Direct suppressive effect of acute metabolic and respiratory alkalosis on parathyroid hormone secretion in the dog.

Acute alkalosis may directly affect PTH secretion. The effect of acute metabolic and respiratory alkalosis was studied in 20 dogs. PTH values were lower in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml). Acute alkalosis is an independent factor that decreases PTH values during normocalcemia and delays the PTH response to hypocalcemia. INTRODUCTION: We recently showed that acute metabolic and respiratory acidosis stimulated PTH secretion. This study was designed to evaluate whether acute metabolic and respiratory alkalosis suppressed parathyroid hormone (PTH) secretion. MATERIALS AND METHODS: Three groups of 10 dogs were studied: control, acute metabolic alkalosis, and acute respiratory alkalosis. Metabolic alkalosis was induced with an infusion of sodium bicarbonate and respiratory alkalosis by hyperventilation. Calcium chloride was infused to prevent alkalosis-induced hypocalcemia during the first 60 minutes. During the next 30 minutes, disodium EDTA was infused to induce hypocalcemia and to evaluate the PTH response to hypocalcemia. Because the infusion of sodium bicarbonate resulted in hypernatremia, the effect of hypernatremia was studied in an additional group that received hypertonic saline. RESULTS: After 60 minutes of a normocalcemic clamp, PTH values were less (p < 0.05) in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml); the respective blood pH values were 7.61 +/- 0.01, 7.59 +/- 0.02, and 7.39 +/- 0.02. The maximal PTH response to hypocalcemia was similar among the three groups. However, the maximal PTH response was observed after a decrease in ionized calcium of 0.20 mM in the control group but not until a decrease of 0.40 mM in the metabolic and respiratory alkalosis groups. In contrast to the metabolic alkalosis group, hypernatremia (157 +/- 2 mEq/liter) in the hypertonic saline group was associated with an increased PTH value (46 +/- 4 pg/ml). Finally, the half-life of intact PTH was not different among the control and two alkalosis groups. CONCLUSIONS: Acute metabolic and respiratory alkalosis markedly decreased PTH values during normocalcemia and delayed the PTH response to hypocalcemia. Whether acute metabolic and respiratory alkalosis affect PTH and calcium metabolism in such settings as the postprandial alkaline tide (metabolic alkalosis) and acute sepsis (respiratory alkalosis) deserves to be evaluated in future studies.     

Effect of rate of calcium reduction and a hypocalcemic clamp on parathyroid hormone secretion: a study in dogs

BACKGROUND: The parathyroid hormone (PTH) calcium curve is used to evaluate parathyroid function in clinical studies. However, unanswered questions remain about whether PTH secretion is affected by the rate of calcium reduction and how the maximal PTH response to hypocalcemia is best determined. We performed studies in normal dogs to determine whether (a) the rate of calcium reduction affected the PTH response to hypocalcemia and (b) the reduction in PTH values during a hypocalcemic clamp from the peak PTH value observed during the nadir of hypocalcemia was due to a depletion of stored PTH. METHODS: Fast (30 min) and slow (120 min) ethylenediamine-tetraacetic acid (EDTA) infusions were used to induce similar reductions in ionized calcium. In the fast EDTA infusion group, serum calcium was maintained at the hypocalcemic 30-minute value for an additional 90 minutes (hypocalcemic clamp). To determine whether the reduction in PTH values during the hypocalcemic clamp represented depletion of PTH stores, three subgroups were studied. Serum calcium was rapidly reduced from established hypocalcemic levels in the fast-infusion group at 30 and 60 minutes (after 30 min of a hypocalcemic clamp) and in the slow-infusion group at 120 minutes. RESULTS: At the end of the fast and slow EDTA infusions, serum ionized calcium values were not different (0.84 +/- 0.02 vs. 0.82 +/- 0.03 mM), but PTH values were greater in the fast-infusion group (246 +/- 19 vs. 194 +/- 13 pg/ml, P < 0.05). During the hypocalcemic clamp, PTH rapidly decreased (P < 0.05) to value of approximately 60% of the peak PTH value obtained at 30 minutes. A rapid reduction in serum calcium from established hypocalcemic levels at 30 minutes did not stimulate PTH further, but also PTH values did not decrease as they did when a hypocalcemic clamp was started at 30 minutes. At 60 minutes, the reduction in serum calcium increased (P < 0.05) PTH to peak values similar to those before the hypocalcemic clamp. The reduction in serum calcium at 120 minutes in the slow EDTA infusion group increased PTH values from 224 +/- 11 to 302 +/- 30 pg/ml (P < 0.05). CONCLUSIONS: These results suggest that (a) the reduction in PTH values during the hypocalcemic clamp may not represent a depletion of PTH stores. (b) The use of PTH values from the hypocalcemic clamp as the maximal PTH may underestimate the maximal secretory capacity of the parathyroid glands and also would change the analysis of the PTH-calcium curve, and (c) the PTH response to similar reductions in serum calcium may be less for slow than fast reductions in serum calcium.     

