Congenital Hypoparathyroidism Associated With Elevated Circulating Nonfunctional Parathyroid Hormone Due to Novel PTH Mutation

Abstract Context Familial hypoparathyroidism has a heterogeneous presentation where patients usually have low parathyroid hormone (PTH) levels due to impaired production or secretion. This contrasts with pseudohypoparathyroidism, in which PTH resistance is usually associated with an elevated serum PTH. High levels of circulating PTH can also be due to bioinactive PTH, which is difficult to distinguish from pseudohypoparathyroidism on biochemical grounds. Case Description We report on 2 sisters from consanguineous parents who presented with tetany at birth and were diagnosed with congenital hypocalcemia. Serum PTH levels were normal for many years, but progressively increased in midadulthood to greater than 100x the upper limit of normal on multiple assays. Homozygosity mapping was performed on 1 sister that demonstrated loss of heterozygosity (LOH) around PTH. Sequencing revealed a previously unreported variant, c.94T>C, predicting a codon change of p.Ser32Pro that is biologically inactive. Conclusions This case report shows a previously unreported unusual biochemical phenotype of a rising PTH in the context of a novel PTH mutation. This expands the evolving genotypes associated with hypoparathyroidism without established gene mutations.

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Performance and Clinical Utility of a Commercially Available ‘C-terminal’ PTH Assay

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328602300409 ◽

1986 ◽

Vol 23 (4) ◽

pp. 434-439 ◽

Cited By ~ 7

Author(s):

A R Ingle ◽

J E Bailey ◽

H L Matthews ◽

J S Harrop

Keyword(s):

Renal Failure ◽

Parathyroid Hormone ◽

Clinical Utility ◽

Blood Samples ◽

Upper Limit ◽

Whole Blood Samples ◽

Serum Pth ◽

Pth Radioimmunoassay ◽

Detectable Serum

The performance and clinical utility of a ‘C-terminal’ parathyroid hormone (PTH) radioimmunoassay (Dac-Cel, Wellcome Diagnostics) is described. Parathyroid hormone, as measured by the Dac-Cel method, is stable in whole blood samples for at least 24 h. 84% of patients with hypercalcaemia due to primary hyperparathyroidism have values above the upper limit seen in normocalcaemic subjects (0·5 μg/L), with detectable serum PTH demonstrable in the remaining 16%. In patients with hypocalcaemia due to hypoparathyroidism serum PTH was undetectable in 73% and ‘inappropriately’ low in the remainder. In 50% of patients with malignancy-associated hypercalcaemia serum PTH was undetectable, but was above 0·5 μg/L in 13%. Increased PTH concentrations were invariably found in patients with renal failure. The Dac-Cel method is a reliable and robust technique for measurement of PTH and in conjunction with determination of calcium facilitates the diagnosis of primary parathyroid disorders. Caution is required in the interpretation of PTH measurements in patients with renal failure; the significance of detectable PTH in some patients with malignancy-associated hypercalcaemia is not clear.

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OR07-01 Identification of the First Case of Acquired Autoimmune Parathyroid Hormone (PTH) Resistance Due to PTH1 Receptor (PTH1R) Autoantibodies

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1844 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Adel Mandl ◽

Peter D Burbelo ◽

Giovanni DiPasquale ◽

James Welch ◽

William F Simonds ◽

...

Keyword(s):

