Parathyroid Hormone Level Changes Following Radioiodine Therapy for Thyroid Cancer: A Prospective Observational Study

ObjectiveOur objective was to analyze the effect of radioiodine (RAI) therapy on parathyroid hormone (PTH) secretion.MethodsA total of 137 patients were included and divided into 2 groups based on pretherapy PTH levels. The residual thyroid tissue volume was classified into 4 grades (0-3), and a value of 0 indicated that there was no apparent residual tissue. We analyzed the PTH level changes among different time points in each group and the factors that could predict the PTH level changes.ResultsIn 113 patients with normal parathyroid gland function, the PTH level at baseline, 1 day, 7 days, 1 month, 3 months, and 6 months after RAI therapy did not show any significant difference; in 24 patients with decreased parathyroid gland function, the level of PTH immediately decreased after the implementation of RAI therapy but gradually returned to a pre-RAI therapy level within 6 months. On the seventh day after therapy, the mean value of PTH in patients with a residual thyroid tissue volume of extent of 0/1 was 8.0 ± 2.3 pg/mL, which was significantly higher than that in patients with a residual thyroid tissue volume of extent of 2/3 (P = .011). Similar phenomena were observed 1 month, 3 months, and 6 months after therapy.ConclusionRAI therapy had a significant transient adverse effect on parathyroid gland function in patients with decreased PTH secretion pretherapy, and the extent was associated with the amount of residual thyroid tissue.     

A new, vitamin D-based, multidimensional nomogram for the diagnosis of primary hyperparathyroidism

ObjectiveTo refine the diagnostic criteria for primary hyperparathyroidism (1°HPT) to identify atypical patients, in whom serum calcium, parathyroid hormone (PTH), or both are within the “normal” range.MethodsTotal serum calcium, intact PTH, and 25-hydroxyvitamin D [25(OH)D] levels were measured in patients with 1°HPT and healthy patient groups. Multivariate analysis of healthy patient data first identified factors that significantly affected PTH levels and defined a new PTH reference range with a mathematical model. That nomogram was then validated for prediction of atypical 1°HPT in patients with surgically confirmed disease.ResultsOn multivariate analysis, calcium (P = .0002), 25(OH)D (P < .0001), and age (P = .015) independently affected PTH. With these variables, we created a 4-dimensional nomogram that distinguished normal patients from those with hyperparathyroid states. Mathematically, this nomogram predicts 1°HPT when the measured serum PTH value is higher than PTH calculated by the following formula: PTH (pg/mL) = 120-[6 × calcium (mg/dL)]-[0.52 × 25(OH)D (ng/mL)] + [0.26 × patient age (years)]. When applied to our surgical group of patients, this nomogram successfully identified 100% of patients (238 of 238) with classic 1°HPT, 84% (64 of 76) with normocalcemic 1°HPT, and 54% (20 of 37) with 1°HPT and normal PTH.ConclusionThis study uniquely defines a patientspecific upper limit of normal for PTH based on the readily available variables of serum calcium, 25(OH)D, and patient age. Our nomogram may allow for more rapid definitive diagnosis and treatment of 1°HPT in patients with atypical presentations. (Endocr Pract. 2012;18:124-131)     

Selective resistance to parathyroid hormone caused by a novel uncoupling mutation in the carboxyl terminus of G alpha(s). A cause of pseudohypoparathyroidism type Ib

