The usefulness of an oral calcium tolerance test in the choice of management of patients with idiopathic hypercalciuria

We studied 40 patients with calcium urolithiasis and idiopathic hypercalciuria in an attempt to identify patients with an absorptive or renal type of hypercalciuria. An oral calcium tolerance test was performed in all patients, resulting in a rise in serum calcium in all cases (2.35 +/- 0.09 mmol/l vs 2.49 +/- 0.09 mmol/l; P less than 0.001). This was also true for serum phosphate (0.96 +/- 0.17 mmol/l vs 1.09 +/- 0.18 mmol/l; P less than 0.001), TmPO4/GFR (0.95 +/- 0.19 mmol/l vs 1.20 +/- 0.25 mmol/l; P less than 0.001) and fasting calcium excretion (3.14 +/- 1.16 mmol/100 l GF vs 6.17 +/- 2.02 mmol/100 l GF; P less than 0.001). All patients showed a drop in nephrogenous cAMP excretion (1.33 +/- 0.95 nmol/dl GF vs 0.74 +/- 0.72 nmol/dl GF; P less than 0.001). iPTH levels declined significantly (2.70 +/- 1.50 pmol/l vs 2.11 +/- 1.19 pmol/l; P less than 0.001). However, discordant individual changes in suppression of nephrogenous cAMP excretion, and rises in fasting calcium excretion prohibited a distinction between the absorptive or renal type of hypercalciuria. It is concluded that an oral calcium tolerance test is not helpful in the choice of management of patients with idiopathic hypercalciuria.     

Familial hypocalciuric hypercalcaemia: observations on vitamin D metabolism and parathyroid function

Serum vitamin D metabolites, the renal tubular maximum reabsorptive rate for phosphate (TMP/GFR) nephrogenic cyclic AMP (NcAMPI, and CaE (urinary calcium excretion per litre of glomerular filtrate) were measured in 14 adults with familial hypocalciuric hypercalcaemia (FHH). The findings were compared with analyses in 14 patients with surgically proven primary hyperparathyroidism matched for serum calcium, creatinine clearance and vitamin D status (assessed by serum concentrations of 25 hydroxyvitamin D). Vitamin D metabolites were also measured in 16 normocalcaemic relatives of patients with FHH. The serum concentration of 24,25 dihydroxycholecalciferol was appropriate for the prevailing 25 hydroxyvitamin D and no difference was found between groups. The serum concentration of 1,25 dihydroxycholecalciferol was significantly greater in primary hyperparathyroidism (P less than 0.0005) compared with patients with FHH and their normocalcaemic relatives. TMP/GFR was reduced in both primary hyperparathyroidism (0.53 +/- 0.12 mmol/l GF, mean +/- SEM) and FHH (0.86 +/- 0.14 mmol/l GF). Patients with primary hyperparathyroidism showed an increase in NcAMP output in the urine (38.5 +/- 16 mmol/l GF) which was significantly greater (P less than 0.0001) than the normal NcAMP (13.5 +/- 9.2 nmol/l GF) found in FHH. CaE was low in FHH indicating increased renal tubular reabsorption of calcium. It is concluded that there is no abnormality of vitamin D metabolism in FHH comparable with the changes observed in primary hyperparathyroidism. It is suggested that the biochemical abnormalities in FHH cannot be explained solely upon an increased sensitivity of the renal tubules to the effects of endogenous parathyroid hormone.     

Plasma cyclic nucleotide levels in hyperthyroidism.

Plasma cyclic AMP and cyclic GMP levels were studied in a group of normal subjects and 10 subjects with hyperthyroidism. In the control group, mean plasma cyclic AMP levels were 15.3 +/- 1.3 nmol/l (SEM), and plasma cyclic GMP levels were 9.4 +/- 0.58 nmol/l (SEM). In untreated hyperthyroid subjects, both plasma cyclic AMP and cyclic GMP levels were significantly elevated above normal with mean values of 35.0 +/- 2.4 nmol/l (SEM) (P less than 0.001) and 14.7 +/- 0.2 nmol/l (SEM), (P less than 0.001), respectively. Six of the hyperthyroid subjects were re-studied when they became euthyroid; plasma cyclic nucleotide concentrations all fell within the normal range. To evaluate the relative contribution of triiodothyronine and thyroxine to elevated plasma cyclic nucleotide levels, two hyperthyroid subjects were treated with propylthiouracil and iodide. Plasma cyclic nucleotide levels were normalized when plasma triiodothyronine levels declined to normal range, at the time when plasma thyroxine levels were still elevated. These preliminary data suggest that increased triiodothyronine production is responsible for the increased cyclic nucleotide levels in hyperthyroidism.     