Serum calcium metabolism in acute experimental pancreatitis

Serum calcium changes in severe pancreatitis were studied in 23 dogs. Twelve dogs underwent duodenotomy and served as controls. Pancreatitis was induced in the other 11 by autologous bile injection (1 ml/kg) into the pancreatic duct. Serum amylase, total calcium, ionized calcium, albumin, magnesium, chloride, phosphorous, parathyroid hormone (PTH), and calcitonin were measured at 0, 1/2, 1, 3, 6, 24, 48, and 72 hours after duodenotomy or bile injection. Serum amylase levels became significantly elevated in all dogs with pancreatitis at 30 minutes (p less than 0.01) and remained so throughout the entire experiment. Total calcium levels dropped significantly 30 minutes after pancreatitis was induced from 10.0 +/- 0.3 mg/dl compared with 8.8 +/- 0.4 mg/dl in control dogs (p less than 0.05) and remained statistically lower for as long as 1 hour. Ionized calcium levels were significantly lower than were those of control dogs at 1/2, 1, 3, and 6 hours (p less than 0.05). Serum magnesium and chloride levels showed no significant changes between both groups. The only significant difference in phosphorus values was at 6 hours when they were higher in dogs with pancreatitis than in controls (6.2 +/- 0.3 mg/dl versus 4.8 +/- 0.4 mg/dl; p less than 0.05). Serum albumin levels remained unchanged throughout the study except for 48 hours when they were significantly lower in animals with pancreatitis (p less than 0.02). PTH levels were significantly greater in dogs with pancreatitis than in controls at 1, 3, 6, and 24 hours (p less than 0.05). There was no significant difference in calcitonin levels between both groups. Ionized calcium is a more reliable indicator of calcium fluxes in acute experimental pancreatitis since it remains depressed longer than total serum calcium. The time course of PTH elevation indicates a reaction to hypocalcemia, and failure of PTH secretion is not the cause of hypocalcemia in pancreatitis. This study does not support elevation of calcitonin as a cause of hypocalcemia in acute pancreatitis.     

Direct inhibitory effect of calcitriol on parathyroid function (sigmoidal curve) in dialysis

The effect of intravenous calcitriol on parathyroid function was evaluated in nine chronic hemodialysis patients with secondary hyperparathyroidism. Two micrograms of calcitriol were administered intravenously after dialysis thrice weekly for ten weeks. Parathyroid function was assessed by inducing hypo- and hypercalcemia with low calcium (1.0 mEq/liter) and high calcium (4.0 mEq/liter) dialyses before and after ten weeks of intravenous calcitriol therapy. To avoid hypercalcemia during calcitriol administration, the dialysate calcium was reduced to 2.5 mEq/liter. Parathyroid hormone (PTH) values (pg/ml) from dialysis-induced hypo- and hypercalcemia were plotted against serum ionized calcium, and the sigmoidal relationship between PTH and calcium was evaluated. Basal PTH levels fell from 902 +/- 126 pg/ml to 466 +/- 152 pg/ml (P less than 0.01) after therapy without a significant change in the serum total calcium concentration. The ionized calcium-PTH sigmoidal curve shifted to the left and downward after calcitriol therapy. The maximal PTH response during hypocalcemia decreased after calcitriol from 1661 +/- 485 pg/ml before calcitriol to 1031 +/- 280 pg/ml afterward (P less than 0.05). The PTH level at maximal inhibition due to hypercalcemia decreased from 281 +/- 76 pg/ml before calcitriol to 192 +/- 48 pg/ml afterward (P less than 0.05). The slope of the sigmoidal curve changed from -2125 +/- 487 to -1563 +/- 385 (P less than 0.05). The set point of ionized calcium (4.60 +/- .11 mg/dl before vs. 4.44 +/- .07 mg/dl after) did not change significantly with calcitriol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of a low calcium dialysate on parathyroid hormone secretion in diabetic patients on maintenance hemodialysis.