G(s) is a heterotrimeric (alpha, beta, and gamma chains) G protein that couples heptahelical plasma membrane receptors to stimulation of adenylyl cyclase. Inactivation of one GNAS1 gene allele encoding the alpha chain of G(s) (G alpha(s)) causes pseudohypoparathyroidism type Ia. Affected subjects have resistance to parathyroid hormone (PTH) and other hormones that activate adenylyl cyclase plus somatic features termed Albright hereditary osteodystrophy. By contrast, subjects with pseudohypoparathyroidism type Ib have hormone resistance that is limited to PTH and lack Albright hereditary osteodystrophy. The molecular basis for pseudohypoparathyroidism type Ib is unknown. We analyzed the GNAS1 gene for mutations using polymerase chain reaction to amplify genomic DNA from three brothers with pseudohypoparathyroidism type Ib. We identified a novel heterozygous 3-base pair deletion causing loss of isoleucine 382 in the three affected boys and their clinically unaffected mother and maternal grandfather. This mutation was absent in other family members and 15 additional unrelated subjects with pseudohypoparathyroidism type Ib. To characterize the signaling properties of the mutant G alpha(s), we used site-directed mutagenesis to introduce the isoleucine 382 deletion into a wild type G alpha(s) cDNA, transfected HEK293 cells with either wild type or mutant G alpha(s) cDNA, plus cDNAs encoding heptahelical receptors for PTH, thyrotropic hormone, or luteinizing hormone, and we measured cAMP production in response to hormone stimulation. The mutant G alpha(s) protein was unable to interact with the receptor for PTH but showed normal coupling to the other coexpressed heptahelical receptors. These results provide evidence of selective uncoupling of the mutant G alpha(s) from PTH receptors and explain PTH-specific hormone resistance in these three brothers with pseudohypoparathyroidism type Ib. The absence of PTH resistance in the mother and maternal grandfather who carry the same mutation is consistent with current models of paternal imprinting of the GNAS1 gene.     

Pseudohypoparathyroidism Type 1A and Morbid Obesity in Infancy

ObjectiveTo describe an infant with early excessive weight gain as the principle manifestation of pseudohypoparathyroidism (PHP) type 1a and Albright hereditary osteodystrophy (AHO).MethodsWe describe the clinical and laboratory findings in an infant with early excessive weight gain without evidence of hyperphagia and review relevant literature.ResultsThe proband’s birth weight was 4047 g (1.4 SD). She was breastfed from birth. Excessive weight gain was noted by 1 month of age. At 3 months of age, hard subcutaneous nodules were observed, and histologic analysis of a biopsied lesion suggested a possible diagnosis of ossified pilomatricoma. At 6 months of age, she was documented to have mild hypothyroidism. Abnormal weight gain continued despite a caloric intake of about 65 kcal/kg per day. At 11 months of age, 2 new subcutaneous hard nodules were identified, which in the context of excessive weight gain and evolving mild primary hypothyroidism, suggested a unifying diagnosis of PHP type 1a and AHO. GNAS sequence analysis was performed, which revealed a 4-base deletion (Nt565delGACT) in exon 8.ConclusionsAs more monogenic causes of severe early obesity are described, it is important to consider PHP type 1a in the differential diagnosis. Lack of short stature, skeletal abnormalities, or absence of PTH resistance should not exclude this diagnosis in a young child. (Endocr Pract. 2009;15:249-253)     

Separation of inhibitory activity from biologically active parathyroid hormone in patients with pseudohypoparathyroidism type I

Patients with pseudohypoparathyroidism type I have the symptoms of hypoparathyroidism despite elevated levels of immunoreactive parathyroid hormone (PTH). However, the circulating levels of bioactive PTH, as measured in a cytochemical bioassay, are generally within the normal range suggesting that the high levels of immunoreactive PTH are either due to the presence of biologically inactive fragments of parathyroid hormone or to the presence of an 'inhibitor' of PTH bioactivity. Gel-permeation chromatography has been used to fractionate plasma from patients with pseudohypoparathyroidism type I and revealed the presence of high levels of bioactive PTH and of an 'inhibitor'. This inhibitory activity was absent or much lower in plasma from control subjects. These results indicate, therefore, that in pseudohypoparathyroidism type I the expression of the biological activity of PTH at the level of the kidney is affected by the presence of a circulating inhibitor which can be separated from intact PTH by gel-permeation chromatography.     