Actions of synthetic parathyroid hormone-related protein(1-34) on the isolated rat kidney

The isolated perfused rat kidney was used to study the effects of parathyroid hormone-related protein (PTHrP) on renal cyclic AMP (cAMP) and electrolyte excretion. A perfusate of PTHrP(1-34) increased cAMP excretion from 0.14 +/- 0.09 (S.E.M.) nmol/l glomerular filtrate (GF) in controls to 24.67 +/- 5.14 (P less than 0.01) and decreased calcium excretion from 0.278 +/- 0.033 to 0.162 +/- 0.011 mumol/l GF (P less than 0.01). Human PTH(1-34) (0.7 nmol/l) caused no significant change in calcium excretion, whilst the rise in cAMP excretion was similar to that with PTHrP. PTHrP(1-34) (7 nmol/l) further increased cAMP production to 366.7 +/- 100.8 nmol/l GF (P less than 0.01), higher than the rise with hPTH(1-34) (7 nmol/l) which was 76.7 +/- 46.8 (P less than 0.05). With the higher concentrations of both peptides (7 nmol/l), calcium excretion was further reduced to 0.090 +/- 0.009 mumol/l GF (P less than 0.01), whilst phosphate excretion increased with both PTHrP and PTH. PTHrP (7 nmol/l) caused a fall in urinary pH compared with controls (P less than 0.05). At low and high concentrations of both hormones, urinary pH was lower with PTHrP than hPTH (P less than 0.01). Thus PTHrP, like PTH, acts on the kidney to increase cAMP and phosphate excretion and reduce calcium excretion, but PTHrP may be more effective. Disparate effects on urinary pH could be reflected in the clinical features of humoral hypercalcaemia of malignancy.     

Abnormal calcium metabolism in myotonic dystrophy (II): Increased level of nephrogenous cyclic AMP and serum immunoreactive parathyroid hormone

Myotonic dystrophy (MyD) is a multisystemic disorder characterized by muscle atrophy, myotonia and cataract. Although a number of reports have been accumulated showing the presence of bone changes in MyD patients, there are few published papers in which calcium metabolism was precisely examined. In the previous paper, we reported that intestinal calcium absorption was increased in MyD patients due to the elevation of plasma 1,25(OH)2D level. The present study was designed to elucidate the mechanism of increased level of serum 1,25(OH)2D concentration in MyD patients. Calcium tolerance tests were performed in 13 patients with MyD, 13 patients with other neuromuscular disorders (non-MyD) and 12 healthy control subjects according to the method of Broadus et al. Immunoreactive PTH (iPTH) levels and cyclic AMP (cAMP) levels were measured using commercially available RIA kits. The basal plasma calcium levels in MyD were slightly higher than those in the other two groups, but the difference was not statistically significant. The plasma 1,25(OH)2D levels, calcemic responses and calciuric responses in MyD were significantly higher than those in the other two groups. Serum iPTH levels in MyD (0.462 +/- 0.320 ng/ml, Mean +/- SD) were significantly higher than those in the other two groups (normal subjects 0.175 +/- 0.092, non-MyD 0.200 +/- 0.111; p less than 0.02). Nephrogenous cyclic AMP (NcAMP) levels in MyD (2.094 +/- 3.244 nmol/100 ml GF) were also higher than those in normal subjects (0.907 +/- 0.212, p less than 0.05) and in non-MyD (0.929 +/- 0.335, p less than 0.05). There was a significant correlation between serum iPTH levels and NcAMP levels, and therefore it might be possible to accept that these two measurements reflect the level of parathyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)     

A COMPARISON OF NEPHROGENOUS CYCLIC AMP, TOTAL URINARY CYCLIC AMP AND THE RENAL TUBULAR MAXIMUM REABSORPTIVE CAPACITY FOR PHOSPHATE IN THE DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM

A determination was made of total urinary adenosine 3′-5′cyclic monophosphate (UcAMP), nephrogenous cyclic AMP (NcAMP) excretion and also of the renal tubular maximum reabsorptive capacity for phosphate T_mPO₄/GFR (all expressed as a function of the glomerular filtrate) in fourteen patients with primary hypercalcaemic hyperparathyroidism and twelve control normal subjects. The hyperparathyroid patients gave a mean excretion of UcAMP (7·0 ± 45·68 nmol/100 ml GF; mean ± SEM), NcAMP (6·19 ± 0·64 nmol/100 ml GF) which were significantly greater (P < 0·001) than those of normal controls, (2′45 ± 0·15nmol/100 ml GF and 1·25 ± 0·12nmol/100 ml GF) respectively. The difference between the patients and controls for the maximum renal tubular reabsorptive capacity for phosphate (T_mPO₄/GFR) (patients 0·55 ± 0·04, controls 1·05 ± 0·05 mmol/l GFR) was also highly significant (P<0·001). Statistical evaluation of the results obtained from the patients with primary hyperparathyroidism revealed that there was a positive correlation between the level of plasma calcium and immunoreactive parathyroid hormone (PTH) (r=+0·46), NcAMP(r=+0·337), UcAMP (r=+0·36), and an inverse correlation with the T_mPO₄/GFR (r=?0·62). There was also a positive correlation between plasma immunoreactive PTH and NcAMP(r=+0·31), and UcAMP(r=+0·35), and an inverse correlation with the T_mPO₄/GFR (r=?0–39). Successful removal of a single parathyroid adenoma in six patients was associated with a highly significant fall in the excretion of UcAMP, NcAMP, and a rise in the T_mPO₄/GFR (P<0·005). The combination of a low T_mPO₄/GFR and a high excretion of UcAMP or NcAMP in the presence of hypercalcaemia is highly suggestive of primary hyperparathyroidism in the absence of clinical evidence of malignant disease.     

Epinephrine-induced alterations in urinary cyclic AMP in hyper- and hypothyroidism.

Although ratios of urinary cyclic AMP (cAMP) to creatinine were found in this study to be elevated in hyperthyroidism, as previously reported, this elevation appears to result primarily from a decrease in the rate of urinary creatinine excretion associated with the hyperthyroid state and not to be due to an increase in the urinary cAMP production rate. Indeed, there was no significant alteration observed in the urinary cAMP excretion found in 15 hyper-, 12 eu-, and 5 hypothyroid subjects. However, a slight, but significant increase in the 24-hour urinary cAMP excretion was noted in ambulating hyperthyroid subjects (8.5 +/- 2.4 muMol/day; normal 5.2 +/- 1.6 muMol/day; P less than .05). In contrast, the effect of the infusion of 0.05 mug/kg/min of epinephrine over a 2-hour period, resulted in a significantly greater rise in urinary cAMP excretion in hyperthyroid patients (0.83 +/- 0.07 muMol/h) compared to euthyroid subjects (0.53 +/- 0.4 muMol/h; P less than .005). Furthermore, hypothyroid subjects had no significant rise in urinary cAMP excretion after epinephrine infusion (P less than .001). Cardiovascular end-organ response to the epinephrine infusion was also greater in the hyperthyroid subjects and virtually absent in the hypothyroid group. These results suggest that there may be a significant alteration in the cAMP generating systems in states of thyroid hormone excess or insufficiency, and that provocative stimuli, such as epinephrine, may have its end-organ response modified by thyroid hormone effects on adenylate cyclase-cyclic AMP generating systems.     

The effect of treatment of hyper- and hypothyroidism on urinary excretion of cyclic adenosine 3',5'-monophosphate.

The urinary excretion of cyclic adenosine 3',5'-monophosphate (cyclic AMP) was examined in patients with hyperthyroidism and primary hypothyroidism, before treatment and at least six months later on return to euthyroid status. Urinary cyclic AMP excretion was significantly greater in the hyperthyroid group than in the hypothyroid group both in the basal state (P less than 0.01) and the ambulant state (P less than 0.001). In ambulant hyperthyroid patients absolute urinary cyclic AMP excretion (mumol/24 h) was significantly greater (P less than 0.05) prior to treatment than on return to euthyroid status. In the hypothyroid group no significant change occurred after treatment with 1-thyroxine (P greater than 0.05). The mechanism of changes in urinary cyclic AMP excretion in thyroid disease are discussed.     

