Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review.

The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Development of a Hypoparathyroid Male Rodent Model for Testing Delayed-Clearance PTH Molecules.

CONTEXT: Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH). OBJECTIVE: The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues. METHODS: Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64. RESULTS: Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P < .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity. CONCLUSION: The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.

Hypoparathyroidism: State of the Art on Cell and Tissue Therapies.

Hypoparathyroidism is an endocrine disorder characterized by low serum calcium levels, high serum phosphorus levels, and by inappropriate or absent secretion of the parathyroid hormone (PTH). The most common therapeutic strategy to treat this condition is hormone replacement therapy with calcium and vitamin D but, unfortunately, in the long term this treatment may not be sufficient to compensate for the loss of endocrine function. Glandular autotransplantation is considered the most effective technique in place of replacement therapy. Although it leads to excellent results in most cases, autotransplantation is not always possible. Allograft is a good way to treat patients who have not been able to undergo autograft, but this technique has limited success due to side effects related to tissue rejection. This therapy is supported by systemic immunosuppression, which leads to the onset of serious side effects in patients, with a risk of endocrine toxicity. Today, research on endocrine disorders is focused on discovering alternative graft therapies that can allow optimal results with the fewest possible side effects. In this review, we will make an update on the current state of the art about the cell and tissue therapy as treatment for hypoparathyroidism, to identify which type of therapeutic strategy could be valid for a future clinical use.

Late Recovery of Parathyroid Function After Total Thyroidectomy: A Case-Control Study.

The clinical characteristics of patients with postoperative hypoparathyroidism who recover parathyroid function more than 12 months after surgery have not been studied. We aimed to evaluate whether the intensity of replacement therapy with calcium and calcitriol is related to the late recovery of parathyroid function. We compared the demographic, surgical, pathological, and analytical features of two groups of patients: cases, i. e., late recovery patients (those who recover parathyroid function>1 year after thyroidectomy, n=40), and controls, i. e., patients with permanent hypoparathyroidism (n=260). Replacement therapy with calcium and calcitriol was evaluated at discharge of surgery, 3-6 months, 12 months, and last visit. No significant differences were found in clinical, surgical, pathological, or analytical characteristics between cases and controls. The proportion of cases who required treatment with calcium plus calcitriol at 12 months was significantly lower than that found in controls (p<0.001). Furthermore, daily calcium and calcitriol doses in controls were significantly higher than those in cases at 3-6 months (p=0.014 and p=0.004, respectively) and at 12 months (p<0.001 and p=0.043, respectively). In several models of logistic regression analysis therapy with calcium and calcitriol at 12 months was negatively related to late recovery of parathyroid function. Although delayed recuperation of parathyroid function after total thyroidectomy is uncommon (13%), follow-up beyond 12 months is necessary in patients with postoperative hypoparathyroidism, especially in those whose needs of treatment with Ca and calcitriol are reducing over time.

Impact of Permanent Post-thyroidectomy Hypoparathyroidism on Self-evaluation of Quality of Life and Voice: Results From the National QoL-Hypopara Study.

OBJECTIVE: The aim of this study was to compare the quality of life (mental health) and voice in patients with or without permanent hypoparathyroidism after total thyroidectomy. SUMMARY BACKGROUND DATA: Permanent hypoparathyroidism is an underestimated complication of thyroid surgery owing to suppression of parathormone secretion. Few studies have evaluated the consequences of hypoparathyroidism on quality of life and none has studied its effects on voice. METHODS: The QoL-hypopara study (ClinicalTrial.gov NCT04053647) was a national observational study. Adult thyroidectomized patients were included between January and June 2020. A serum parathormone level <15 pg/mL >6 months after surgery defined permanent hypoparathyroidism. Patients answered the MOS-36-item short-form health (SF-36), the Voice Handicap Index (VHI) surveys, and a list of questions regarding their symptoms. RESULTS: A total of 141 patients were included, 45 with permanent hypoparathyroidism. The median period between thyroid surgery and the questionnaire was 6 (Q1-Q3 4-11) and 4 (4-5) years in hypoparathyroid patients and controls respectively. Hypoparathyroid patients presented a reduced median mental score ratio (SF-36) [0.88 (Q1-Q3 0.63-1.01) vs 1.04 (0.82-1.13), P = 0.003] and a lower voice quality (incidence rate ratio for total VHI 1.83-fold higher, P < 0.001). In multivariable analysis, hypoparathyroidism [-0.17 (95% confidence interval -0.28 to -0.07), P = 0.002], but not age, female sex, thyroid cancer, or abnormal TSH level, was associated with the reduced mental score ratio. Myalgia, joint pain, paresthesia, tetany, anxiety attack, and exhaustion were the most common symptoms among hypoparathyroid patients (>50%). CONCLUSIONS: Hypoparathyroid patients present significantly impaired quality of life, lower voice quality, and frequent symptoms. These results reinforce the importance of preventing this complication.