Falsely Low Parathyroid Hormone Secondary to Biotin Interference: A Case Series

ObjectiveTo present a case series on biotin interference in parathyroid hormone (PTH) level measurement.MethodsWe review the presentation and management of patients at our institution evaluated for unexpectedly low PTH levels while taking biotin supplements in the setting of high or normal serum calcium.ResultsTwo patients presented with surprising low parathyroid levels—one during preoperative evaluation for hyperparathyroidism and another during postoperative follow-up after subtotal parathyroidectomy. The patients were found to be taking 1,500 mcg and 5,000 mcg of biotin per day, respectively. The role of biotin interference was confirmed in one of the patients when she was retested off biotin, and PTH levels responded appropriately. Biotin supplements remain as unbound molecules in the serum, thus interfering with PTH enzyme-linked immunosorbent assay (ELISA) results and falsely depressing the PTH level.ConclusionBiotin supplement use has expanded over the years, ranging from medically endorsed therapies to home remedies. Review of the 2 ELISA systems used at our institution demonstrates that free biotin mimics the biotinylated antibody used in the detection process. Screening for biotin use prior to PTH measurement and automatic biotin levels for clinically aberrant PTH levels provide the clinician with a true PTH level-lowering the disease burden of untreated hyperparathyroidism while avoiding unnecessary work-ups for other processes. (Endocr Pract. 2013;19:451-455)     

Insulin Resistance in Relation to Lipids and Inflammation in Type-2 Diabetic Patients and Non-Diabetic People

BackgroundWe demonstrated in experimental studies that hypercholesterolaemia enhances the proliferation of haematopoietic stem cells and the subsequent differentiation to neutrophils, whereas HDL-cholesterol inhibits these processes. To translate our experimental findings to clinical practice, we investigated in Chinese type-2 diabetic patients and in Flemish non-diabetic people the independent and joint associations of insulin resistance with markers of dyslipidaemia and inflammation, while looking for consistency between ethnicities and across the spectrum of insulin resistance.MethodsWe studied 798 Chinese patients with type-2 diabetes (53.6% women; mean age, 60.6 years) admitted to a tertiary referral centre and 1060 white Flemish (50.5%; 51.1 years) randomly recruited in Northern Belgium. Fasting insulin resistance (HOMA-IR) was derived from C-peptide in Chinese and from insulin in Flemish using the Homeostasis Model of Assessment algorithm. In multivariable-adjusted analyses, HOMA-IR was regressed on triglycerides, HDL-cholesterol and neutrophil count.ResultsIn Chinese patients, the percentage changes in HOMA-IR associated with triglycerides, HDL-cholesterol and neutrophils (per 1-SD increment) amounted to 8.1 (95% confidence interval, 3.0 to 13.4; p = 0.0015), -8.7 (-13.0 to -4.2; p = 0.0002) and 5.6 (1.0 to 10.4; p = 0.017). In non-diabetic Flemish, the corresponding estimates were 11.7 (8.3 to 15.1; p<0.0001), -1.7 (-4.6 to 1.4; p = 0.28) and 3.3% (0.5 to 6.3; p = 0.022), respectively. None of the interaction terms between the three explanatory variables reached significance in Chinese or Flemish (p≥0.10).ConclusionsInsulin resistance increases with the serum level of triglycerides and the blood neutrophil count, but decreases with serum HDL-cholesterol concentration. These associations were consistent in Chinese type-2 diabetic patients and non-diabetic Flemish people and were independent from one another. The clinical implications are that future studies should focus on intervening with serum triglyceride and HDL-cholesterol levels or controlling inflammation as a way to prevent or treat insulin resistance.     

A Parathyroid Hormone–Guided Calcium and Calcitriol Supplementation Protocol Reduces Hypocalcemia-Related Readmissions Following Total Thyroidectomy

ObjectiveTo determine the effect of a 4-hour postoperative serum parathyroid hormone (PTH)–guided calcium (Ca) and calcitriol supplementation protocol on the incidence of hypocalcemia and hospital readmissions in patients undergoing total thyroidectomy.MethodsThis was a single-institution, retrospective chart review of patients who underwent total thyroidectomy; 148 and 389 of the patients underwent surgery prior to and after the protocol implementation, respectively. The risk of hypocalcemia was stratified as low (PTH level of >30 pg/mL), medium (15-30 pg/mL), and high (<15 pg/mL), using serum PTH values obtained 4 hours postoperatively. Hypocalcemia was defined as a total serum Ca level of <8 mg/dL. Baseline demographic and operative characteristics and postoperative outcome were recorded for both groups. The Fisher exact test and Wilcoxon rank sum test were used to compare the characteristics of the 2 groups. A multivariate logistic regression model was applied to account for potentially confounding variables.ResultsPostoperative hypocalcemia occurred significantly less frequently in the protocol group compared with that in the preprotocol group (10.3% vs 20.9%, P = .002). The reduction in hypocalcemia in the protocol group was observed in both patients with (16.3% vs 25.6%) and without (8.4% vs 19.3%) cervical lymph node dissection. The protocol group had a significantly lower incidence of hospital readmission events than the preprotocol group (1.0% vs 4.7%, P = .013).ConclusionCompared with a historical cohort, a PTH-guided protocol for Ca and calcitriol supplementation significantly reduces the postoperative hypocalcemia and hospital readmission rates in patients undergoing total thyroidectomy.     