Parathyroid Hormone ◽

Autoimmune Diseases ◽

Elevated Serum ◽

American Woman ◽

Dependent Manner ◽

Hormone Resistance ◽

First Case ◽

Symptomatic Hypocalcemia ◽

Pth Resistance ◽

Autoimmune Etiology

Abstract Background: Here we describe a patient who presented with symptomatic hypocalcemia and a biochemical picture suggestive of PTH resistance. PTH resistance is a hallmark of pseudohypoparathyroidism, a heterogeneous group of rare disorders caused by genetic or epigenetic alterations of PTH/PTHrP signaling. However, PTH receptor-related autoimmune etiology has not been identified as the underlying mechanism for PTH resistance. Here we describe the first case of acquired autoimmune PTH resistance that is secondary to PTH1R autoantibodies. Clinical Case: A 60-year-old African-American woman, who previously had normal calcium homeostasis, presented with acute, symptomatic hypocalcemia, hyperphosphatemia and markedly elevated serum PTH, consistent with parathyroid hormone resistance. She did not have other hormone resistance or a clinical phenotype suggestive of pseudohypoparathyroidism. Whole-exome sequencing and GNAS methylation analysis revealed no genetic or epigenetic defects of the PTH/PTHrP signaling pathway. Treatment with Calcitriol and Calcium supplements was initiated with good clinical response. Within 10 years of follow-up, the patient developed autoimmune hypothyroidism, alopecia and an unusual form of membranous glomerulonephritis, raising the suspicion for an autoimmune etiology for PTH resistance. Luciferase immunoprecipitation system assay identified antibodies against PTH1R with mapping to the N-terminal extracellular ligand-binding domain (amino acids 1- 178). Using an in vitro biological assay in GP-2.3 cells, we found that the antibodies derived from the patient’s serum blocked PTH downstream signaling via Gsalpha/cAMP/protein kinase A pathway in a concentration-dependent manner. The patient’s autoantibody profile led to the diagnosis of additional autoimmune diseases, including atrophic gastritis and Sjogren syndrome. Lymphocyte immunophenotyping using flow cytometry revealed an overall normal B and T cell profile, but with decreased frequencies and numbers of switched and non-switched memory B cell subsets and an increased frequency and number of the CD8+ naïve cell population. Genes associated with autoimmune inflammatory disorders were sequenced but no pathologic changes were detected. Conclusions: Identification of the first case of autoimmune PTH resistance secondary to PTH1R autoantibodies extends the etiologic spectrum of hypoparathyroidism and should be considered when a patient presents with findings consistent with pseudohypoparathyroidism, especially in the presence of additional autoimmune diseases.

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Elevated serum parathyroid hormone predicts impaired survival prognosis in a general aged population

Acta Endocrinologica ◽

10.1530/eje-07-0849 ◽

2008 ◽

Vol 158 (5) ◽

pp. 749-753 ◽

Cited By ~ 35

Author(s):

Mikko P Björkman ◽

Antti J Sorva ◽

Reijo S Tilvis

Keyword(s):

Parathyroid Hormone ◽

Elevated Serum ◽

Mortality Data ◽

Prognostic Impact ◽

Serum Parathyroid Hormone ◽

Survival Prognosis ◽

Aged Population ◽

Co Morbidity ◽

Serum Pth

ObjectiveShort-term studies on selected patients have indicated that elevated serum parathyroid hormone (PTH) is an independent risk factor of death. However, long-term data on unselected populations are lacking, thus far. In order to evaluate the predictive value of elevated serum PTH during the last years of life, random persons of age cohorts of 75, 80 and 85 years were followed for 17 years.DesignA prospective cohort study.MethodsSubjects (n=567) were investigated for calcaemic status including serum intact PTH, serum total calcium (CaT) and ionized calcium (Ca2+). Thorough clinical examinations included an assessment of co-morbidity. Mortality data were collected from National Census Records.ResultsUp to 93% of the subjects died within the follow-up. In contrast to Ca2+ levels, high serum PTH (≥63 ng/l, IV quartile cut point) was associated with significant over-mortality (HR=1.56, 95% CI: 1.29–1.88) and a 2.3-year reduction of median life expectancy. After controlling for age, gender, co-morbidity and creatinine, the prognostic impact of elevated serum PTH was still significant (HR=1.24, 95% CI: 1.01–1.53). The tendency for over-mortality was consistent in both genders, in all age groups as well as in subjects with varying co-morbidity, renal function, body mass index categories and Ca2+ levels.ConclusionsElevated serum PTH level is an independent predictor of impaired long-term survival prognosis in unselected aged population. Serum Ca2+ did not emerge as a significant prognostic indicator. The long-term prognostic impact of vitamin D deficiency, the most common cause of elevated PTH levels in the elderly, remains to be investigated.