Women With Chronic Hypoparathyroidism Have Low Risk of Adverse Pregnancy Outcomes.

CONTEXT: There are scarce data on the management of chronic hypoparathyroidism (hypoPT) in pregnant women. OBJECTIVE: The aim of this study was to evaluate pregnancy outcome and total number of births in maternal chronic hypoPT. METHODS: The Swedish National Patient Register, The Swedish Prescribed Drug Register, Swedish Medical Birth Register, and the Total Population Register were used to identify 97 women with chronic hypoPT and 1030 age-matched controls who delivered 139 and 1577 singleton infants, respectively, following diagnosis between 1997 and 2017. RESULTS: Women in the chronic hypoPT group had more frequent diabetes (DM) and chronic kidney disease (CKD) compared with the control group (P = 0.043 and P < 0.001, respectively). After adjusting for DM, CKD, maternal age at delivery, and calendar year of delivery, chronic hypoPT cases were associated with increased risk of induction of labor (OR, 1.82; 95% CI, 1.13-2.94) and birth of infants with lower birth weight (ß-coefficient -188 g; 95% CI, -312.2 to -63.8) compared with controls. No difference was found in infant length, small for gestational age, or head circumference after adjustments. Mean gestational age at delivery after controlling for DM, CKD, and pre-eclampsia was not significantly younger (P = 0.119). There was no difference in congenital malformations or perinatal death and no difference in the total number of infants born between groups (P = 0.518). CONCLUSION: The majority of women with chronic hypoPT had normal pregnancy outcomes, and the overall risks appear low. Maternal chronic hypoPT is, however, associated with higher risk of induction of labor and slightly lower infant birth weight.

Combined Effects of Vitamin D Status, Renal Function and Age on Serum Parathyroid Hormone Levels.

Background: Vitamin D status and renal function are well-known independent predictors of serum parathyroid hormone (PTH) levels. We aimed to describe the combined effects of 25-hydroxy vitamin D (25(OH)D), glomerular filtration rate (GFR) and age on serum PTH levels across the whole clinical spectrum. Methods: We retrieved from our endocrinology center database all PTH measurement between 2012 and 2020 for which a simultaneous measurement of serum 25(OH)D, calcium and creatinine was available. Age, sex and diagnosis were available for all subjects. Intact PTH was measured using the same electrochemiluminescence assay. Results: There were 6,444 adults and 701 children without a diagnosis of hyper- or hypoparathyroidism or abnormal serum calcium levels. In adults with 25(OH)D≥12 ng/mL multiple regression models showed that serum PTH was negatively correlated with both 25(OH)D and GFR. Regression (-0.68 and -1.59 vs. -0.45 and -0.22 respectively), partial correlation (-0.16 and -0.35 vs. -0.12 and -0.10 respectively) and determination coefficients (0.14 vs. 0.031) were higher in CKD than in normal renal function. In subjects with 25(OH)D<12 ng/mL, GFR was the only significant predictor in those with CKD (ß-coefficient=-2.5, r=-0.55) and 25(OH)D was the only significant predictor in those with normal renal function (ß-coefficient=-2.05, r=-0.11). Increasing age was associated with higher PTH levels only in those with normal renal function and 25(OH)D≥12 ng/mL. Conclusions: We showed that declining vitamin D and renal function have additive effects on serum PTH in subjects without vitamin D deficiency. In vitamin D deficient subjects this dependency is stronger but is not additive anymore.

Osteogenic Mechanisms of Basal Ganglia Calcification and its ex vivo Model in the Hypoparathyroid Milieu.