Expression - Level Dependent Activation of Recombinant Human Parathyroid Hormone/Parathyroid Hormone-Related Peptide Receptor: Effect of Human Parathyroid Hormone (1-34), (1-31), and (28-48)

Abstract

A stable recombinant Chinese hamster ovary (CHO) cell model system expressing the human type-1 receptor for parathyroid hormone and parathyroid hormone-related peptide (hPTH-R) was established for the analysis of human PTH (hPTH) variants. The cell lines showed receptor expression in the range from 10⁵ to 1.9xl0⁶ receptors per cell. The affinity of the receptors for hPTH-(l-34) was independent of the receptor number per cell (K<j = 8 nmol/1). The induction of cAMP by hPTH-(l-34) is maximal in clones expressing >2xl0⁵ receptors per cell and Ca⁺⁺ signals were maximal in cell lines expressing >1.4xl0⁶ receptors per cell. Second messenger specific inhibitors demonstrated that PTH-induced increases in intracellular cAMP and Ca⁺⁺ are independent and Ca⁺⁺ ions are derived from intracellular stores. The cAMP-specific receptor activator hPTH-(l-31) showed also an increase in intracellular Ca⁺⁺. Even in cell lines expressing more than 10 receptors per cell the Ca⁺⁺/PKC specific activator hPTH-(28-48) did not activate hPTH-Rs. Based on these results, synthesis of further derivatives of PTH is required to identify pathway-specific ligands for the type-1 hPTH-R.     

Three large, functioning cystic parathyroid adenomas

ObjectiveTo report a very rare case of 3 large, functioning cystic parathyroid adenomas causing primary hyperparathyroidism.MethodsWe present the history, clinical findings, laboratory test results, radiologic findings, endocrine workup results, intraoperative surgical challenges, and surgical pathology report of the study patient. We review the literature and discuss the importance of intraoperative parathyroid hormone (PTH) measurement in such cases.ResultsA 79-year-old woman presented with primary hyperparathyroidism and elevated levels of calcium and PTH. Localization studies confirmed the presence of a large right upper parathyroid adenoma. On exploration, a very large cystic parathyroid gland was identified at that location. Because intraoperative PTH levels remained elevated, further exploration was pursued, which revealed 2 more large cystic glands on the left side that were resected. This resulted in an adequate but slow PTH drop. The right lower gland appeared normal. On follow-up 4 days and 6 weeks after surgery, the calcium and PTH levels had normalized.ConclusionThis case highlights the aspects of intraoperative PTH use and underscores the need to exclude multigland disease even in the setting of a very large parathyroid cyst with concordant localization studies. (Endocr Pract. 2012;18:e14-e16)     