Nephrogenous cyclic AMP in primary hepatocellular carcinoma patients with or without hypercalcaemia

OBJECTIVE: To study the relationship between the excretion of nephrogenous cyclic AMP (NcAMP) and other blood and urine parameters as an index of PTH-like activity in patients with primary hepatocellular carcinoma. DESIGN: After overnight fast, a double voided urine and a blood sample were collected from each subject for determination of various analytes and results compared between various groups. PATIENTS: Fifty-five consecutive untreated patients with primary hepatocellular carcinoma, 14 healthy controls and eight patients with cirrhosis only. MEASUREMENTS: Serum calcium, phosphate, alkaline phosphatase, albumin, creatinine and urinary calcium, creatinine and hydroxyproline were measured by routine methods. cAMP was measured in plasma and urine by a radioimmunoassay (Diagnostic Products Corporation) and PTH measured in serum by an immunoradiometric assay (Nichols Institute). TmP/GFR, NcAMP etc. were calculated according to various published methods. RESULTS: Four out of 55 patients (7%) with primary hepatocellular carcinoma had hypercalcaemia. These four patients had significantly lower (P less than 0.05) phosphate, PTH and TmP/GFR and elevated NcAMP (P less than 0.001) compared with normocalcaemic hepatocellular carcinoma and cirrhotic patients, and healthy controls. The excretion of hydroxyproline and calcium was significantly elevated (P less than 0.001) in the hypercalcaemic patients. Bone resorption was found to be the major cause of hypercalcaemia in three of the four hypercalcaemic patients. Fifteen hepatocellular carcinoma patients (29%) with normocalcaemia had suppressed PTH. CONCLUSION: We conclude that a PTH-like humoral factor such as PTH related peptide is the cause of hypercalcaemia in patients with primary hepatocellular carcinoma, and that in some normocalcaemic patients with this tumour PTH is suppressed.     

Suppressibility of parathyroid function in primary hyperparathyroidism as estimated by nephrogenous cyclic AMP (author's transl)

The effects of calcium injection (3 mg/Kg/10 min) or oral calcium administration (calcium lactate 7.7 g) on plasma iPTH and Nephrogenous cyclic AMP (NcAMP) were studied in 6 normal controls and 13 patients with primary hyperparathyroidism. In the control subjects, plasma iPTH determined by a predominantly carboxyl-terminal antiserum was less than 0.3 ng/ml before and after both calcium loads, whereas 41 approximately 98% (mean 67%) of NcAMP was rapidly and uniformly suppressed to a level lower than the normal value. In 2 patients with primary hyperparathyroidism, iPTH was clearly reduced from 8.0 to 4.6 ng/ml and 1.6 to 0.96 ng/ml, respectively, by the calcium load. However, in the other 7 patients with primary hyperparathyroidism who showed only a slight elevation of iPTH: less than 0.3 approximately 0.9 ng/ml, the reductions in iPTH were not detected after the calcium load: less than 0.3 approximately 0.7 ng/ml. In contrast, 30 approximately 54% (1.02 approximately 3.85 nmol/dl GF) of NcAMP, which was greater than the diurnal variation, was suppressed after calcium injection in 5 patients with primary hyperparathyroidism (2 of 4 patients with urological, and 3 of 5 patients with chemical hyperparathyroidism). But NcAMP was not suppressed in all 4 patients with skeletal hyperparathyroidism including one with proximal renal tubular dysfunction whose basal iPTH was elevated markedly but reduced clearly by the calcium load. In general, suppression of NcAMP was followed by a decrease of phosphate excretion. On the other hand, even in a patient with primary hyperparathyroidism whose NcAMP was not suppressed at all after the calcium injection, calcium infusion (15 mg/Kg/3h) resulted in some (23%) decrease in NcAMP. Oral calcium administration resulted in responses which were almost the same as those produced by calcium injection. These results suggest that NcAMP provides a useful index in the parathyroid suppression test in patients with primary hyperparathyroidism, especially those who display a rather mild elevation of iPTH. This is not the case, however, in a few patients who show a marked elevation of iPTH and/or proximal renal tubular dysfunction.     

