Abnormal PTH Research Articles

Current therapeutic approach of chronic kidney disease-mineral and bone disorder.

Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD-mineral and bone disorder (CKD-MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD-MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD-MBD, anti-osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD-MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD-MBD based on the current literature with special attention to recent advances.

654 Successful Wound Closure in Patients with Large Total Body Surface Area Calciphylaxis with Aggressive Multi-modal Therapy Including Excision and Skin Grafting

Abstract Introduction Calcific Uremic Arteriolopathy (CUA), commonly known as Calciphylaxis, is a rare disorder characterized by ischemic necrosis of the skin and histologically by arteriolar calcification. CUA is most commonly seen in patients with end-stage renal disease (ESRD) but can be seen in other patients as well. CUA carries an extremely high mortality rate, with up to 80% in some studies, even in patients with limited disease. In light of this, many surgeons have adopted a “do-not-touch” practice with these patients. Over the past several years, our institution has seen an increase in referrals for the management of large total-body-surface-area (TBSA) CUA. Methods Retrospective review of all patients with biopsy-proven (by dermatopathology) large TBSA (>=5% TBSA) CUA admitted to a Verified Adult and Pediatric Burn Center from 2015 to present. Demographics, laboratory data, treatment modalities and outcomes including mortality and wound closure were recorded. Results A total of 8 patients with large TBSA CUA were admitted after being transferred from outside hospitals. Average TBSA affected was 13.76% (SD 7.27). 6 of these patients (75%) were noted to have non-uremic calciphylaxis. All patients had positive wound cultures on admission, and 1 patient (12.5%) developed a bacteremia in hospital. There were no central line associated bloodstream infections, catheter associated urinary tract infections or ventilator associated infections. All patients underwent surgical debridement (average 4.125, range 2–5), and 5 patients (62.5%) underwent grafting, (average 1.6, range 2–5) and subsequently proceeded to wound closure. In-hospital mortality was 25% and another patient was referred to a hospice facility after being readmitted with medical complications of her calciphylaxis. Secondary findings included 50% of the patients recently experienced significant weight loss (>100 lbs). On admission, 2 patients (25%) had abnormal serum calcium, 3 patients (37.5%) had abnormal serum PO4, and 4 (50%) patients had abnormal PTH levels. 2 patients (25%) had a recent exposure to warfarin (within 6 months). Conclusions Utilizing a multi-modal management strategy that includes surgical debridement and skin grafting, patients with calciphylaxis can progress to wound closure.

Bone Metabolism Disorder in Epileptic Children.

There are frequent anti-epileptic drugs used in management of epilepsy. Anti-epileptic drugs may have some complications on bone and vitamin D metabolism. This study aimed to comparison the bone metabolism disorder in epileptic children with healthy child in Zahedan, eastern Iran from Jul 2014 to Jun 2015. This case-control study was performed on bone metabolism disorder in epileptic children between 2014-2015. Forty epileptic children were enrolled based on accessibility scheme and 40 participants randomly selected for control group from those referred to the pediatric ward and clinic of Ali Ebn Abi Talib Hospital and Ali Asghar Clinic in Zahedan City, Sistan & Baluchestan Province, eastern Iran. Blood samples were collected from all participants to assess serum calcium, phosphorus, parathyroid hormone, magnesium, vitamin D, serum albumin, creatinine random urine. Of 40 epileptic children, 23 (57.5%) and 17 (42.5%) were male and female respectively, The prevalence of lower mean vitamin D levels was 37.5% for patients compared to 12.5% for controls (chi-square=6.667 and P=0.010). Of 80 participants, 15 individuals had abnormal PTH levels detected of 2 and 13 for patients and control groups, respectively (chi-square =9.928 and P=0.002). Serum calcium and magnesium levels were comparable in both groups. The status of the parameters in the classification of normal and abnormal assessed based on number of medications intake resulted that number of medications intake had no effect on the status of the parameter. The frequency of hyperparathyroidism and vitamin D deficiency is increased in epileptic children.