Diabetic patients on maintenance dialysis often are characterized by a relative parathyroid hormone (PTH) deficiency and a form of renal osteodystrophy with low bone turnover known as adynamic bone. The goal of the present study was to determine whether a reduction in the dialysate calcium concentration would increase the predialysis (basal) PTH and maximal PTH level. Thirty-three diabetic maintenance hemodialysis patients with basal PTH values less than 300 pg/ml were randomized to be dialyzed with either a regular (3.0 mEq/liter or 3.5 mEq/liter, group I) or low (2.25 mEq/liter or 2.5 mEq/liter, group II) calcium dialysate for 1 year. At baseline and after 6 months and 12 months of study, low (1 mEq/liter) and high (4 mEq/liter) calcium dialysis studies were performed to determine parathyroid function. At baseline, basal (I, 126+/-20 vs. II, 108+/-19 pg/ml) and maximal (I, 269 pg/ml+/-40 pg/ml vs. II, 342 pg/ml+/-65 pg/ml) PTH levels were not different. By 6 months, basal (I, 98+/-18 vs. II, 200+/-34 pg/ml, p = 0.02) and maximal (I, 276 pg/ml+/-37 pg/ml vs. II, 529 pg/ml+/-115 pg/ml; p = 0.05) PTH levels were greater in group II. Repeated measures analysis of variance (ANOVA) of the 20 patients who completed the entire 12-month study showed that only in group II patients were basal PTH (p = 0.01), maximal PTH (p = 0.01), and the basal/maximal PTH ratio (p = 0.03) different; by post hoc test, each was greater (p < 0.05) at 6 months and 12 months than at baseline. When study values at 0, 6, and 12 months in all patients were combined, an inverse correlation was present between basal calcium and both the basal/maximal PTH ratio (r = -0.59; p < 0.001) and the basal PTH (r = -0.60; p < 0.001). In conclusion, in diabetic hemodialysis patients with a relative PTH deficiency (1) the use of a low calcium dialysate increases basal and maximal PTH levels, (2) the increased secretory capacity (maximal PTH) during treatment with a low calcium dialysate suggests the possibility of enhanced parathyroid gland growth, and (3) the inverse correlation between basal calcium and both the basal/maximal PTH ratio and the basal PTH suggests that the steady-state PTH level is largely determined by the prevailing serum calcium concentration.     

Hysteresis of the parathyroid hormone response to hypocalcemia in hemodialysis patients with low turnover aluminum bone disease.

During the study of parathyroid function in 19 hemodialysis patients with low turnover aluminum bone disease, it was observed that serum parathyroid hormone (PTH) levels were higher during the induction of hypocalcemia than during the recovery from hypocalcemia. This type of PTH response has been termed hysteresis. Hypocalcemia was induced during hemodialysis with a calcium-free dialysate. When the total serum calcium level decreased to 7 mg/dL, the dialysate calcium concentration was changed to 3.5 mEq/L and the dialysis session was completed. One week later, hypercalcemia was induced during hemodialysis with a high-calcium dialysate. The mean basal PTH level was 132 +/- 37 pg/mL (normal, 10 to 65 pg/mL; immunoradiometric (IRMA), Nichols Institute, San Juan Capistrano, CA) and increased to a maximal PTH level of 387 +/- 91 pg/mL during hypocalcemia. For the same ionized calcium concentration, the PTH level was higher during the induction of hypocalcemia than during the recovery from hypocalcemia. Conversely, for the same ionized calcium concentration, the PTH level was greater when hypercalcemia was induced from the nadir of hypocalcemia than when hypercalcemia was induced from basal serum calcium. The set point of calcium (defined as the serum calcium concentration required to reduce maximal PTH by 50%) was greater during the induction of hypocalcemia than during the recovery from hypocalcemia (4.44 +/- 0.10 versus 4.25 +/- 0.09 mg/dL; P = 0.03). The mean basal ionized calcium concentration and the mean ionized calcium concentration at the intersection of the two PTH-calcium curves were the same (4.61 +/- 0.13 versus 4.61 +/- 0.12 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral high dose 1,25(OH)2D3 pulse therapy