CONTEXT: Basal-ganglia calcification (BGC) is common (70%) in patients with chronic hypoparathyroidism. Interestingly, cortical gray matter is spared from calcification. The mechanism of BGC, role of hyperphosphatemia, and modulation of osteogenic molecules by parathyroid hormone (PTH) in its pathogenesis is not clear. OBJECTIVE: We assessed the expression of a large repertoire of molecules with proosteogenic or antiosteogenic effects, including neuroprogenitor cells in caudate, dentate, and cortical gray matter from normal autopsy tissues. The effect of high phosphate and PTH was assessed in an ex vivo model of BGC using striatum tissue culture of the Sprague-Dawley rat. METHODS: The messenger RNA and protein expression of 39 molecules involved in multiple osteogenic pathways were assessed in 25 autopsy tissues using reverse-transcriptase polymerase chain reaction, Western blot, and immunofluorescence. The striatal culture was maintained in a hypoparathyroid milieu for 24 days with and without (a) high phosphate (10-mm ß-glycerophosphate) and (b) PTH(1-34) (50 ng/mL Dulbecco's modified Eagle's medium-F12 media) for their effect on striatal calcification and osteogenic molecules. RESULTS: Procalcification molecules (osteonectin, ß-catenin, klotho, FZD4, NT5E, LRP5, WNT3A, collagen-1α, and SOX2-positive neuroprogenitor stem cells) had significantly higher expression in the caudate than gray matter. Caudate nuclei also had higher expression of antiosteogenic molecules (osteopontin, carbonic anhydrase-II [CA-II], MGP, sclerostin, ISG15, ENPP1, and USP18). In an ex vivo model, striatum culture showed an increased propensity for calcified nodules with mineral deposition similar to that of bone tissue on Fourier-transformed infrared spectroscopy, alizarin, and von Kossa stain. Mineralization in striatal culture was enhanced by high phosphate and decreased by exogenous PTH through increased expression of CA-II. CONCLUSION: This study provides a conceptual advance on the molecular mechanisms of BGC and the possibility of PTH therapy to prevent this complication in a hypoparathyroid milieu.

Basal ganglia calcification in hypoparathyroidism and pseudohypoparathyroidism: local and systemic metabolic mechanisms.

BACKGROUND: Hypoparathyroidism and pseudohypoparathyroidism are rare disorders of mineral metabolism which may be associated with soft tissue calcification in the basal ganglia in the brain, and occasionally the skin and other tissues. The basal ganglia are the most common sites of calcification in the central nervous system in these disorders, and were first associated with this manifestation in a report from the Mayo Clinic in 1939. The reasons why the basal ganglia are a common site of soft tissue calcification in these rare disorders has been a matter of investigation for many years. FINDINGS: Due to recent increased understanding of phosphate transport and new insights gained from mRNA expression in the basal ganglia, the pathophysiology of basal ganglia calcification (BGC) is now clearer. There is evidence that the absence of parathyroid hormone in hypoparathyroidism may play a direct role, but this is clearly not the case in pseudohypoparathyroidism, which is associated with increased parathyroid hormone levels. Maintaining the calcium/phosphorus ratio as close to normal as possible, and maintaining normal serum phosphate levels, may help mitigate the progression of BGC. There is no evidence of regression of BGC with conventional treatment, and long-term data with adjunctive or replacement therapy with parathyroid hormone or its analogues are not yet available. PURPOSE OF THE REVIEW: This review will focus on the pathophysiology of BGC in hypoparathyroidism and pseudohypoparathyroidism, and review the proposed pathophysiologic mechanisms, as well as the clinical implications of BGC on patient quality of life.

Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84).

CONTEXT: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. OBJECTIVE: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. DESIGN/SETTING: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). PATIENTS: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. INTERVENTIONS: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). MAIN OUTCOME MEASURES: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. RESULTS: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). CONCLUSIONS: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).

Recurrent fifth metatarsal stress fractures in a professional soccer player with hypoparathyroidism: a case report.

BACKGROUND: Hypoparathyroidism is characterized by low or inappropriately normal levels of parathyroid hormone leading to hypocalcemia. In this report, a case of recurrent fifth metatarsal stress fractures in a professional soccer player with hypoparathyroidism is presented. CASE PRESENTATION: A 23-year-old male professional soccer player developed left foot pain. He had no specific medical or family history. He was diagnosed with a fifth metatarsal stress fracture and underwent osteosynthesis with a cannulated cancellous screw 3 days after the injury. After three and a half months, the X-ray showed bone union, and he returned to full sports activity. However, he felt pain in his left foot again, and a re-fracture was found on X-ray a week later. Osteosynthesis was performed again. Two months after re-operation, the cause of re-fracture was investigated. Laboratory results showed abnormally low levels of serum calcium (8.4 mg/dL) and intact parathyroid hormone (i-PTH: 19.0 pg/mL). However, other laboratory examinations were normal. Therefore, he was diagnosed with primary hypoparathyroidism according to the diagnostic criteria. Medical treatment was started with alfacalcidol 1.0 µg/day. One month after starting medication, the serum calcium improved to 9.4 mg/dL. Four months after the re-operation, the X-ray showed bone union, and he was therefore allowed to play soccer. While he played professional soccer, there were no new subjective complaints. CONCLUSIONS: Hypoparathyroidism may be one of the risk factors for stress fractures. We believe that serum calcium levels should be checked in patients with stress fractures, and if the serum calcium is low, hypoparathyroidism should be considered.