Nutrient Status 9Years After Biliopancreatic Diversion with Duodenal Switch (BPD/DS): an Observational Study.

Since biliopancreatic diversion with duodenal switch (BPD/DS) produces hypoabsorption, evaluation of long-term nutrient changes is appropriate. Measurements of micronutrients, trace elements, PTH, iron studies, and protein were completed for consented patients at baseline prior to surgery and at yearly intervals. The patients were advised and supplements were adjusted by blood studies with compliance checks. Independent t tests and ANOVAs compared changes between cross-sectional cohorts based on follow-up time from surgery. A p value of 0.05 was considered significant. Between 1999 and 2010, 284 patients had BPD/DS. At baseline, nutrient analysis was available for only 190 patients (70% women), age 42.7±10.0years, BMI 53.0±11.9kg/m2; at year 1, 189 were available; at year 3, 193; at year 5, 132; at year 7, 98; and at year 9, 68. Gender distribution was not significantly different between cohorts. Baseline vitamin D was low and PTH high. All of the patients took some supplements. Fat-soluble vitamins remained low. Protein deficiency appeared at year 3 and increased to 30% at year 9. Baseline zinc was normal, but at year 5, 45% were low. Over time, hematocrit was low for 40% and hemoglobin for 46%. Iron deficiency continued through year 9, more marked in males. Calcium deficiency increased from year 3 and remained steady. Half of the patients had abnormal PTH at baseline, and the percentage increased over time. Twenty percent had abnormal baseline magnesium values. Magnesium fluctuated during observation. Major deficits in nutrient status occurred and persisted after surgery although supplementation was prescribed. Interventions are mandated to avoid nutrient deficiency.

Identifying Parathyroid Hormone Disorders and their Phenotypes through a Bone Health Screening Panel: It's not Simple Vitamin D Deficiency!

To determine the utility of bone health screening panels in identifying disorders of parathyroid gland secretions. A retrospective analysis of biochemical parameters in a bone health screening panel (BHSP) was conducted. Low and high cutoffs were applied to determine hypofunctioning and hyperfunctioning conditions related to parathyroid hormone. Clinical phenotypes of parathyroid gland abnormalities were determined using a combination of levels of calcium, 25-hydroxyvitamin D, and intact parathyroid hormone (iPTH). A PTH nomogram was applied to calculate the maximum expected PTH for existing levels of 25-hydroxyvitamin D. Medical records of patients were reviewed for clinical validation of biochemical findings. Sixty-eight percent of subjects showed abnormal PTH secretion. Primary hyper- and hypoparathyroidism were detected in 1% (n = 5) and 0.4% (n = 2) of subjects, respectively. Normocalcemic hyperparathyroidism and hypercalcemia with inappropriately high-normal PTH were identified in 8.5% (n = 37) and 2% (n = 10) of subjects, respectively. All subjects with primary and normocalcemic hyperparathyroidism had higher measured PTH than calculated maximum PTH using the PTH nomogram. Secondary hyperparathyroidism and functional hypoparathyroidism were present in 18% (n = 88) and 39% (n = 194) of subjects, respectively. High prevalence of bone pains, renal stones, and low bone mineral density were identified in patients with abnormal PTH secretion. Panel testing is useful in early diagnosis of metabolic bone disorders related to PTH. A BHSP helps identify normocalcemic hyperparathyroidism and hypercalcemia with inappropriately high PTH. 25OHD = 25-hydroxyvitamin D AKUH = Aga Khan University Hospital BHSP = bone health screening panel iPTH = intact parathyroid hormone maxPTH = maximum parathyroid hormone MBD = metabolic bone disease NCHPT = normocalcemic hyperparathyroidism PHPT = primary hyperparathyroidism PTH = parathyroid hormone SHPT = secondary hyperparathyroidism VDD = vitamin D deficiency.