To 13 uremic patients with secondary hyperparathyroidism, 4 micrograms of 1,25(OH)2D3 were given orally twice a week for 4 weeks. Intact PTH values fell from 488.3 +/- 84.2 to 235.2 +/- 59.6 pg/ml (Mean +/- SE, p less than 0.01), while serum total and ionized calcium elevated from 10.3 +/- 0.2 to 11.8 +/- 0.6 mg/dl (p less than 0.01), from 1.43 +/- 0.03 to 1.64 +/- 0.06 mmol/l (p less than 0.05), respectively, in 9 patients whose initial intact PTH level had been below 1000 pg/ml. The other 4 patients, of whom intact PTH level had been above 1000 pg/ml, did not show significant change in intact PTH values, though serum ionized calcium elevated slightly after this treatment. The correlation curve, determined by ionized calcium and intact PTH values in each period, was found to shift in only 2 out of 5. During the 4 weeks of high dose oral 1,25(OH)2D3 therapy, mean blood pressure elevated from 92.4 +/- 3.3 to 103.5 +/- 3.5 mmHg (p less than 0.01) in general, and 7 patients out of 13 complained of mental irritability. These data suggest that oral administration of high dose 1,25(OH)2D3 suppresses PTH secretion of uremic patients directly, however, reliability of this effect is still controversial. Indication of this therapy and adverse effects caused by rapid increase in serum calcium should be studied in more detail.     

Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.     

Dynamics of PTH secretion in hemodialysis patients as determined by the intact and whole PTH assays

BACKGROUND: Renal hyperparathyroidism is assessed by measurement of parathyroid hormone (PTH) levels. The intact PTH assay (I-PTH) not only reacts with 1-84 PTH but also with large, truncated fragments of non-1-84 PTH. Because the whole PTH assay (W-PTH) is specific for 1-84 PTH, non-1-84 PTH is determined by subtracting W-PTH from I-PTH values. These large circulating PTH fragments may exert a hypocalcemic effect by contributing to skeletal resistance to 1-84 PTH. METHODS: The dynamic secretion of both 1-84 PTH and non-1-84 PTH was evaluated during the induction of hypo- and hypercalcemia in eight hemodialysis patients. RESULTS: The basal ionized calcium concentration was 1.23 +/- 0.03 mmol/L at which time I-PTH, W-PTH, and non-1-84 PTH values were 276 +/- 78 pg/mL, 164 +/- 48 pg/mL, and 102 +/- 28 pg/mL, respectively. The induction of hypo- and hypercalcemic changes resulted in a sigmoidal response for all three PTH moieties, I-PTH, W-PTH, and non-1-84 PTH. During hypocalcemia, maximal values of W-PTH were greater than those of non-1-84 PTH. But during hypercalcemia, minimal values of W-PTH and non-1-84 PTH were similar. Neither the set points nor the basal/maximal ratios for W-PTH, I-PTH, and non-1-84 PTH were different. At the baseline ionized calcium concentration, the W-PTH (1-84 PTH)/non-1-84 PTH ratio was 1.53 +/- 0.15. Changes in ionized calcium resulted in a sigmoidal relationship with hypocalcemia, increasing this ratio to a maximum of 2.01 +/- 0.30 and hypercalcemia decreasing this ratio to a minimum of 1.18 +/- 0.15 (P < 0.01 vs baseline for both hypo- and hypercalcemia). CONCLUSION: Although acute changes in serum calcium produce similar secretory responses in 1-84 PTH and non-1-84 PTH, the secretory responses are not proportional for these PTH moieties. Changes in the serum calcium concentration modulate the ratio of 1-84 PTH/non-1-84 PTH in a sigmoidal pattern with hypocalcemia maximizing this ratio. Whether changes in the 1-84 PTH/non-1-84 PTH ratio specifically modulate the calcemic action and other biologic effects of 1-84 PTH remain to be determined.     

Effects of estrogen on daylong circulating calcium, phosphorus, 1,25-dihydroxyvitamin D, and parathyroid hormone in postmenopausal women