Manifestations of left ventricular dysfunction and arrhythmia in patients with chronic hypoparathyroidism and pseudohypoparathyroidism: a preliminary study.

BACKGROUND: Cardiac damage triggered by severe hypocalcemia is well known. However, the role of chronic hypoparathyroidism (HP) and pseudohypoparathyroidism (PHP) in cardiac health is still unclear. We investigated the effect of chronic HP and PHP on cardiac structure and conductive function in patients compiling with treatment. METHODS: The study included 18 patients with HP and eight with PHP aged 45.4 ± 15.4 and 22.1 ± 6.4 years, respectively with a previously regular follow-up. In addition, 26 age- and sex-matched healthy controls were included. General characteristics and biochemical indices were recorded. Cardiac function and structure were assessed by estimation of myocardial enzymes, B-type natriuretic peptide (BNP), and echocardiography. The 12-lead electrocardiogram and 24-h Holter electrocardiography were performed to evaluate the conductive function. RESULTS: Levels of serum calcium in HP and PHP were 2.05 ± 0.16 mmol/L and 2.25 ± 0.19 mmol/L, respectively. The levels of myocardial enzyme and BNP were within the normal range. Adjusting for age at evaluation and body mass index, all M-mode measurements, left ventricular mass (LVM), LVM index (LVMI) and relative wall thickness (RWT) were comparable between patients and controls. Prolongation of corrected QT (QTc) intervals occurred in 52.6% (10/19) of patients, and 6.7% (1/15) of patients manifested more than 100 episodes of supraventricular and ventricular extrasystoles, as well as supraventricular tachycardia. None of the above arrhythmias was related to a severe clinical event. CONCLUSIONS: From this pilot study, patients diagnosed with HP and PHP and well-controlled serum calcium levels manifested normal cardiac morphology and ventricular function, except for prolonged QTc intervals, and a small percentage of mild arrhythmias needing further investigation.

Assessing the Patient Experience of Hypoparathyroidism Symptoms: Development of the Hypoparathyroidism Patient Experience Scale-Symptom (HPES-Symptom).

BACKGROUND AND OBJECTIVE: Hypoparathyroidism is a rare endocrine disorder characterized by absent or inappropriately low levels of circulating parathyroid hormone. Patients with hypoparathyroidism receiving standard-of-care therapy report debilitating physical and cognitive symptoms, which may indicate a reduced health-related quality of life. The purpose of this study was to develop a new disease-specific measure of the signs and symptoms of hypoparathyroidism, the Hypoparathyroidism Patient Experience Scale-Symptom (HPES-Symptom), and provide evidence for the content validity of items in the measure based on rigorous qualitative research methodologies for patient-reported outcome development. METHODS: Semi-structured, individual concept elicitation interviews were conducted with five clinical experts and 42 adults with hypoparathyroidism in the USA to identify the signs and symptoms of relevance and importance to those with the condition. Transcripts were coded and analyzed using an adapted grounded theory approach. Following item generation, cognitive debriefing interviews of the draft measure were conducted in an independent sample of 16 adults with hypoparathyroidism. RESULTS: One hundred percent of the concept elicitation patient sample reported experiencing physical symptoms that were attributed to hypoparathyroidism, including tingling/numbness/paresthesia (n = 37, 88%), muscle cramping (n = 36, 86%), and physical fatigue (n = 35, 83%). The majority of patients (n = 36, 86%) further reported experiencing cognitive dysfunction, including impaired memory (n = 24, 57%), impaired ability to have a conversation (n = 21, 50%), and lack of concentration/focus (n = 18, 43%). Seventeen major signs and symptoms were identified during item generation and included in the preliminary measure. After the cognitive debriefing, the 17-item HPES-Symptom was generated. CONCLUSIONS: The findings provided evidence of content validity for the HPES-Symptom in US adults with hypoparathyroidism. Additional research is needed to validate the measure in patients with hypoparathyroidism to assess its psychometric properties.

PTH and bone material strength in hypoparathyroidism as measured by impact microindentation.