Hypomagnesemia with Secondary Hypocalcemia Linked to a Novel TRPM6 Gene Mutation

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disorder, characterized by extremely low levels of serum magesium associated with symptomatic hypocalcemia. HSH manifests in the new born period with neurological symptoms, including generalized seizures, which are refractory to anticonvulsant treatment. In this disorder, the basic abnormality is the defective intestinal absorption of magnesium. Mutations in TRPM6, the gene encoding the transient receptor potential cation channel subfamily member 6 have been found to be responsible for this disease. We report on a four-month-old Tunisian girl who presented with convulsions. Laboratory evaluation yielded extremely low serum magnesium levels, low calcium levels, and abnormal PTH levels. The diagnosis of HSH was confirmed by mutation analysis which identified the novel mutation c.1307A >G in exon 11 of TRPM6 (Lys436Arg). Our patient was homozygous for this mutation. Prenatal diagnosis was done during second pregnancy. DNA from trophoblast biopsy showed the same mutation as the proband.

CHRONIC KIDNEY DISEASE—MINERAL AND BONE DISORDER (CKD‐MBD): A NEW TERM FOR A COMPLEX APPROACH

The global widespread of the chronic kidney disease (CKD) is a worldwide health problem. Its increasing incidence and prevalence and adverse outcomes (including decreased quality of life, increased morbidity and mortality) represents a huge challenge for all recent health are systems. Reflecting this situation, the new, global initiative (KDIGO) was established to enhance communication and clinical decision-making, promote the use of evidence based medicine and facilitate clinical research. The new definition, evaluation and classification of "renal osteodystrophy"; has been one of the first outcome of this initiative, suggesting the topic of chronic kidney disease--mineral and bone disorder (CKD-MBD) to be a hot problem of recent nephrology. The new terminology is consistent with a recent view on this topic and describes CKD-MBD as a complex syndrome, including abnormal mineral and PTH metabolism, altered bone structure as far as extra-skeletal calcifications.

Type I Membrane Klotho Expression Is Decreased and Inversely Correlated to Serum Calcium in Primary Hyperparathyroidism

The type I membrane protein Klotho was recently shown to mediate PTH secretion in parathyroid cells in response to low extracellular calcium. In contrast, Klotho inhibits PTH secretion indirectly through the action of fibroblast growth factor-23. Abnormal Klotho expression in parathyroid disorders remains to be elucidated. The aim of the study was to determine: 1) Klotho expression in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT) compared to normal tissue; and 2) its relation to the serum calcium and PTH levels. Surgically removed parathyroid glands (n = 40) and four normal parathyroid tissue specimens were analyzed for Klotho mRNA and protein levels by quantitative real-time PCR and immunohistochemistry. In vitro effects of calcium on Klotho mRNA expression were studied in bovine parathyroid cells. Klotho mRNA levels were significantly decreased (n = 23) or undetectable (n = 17) in parathyroid adenomas compared to normal tissues (P < 0.001). Reduced Klotho protein expression was confirmed by immunohistochemistry. Klotho mRNA levels were inversely correlated to serum calcium (r = -0.97; P < 0.0001), and calcium dose-dependently decreased Klotho mRNA expression in normal parathyroid cells in vitro (P < 0.01). Serum calcium was the only significant marker of Klotho expression in multivariate analysis with calcium, phosphate, PTH, and adenoma weight as independent variables. Parathyroid Klotho expression is decreased or undetectable in pHPT. We provide evidence that 1) serum calcium is strongly associated with parathyroid Klotho expression in pHPT; and 2) abnormal PTH secretion in hypercalcemic pHPT subjects is mediated by Klotho-independent mechanisms.