We studied the effects of estrogen on daylong circulating levels of calcium, inorganic phosphorus, parathyroid hormone (PTH), and 1,25-(OH)2D3 (calcitriol) in a group of 10 postmenopausal women (68.5 +/- 1.4 years, mean +/- SEM). The study was conducted under strict dietary control, with mean calcium and phosphorus intakes of 845 and 970 mg. After treatment with conjugated equine estrogens, 1.25 mg/day, for 1 month, significant decreases in fasting (0800 h) serum levels were observed for calcium (9.09 +/- 0.08 versus 9.46 +/- 0.10 mg/dl, p less than 0.01) and phosphorus (3.38 +/- 0.10 versus 3.73 +/- 0.08 mg/dl, p less than 0.01). On the 0800 h fasting specimen, midmolecule PTH concentrations were higher (44.0 +/- 7.9 versus 34 +/- 8.2 pg/ml, p less than 0.05), but intact PTH was unchanged (28.6 +/- 2.7 versus 29.1 +/- 1.7 pg/ml) and a rise in circulating calcitriol (39.8 +/- 4.3 versus 31.6 +/- 2.1 pg/ml) was marginally significant (p = 0.07). When data represented multiple samples averaged over 7 and 15 h, significant estrogen-related reductions in serum calcium and phosphorus concentrations were observed. In addition, estrogen was associated with a significant rise in the daylong (15 h) level of calcitriol (39.4 +/- 4 versus 30.5 +/- 2.4 pg/ml, p less than 0.01). Daylong mid- and intact PTH concentrations were unchanged on estrogen compared to baseline values. No significant correlations were observed between changes in fasting calcitriol level and changes in fasting concentrations of calcium, phosphorus, or PTH. Further, the rise in daylong calcitriol concentration did not correlate significantly with changes in fasting or integrated values of calcium or PTH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dynamics of secretion and metabolism of PTH during hypo- and hypercalcaemia in the dog as determined by the 'intact' and 'whole' PTH assays.

BACKGROUND: Recent evidence has shown that the assay for 'intact' parathyroid hormone (I-PTH) not only reacts with 1-84 PTH but also with large non-1-84 PTH fragments, most of which is probably 7-84 PTH. As a result, an assay specific for 1-84 PTH named 'whole' PTH (W-PTH) has been developed. The present study was designed: (i) to determine whether the W-PTH assay reliably measures PTH values in the dog; (ii) to evaluate differences between the W-PTH and I-PTH assays during hypo- and hypercalcaemia; and (iii) to assess the peripheral metabolism of W-PTH and I-PTH. METHODS :In normal dogs, hypocalcaemia was induced by EDTA infusion and was followed with a 90 min hypocalcaemic clamp. Hypercalcaemia was induced with a calcium infusion. RESULTS: I-PTH and W-PTH values increased from 36+/-8 and 13+/-3 pg/ml (P=0.01) at baseline to a maximum of 158+/-40 and 62+/-15 pg/ml (P=0.02 vs I-PTH) during hypocalcaemia. The W-PTH/I-PTH ratio, 38+/-4% at baseline, did not change during the induction of hypocalcaemia, but sustained hypocalcaemia increased (P<0.05) this ratio. During hypercalcaemia, maximal suppression for I-PTH was 2.0+/-0.5 and only 5.7+/-0.6 pg/ml for W-PTH, due to a decreased sensitivity of the W-PTH assay at values <5 pg/ml. The disappearance rate of PTH was determined in five additional dogs which underwent a parathyroidectomy (PTX). At 2.5 min after PTX, W-PTH was metabolized more rapidly, with a value of 25+/-2% of the pre-PTX value vs 30+/-3% for I-PTH (P<0.05). CONCLUSIONS: (i) The W-PTH/I-PTH ratio is less in the normal dog than in the normal human, suggesting that the percentage of non-1-84 PTH measured with the I-PTH assay is greater in normal dogs than in normal humans; (ii) the lack of change in the W-PTH/I-PTH ratio during acute hypocalcaemia is different from the situation observed in humans; and (iii) the dog appears to be a good model to study I-PTH and W-PTH assays during hypocalcaemia.     

PTHrP enhances the secretory response of PTH to a hypocalcemic stimulus in rat parathyroid glands