Scrutinization of the direct assay method for plasma cyclic AMP and clinical applications of nephrogenous cyclic AMP

Several problems in the measurement of plasma cyclic AMP (PcAMP) and nephrogenous cyclic AMP were studied using a YAMASA RIA Kit (YAMASA Shoyu, Choshi, Japan). In this assay method, cAMP in plasma is directly succinylated without prior deproteinization, and then it is bound to antibody in an imidazole buffer. So far as the blood samples were obtained with EDTA-4Na at least 5.0 mM in the final concentration, PcAMP was not reduced until 16 hours after the blood samples were drawn. Even without EDTA, the reductions in PcAMP were not detected within 1 hour after the blood samples were drawn. This assay method for PcAMP showed parallelism in the dilution curve. Recovery was almost complete. Intra- and interassay variations were low. When plasma was incubated at 37 degrees C for 24 hours, PcAMP became negligible. Furthermore, the values of PcAMP measured with this direct assay system almost agreed with those obtained after the purification by deproteinization and Dowex column chromatography through an anion-exchange resin. The normal values of PcAMP were 13.6 +/- 3.62 pmol/ml [mean +/- SD, n = 43]. Nephrogenous cAMP expressed as a function of GFR never did show any negative values in various clinical situations. From the data of basal levels and the oral calcium tolerance test, nephrogenous cAMP appeared to be more useful than total urinary cAMP in the diagnosis of parathyroid disorders, especially hyperparathyroidism.     

Calcium potentiates the cyclic nucleotide and phosphaturic response to parathyroid hormone infusion

To determine whether calcium modulates the action of PTH, we measured the cyclic nucleotide and phosphaturic response to PTH following a 4-h infusion of glucose (day 1) and calcium (day 2). The 12 subjects were selected to provide a range of low, normal, and high endogenous PTH function. PTH stimulated nephrogenous cAMP [185 +/- 31 nmol/100 ml glomerular filtrate (GF)], cyclic guanosine monophosphate (0.44 +/- 0.09 mumol/g creatinine), and phosphate (367 +/- 59 mg P/g creatinine) excretion. Calcium infusion stimulated nephrogenous cAMP excretion in the hypoparathyroid subjects (1.42 +/- 0.35 nmol/100 ml GF) but reduced it in subjects with normal parathyroid function (-2.22 +/- 0.46 nmol/100 ml GF). Calcium infusion stimulated cGMP (0.64 +/- 0.1 mumol/g creatinine) and phosphate (113 +/- 48 P/g creatinine) excretion in all subject groups. Calcium infusion led to a 2-fold increase in the cyclic nucleotide and phosphaturic response to PTH in the normal and hypoparathyroid subjects, but had little effect on the PTH response in hyperparathyroid subjects. The extent to which calcium potentiated the ability of PTH to stimulate nephrogenous cAMP excretion correlated negatively with the basal nephrogenous cAMP excretion (r = -0.685, P less than 0.01). We conclude that calcium potentiates the acute effects of PTH on renal cyclic nucleotide and phosphate excretion. This effect is modified by the basal levels of PTH stimulation of the kidney such that it is reduced in magnitude when basal PTH stimulation is increased.     

Increase in plasma concentrations of atrial natriuretic peptide during infusion of hypertonic saline in conscious newborn calves

Plasma concentrations of atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma concentrations of aldosterone, urine flow rate and sodium and potassium excretion were studied in two groups of four conscious 3-day-old male calves, infused with hypertonic saline or vehicle. Hypertonic saline infusion (20 mmol NaCl/kg body weight) was accompanied by a progressive rise in plasma concentrations of ANP (from 16.5 +/- 0.2 pmol/l at time 0 to 29.3 +/- 3.0 pmol/l at 30 min; P less than 0.05) and by a gradual decrease in PRA (from 1.61 +/- 0.23 nmol angiotensin I/l per h at time 0 to 0.54 +/- 15 nmol angiotensin I/l per h at 90 min; P less than 0.05); there was no change in the plasma concentration of aldosterone. Within the first 2 h of the 24-h urine collection period there was a marked rise in urine flow rate and sodium excretion in treated calves when compared with control animals (66.0 +/- 8.3 vs 15.9 +/- 1.2 ml/kg body weight per 2 h (P less than 0.05) and 6.7 +/- 1.3 vs 0.4 +/- 0.02 mmol/kg body weight per 2 h (P less than 0.01) respectively). During the following 22 h, urinary water and sodium excretion remained at significantly high levels. Thus, in the conscious newborn calf, changes in plasma ANP levels and urinary water and sodium excretion during hypertonic saline infusion are compatible with the hypothesis that endogenous ANP participates, at least in part, in the immediate diuretic and natriuretic renal response induced by the sodium overload.     