Response to Teriparatide in Patients with Baseline 25-Hydroxyvitamin D Insufficiency or Sufficiency

Serum 25-hydroxyvitamin D (25OHD) concentrations greater than 30 ng/ml have been recommended for lowering fracture risk. Our objective was to determine whether 25OHD sufficiency is a prerequisite for effective response to teriparatide (TPTD). Data were from 1620 osteoporotic postmenopausal women in the Fracture Prevention Trial. The response to TPTD was assessed in women subgrouped by having 25OHD insufficiency (>10 but <or=30 ng/ml) or 25OHD sufficiency (>30 but <or=183 ng/ml) at the baseline (randomization) visit. An abnormal intact PTH was exclusionary. At baseline, after at least 1 month of supplementation with calcium (1000 mg) and vitamin D (400-1200 IU) daily, women were randomized to placebo or 20 or 40 microg TPTD by daily sc injection for a median of 19 months. Observation was for a median of 21 months. Main outcome measures included vertebral and nonvertebral fractures, change in bone mineral density at the lumbar spine and femoral neck, change in bone formation marker amino-terminal extension peptide of procollagen type 1, and the proportion of women with serum calcium at least 2.76 mmol/liter 4-6 h after dosing. TPTD reduced vertebral and nonvertebral fracture risk, increased lumbar spine and femoral neck bone mineral density, and increased amino-terminal extension peptide of procollagen type 1 relative to placebo in the two 25OHD subgroups. There were no significant differences in these endpoints between the subgroups (each treatment by subgroup interaction, P > 0.10). However, it should be noted that because of the limited number of fractures, this study does not exclude the possibility of differences in fracture outcome between the subgroups. In postmenopausal women with osteoporosis and normal intact PTH, the responses to TPTD did not differ significantly in women with baseline 25OHD insufficiency or sufficiency.

Surgery for hyperparathyroidism: Does morphology or function matter most?

With minimally invasive parathyroidectomy (MIP) not all enlarged parathyroid glands are necessarily removed, and intraoperative measurement of parathyroid hormone levels (IO-PTH) does not necessarily predict multiple enlarged glands. The aim of this study was to compare morphology with function, using Ca(2+)-regulated PTH secretion. PTH secretion was determined by perifusion: (1) cells from 12 normal parathyroids were compared with 14 parathyroid adenomas; (2) functional characteristics (PTH secretion, sestamibi uptake, IO-PTH decrease) were correlated with morphologic characteristics; (3) PTH secretion as a predictor of IO-PTH decrease was determined in 7 patients with 2 enlarged parathyroids. (1) There were significant differences between normal and pathological parathyroid cells consistent with reduced sensitivity to Ca(2+). Maximum secretion rates for normal and adenomatous cells were, respectively, 3.9 +/- 0.4 fg min(-1) cell(-1) and 2.0 +/- 0.4 fg min(-1) cell(-1) (P = .002) and minimum secretion rates, 0.7 +/- 0.1 fg min(-1) cell(-1) and 0.4 +/- 0.1 fg min(-1) cell(-1) (P = .008). However, the IC(50) value for Ca(2+) was elevated in adenomatous cells indicating an apparent loss of extracellular Ca(2+) sensitivity being 1.1 +/- 0.02 mmol/L for normal and 1.2 +/- 0.02 mmol/L for adenomatous cells (P = .02). (2) There was no overall correlation between PTH secretion and gland morphology. (3) In 5 of 7 cases, PTH secretion correctly predicted the decrease in IO-PTH. Parathyroid adenomas generally exhibit abnormal PTH secretory function; however, enlarged parathyroid glands that do not contribute to the biochemical changes of hyperparathyroidism do exist, and, in these cases, cellular secretory function is a useful predictor of IO-PTH dynamics.

Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the occurrence of multiple endocrine tumors of the parathyroid, pancreas, and anterior pituitary in patients. To study tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach. Heterozygous Men1 mutant mice developed the same range of major endocrine tumors as is seen in MEN1 patients, affecting the parathyroid, pancreatic islets, pituitary and adrenal glands, as well as the thyroid, and exhibiting multistage tumor progression with metastatic potential. In particular, extrapancreatic gastrinoma, pancreatic glucagonoma, and mixed hormone-producing tumors in islets were observed. In addition, there was a high incidence of gonadal tumors of endocrine origin, i.e. Leydig cell tumors, and ovary sex-cord stromal cell tumors in heterozygous Men1 mutant mice. Hormonal disturbance, such as abnormal PTH and insulin levels, was also observed in these mice. These tumors were associated with loss of heterozygosity of the wild-type Men1 allele, suggesting that menin is involved in suppressing the development of these endocrine tumors. All of these features are reminiscent of MEN1 symptoms in humans and establish heterozygous Men1 mutant mice as a suitable model for this disease.

Relationship between Ca-dependent change of serum PTH and extracellular Ca2+-sensing receptor expression in parathyroid adenoma.

Abnormal PTH secretion and cell growth in hyperparathyroid tissues are accompanied with reduced expression of Ca2+-sensing receptor (CaR) which plays a key role in Ca-regulated PTH release. In this study, we examined the receptor expression in parathyroid adenomas using specific anti-CaR antibody and investigated relationship between CaR expression in adenomatous tissues and parameters of Ca-dependent change of serum PTH. The results show a considerable variation in the number of CaR positive cells among the adenomatous tissues. Expression of the receptor protein was not related to set-point error but was more reduced in the patients with more elevated minimum or baseline levels of serum PTH. CaR expression was severely reduced in the patients with highly elevated maximum serum PTH, while the receptor expression was also decreased in some patients with normal maximum serum PTH. Baseline level / maximum level ratio of serum PTH was increased in these patients. In conclusion, reduced CaR expression is related to abnormality in three parameters of PTH secretion (minimum serum PTH, maximum serum PTH, and baseline level / maximum level ratio of serum PTH) and may contribute to hypersecretion from parathyroid adenomas.

Abnormalities of parathyroid hormone secretion in elderly women that are reversible by short term therapy with 1,25-dihydroxyvitamin D3.

Serum PTH concentrations increase with aging and may play an important causal role in age-related bone loss. To better define possible PTH secretory abnormalities with aging, we studied 10 young (aged 27-34 yr) and 10 elderly (aged 71-77 yr) women using sequential infusions of calcium and EDTA. To assess possible age-related resistance of PTH secretion to modulation by 1,25-dihydroxyvitamin D [1,25-(OH)2D], the infusions were repeated after 1 week of oral 1,25-(OH)2D3 therapy (1 microgram/day). Baseline serum intact PTH concentrations were higher in the elderly compared to the young women (mean +/- SEM, 3.8 +/- 0.5 vs. 2.7 +/- 0.4 pmol/L; P = 0.03). In addition, the elderly women had a significantly higher maximal PTH response to hypocalcemia compared to the young women (16.6 +/- 1.1 vs. 12.8 +/- 1.0 pmol/L; P = 0.03). The elderly women also had a greater nonsuppressible component of PTH secretion (0.8 +/- 0.1 vs. 0.4 +/- 0.1 pmol/L; P < 0.001). The set-point for PTH secretion, however, was identical in the elderly and young women (1.18 +/- 0.01 vs. 1.19 +/- 0.01 mmol/L; P = NS). After 1,25-(OH)2D3 administration, both groups had similar reductions in baseline and maximally stimulated PTH levels, indicating that elderly women have normal responsiveness to 1,25-(OH)2D3 suppression of PTH secretion. In addition, maximally stimulated PTH levels in the 1,25-(OH)2D3-treated elderly women decreased to the pretreatment values of young women (13.3 +/- 1.1 vs. 12.8 +/- 1.0 pmol/L; P = NS). thus, elderly women have greater basal, maximal, and nonsuppressible levels of PTH secretion, without alterations in the set-point. These abnormalities are similar to those found in patients with secondary hyperparathyroidism and parathyroid hyperplasia. Further, the abnormal PTH secretory dynamics in elderly women are reversible by short term 1,25-(OH)2D3 therapy.