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Moderators of the Association Between Serum Parathyroid Hormone and Metabolic Syndrome in Participants with Elevated Parathyroid Hormone: NHANES 2003–2006

Hormone and Metabolic Research ◽

10.1055/a-1148-2546 ◽

2020 ◽

Vol 52 (07) ◽

pp. 509-516

Author(s):

Liang Chen ◽

Jian-Hao Pei ◽

Jian Kuang

Keyword(s):

Physical Activity ◽

Metabolic Syndrome ◽

Vitamin D ◽

Parathyroid Hormone ◽

Protein Intake ◽

Elevated Serum ◽

Vitamin D Supplementation ◽

Serum Parathyroid Hormone ◽

Severity Scores ◽

Serum Pth

AbstractThis cross-sectional study extracted data of 392 NHANES participants with elevated serum parathyroid hormone (PTH) concentrations from 2 cycles of the US National Health and Nutrition Examination Survey (NHANES) 2003–2006 and evaluated the association between serum (PTH) concentration and metabolic syndrome (MetS) to identify dietary and lifestyle factors that may modify that association. The primary outcome was MetS severity scores. Results of univariate linear regression analyses revealed that serum PTH concentrations correlated positively and significantly with MetS severity scores (β=0.399, p=0.030). After adjusting for gender, age, race, and alcohol consumption, results of multivariate analysis revealed that increased serum PTH concentration correlated significantly with higher MetS severity scores (β=0.413, p=0.045) in participants with moderate physical activity over the past 30 days. Serum PTH concentration also correlated significantly with higher MetS severity scores in participants with serum 25-hydroxyvitamin D deficiency (β=0.456 and p=0.014), those without vitamin D supplementation (β=0.524, p=0.028) and with higher protein intake (β=0.586 and p=0.030). In conclusion, increased serum PTH concentration is associated with higher MetS severity scores in participants with elevated serum PTH at baseline. The association between PTH concentration and MetS severity is moderated by participants’ physical activity levels, status of serum vitamin D, vitamin D supplementation, and daily protein intake.

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Low serum parathyroid hormone is a risk factor for peritonitis episodes in incident peritoneal dialysis patients: a retrospective study

BMC Nephrology ◽

10.1186/s12882-021-02241-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuqi Yang ◽

Jingjing Da ◽

Yi Jiang ◽

Jing Yuan ◽

Yan Zha

Keyword(s):

Risk Factor ◽

Peritoneal Dialysis ◽

Parathyroid Hormone ◽

Proportional Hazard ◽

Serum Parathyroid Hormone ◽

Cox Proportional Hazard ◽

Cox Proportional Hazard Regression ◽

Gram Negative Organisms ◽

Serum Pth

Abstract Background Serum parathyroid hormone (PTH) levels have been reported to be associated with infectious mortality in peritoneal dialysis (PD) patients. Peritonitis is the most common and fatal infectious complication, resulting in technique failure, hospital admission and mortality. Whether PTH is associated with peritonitis episodes remains unclear. Methods We examined the association of PTH levels and peritonitis incidence in a 7-year cohort of 270 incident PD patients who were maintained on dialysis between January 2012 and December 2018 using Cox proportional hazard regression analyses. Patients were categorized into three groups by serum PTH levels as follows: low-PTH group, PTH < 150 pg/mL; middle-PTH group, PTH 150-300 pg/mL; high-PTH group, PTH > 300 pg/mL. Results During a median follow-up of 29.5 (interquartile range 16–49) months, the incidence rate of peritonitis was 0.10 episodes per patient-year. Gram-positive organisms were the most common causative microorganisms (36.2%), and higher percentage of Gram-negative organisms was noted in patients with low PTH levels. Low PTH levels were associated with older age, higher eGFR, higher hemoglobin, calcium levels and lower phosphate, alkaline phosphatase levels. After multivariate adjustment, lower PTH levels were identified as an independent risk factor for peritonitis episodes [hazard ratio 1.643, 95% confidence interval 1.014–2.663, P = 0.044]. Conclusions Low PTH levels are independently associated with peritonitis in incident PD patients.