BACKGROUND: The secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine/paracrine factors, and a feedback regulatory mechanism of PTH on the secretion of PTH has been suggested. Because of the existence of a common receptor between PTH and PTH-related peptide (PTHrP), the aim of the present study was to examine the possible effects of PTHrP 1-40 and 1-86 on PTH secretion in rats. METHODS: In vivo, the effect of PTHrP on Ca++-regulated PTH secretion was examined by the induction of hypocalcemia and hypercalcemia by an infusion of EGTA and Ca++, with and without PTHrP. The eventual effects of PTHrP on the peripheral metabolism of PTH were examined by infusion of human PTH (hPTH) with and without PTHrP. hPTH was measured by an intact hPTH assay not cross reacting with rat PTH or PTHrP. To examine whether near physiological levels of circulating PTH have an autoregulatory effect in vivo on PTH secretion from the parathyroid gland, an acute reduction of the circulating PTH was induced by an acute unilateral parathyroidectomy (UPTX). PTH secretion from the remaining parathyroid gland was followed in response to EGTA-induced hypocalcemia. In vitro investigations on the effect of PTHrP 1-40 on PTH secretion from whole rat parathyroid glands incubated in media containing a calcium concentration of 0.6 or 1.35 mmol/L were performed to confirm whether the effect of PTHrP was directly on the gland. The rat PTH assay was examined for cross reaction with PTHrP. RESULTS: In vivo, the same rate of decrease of plasma Ca++ was induced in the experimental groups. The maximal response of PTH to hypocalcemia (218 +/- 16 pg/mL, N = 6) was significantly enhanced by PTHrP 1-40 (525 +/- 79 pg/mL, N = 6) and by PTHrP 1-86 (465 +/- 29 pg/mL, N = 6, P < 0.001). No effect of PTHrP on PTH secretion was found during normocalcemia or hypercalcemia. UPTX resulted in a 50% reduction of PTH secretion, and no compensatory increase of PTH was observed. PTHrP had no effect on the metabolism of PTH. In vitro, low-Ca++-induced PTH secretion was significantly augmented by 300% (P < 0.01) when the medium contained PTHrP 1-40. PTHrP did not cross react with the PTH assay. CONCLUSIONS: PTHrP significantly enhanced the low-Ca++-stimulated PTH secretion in vivo and in vitro. An autocrine/paracrine role of PTHrP in the parathyroid glands is suggested. An autoregulatory effect of circulating PTH on the PTH secretion from parathyroid glands seems unlikely. The "maximal secretory capacity" of the parathyroid glands induced by hypocalcemia in vivo and in vitro is not the maximum, as PTH secretion can be increased even further, by several-fold.     

Intraperitoneal free fatty acids induce severe hypocalcemia in rats: a model for the hypocalcemia of pancreatitis

Indirect evidence suggests a causative role for intraperitoneal free fatty acids (FFA) in hypocalcemia associated with pancreatitis. We examined the effects of intraperitoneal injection of four naturally occurring FFAs on serum calcium in rats. Two saturated FFAs, stearate and palmitate, induced little or no hypocalcemia. Two unsaturated FFAs, oleate and linoleate, caused dramatic hypocalcemia in treated versus control rats (6.3 +/- 1.4 and 5.3 +/- 0.7 mg/dl, respectively, versus 10.1 +/- 0.6). Dose-response studies demonstrated that minute quantities of oleate (100 microliters per 250 g rat) caused marked hypocalcemia (7.2 +/- 0.3 mg/dl). Treated versus control rats also revealed a decrease in ionized calcium (3.15 +/- 0.2 versus 5.6 +/- 0.05 mg/dl) and magnesium (1.4 +/- 0.15 versus 2.0 +/- 0.10), an appropriate increase in PTH levels (1670 +/- 451 versus 396 +/- 235 pg/ml), and a fall in calcitonin levels (70.4 +/- 21.3 versus 47.5 +/- 16.4 pg/ml) but no change in albumin or phosphate levels. In vitro, the Ksp of calcium dioleate was shown to be 5.3 x 10(-8) m3/liter3; thus under physiologic conditions 100 microliters oleate binds 7.2 mg calcium, or approximately twice the total ECF ionized calcium in the rat. The amounts of intraperitoneal FFA that can easily be achieved in pancreatitis complex pathophysiologically significant amounts of calcium and may lead to severe hypocalcemia.     

Hypercalcemia in critically ill surgical patients.

Critical surgical illness, commonly accompanied by shock, sepsis, multiple transfusions, and renal failure, is usually associated with low total calcium and/or low or normal ionized calcium. A seminal case of hypercalcemia in a surgical intensive care unit (SICU) patient prompted the review of 100 patients with longer than average SICU days (greater than 12) to determine the incidence, associated factors, and possible etiologies of this condition. Ten patients had elevated measured, and five others had elevated calculated, ionized calcium (5.9 +/- 0.25 mg%), an incidence of 15%. Compared to the 85 patients who did not develop hypercalcemia, this population had a significantly higher frequency of the following: renal failure, dialysis, total parenteral nutrition (TPN) usage greater than 21 days, bacteremic days greater than 1, transfusions greater than 24 units, shock greater than 1 day, SICU days greater than 36, and antibiotics used greater than 7. In addition, this group had significantly more days of hypocalcemia early in their hospital course. There was no difference in sex, age, mortality, or incidence of respiratory failure. Two patients studied in depth had renal failure requiring dialysis and no malignancy, milk-alkali syndrome, hyperthyroidism, or hypoadrenalism. Parathormone (PTH) concentrations were high normal or elevated (N terminal 20 and 21 pg/ml; C terminal 130 microliters Eq/ml and 1009 pg/ml) at the time of elevated calcium (total 9.2 to 14.6 mg%; ionized 4.9 to 8.2 mg%). Immobilization does not increase PTH. In renal failure, PTH elevation is a consequence of hypocalcemia rather than hypercalcemia. Moreover, five patients did not have renal failure. Shock, sepsis, and multiple transfusions containing citrate may lower total and/or ionized calcium and thus stimulate PTH secretion. Whatever the mechanism, approximately 15% of critically ill surgical patients develop hypercalcemia, which may represent a new form of hyperparathyroidism.     