Parathyroid hormone does not increase nephrogenous cyclic AMP excretion by the dog

The renal excretion of nephrogenous cyclic AMP (NcAMP) increases in response to parathyroid hormone (PTH) in man, and thereby serves as a test of parathyroid function. However, during studies of calcium-PTH (PTH) in man, and thereby serves as a test of parathyroid function. However, during studies of calcium-PTH interrelationships in dogs we observed no change in total urinary cAMP (UcAMP) excretion when endogenous plasma PTH levels were increased up to 10-fold. This study was designed to investigate the effects of physiologic and pharmacologic levels of PTH on NcAMP and UcAMP excretion in the dog. Maintaining plasma Ca 2 mg/dl below normal for 40 minutes caused an 8-fold increase in plasma PTH concentration, a 50% increase in the urinary fractional excretion of phosphate (FEP) but no changes in plasma cAMP levels or in UcAMP or NcAMP excretion. Infusion of a pharmacologic amount of parathyroid extract (15 U/min for 20 min) increased plasma cAMP 5-fold, UcAMP excretion 3-fold and FEP by 50% but was without effect on NcAMP excretion. We conclude that NcAMP excretion is not stimulated by PTH in the dog and thus cannot be used as an index of PTH action in vivo. The increase in UcAMP excretion by pharmacologic amounts of PTH results from glomerular filtration of increased plasma cAMP, which may be generated in bone.     

THE EFFECT OF THYROID DISEASE ON PROINSULIN AND C-PEPTIDE LEVELS

C-peptide and proinsulin levels were studied in hyper and hypothyroidism both pre and post-treatment and in comparison to matched normals. Fasting C-peptide was reduced in untreated hyperthyroidism (0.4 +/- 0.2 (mean +/- SEM) vs 0.7 +/- 0.2 nmol/l, P less than 0.05) but returned to normal levels following treatment. Fasting proinsulin was elevated in untreated hyperthyroidism (3.6 +/- 0.7 vs 2.4 +/- 0.5 pmol/l, P less than 0.05) also returning to normal after treatment. A similar pattern was seen after oral glucose. The increased proinsulin and reduced C-peptide suggest there may be a defect of proinsulin processing in hyperthyroidism. Fasting C-peptide was reduced in untreated hypothyroidism (0.4 +/- 0.1 vs 0.7 +/- 0.1 nmol/l, P less than 0.05) and also returned to normal after treatment. Fasting proinsulin did not differ significantly from controls. However, proinsulin was reduced after oral glucose (4.7 +/- 0.7 vs. 7.9 +/- 2.0 pmol/l, P less than 0.05) as was C-peptide (0.9 +/- 0.2 vs 2.6 +/- 0.3 nmol/l, P less than 0.05). Both returned to normal after treatment. These findings suggest there are abnormalities of proinsulin and C-peptide levels in both hyper and hypothyroidism.     

Altered plasma catecholamines and numbers of alpha- and beta-adrenergic receptors in platelets and leucocytes in hyperthyroid patients normalized under antithyroid treatment