PTH levels might be associated with bone material strength as measured by impact microindentation. Resistance to microfracture is decreased in hypoparathyroidism and appears to be associated with more severe disease and to improve with PTH replacement. INTRODUCTION: PTH is a key regulator of bone structure and remodeling. When PTH is absent in hypoparathyroidism (HypoPT), bone mass is increased and remodeling is decreased. In addition to bone structure and remodeling, bone material properties contribute to fracture resistance. Yet little is known about the relationship between PTH and bone material properties. Impact microindentation provides a clinical assessment of microfracture resistance, measured as the bone material strength index (BMSi). METHODS: Case-control cross-sectional study of PTH levels and in vivo BMSi measurement by impact microindentation at the anterior tibia in HypoPT patients (n = 17) and in controls matched for age, sex, and menopausal status (n = 17), with follow-up in a subgroup of HypoPT patients (n = 5) after recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] treatment. RESULTS: BMSi was positively associated with PTH levels in controls (r = 0.58, p = 0.02) and was 11% lower (p = 0.01) in HypoPT patients as compared with controls. In HypoPT, lower BMSi was associated with a trend toward greater supplemental calcium doses (p = 0.07). BMSi increased after rhPTH(1-84) treatment in the HypoPT patients who underwent repeat microindentation. CONCLUSIONS: PTH levels might be associated with bone material strength, although other factors might be contributory. In HypoPT, resistance to microfracture is decreased and may be associated with greater supplemental calcium doses and might increase with PTH replacement. It remains to be determined whether changes in bone remodeling and microarchitecture contribute to the effects of PTH on microfracture resistance.

Postoperative Hypoparathyroidism in Thyroid Surgery: Anatomic-Surgical Mapping of the Parathyroids and Implications for Thyroid Surgery.

Hypoparathyroidism remains one of the most common complications in thyroid surgery. This study aims for an improved understanding of the complexity of the blood supply and the localisation of the parathyroids compared to the two most important intraoperative landmarks: the inferior laryngeal nerve (ILN) and Zuckerkandl's tubercle (ZT). We examined 103 laryngeal compounds to classify the blood supply and the localisation of the parathyroids. For intraoperative localisation we defined a Cartesian coordinate system with the ZT plane as x-axis and the course of the inferior laryngeal nerve as y-axis. The inferior thyroid artery (ITA) mainly supplies the parathyroids, whereas the superior thyroid artery provides a backup supply. It must be pointed out that 8.2% of parathyroids receive their blood directly from the thyroid gland. 73.5% of all parathyroids lie within 1 cm of the ILN and 1 cm cranial and 2.5 cm caudal to the ZT plane. Our described perimeters mark the most crucial areas during surgery and provide the surgeon with an anatomic mapping showing areas of special carefulness needed. One should keep bearing in mind all possible blood supply types of the parathyroids and therefore all branches should be handled with care.

Development of a Patient-Reported Outcome Measure for Chronic Hypoparathyroidism.

INTRODUCTION: A patient-reported outcome (PRO) measure specific to chronic hypoparathyroidism is lacking to facilitate the evaluation of treatment. A PRO measure that followed the recommendations of the US Food and Drug Administration (FDA) PRO guidance was created to address key hypoparathyroidism symptoms. METHODS: A literature review was conducted to identify symptoms of hypoparathyroidism and any existing PRO measures appropriate for evaluating these symptoms, followed by concept elicitation interviews involving six individuals with hypoparathyroidism. On the basis of the results of the literature review and interviews, a draft item pool was developed and refined through two sets of cognitive debriefing interviews with six additional patients. A translatability assessment was also conducted to evaluate concepts, phrases, or components of the items that could be problematic in future translations and to identify culturally specific phrasing. RESULTS: No PRO measures appropriate to address hypoparathyroidism symptoms documented in the literature were identified. Qualitative research participants included 11 women and one man, with an average age of 49 years; the majority (10) of these participants were white. Concept elicitation interview results were generally consistent with the results of the literature review; the most commonly reported symptoms included issues with cognition, often described as "brain fog" (n = 6), muscle cramping (n = 5), tingling (n = 5), and muscle spasms or twitching (n = 4). The initial draft item pool included 20 items; based upon participant feedback, the final Hypoparathyroidism Symptom Diary comprised 13 items and was found to be easily understood and relevant to the participants. No significant issues were identified by the translatability assessment. CONCLUSION: The Hypoparathyroidism Symptom Diary was developed following the recommendations of the FDA's PRO guidance. The measure addresses a comprehensive set of symptoms, as well as key impacts of hypoparathyroidism deemed important by patients. FUNDING: Shire Human Genetic Therapies, Inc., Lexington, MA, USA, a member of the Takeda group of companies.