Thyroidectomy and parathyroid hormone: tracing hypocalcemia-prone patients

BACKGROUND: The aim of this prospective study was to identify patients at high risk of developing hypocalcemia after thyroidectomy on the basis of the parathyroid hormone (PTH) level on the first postoperative day. METHODS: We included 160 patients undergoing total thyroidectomy in a period of 6 months by the same surgical team in this study. In all patients the PTH level was measured before surgery on the day of surgery (PTH1), and on the first postoperative day (PTH2), whereas serum calcium level was measured daily until discharge. Patients were classified as hypocalcemic if they had a serum calcium level less than the normal range on the first postoperative day, independently of symptoms of hypocalcemia. RESULTS: At an average follow-up period of 5.9 months (range, 4-9 mo), 66 patients were considered hypocalcemic, 57 patients (35.6%) had a transient hypocalcemia, and 9 patients (5.6%) required calcium-vitamin D supplementation for persistent hypocalcemia. The mean PTH1 value was 54.4 +/- 17.2 pg/mL (median, 53.85 pg/mL), the mean PTH2 value was 22.8 +/- 13.3 pg/mL (median, 21 pg/mL). The mean PTH decrease in value was 51.54% +/- 27.4% (median, 51.83%; range, 4%-94%) and 43.7% of patients presented a PTH decrease of more than 50%. The presence of a postoperative hypocalcemia was statistical correlated both with the PTH2 level and with the PTH drop percent value (P < .001 and P = .002, respectively). With the use of the receiver operating characteristic curve, the maximum sum of the sensitivity and specificity for the correlation of PTH2 levels and hypocalcemia occurred at a PTH2 level of 9.6 pg/mL. CONCLUSIONS: The PTH measurement on the first postoperative day may be considered a useful method to predict postthyroidectomy hypocalcemia, thus avoiding prolonged hospitalization. Moreover, PTH dosage at first postoperative day is more reliable and less expensive than intraoperative quick PTH assay.     

Elevated bone aluminum and suppressed parathyroid hormone levels in hypercalcemic dialysis patients

We studied 21 dialysis patients who became hypercalcemic without vitamin D or calcium therapy and compared them to 28 dialysis patients who were not hypercalcemic. In the hypercalcemic group, the mean ionized-calcium level was elevated compared to normal subjects (5.4 +/- 0.4 vs. 4.9 +/- 0.1; p less than 0.001), while the ionized-calcium level in the control dialysis patients was below normal (4.5 +/- 0.4 vs. 4.9 +/- 0.1; p less than 0.001). Bone biopsies were performed in all patients. Two thirds of the hypercalcemic patients had low-turnover osteodystrophy (LTO, predominantly osteomalacia), a fraction significantly higher than in the control dialysis patients (13/21 vs. 8/28, respectively; p less than 0.05). The hypercalcemic patients with LTO had markedly elevated surface bone aluminum (63 +/- 24% of all trabecular surfaces). In contrast, the nonhypercalcemic dialysis patients with LTO and all patients with osteitis fibrosa had minimal surface bone aluminum. Hypercalcemic patients with osteitis fibrosa had a significantly lower mean N-terminal parathyroid hormone (PTH) value than did nonhypercalcemic patients with osteitis fibrosa (149 +/- 81 vs. 278 +/- 135 pg/ml, respectively; p less than 0.005). Both mean values were markedly elevated in comparison with those obtained in normal subjects (16 +/- 5 pg/ml). In contrast, patients with LTO, irrespective of the calcium level, had mean PTH values that were not significantly different from those of normal subjects. A PTH level greater than 100 pg/ml was 95% sensitive and 87% specific for osteitis fibrosa, as demonstrated by histomorphometry in nonhypercalcemic dialysis patients. However, this level was only 62% sensitive and 77% specific for a diagnosis of osteitis fibrosa in hypercalcemic dialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced parathyroid functional mass after successful kidney transplantation.