Normocalcemic Hyperparathyroidism and Insulin Resistance

ObjectiveTo determine whether insulin resistance (IR) accompanies normocalcemic primary hyperparathyroidism (NCPHP).MethodsTwenty-five patients with NCPHP and 25 age-, sex-, and body mass index (BMI)-matched controls were included the study. Patients were diagnosed NCPHP if their serum calcium (Ca) concentrations and ionized serum Ca levels were in the normal range but parathyroid hormone (PTH) levels were inappropriately and persistently high. Subjects with 25-hydroxyvitamin D (25[OH]D) levels ≥ 20 ng/dL were included in the study. The upper limit of PTH was calculated using a nomogram for each subject. Patients and controls underwent a standard 75-gram oral glucose tolerance test (OGTT). IR was assessed by the homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISogtt).ResultsThere were no differences between the demographic features of patients with NCPHP and the control group. IR frequency was not different between groups (P = .14). HOMA-IR was higher and ISogtt was lower in patients with NCPHP than the control group, but the differences were not significant (P = .17 and P = .22, respectively). We did not find any correlation between PTH and glucose metabolism markers (HOMA-IR, ISogtt, glycated hemoglobin [HbAlc], and BMI) in either of the groups.ConclusionThe results of this study indicate that IR is not more common in patients with NCPHP, and PTH is not related to ISogtt or HOMA-IR. (Endocr Pract. 2015; 21:23-29)     

Suppressibility of Parathyroid Hormone in Primary Hyperparathyroidism

ObjectiveTo describe an unusual case of pathologically confirmed primary hyperparathyroidism in a patient presenting with severe hypercalcemia and an undetectable parathyroid hormone (PTH) level.MethodsWe present a detailed case report and outline the serial laboratory findings. In addition, the possible causes of low serum PTH levels in the setting of primary hyperparathyroidism are discussed.ResultsA 16-year-old female patient presented with severe epigastric pain, found to be attributable to acute pancreatitis. At hospital admission, her serum calcium concentration was high (14.0 mg/dL); the patient also had a normal serum phosphorus level of 3.6 mg/dL and an undetectable PTH level (< 0.2 pmol/L). An evaluation for non-PTH-mediated causes of hypercalcemia revealed a partially suppressed thyroid-stimulating hormone concentration and a below normal 1,25-dihydroxyvitamin D level, consistent with her suppressed PTH. One week after the patient was dismissed from the hospital, repeated laboratory studies showed a serum calcium value of 11.1 mg/dL, a serum phosphorus level of 2.8 mg/dL, and an elevated PTH concentration of 11.0 pmol/L, consistent with primary hyperparathyroidism. A repeated 1,25-dihy-droxyvitamin D measurement was elevated. A parathyroid scan showed a parathyroid adenoma in the left lower neck area, and she subsequently underwent successful surgical resection of a pathologically confirmed parathyroid adenoma.ConclusionThis case demonstrates that the serum PTH level can be suppressed in patients with primary hyperparathyroidism. Moreover, it emphasizes the need for careful evaluation of the clinical context in which the PTH measurement is determined. Consideration should be given to repeating measurement of PTH and serum calcium levels when the initial laboratory evaluation of hypercalcemia is unclear because dynamic changes in calcium metabolism may occur in the presence of secondary contributing factors. (Endocr Pract. 2007;13:785-789)     

Greater Than Age-Predicted Functional Deficits In Older Patients with Primary Hyperparathyroidism

ObjectiveTo compare the functional capacity of “asymptomatic” patients with primary hyperparathyroidism (PHPT) with normative values of healthy age-matched subjects.MethodsEighteen asymptomatic patients with PHPT met the study inclusion criteria: age > 55 years, serum calcium concentration elevated ≤ 1 mg/dL above normal, inappropriate elevation of parathyroid hormone (PTH) level, and no objective symptoms of PHPT. Functional capacity was assessed by (1) a 6-minute walk test, (2) time to complete 2 sit-to-stand maneuvers, (3) gait velocity, and (4) forward reach. Serum calcium, 25-hydroxyvitamin D, and PTH levels were measured by standard laboratory assays. Functional outcomes of the study patients were compared with age-matched normative values (unpaired t test) and correlated with these biomarkers. Because these patients often have weakness, fatigue, and malaise, we hypothesized that their functional capacity would be compromised relative to that of healthy, age-matched persons.ResultsThe mean age of the patients was 65.6 years, and the mean serum calcium, PTH, and 25-hydroxyvitamin D levels (and standard deviations) were 10.36 ± 0.37 mg/dL, 122.22 ± 39.54 pg/mL, and 44.4 ± 14.27 ng/mL, respectively. Relative to normative values of healthy, agematched subjects, these patients had comparable 6-minute walk distances but required a 37% longer time to complete a repeated sit-to-stand maneuver (P < .05), demonstrated a 52% slower gait speed (P < .001), and had a greater forward reach (P = .05).ConclusionOur findings suggest that older asymptomatic patients with PHPT may have significant functional deficits that can affect their safety and quality of life. Therefore, their functional capacity should be routinely evaluated, and identified deficits should be treated with appropriate interventions. (Endocr Pract. 2012;18: 450-455)     