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Use of CA-125 to Define Progression of Ovarian Cancer in Patients With Persistently Elevated Levels

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.20.4054 ◽

2001 ◽

Vol 19 (20) ◽

pp. 4054-4057 ◽

Cited By ~ 139

Author(s):

Gordon J.S. Rustin ◽

Maria Marples ◽

Ann E. Nelstrop ◽

Mohamed Mahmoudi ◽

Tim Meyer

Keyword(s):

Ovarian Cancer ◽

Clinical Trials ◽

Myocardial Infarct ◽

Elevated Serum ◽

Epithelial Ovarian Carcinoma ◽

Ca 125 ◽

Clinical Progression ◽

False Positive Prediction ◽

Upper Limit ◽

Accurate Definition

PURPOSE: To determine an accurate definition for progression of ovarian cancer in patients with a persistently elevated serum CA-125. PATIENTS AND METHODS: A retrospective analysis was performed on 300 patients with epithelial ovarian carcinoma with at least one measurement of CA-125. The date of progression according to clinical or radiologic criteria was ascertained in the 88 patients with persistently elevated CA-125 levels (> 23 U/mL). This was compared with the date of progression according to CA-125, defined as the date on which the CA-125 level first increased to ≥ twice its nadir level, confirmed by a second sample also ≥ twice the nadir. RESULTS: Eighty of the 88 patients had evidence of progression by both standard and CA-125 criteria, giving a sensitivity of 94%. In six of these patients, no sample was taken to confirm CA-125 doubling. In 13 patients, CA-125 doubling occurred after the date of clinical progression. Only one patient had a false-positive prediction of progression according to CA-125; the patient died as a result of a myocardial infarct before evidence of clinical progression. CONCLUSION: In patients whose CA-125 level decreases to normal after chemotherapy, a doubling from the upper limit of normal has been shown to predict progression. In those with persistently elevated levels, doubling of CA-125 from its nadir level has now been shown to accurately define progression. If confirmed, these CA-125 criteria should be used as additional end points in clinical trials.

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Abstract P036: Parathyroid Hormone is Associated with All-Cause and Cardiovascular Mortality: The Hoorn Study

Circulation ◽

10.1161/circ.127.suppl_12.ap036 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Adriana J van Ballegooijen ◽

Ilse Reinders ◽

Marjolein Visser ◽

Jacqueline M Dekker ◽

Giel Nijpels ◽

...

Keyword(s):

Parathyroid Hormone ◽

Cox Regression ◽

Threshold Model ◽

Older Men ◽

Population Based ◽

Survival Curves ◽

Men And Women ◽

Serum Pth ◽

Older Men And Women ◽

Cvd Mortality

Introduction Higher parathyroid hormone (PTH) concentrations have been associated with increased cardiovascular disease (CVD) mortality, although data in the general population are scarce. Hypothesis We hypothesize that higher serum PTH concentrations are associated with all-cause and CVD mortality in a prospective, population-based cohort of older men and women. Methods We included 633 participants of the Hoorn Study, a population-based cohort with oversampling of subjects with impaired glucose regulation; mean age 70.1±6.6 years, 50.7% female. Serum intact PTH concentrations were measured using a 2-site immunoassay. Outcomes were all-cause and CVD mortality based on clinical files and coded according to the ICD-9. We used Cox-regression to estimate survival curves and hazard ratios (HR 95% CI) for all-cause and CVD mortality adjusted for potential confounders using season-specific PTH quartiles. Results During a median follow-up of 7.8 years, 112 participants died, of which 26 deaths (23%) were due to CVD. Survival curves showed an impaired survival for all-cause (Log-rank p=0.054) and CVD mortality (Log-rank p=0.022) for people in the highest PTH quartile (Figure 1). In a multivariate model adjusted for age, sex, smoking, education level, BMI, glucose status, systolic blood pressure, anti-hypertensive drug use, the highest PTH quartile was associated with higher all-cause mortality; HR 1.98 (1.08, 3.64). Kidney function (estimated glomerular filtration rate and micro-albuminuria) attenuated the PTH risk association, but risk persisted; HR 1.93 (95% CI 1.04, 3.58). The results for CVD mortality showed a similar pattern, although the association was only significant in a threshold model (Quartile 4 vs. Quartile 1-3) HR 2.56 (1.11, 5.94). Conclusion In conclusion, among older men and women, higher PTH concentrations are associated with higher mortality risk. We suggest to evaluate whether individuals with high PTH concentrations benefit from therapeutic approaches targeted to decrease PTH concentrations.