We measured plasma catecholamines, alpha- and beta-adrenoreceptor numbers and the accumulation of cyclic adenosine monophosphate (cAMP) in the unstimulated state and in response to 10 mumol/l (-) isoproterenol in blood cells from 29 euthyroid controls and from 18 patients with spontaneous hyperthyroidism. In the thyrotoxic patients plasma norepinephrine (1.14 +/- 0.5 nmol/l) and epinephrine (0.3 +/- 0.14 nmol/l) were significantly decreased compared with plasma norepinephrine (1.87 +/- 0.7 nmol) and epinephrine (0.41 +/- 0.19 nmol/l) in the controls (P less than 0.01 and P less than 0.05, respectively) and the values obtained in subjects rendered euthyroid by antithyroid treatment (P less than 0.001, respectively). alpha-adrenoceptor density in platelet membranes obtained from patients in the hyperthyroid state (114 +/- 38 sites per cell) was significantly decreased when compared with controls (159 +/- 48 sites per cell, P less than 0.01) and the values from patients under effective antithyroid treatment (136 +/- 35 sites per cell, P less than 0.01). On the contrary, a significant increase in beta-adrenoceptor density in mononuclear leucocyte (MNL) membranes was found in hyperthyroid patients (1751 +/- 237 sites/cell) when compared with controls (1510 +/- 351 sites/cell, P less than 0.05) and the same patients following antithyroid treatment (1455 +/- 260 sites/cell, P less than 0.001). The equilibrium dissociation constants (KD) did not change in hyperthyroidism. Basal cAMP concentrations in MNL were higher in untreated thyrotoxicosis (45 +/- 18 pmol/10(6) cells/10 min) than in patients in the euthyroid state (35 +/- 9 pmol/10(6) cells/10 min, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of growth hormone replacement therapy on 1,25-dihydroxyvitamin D and calcium metabolism

To elucidate the changes in mineral metabolism and blood concentrations of calciotropic hormones which accompany GH therapy, we studied 12 GH-deficient children for 5 days before and for 1 week after high dose (5 IU/day) GH therapy, and again at 1 month, 3 months, and 1 yr of replacement therapy (0.1 IU/kg to a maximum dose of 2 IU three times weekly). All responded with acceleration of height velocity, and bone ages advanced appropriately. Fasting serum ionized calcium levels did not change: 4.11 +/- 0.06 (SEM) mg/dl before, 4.19 +/- 0.05 for the week of high dose therapy, and 4.20 +/- 0.14 during replacement therapy. Likewise, fasting serum parthormone did not vary: 38.9 +/- 2.6 muleq/ml before to 44.1 +/- 9.2 at 1 yr. Twenty four-hour nephrogenous cyclic AMP (NcAMP) did not vary over the first week (1.2 +/- 0.7 nmol/dl glomerular filtrate before, 1.3 +/- 0.4 after 1 week), but increased to 5.3 +/- 1.9 after 1 yr (alpha less than 0.001). The response of ionized calcium and parathormone to a standardized disodium EDTA infusion of 50 mg/kg also did not change. The mean fasting serum calcitonin level was not different before therapy (29.4 +/- 2.8 pg/ml), after 1 week (21.5 +/- 1.8), or after 1 yr (42.4 +/- 11.0). However, the mean serum 1,25-dihydroxyvitamin D concentration rose from 33.1 +/- 3.3 pg/ml before therapy to 68.3 +/- 12.3 on the seventh day of high dose therapy (alpha less than 0.01), returning to pretherapy values by 1 month. We conclude that high dose GH therapy in GH-deficient children raises 1,25-dihydroxyvitamin D concentration acutely, but that long term, physiological replacement therapy does not cause such an effect. Because NcAMP excretion rose in the absence of an increase in serum parathormone concentration, we conclude that GH sensitizes the kidney to a cAMP-mediated effect of parathormone.     

PRIMARY HYPERPARATHYROIDISM WITH INTERMITTENT HYPERCALCAEMIA: SERIAL OBSERVATIONS AND SIMPLE DIAGNOSIS BY MEANS OF AN ORAL CALCIUM TOLERANCE TEST

Ten patients with subtle primary hyperparathyroidism and intermittent hypercalcaemia were followed serially for periods of 2--18 months (mean 10 months). Fasting serum calcium was elevated (greater than 10.6 mg/dl) in only 20% of determinations and fluctuated widely (9.1--11.2 mg/dl), yet the patients displayed a continuous, rather than episodic, basic disease process as defined by increases in nephrogenous cyclic AMP and serum iPTH. Identical findings were noted in short-term (2--3 successive days) studies in twelve patients. In response to a 1000 mg oral calcium tolerance test, twelve patients with primary hyperparathyroidism and intermittent hypercalcaemia (basal serum calcium 10.2 +/- 0.2 mg/dl, mean +/- SD) displayed: (1) hyperabsorption of calcium (mean calciuric response twice normal); (2) induced-hypercalcaemia (mean serum calcium 11.4 mg/dl, with a mean increase of 1.2 mg/dl versus 0.2 mg/cl in normal subjects); and (3) abnormal parathyroid suppressibility (nephrogenous cyclic AMP 2.66 +/- 0.57 nmol/100 ml GF versus 0.95 +/- 0.40 nmol/100 ml GF in normal subjects, mean +/- SD). The patients demonstrated striking hypercalciuria (452 +/- 123 mg/24 h) on a 1000 mg metabolic calcium diet. Serum levels of 1,25(OH)2D3, measured in ten patients, were markedly elevated at 90 +/- 20 pg/ml (mean +/- SD), and there was a strong positive correlation between the values for 1,25(OH)2D3 and the calciuric response to the calcium tolerance test (r = 0.75, P less than 0.001). These results (1) indicate that the calcium tolerance test is a simple and reliable technique for diagnosis of patients with primary hyperparathyroidism and intermittent hypercalcaemia, and (2) emphasize the important pathophysiologic features of this subtle clinical variant of primary hyperparathyroidism.     