Use of Xpert MTB/RIF in Decentralized Public Health Settings and Its Effect on Pulmonary TB and DR-TB Case Finding in India

BackgroundXpert MTB/RIF, the first automated molecular test for tuberculosis, is transforming the diagnostic landscape in high-burden settings. This study assessed the impact of up-front Xpert MTB/RIF testing on detection of pulmonary tuberculosis (PTB) and rifampicin-resistant PTB (DR-TB) cases in India.MethodsThis demonstration study was implemented in 18 sub-district level TB programme units (TUs) in India in diverse geographic and demographic settings covering a population of 8.8 million. A baseline phase in 14 TUs captured programmatic baseline data, and an intervention phase in 18 TUs had Xpert MTB/RIF offered to all presumptive TB patients. We estimated changes in detection of TB and DR-TB, the former using binomial regression models to adjust for clustering and covariates.ResultsIn the 14 study TUs, which participated in both phases, 10,675 and 70,556 presumptive TB patients were enrolled in the baseline and intervention phase, respectively, and 1,532 (14.4%) and 14,299 (20.3%) bacteriologically confirmed PTB cases were detected. The implementation of Xpert MTB/RIF was associated with increases in both notification rates of bacteriologically confirmed TB cases (adjusted incidence rate ratio [aIRR] 1.39; CI 1.18-1.64), and proportion of bacteriological confirmed TB cases among presumptive TB cases (adjusted risk ratio (aRR) 1.33; CI 1.6-1.52). Compared with the baseline strategy of selective drug-susceptibility testing only for PTB cases at high risk of drug-resistant TB, Xpert MTB/RIF implementation increased rifampicin resistant TB case detection by over fivefold. Among, 2765 rifampicin resistance cases detected, 1055 were retested with conventional drug susceptibility testing (DST). Positive predictive value (PPV) of rifampicin resistance detected by Xpert MTB/RIF was 94.7% (CI 91.3-98.1), in comparison to conventional DST.ConclusionIntroduction of Xpert MTB/RIF as initial diagnostic test for TB in public health facilities significantly increased case-notification rates of all bacteriologically confirmed TB by 39% and rifampicin-resistant TB case notification by fivefold.     

Paternal uniparental isodisomy of chromosome 20q--and the resulting changes in GNAS1 methylation--as a plausible cause of pseudohypoparathyroidism

Heterozygous inactivating mutations in the GNAS1 exons (20q13.3) that encode the alpha-subunit of the stimulatory G protein (Gsalpha) are found in patients with pseudohypoparathyroidism type Ia (PHP-Ia) and in patients with pseudo-pseudohypoparathyroidism (pPHP). However, because of paternal imprinting, resistance to parathyroid hormone (PTH)-and, sometimes, to other hormones that require Gsalpha signaling-develops only if the defect is inherited from a female carrier of the disease gene. An identical mode of inheritance is observed in kindreds with pseudohypoparathyroidism type Ib (PHP-Ib), which is most likely caused by mutations in regulatory regions of the maternal GNAS1 gene that are predicted to interfere with the parent-specific methylation of this gene. We report a patient with PTH-resistant hypocalcemia and hyperphosphatemia but without evidence for Albright hereditary osteodystrophy who has paternal uniparental isodisomy of chromosome 20q and lacks the maternal-specific methylation pattern within GNAS1. Since studies in the patient's fibroblasts did not reveal any evidence of impaired Gsalpha protein or activity, it appears that the loss of the maternal GNAS1 gene and the resulting epigenetic changes alone can lead to PTH resistance in the proximal renal tubules and thus lead to impaired regulation of mineral-ion homeostasis.     