Quality of Life in Hypoparathyroidism Improves With rhPTH(1-84) Throughout 8 Years of Therapy.

CONTEXT: Calcium and vitamin D treatment does not improve reduced quality of life (QOL) in hypoparathyroidism. Recombinant human (rh) PTH(1-84) therapy improves QOL metrics for up to 5 years. Data on QOL beyond this time point are not available. OBJECTIVES: To evaluate the effects of 8 years of rhPTH(1-84) therapy on QOL and factors associated with long-term benefit. DESIGN: Prospective, open-label trial. SETTING: Referral center. PATIENTS: Twenty patients with hypoparathyoidism. MAIN OUTCOME MEASURES: RAND 36-Item Short Form Health Survey (SF-36). RESULTS: rhPTH therapy led to substantial improvement in five of the eight SF-36 domains [vitality, social functioning (SF), mental health (MH), bodily pain (BP) and general health] and three of these domains (SF, MH, BP) were no longer lower than the reference population. The improvement in the mental component summary (MCS) score was sustained through 8 years, while the physical component summary (PCS) score improved through 6 years. A lower baseline QOL score was associated with greater improvement. A threshold value <238 (MCS) and <245 (PCS) predicted long-term improvement in 90% and 100% of the cohort, respectively. In patients whose calcium supplementation was reduced, MCS and PCS scores improved more than those whose supplementation did not decline to the same extent. Improvement in PCS was greater in patients whose calcitriol dosage was reduced and duration of disease was shorter. CONCLUSIONS: rhPTH(1-84) improves long-term well-being in hypoparathyroidism. The improvements are most prominent in those with impaired SF-36 at baseline and those whose requirements for conventional therapy decreased substantially.

Parathyroid autotransplantation at a novel site for better evaluation of the grafted gland function: study protocol for a prospective, randomized controlled trial.

BACKGROUND: Hypoparathyroidism is one of the most common complications encountered in thyroidectomy. In addition to parathyroid in-situ preservation, parathyroid autotransplantation (PA) is another important remedial method for patients whose parathyroid glands have been removed. However, an accurate evaluation method for the function of a transplanted parathyroid is lacking. Our preliminary study indicated that patients with PA at novel sites near antecubital veins had higher serum concentrations of parathyroid hormone (PTH). Therefore, the main hypothesis is that a grafted site closer to the cephalic vein is more useful for better evaluation of transplanted parathyroid function. This study aims to confirm the more efficient and accurate evaluation system through a prospective, randomized controlled trial. METHODS: In total, 280 patients will be enrolled in this study and randomly divided into two groups: 140 patients with transplanted parathyroid glands in the traditional sites (group A) and the other 140 transplanted in the novel sites (group B), close to the antecubital veins. The serum concentration of PTH and calcium ion from both forearms will be measured and monitored regularly for 12 months. The primary outcome of this trial will be the survival of grafted glands, defined as the ratio of PTH between the grafted vs. the non-grafted forearms being no less than 1.5. The secondary outcome is hypoparathyroidism, defined as the PTH level from the non-grafted forearms being less than 15 pg/ml (normal range 15-65 pg/ml). DISCUSSION: Our results from this study should provide a more accurate method to evaluate the function of transplanted parathyroid glands by comparing PTH concentrations in both the grafted and non-grafted forearms following PA at novel sites. A better PTH measurement is helpful not only for the management of postoperative patients, but also for further identification of factors affecting PA success. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02906748 . Registered on 16 March 2016.

Clinical Presentation of Hypoparathyroidism.

Parathyroid hormone (PTH) is one of the major hormones that regulates serum calcium. Hypoparathyroidism occurs when PTH secretion is insufficient. The main symptoms of hypoparathyroidism are the result of low blood calcium levels, hypocalcemia, which interferes with normal muscle contraction and nerve conduction. As a result, people with hypoparathyroidism can experience paresthesia, an unpleasant tingling sensation around the mouth and in the hands and feet, as well as muscle cramps and severe spasms known as "tetany" that affect the hands and feet. Many also report a number of other subjective symptoms. Hypocalcemia can be the cause of medical emergencies, for example seizures, severe irregularities in the normal heart beat, as well as laryngospasm, stridor, bronchospasm, and wheezing.