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Purpose The main purpose of this study was to investigate the effects of 12 months of rhPTH (1–84) (Natpar®) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1–84) [rhPTH (1–84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. Methods It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations. Results Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1–84) for 12 months. At 12 months of rhPTH (1–84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1–84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described. Conclusions Biochemical and clinical results confirm the efficacy and safety of rhPTH (1–84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy.

Introduction In patients with chronic hypoparathyroidism disordered calcium homeostasis has been associated with risk of cardiovascular diseases, including cardiomyopathy, congestive heart failure, and arrhythmia; however, larger-scale studies are needed to examine these risks. This study evaluated the risk of cardiovascular conditions among patients with chronic hypoparathyroidism. Methods Adults with and without chronic hypoparathyroidism were selected from a medical insurance claims database in the USA from January 2007 to June 2017, and were followed for up to 5 years. Associations between chronic hypoparathyroidism and incident atrial fibrillation (AF), tachyarrhythmia, myocardial infarction (MI), coronary artery disease (CAD), heart failure (HF), stroke, cerebrovascular disease, peripheral vascular disease (PVD), and a combined cardiovascular endpoint of cerebrovascular disease, CAD, HF, and PVD were compared between cohorts using Kaplan–Meier analyses and unadjusted and adjusted Cox proportional hazards models. Results In 8097 patients with chronic hypoparathyroidism compared with 40,485 patients without, respectively, mean ± SD ages were 58.6 ± 16.3 and 47.3 ± 18.0 years, 76.2% and 54.4% were female, and 19.4% and 9.5% had the combination of cardiovascular findings at baseline. In adjusted analyses, patients with chronic hypoparathyroidism had significantly higher risk (adjusted hazard ratio and 95% confidence interval) of incident AF (1.72; 1.51–1.97), tachyarrhythmia (1.68; 1.32–2.14), MI (1.18; 1.01–1.38), CAD (1.39; 1.26–1.54), HF (1.64; 1.46–1.84), stroke (1.45; 1.31–1.62), cerebrovascular disease (1.48; 1.34–1.62), PVD (1.66; 1.51–1.81), and combined cardiovascular endpoint (1.63; 1.52–1.75), all P

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).

Introduction Chronic hypoparathyroidism managed with conventional treatment, comprising oral administration of calcium and active vitamin D, has been associated with renal complications, including nephrolithiasis and nephrocalcinosis. Further larger-scale studies are needed to examine these risks. This study evaluated the risk of nephrolithiasis and nephrocalcinosis in patients with chronic hypoparathyroidism. Methods A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017. Included patients were those with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism over a maximum of 5-year follow-up. The main outcome measures were nephrolithiasis, identified by diagnosis codes or procedure codes for removing kidney stones, and nephrocalcinosis, identified by diagnosis codes. Results The nephrolithiasis analyses included 8097 adult patients with hypoparathyroidism and 40,485 adult patients without hypoparathyroidism. After excluding patients with a diagnosis of nephrocalcinosis at baseline, nephrocalcinosis analyses included 8051 patients with hypoparathyroidism and 40,466 patients without hypoparathyroidism. During 5 years of follow-up, patients with chronic hypoparathyroidism had significantly increased risk of nephrolithiasis and nephrocalcinosis in Kaplan–Meier analysis compared with patients without hypoparathyroidism (both P

Introduction Chronic hypoparathyroidism, treated with conventional therapy of oral calcium supplements and active vitamin D, may increase the risk of kidney complications. This study examined risks of development and progression of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) decline in patients with chronic hypoparathyroidism. Methods A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017 included patients with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism followed for up to 5 years. Main outcome measures were (1) development of CKD, defined as new diagnosis of CKD stage 3 and higher or ≥ 2 eGFR measurements

Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. Conclusions In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Background. Autoimmune polyglandular syndrome type 1 (APS-1) with or without reversible metaphyseal dysplasia is a rare genetic disorder due to inactivating variants of the autoimmune regulator, AIRE, gene. Clinical variability of APS-1 relates to pleiotropy, and the general dysfunction of self-tolerance to organ-specific antigens and autoimmune reactions towards peripheral tissues caused by the underlying molecular defect. Thus, early recognition of the syndrome is often delayed, mostly in cases with atypical presentation, and the molecular confirm through the genetic analysis of the AIRE gene might be of great benefit. Methods. Our methods were to investigate, with a multigene panel next generation sequencing approach, two clinical cases, both presenting with idiopathic hypoparathyroidism, also comprising the AIRE gene, as well as to comment our findings as part of a more extensive review of literature data. Results. In the first clinical case, two compound heterozygote pathogenic variants of the AIRE gene were identified, thus indicating an autosomal recessive inheritance of the disease. In the second case, only one AIRE gene variant was found and an atypical dominant negative form of APS-1 suggested, later confirmed by further medical ascertainments. Conclusions. APS-1 might present with variable and sometimes monosymptomatic presentations and, if not recognized, might associate with severe complications. In this context, next generation diagnostics focused on a set of genes causative of partially overlapping disorders may allow early diagnosis.

Purpose To determine the burden of illness in patients with not adequately controlled chronic hypoparathyroidism receiving conventional therapy in Belgium and the Netherlands. Methods Data were generated from a cross-sectional, two-part online survey where endocrinologists from both countries and nephrologists from Belgium were invited by phone to participate. Part 1 included collecting data on general management of patients with hypoparathyroidism. In Part 2, physicians were requested to provide data on one or two current cases of patients with chronic hypoparathyroidism not adequately controlled on conventional therapy. Data collected included aetiology of hypoparathyroidism, clinical manifestations, comorbidities, results of laboratory and other investigations used for diagnosis and screening for complications, therapy received, and physician’s perception of impaired quality of life (QoL). Results Thirty-six endocrinologists and 29 nephrologists from Belgium and 28 endocrinologists from the Netherlands participated in the survey. Data included clinical symptoms, biochemical parameters, and QoL for 97 current patients with not adequately controlled chronic hypoparathyroidism on conventional therapy. Median duration of not adequately controlled hypoparathyroidism was 2.2 years, range 0.17–20.0. Most patients had neuromuscular (85%) and/or neurological (67%) symptoms, 71% had abnormal biochemical parameters, 10% were overweight, and physicians perceived that 71% had impaired QoL. Most frequently reported comorbidities included hypertension (25%), renal comorbidity (20%), diabetes mellitus (12%), and dyslipidaemia (11%). Conclusion Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy experience a substantial burden of illness, mainly due to persistence of symptoms and presence of multiple comorbidities.

Purpose To determine the burden of illness in patients with not adequately controlled chronic hypoparathyroidism receiving conventional therapy in Belgium and the Netherlands. Methods Data were generated from a cross-sectional, two-part online survey where endocrinologists from both countries and nephrologists from Belgium were invited by phone to participate. Part 1 included collecting data on general management of patients with hypoparathyroidism. In Part 2, physicians were requested to provide data on one or two current cases of patients with chronic hypoparathyroidism not adequately controlled on conventional therapy. Data collected included aetiology of hypoparathyroidism, clinical manifestations, comorbidities, results of laboratory and other investigations used for diagnosis and screening for complications, therapy received, and physician's perception of impaired quality of life (QoL). Results Thirty-six endocrinologists and 29 nephrologists from Belgium and 28 endocrinologists from the Netherlands participated in the survey. Data included clinical symptoms, biochemical parameters, and QoL for 97 current patients with not adequately controlled chronic hypoparathyroidism on conventional therapy. Median duration of not adequately controlled hypoparathyroidism was 2.2 years, range 0.17-20.0. Most patients had neuromuscular (85%) and/or neurological (67%) symptoms, 71% had abnormal biochemical parameters, 10% were overweight, and physicians perceived that 71% had impaired QoL. Most frequently reported comorbidities included hypertension (25%), renal comorbidity (20%), diabetes mellitus (12%), and dyslipidaemia (11%). Conclusion Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy experience a substantial burden of illness, mainly due to persistence of symptoms and presence of multiple comorbidities.

Background The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration EUPAS16927, NCT01922440

Hypoparathyroidism, a disorder characterized by hypocalcemia ensuing from inadequate parathyroid hormone secretion, is a rather rare disorder caused by multiple etiologies. When not caused by inadvertent damage or removal of the parathyroids during neck surgery, it is usually genetically determined. Epidemiological figures of this disease are still scarce and mainly limited to countries where non-anonymous databases are available and to surgical case series. Both the surgical and non-surgical forms pose diagnostic challenges. For surgical hypoparathyroidism, transient forms have to be ruled out even in the long term, in order to avoid unnecessary chronic replacement therapy with calcium and calcitriol. Regarding non-surgical hypoparathyroidism, once referred to as idiopathic, a systematic clinically and genetically-driven approach to define the precise diagnosis have to be pursued. In the case of syndromic hypoparathyroidism, patients have to be screened for associated abnormalities. Autoimmune, non-genetic hypoparathyroidism is still a diagnosis of exclusion, since no specific autoantibodies are specific for this condition.