Pseudohypoparathyreoidismus und epigenetische Veränderungen des GNAS-Genlocus

The term pseudohypoparathyroidism (PHP) describes a heterogeneous group of related disorders characterized by end-organ resistance to parathyroid hormone (PTH). PHP is caused by deficiency of the α-subunit of stimulatory G proteins (Gsα), which is crucial for signal transduction of more than 1000 G protein-coupled receptors into the cell. PHP type Ia is caused by heterozygous, maternally inherited inactivating mutations involving those exons of the GNAS locus that encode Gsα. In addition, PHP Ia and Ic patients present with features of Albright hereditary osteodystrophy (AHO), which includes round face, short stature, brachymetacarpia, ectopic ossification, and mental retardation. Paternally inherited GNAS mutations lead to pseudo-PHP and are characterized by only some features of AHO in the absence of hormone resistance. PHP type Ib is caused by heterozygous, maternally inherited deletions up-stream of or within the GNAS locus that are associated with the loss of methylation at one or more maternally methylated regions within GNAS . Typically, these patients lack AHO features. This article provides an overview of the role of epigenetic factors for different PHP subtypes.     

A Sporadic Case of Pseudohypoparathyroidism Type 1 and Idiopathic Primary Adrenal Insufficiency Associated with a Novel Mutation in the Gnas1 Gene

ObjectiveWe report an atypical association of primary adrenal insufficiency and pseudohypoparathyroidism (PHP) and a novel GNAS1 gene mutation in a Caucasian female who initially presented with adrenal crisis.MethodsA case report and literature review.ResultsA 37-year-old female presented with shock at 11 years of age, and investigations revealed primary adrenal insufficiency and pseudohypoparathyroidism (PHP). She had typical features of Albright hereditary osteodystrophy (AHO) and evidence of thyroid-stimulating hormone (TSH), growth-hormone-releasing hormone (GHRH), and gonadotrophin resistance fitting with the diagnosis of PHP type 1a/1c. She did not have a family history of any autoimmune disease or PHP. Her mother was phenotypically normal. Genomic DNA sequencing of those GNAS exons and adjacent intronic regions that encode the stimulatory guanine nucleotide-binding protein Gsαrevealed a novel heterozygous mutation in exon 11, c.857-858delCT.ConclusionThe association of primary adrenal insufficiency and PHP has not been reported in literature and may prove an area for further research. The novel mutation in this case adds to the spectrum of mutations associated with these disorders. (Endocr Pract. 2014;20:e202-e206)     

Serum intact parathyroid hormone concentration measured by a two-site immunoradiometric assay in normal subjects and patients with various parathyroid disorders.

Serum intact parathyroid hormone (PTH) concentration was measured by a two-site immunoradiometric assay (IRMA) in normal subjects and patients with various parathyroid disorders. Serum intact PTH levels were all within the detection limit of the IRMA in normal subjects, and there was a significant negative correlation between serum calcium (Ca) and intact PTH levels. Although 3 out of 26 patients (11.5%) with primary hyperparathyroidism had a normal serum intact PTH concentration, these patients could be readily discriminated from normal subjects by plotting serum intact PTH against the serum Ca concentration. In contrast, serum intact PTH was undetectable in 16 out of 17 patients (94.1%) with idiopathic hypoparathyroidism. Patients with pseudohypoparathyroidism (PHP) type I, mostly under treatment with active vitamin D, exhibited wide distribution of serum intact PTH concentration, and appeared to belong to two distinct subgroups. One group of patients demonstrated a similar relationship between serum intact PTH and Ca levels to normal subjects. The other exhibited much higher serum intact PTH levels despite a normal serum Ca concentration, and no obvious relationship could be observed between the two parameters. These results demonstrate that an inverse relationship between serum Ca and intact PTH can be demonstrated in normal subjects with normocalcemia, that most of the parathyroid disorders can be diagnosed by measuring serum Ca and the intact PTH concentrations simultaneously, and that patients with PHP can be divided into two subgroups: one with a normal relationship between serum Ca and intact PTH, and the other with a high serum PTH level in the face of normocalcemia.     

Association Between Aldosterone and Parathyroid Hormone Levels in Patients With Adrenocortical Tumors

ObjectivePatients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency.MethodsWe enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed.ResultsAldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism.ConclusionPTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established.