Parathyroidectomy for patients with renal hyperparathyroidism refractory to calcitriol pulse therapy

Since Slatopolsky reported that the intermittent high doses of calcitriol could suppress PTH secretion effectively in secondary hyperparathyroidism due to chronic renal failure, intravenous and oral calcitriol pulse therapy have enjoyed widespread acceptance. However, patients with far-advanced renal hyperparathyroidism are refractory to calcitriol pulse therapy and parathyroidectomy is required. Out of 157 cases who underwent parathyroidectomy for renal hyperparathyroidism between January 1991 and April 1994 at our department, 37 cases (23.6%) required parathyroidectomy because they were refractory to calcitriol pulse therapy. From evaluation of the preoperative and histopathological findings, we assessed the limitations of calcitriol pulse therapy. Our criteria as indications for parathyroidectomy in renal hyperparathyroidism include high PTH (C-PTH ≧20 ng/ml or M-PTH ≧50 ng/ml), the detection of swollen parathyroid glands by image diagnosis, high turnover bone or osteitis fibrosa findings on X-ray film and being refractory to medical treatment. In all but one case, the PTH level exceeded our citeria. In 4 cases, ectopic calcification, especially vascular calcification advanced and patients complained of ischemic symptoms. We emphasize that parathyroidectomy should be performed in patients with our criteria, before progression of vascular calcification and skeletal deformity. Some, 95% of these cases had more than one nodular hyperplastic glands. We estimated by previous pathophysiological examination that nodular hyperplasia was aggressively hyperplastic, with a high growth potential, abnormal PTH secretion and a diminished number of vitamin D receptors. These clinical and pathophysiological results imply that when renal hyperparathyroidism is advanced, our criteria for parathyroidectomy indication are met, or when the parathyroid glands develop nodular hyperplasia, even calcitriol pulse therapy is not effective for hyperparathyroidism and so parathyroidectomy is required.

Journal of Bone and Mineral Research

One of the common dilemmas in clinical endocrine practice is the management of patients with hyperparathyroidism (HPT) who either cannot or will not undertake definitive surgical treatment. Therapeutic decisions would be simplified by the availability of a nonsurgical approach to control biochemical abnormalities and forestall the consequences of this condition. In the short term, oral phosphorus salts can be safe and effective. For chronic therapy, only estrogens and progestins have been examined in sufficient detail to merit discussion. Estrogens normalize serum and urinary calcium in the majority of older women with HPT. Biochemical control is generally maintained for as long as patients continue treatment. The data support the view that estrogen inhibits the actions of PTH, particularly on bone, but does not reduce the abnormal PTH secretion. Androgenic progestins may also lower serum and urinary calcium in HPT, but current data suggest that normalization of serum calcium levels is more likely to occur with estrogen. Although reduction in urinary calcium excretion should prove effective in preventing nephrolithiasis, it is unclear whether hormone therapy provides protection against fracture. Whether or not hormone replacement is prescribed, nonsurgical management requires a highly committed patient who is willing to undergo extensive and prolonged follow-up.