Epidemiological data on prevalence and incidence of chronic hypoparathyroidism are still scarce. This study aimed to establish prevalence of chronic hypoparathyroidism and incidence of surgical hypoparathyroidism using the analysis of electronic anonymous public health care database. Data referred to a 5-year period (2009–2013, Region of Tuscany, Italy, as a sample representative of the whole Mediterranean/European population, estimated mean population: 3,750,000 inhabitants) were retrieved by the analysis of pharmaceutical distribution dataset, containing data related to drugs reimbursed by public health system, hospital discharge and procedures codes, and ICD9 exemption codes for chronic diseases. The application of a specific algorithm was applied to indirectly identify people with chronic hypoparathyroidism as assuming chronic therapy with active vitamin D metabolites (AVDM). The number of people taking AVDM for a period equal to or longer than 6 months till the end of the study period, with ICD9 exemption code for hypoparathyroidism, and with a disease-related discharge code were identified. Within this restricted group, patients with chronic kidney disease and osteoporosis were excluded. The indirect estimate of chronic hypoparathyroidism in a European Mediterranean subpopulation by means of the analysis of chronic therapy with AVDM was 27/100,000 inhabitants (female:male ratio = 2.2:1), with a mean age of 63.5 ± 16.7 years. The risk of developing hypoparathyroidism after neck surgery was 1.5%. While the epidemiological approaches based on disease code and hospital discharge code greatly underestimates the prevalence of hypoparathyroidism, the indirect estimate of this disease through the analysis of prescriptions of AVDM in a European region is in line with the results of studies performed in other regions of the world.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator gene. The clinical spectrum of the disease encompasses several autoimmune endocrine and non-endocrine manifestations, which may lead to acute metabolic alterations and eventually life-threatening events. The clinical diagnosis is defined by the presence of at least two components of the classic triad including chronic mucocoutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), Addison's disease (AD). Other common features of the disease are hypergonadotropic hypogonadism, alopecia, vitiligo, autoimmune hepatitis, Type 1 diabetes, gastrointestinal dysfunction. APECED usually begins in childhood. CMC is the first manifestation to appear, usually before the age of 5 yr, followed by CH and then by AD. The clinical phenotype may evolve over several years and many components of the disease may not appear until the 4th or 5th decade of life. The phenotypical expression of the syndrome shows a wide variability even between siblings with the same genotype. In view of this heterogeneity, an early diagnosis of APECED can be very challenging often leading to a considerable diagnostic delay. Therefore, clinicians should be aware that the presence of even a minor component of APECED in children should prompt a careful investigation for other signs and symptoms of the disease, thus allowing an early diagnosis and prevention of severe and life-threatening events. Aim of this review is to focus on clinical presentation, diagnosis and management of the major components of APECED in children particularly focusing on endocrine features of the disease.

Background: Autoimmune polyendocrinopathycandidiasis-ectodermal-dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1) (OMIM 240300), is a very rare disease. Accepted criteria for diagnosis require the presence of at least 2 of 3 major clinical features: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), and Addison's disease (AD). Aim: We analyzed AIRE gene mutations and genotype-phenotype correlation in APECED patients originating from Sicily and in their relatives. Subjects and methods: In 4 patients, clinical evaluations, genetic analysis of AIRE, and APECED-related autoantibodies were performed. Results: Two patients carried the mutation R203X in homozygosis on exon 5. One had the mutation R203X combined with R139X. The fourth had the R203X mutation in heterozygosis with R257X. Expression of the disease showed wide variability of clinical manifestations. Analysis of relatives allowed the identification of 10 heterozygotes for AIRE gene mutations. None of these subjects presented major findings of APECED. Three of the 4 patients were positive for autoantibodies to interferon-γ. Conclusions: In Sicily, R203X is confirmed to be the typical recessive and prevalent AIRE gene mutation on exon 5. Genotype-phenotype correlation failed to reveal a relationship between detected mutations and clinical expression. Mutations in heterozygosity in AIRE gene are not associated with major findings of APECED. ©2012, Editrice Kurtis.