INSULIN SENSITIVITY IN HYPERTHYROIDISM: MEASUREMENT BY THE GLUCOSE CLAMP TECHNIQUE

Sensitivity to porcine insulin has been compared in overnight fasted hyperthyroid and control subjects using a euglycaemic clamp technique. Basal values for blood glucose, lactate, pyruvate, alanine, serum insulin and C-peptide were similar in the two groups, whilst blood glycerol (hyperthyroid 0.11 +/- 0.02 (mean +/- S.E.) vs. control 0.06 +/- 0.01 mmol/l, P less than 0.01) and blood 3-hydroxybutyrate (0.28 [0.03-0.79, range ]vs 0.09 [0.01-0.29 ]mmol/l, P less than 0.05) were increased in hyperthyroidism. During the 2 hour insulin infusion (0.05 U/kg/h), serum insulin plateaued at the same level (44 +/- 4 vs 44 +/- 1 mU/l) and insulin metabolic clearance rates were similar (1.21 +/- 0.10 vs 1.25 +/- 0.03 l/min). Serum C-peptide levels also decreased by similar amounts (40 +/- 8 vs 47 +/- 6%). The amount of glucose infused to maintain euglycaemia was identical during the second hour of insulin infusion (290 +/- 50 vs 330 +/- 30 mg/kg) as were the increments in lactate and pyruvate concentrations. Blood glycerol values decreased in both groups although values in hyperthyroid patients remained significantly higher than in controls. 3-Hydroxybutyrate concentrations fell to similar values in the two groups. These findings suggest that insulin-stimulated glucose metabolism and inhibition of ketogenesis are normal in hyperthyroidism.     

EFFECTS OF INHIBITION OF CHOLESTEROL SYNTHESIS BY SIMVASTATIN ON THE PRODUCTION OF ADRENOCORTICAL STEROID HORMONES AND ACTH

Simvastatin, a derivative of lovastatin, is a potent inhibitor of cholesterol biosynthesis and may interfere with steroid hormone production, for which cholesterol is required. In a single-blind, placebo-controlled study, 24 patients with severe primary hypercholesterolaemia (mean serum cholesterol +/- SD = 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg per day for 8 weeks. Before and after treatment, the following parameters were evaluated: basal levels of ACTH, cortisol, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone; urinary excretion of free cortisol; the cortisol response after short-term infusion of ACTH; the ACTH and cortisol response during insulin-induced hypoglycaemia. Total serum cholesterol decreased by 35.0 +/- 8.1% (P less than 0.001) and low-density lipoprotein (LDL) cholesterol by 39.8 +/- 9.8% (P less than 0.001); high-density lipoprotein (HDL) increased by 9.2 +/- 11.1% (P less than 0.001). Basal levels of ACTH were higher after simvastatin (2.9 +/- 1.9 pmol/l vs 4.1 +/- 2.9 pmol/l; P less than 0.05) whereas basal levels of steroid hormones were not significantly changed. The excretion of free cortisol was unaltered. The peak cortisol after ACTH infusion was lower after treatment (0.87 +/- 0.23 mumol/l vs 0.78 +/- 0.10 mumol/l; P less than 0.05), but was unaltered during insulin-induced hypoglycaemia. We conclude that simvastatin lowers serum cholesterol without clinically relevant effects on the adrenocortical steroid hormone secretion and the hypothalamic-pituitary-adrenal axis.