BACKGROUND: Chronic uremia is responsible for secondary hyperparathyroidism (HPT II). Parathyroid secretion usually tends to normalize after kidney transplantation (KT), but the parameters of the reversibility of HPT II remain poorly defined, particularly the intrinsic mechanisms underlying the improvement of parathyroid function. METHODS: The kinetic functional parameters of the ionized calcium (iCa)/parathormone (PTH) relationship curve were studied in 11 patients with mild to moderate HPT II one and six months after successful KT. Hypercalcemia and hypocalcemia were induced, respectively, by CaCl2 and Na2-ethylenediaminetetraacetic acid (Na2-EDTA) infusions. RESULTS: The mean glomerular filtration rate remained stable during follow-up. Basal PTH decreased from 195 +/- 54 pg/ml before KT to 70 +/- 12 pg/ml six months later (P < 0. 005). During the tests, mean PTH levels decreased significantly between the two measured times for all iCa levels, indicating an improved parathyroid function. An analysis of the kinetic parameters of the curves showed significant decreases of the mean maximal and minimal PTH levels, respectively, from 340 +/- 91 to 220 +/- 30 pg/ml (P = 0.03) and from 25 +/- 6 to 15 +/- 5 pg/ml (P = 0.005). On the other hand, no change was noted in the parathyroid-cell calcium-sensitivity parameters (slope, set point) assessed using two different approaches, either the entire curve or the limited calcium-mediated suppression curve. CONCLUSION: Improvement of the parathyroid function between the first and sixth months post-KT seems mainly attributable to a reduction of the parathyroid functional mass.     

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia

The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and compared to those with osteitis fibrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal parathyroid hormone response (+/- SD) (0.39 +/- 0.33 vs. 0.87 +/- 0.53 ng/ml, P less than 0.05) and maximum carboxy terminal parathyroid hormone response (+/- SD) (0.36 +/- 0.20 vs. 0.84 +/- 0.47, P less than 0.02) to hypocalcemia. The decline in plasma calcium was greater in patients with osteomalacia at 90 (P less than 0.05), 120 (P less than 0.01), and 150 min (P less than 0.01). In osteomalacia patients the surface density of histologically detectable trabecular bone aluminum correlated directly with the percent relative osteoid volume (P less than 0.005) and inversely with the maximum amino terminal parathyroid hormone response to hypocalcemia (P less than 0.025). These results suggest that hemodialysis patients with osteomalacia have diminished secretion of parathyroid hormone and a decreased ability to restore plasma calcium homeostasis during hypocalcemia.     

The effect of long-term intravenous calcitriol administration on parathyroid function in hemodialysis patients.

Secondary hyperparathyroidism is common in dialysis patients. Intravenous calcitriol has proven to be an effective therapy for the reduction of parathyroid hormone (PTH) levels. However, the effect of i.v. calcitriol on parathyroid function, defined as the sigmoidal PTH-calcium curve developed during hypocalcemia and hypercalcemia, has not been evaluated during the prolonged administration of i.v. calcitriol. Six hemodialysis patients with marked secondary hyperparathyroidism, PTH levels greater than 500 pg/mL (normal, 10 to 65 pg/mL), were treated for 42 wk with 2 micrograms of i.v. calcitriol after each hemodialysis. Parathyroid function was evaluated before and after 10 and 42 wk of calcitriol therapy. Between baseline and 42 wk, the basal PTH level decreased from 890 +/- 107 to 346 +/- 119 pg/mL (P less than 0.02) and the maximally stimulated PTH level decreased from 1293 +/- 188 to 600 +/- 140 pg/mL (P less than 0.01). In addition, calcitriol administration significantly decreased PTH levels throughout the hypocalcemic range of the PTH-calcium curve. Although the slope of the PTH-calcium curve (with maximal PTH as 100%) decreased between baseline and 42 wk (P less than 0.05), the set point of calcium did not change. Two patients with a decrease in both basal and maximally stimulated PTH levels after 10 wk of calcitriol, developed marked hyperphosphatemia between 10 and 42 wk; this resulted in an exacerbation of hyperparathyroidism despite continued calcitriol therapy. In conclusion, prolonged i.v. calcitriol administration is an effective treatment for secondary hyperparathyroidism in hemodialysis patients provided that reasonable control of the serum phosphate is achieved. In addition, the slope of the PTH-calcium curve may be a better indicator of parathyroid cell sensitivity than the set point of calcium.