin, was higher in the patients with idiopathic hypercalciuria (2.40 +/- 0.10 mmol/l) than in controls (2.28 +/- 0.05 mmol/l, p less than 0.005). Plasma calcium was intermediate in the normocalciuric stone formers (2.35 +/- 0.08 mmol/l) and elevated in the patients with primary hyperparathyroidism (2.62 +/- 0.07 mmol/l). Nephrogenous cyclic adenosine monophosphate (cAMP) and parathyroid hormone levels were highest in the primary hyperparathyroid group and did not differ significantly within the other groups. Nephrogenous cAMP correlated positively with plasma calcium in the patients with primary hyperparathyroidism and negatively in controls; there was no correlation in the idiopathic hypercalciuria group. Following an oral calcium load, plasma calcium rose and nephrogenous cAMP fell similarly in all groups. Fasting urinary calcium and its increase after load were greatest in the idiopathic hypercalciuria and primary hyperparathyroid groups, with intermediate results in the normocalciuric patients. Neither the initial metabolic patterns nor the response to thiazide fitted with the previously described patterns of absorptive and renal hypercalciuria. Increased parathyroid gland activity is the most probable cause of idiopathic hypercalciuria.

Humoral hypercalcemia of malignancy: A syndrome in search of a hormone

A woman with hypercalcemia and a hypernephroma confined to the left kidney underwent nephrectomy and subsequent resolution of hypercalcemia. Serum parathyroid hormone was undetectable in peripheral blood as well as in the left renal vein at surgery. Parathyroid hormone was also undetectable in the tumor extract using three different antisera to parathyroid hormone. Measurement of plasma prostaglandin E and 13,14-dihydro-15-keto-prostaglandin E 2 revealed levels within the normal range. The serum 1,25-dihydroxyvitamin D concentration was below normal and nephrogenous cyclic adenosine monophosphate was markedly elevated. The humoral agent responsible for hypercalcemia in this patient was not identified. This case emphasizes the need to search for new hypercalcemic factors in patients with hypercalcemia of malignancy.

Mechanisms of hypercalcemia in patients with head and neck cancer.

Hypercalcemia associated with head and neck malignancy is not an uncommon occurrence; its causes are multiple. Eight hypercalcemic patients with head and neck malignancy were studied. Serum calcium, serum phosphorus, tubular phosphorus threshold, fasting calcium excretion, plasma 1,25-dihydroxyvitamin D, nephrogenous cyclic adenosine monophosphate (AMP), and immunoreactive parathyroid hormone were measured. Excessive dietary calcium administration in the form of an oral hyperalimentation preparation appeared to be the cause of hypercalcemia in 2 patients. Six patients demonstrated humorally mediated hypercalcemia. These patients resembled patients with primary hyperparathyroidism in having elevated nephrogenous cyclic AMP excretion and reduced proximal tubular phosphorus reabsorption, but they differed from patients with primary hyperparathyroidism by having normal levels of immunoreactive parathyroid hormone, markedly increased fasting calcium excretion, and strikingly reduced mean plasma levels of 1,25-dihydroxyvitamin D. These data strongly suggest that the humoral factor responsible for hypercalcemia in patients with head and neck cancer is not parathyroid hormone, and that patients with hyperparathyroidism can now be distinguished with confidence from those with malignancy-associated hypercalcemia.

Endocrinology and metabolism: an annotated bibliography of recent literature. References to journal articles and other papers.

Endocrinology and metabolism: an annotated bibliography of recent literature. References to journal articles and other papers.

Hypocalcemia. Differential diagnosis and mechanisms

There is much individual variability in the clinical manifestations of hypocalcemia. The rapidly of the development of hypocalcemia will determine whether or not symptoms will be present. Signs and symptoms of hypocalcemia consisted of tetany (Chvostek's and Trousseau's signs), seizures, diminshed to absent deep tendon reflexes, papilledema, mental changes (weakness, fatigue, irritability, memory loss, confusion, delusion, hallucination), and skin changes. Etiologic factors for hypocalcemia in man include (1) decreased calcium absorption or increased loss from the gastrointestinal tract; (2) parathyroid hormone deficiency; (3) skeletal resistance to parathyroid hormone; (4) ineffective parathyroid hormone; (5) decreased production or increased degradation of 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol; (6) increased complex formation with calcium; (7) increased skeletal uptake of calcium; (8) hypomagnesemic state; and (9) direct inhibition of bone resorption. Measurement of total and ionic calcium, magnesium, parathyroid hormone, vitamin D metabolites (25-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol), and nephrogenous cyclic adenosine monophosphate are especially helpful in the laboratory evaluation of the hypocalcemic patient.

Nephrogenous Cyclic Adenosine Monophosphate as a Parathyroid Function Test

Nephrogenous cyclic AMP (NcAMP), total cyclic AMP excretion (UcAMP), and plasma immunoreactive parathyroid hormone (iPTH), determined with a multivalent antiserum, were prospectively measured in 55 control subjects, 57 patients with primary hyperparathyroidism (1 degrees HPT), and 10 patients with chronic hypoparathyroidism. In the group with 1 degrees HPT, NcAMP was elevated in 52 patients (91%), and similar elevations were noted in subgroups of 26 patients with mild (serum calcium </=10.7 mg/dl) or intermittent hypercalcemia, 19 patients with mild renal insufficiency (mean glomerular filtration rate, 64 ml/min), and 10 patients with moderate renal insufficiency (mean glomerular filtration rate, 43 ml/min). Plasma iPTH was increased in 41 patients (73%). The development of a parametric expression for UcAMP was found to be critically important in the clinical interpretation of results for total cAMP excretion. Because of renal impairment in a large number of patients, the absolute excretion rate of cAMP correlated poorly with the hyperparathyroid state. Expressed as a function of creatinine excretion, UcAMP was elevated in 81% of patients with 1 degrees HPT, but the nonparametric nature of the expression led to a number of interpretive difficulties. The expression of cAMP excretion as a function of glomerular filtration rate was developed on the basis of the unique features of cAMP clearance in man, and this expression, which provided elevated values in 51 (89%) of the patients with 1 degrees HPT, avoided entirely the inadequacies of alternative expressions. Results for NcAMP and UcAMP in nonazotemic and azotemic patients with hypoparathyroidism confirmed the validity of the measurements and the expressions employed.