Regulation of Calciotropic Hormonesin Vivoin the New Zealand White Rabbit*

Serum levels of ionized calcium, 25-hydroxyvitamin D (25OHD), and 1,25-dihydroxyvitamin D[1,25-(OH)2D], intact immunoreactive PTH and calcitonin were measured in the laboratory rabbit to evaluate the role of these calciotropic hormones in calcium homeostasis in this species. We confirm the finding of previous researchers that the resting serum ionized and total calcium concentrations are elevated in rabbits compared to those in other species (ionized calcium, 1.70 +/- 0.13 mmol/liter; total calcium, 3.23 +/- 0.25 mmol/liter). The serum calcium concentrations in animals maintained on a breeding farm or in the laboratory did not differ significantly despite nearly 3-fold higher levels of vitamin D in the feed at the farm, which were associated with 3- to 4-fold higher concentrations of 25OHD and 1,25-(OH)2D. Baseline intact PTH levels for the farm and laboratory populations also did not differ significantly and averaged 69.4 +/- 43.6 human pgeq/ml (laboratory animals, 52.1 +/- 28.4; breeding farm animals, 86.0 +/- 49.5 human pgeq/ml). Infusions of calcium gluconate or EDTA for 15 min into anesthetized animals in the laboratory induced dramatic reciprocal changes in the measured circulating levels of PTH. Calcium gluconate infusions (190-300 nmol/g BW) produced 50-85% increases in serum ionized calcium, which were accompanied by 74-91% decreases in PTH levels (from 68.8 +/- 29.2 at time zero to 10.1 +/- 3.1 human pgeq/ml at 15 min) as well as 7-fold increases in calcitonin levels. EDTA infusions (14-120 nmol/g BW) reduced serum ionized calcium by 9-49%, while PTH levels increased by 68-560% (from 61.4 +/- 32.3 at time zero to a maximum of 138 +/- 48.6 human pgeq/ml at 3 min). During the EDTA infusion, the PTH response was variable after 3 min despite further decreases in ionized Ca2+, indicating either exhaustion of PTH reserves or regulation of the secretory response by some parameter other than ionized calcium concentration per se. Thus, the rabbit appears to defend its serum ionized calcium concentration against hypo- and hypercalcemia by rapid changes in PTH secretion and calcitonin. Unlike other mammalian species, however, the changes in PTH occur at relatively high levels of calcium, suggesting that the parathyroid gland of the rabbit is reset to respond to changes in ionized Ca2+ within the physiological range in that species. The relative insensitivity of the rabbit parathyroid to extracellular calcium is analogous to that observed in primary hyperparathyroidism and may be a useful model to study the control of normal and abnormal PTH secretion.

Mechanisms of parathyroid hormone resistance in pseudohypoparathyroidism.

The problem with PHP is that it is almost certainly a heterogeneous condition encompassing a number of defects within the PTH receptor-adenylate cyclase complex. The clinical manifestations of PTH resistance are amplified and extended by a number of associated abnormalities. These include a low intracellular calcium concentration, secondary hyperparathyroidism, reduced production of 1,25-(OH)2D and perhaps the secretion of an abnormal PTH peptide. Almost every aspect of PTH function seems involved and this makes PHP a fascinating condition in which to test current views of the role of PTH in the integration of the calcium homoeostatic system.

Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma: Brown EM, Wilson RE, Thatcher JG, Marynick SP: Am J Med 1981; 71: 565–570

Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma: Brown EM, Wilson RE, Thatcher JG, Marynick SP: Am J Med 1981; 71: 565–570

Parathyroid response to EDTA in hypoparathyroidism and in tetany.

The parathyroid response to an EDTA infusion was measured in 11 patients with hypoparathyroidism and 22 patients with normocalcaemic tetany, and compared to that of normal controls and of 23 patients with primary hyperparathyroidism. Despite comparable basal PTH values, the patients with hypoparathyroidism and the normocalcaemic patients, with tetany following thyroid surgery, responded less than normals to EDTA, while normocalcaemic patients with tetany due to psychogenic hyperventilation responded more than normals. In hypoparathyroidism, mainly three types of results were observed: no response (total hypoparathyroidism), diminished or delayed response (partial hypoparathyroidism), and discrepant results using different antisera in cases of idiopathic hypoparathyroidism, suggesting the secretion of immunologically abnormal PTH. In tetany due to psychogenic hyperventilation, parathyroid hyperreactivity might be explained by repeated stimulation through respiratory alkalosis. Although the EDTA test rarely improved the diagnostic accuracy of basal PTH measurements in primary hyperparathyroidism, it was useful for differentiating between latent hypoparathyroidism and tetany due to psychogenic hyperventilation, both presenting with normal plasma calcium.