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Aging alters calcium regulation of serum concentration of parathyroid hormone in healthy men

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.1.e139 ◽

1997 ◽

Vol 272 (1) ◽

pp. E139-E146 ◽

Cited By ~ 4

Author(s):

A. A. Portale ◽

E. T. Lonergan ◽

D. M. Tanney ◽

B. P. Halloran

Keyword(s):

Parathyroid Hormone ◽

Young Men ◽

The Elderly ◽

Ionized Calcium ◽

Elderly Men ◽

Elderly Age ◽

Healthy Men ◽

Age Related ◽

Serum Pth ◽

The Relationship

We examined the effect of aging on the relationship between the concentrations of blood ionized calcium and of serum parathyroid hormone (PTH) in 22 healthy men [9 elderly (age 74 +/- 2 yr) and 13 young (age 39 +/- 1 yr)] in whom the glomerular filtration rate was > 70 ml/min. Throughout a 24-h period, serum concentrations of PTH in the elderly men were twice those in the young men, whereas blood ionized calcium did not differ between the two groups. With intravenous infusion of calcium gluconate, the minimum PTH concentration was two- to threefold higher in the elderly men. With infusion of NaEDTA. the maximum PTH concentration was 20% higher in the elderly men. The calcium set point for PTH release was higher in the elderly than in the young men (4.71 +/- 0.04 vs. 4.54 +/- 0.03 mg/dl, respectively, P < 0.005). In these healthy men, the age-related increase in serum PTH could not be attributed to a sustained decrease in concentration of either blood ionized calcium or 1,25-hydroxyvitamin D. These findings suggest that, with aging, the relationship between calcium and PTH is altered such that at any given level of calcium, the concentration of PTH is higher.

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Effects of Orai3-Mediated Store-Operated Calcium Entry on Parathyroid Hormone Release in Secondary Hyperparathyroidism

10.21203/rs.3.rs-205615/v1 ◽

2021 ◽

Author(s):

Zhangying Lin ◽

Shuhao Wang ◽

Yanxun Han ◽

Junwei Zhu ◽

Suwen Bai ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Parathyroid Hormone ◽

Secondary Hyperparathyroidism ◽

Tumor Development ◽

Parathyroid Tissue ◽

Hormone Release ◽

Common Complication ◽

Store Operated Calcium Entry ◽

Serum Pth ◽

Parathyroid Hormone Release

Abstract Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease, is characterized by elevated parathyroid hormone (PTH) secretion and Hypocalcemia. Orai3 is a highly selective calcium (Ca2+) channel that plays important roles in tumor development, cardiovascular disease, and autoimmune diseases; however, its role in SHPT is unclear. In the present study, RNA sequencing and western blot assays were used to detect the expression levels of Orai3 in parathyroid tissue from patients with SHPT and from individuals without SHPT. Ca2+ imaging was used to detect the effect of Orai3 channels on Ca2+ signaling in parathyroid gland cells. Enzyme-linked immunosorbent assays were used to detect changes in PTH release. Orai3 knockout rats were used to detect the effect of decreased Orai3 expression on serum PTH levels. We found that the expression of Orai3 in parathyroid tissue obtained from patients with SHPT was significantly higher than that in patients without SHPT. Knockdown of Orai3 in parathyroid cells by transfection with Orai3-specific small inhibitor RNA inhibited store-operated Ca2+ entry (SOCE) in parathyroid cells. Inhibition of SOCE or knockdown of Orai3 significantly inhibited PTH release in parathyroid cells. PTH levels in the blood of Orai3 knockout rat were significantly reduced. Therefore, Orai3 expression and Orai3-mediated Ca2+ signaling may be a mechanism underlying PTH release, and Orai3 may play a role in the development of SHPT.

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