Central node dissection in papillary thyroid carcinoma in the era of near-infrared fluorescence.

The most common site of lymph node metastases in papillary thyroid carcinoma is the central compartment of the neck (level VI). In many patients, nodal metastases in this area are not clinically apparent, neither on preoperative imaging nor during surgery. Prophylactic surgical clearance of the level VI in the absence of clinically suspicious lymph nodes (cN0) is still under debate. It has been suggested to reduce local recurrence and improve disease-specific survival. Moreover, it helps to accurately diagnose the lymph node involvement and provides important staging information useful for tailoring of the radioactive iodine regimen and estimating the risk of recurrence. Yet, many studies have shown no benefit to the long-term outcome. Arguments against the prophylactic central lymph node dissection (CLND) cite minimal oncologic benefit and concomitant higher operative morbidity, with hypoparathyroidism being the most common complication. Recently, near-infrared fluorescence imaging has emerged as a novel tool to identify and preserve parathyroid glands during thyroid surgery. We provide an overview of the current scientific landscape of fluorescence imaging in thyroid surgery, of the controversies around the prophylactic CLND, and of fluorescence imaging applications in CLND. To date, only three studies evaluated fluorescence imaging in patients undergoing thyroidectomy and prophylactic or therapeutic CLND for thyroid cancer. The results suggest that fluorescence imaging has the potential to minimise the risk of hypoparathyroidism associated with CLND, while allowing to exploit all its potential benefits. With further development, fluorescence imaging techniques might shift the paradigm to recommend more frequently prophylactic CLND.

Bone Marrow Adipose Tissue Is Increased in Postmenopausal Women With Postsurgical Hypoparathyroidism.

CONTEXT: Suppression of bone turnover, greater trabecular volume, and normal-high normal all-site bone mineral density (BMD) are hallmarks of postsurgical hypoparathyroidism (HypoPT). Impairment in the trabecular microarchitecture with possible higher risk of vertebral fractures (VF) in women with postmenopausal HypoPT has also been described. Currently, no data on bone marrow adipose tissue (BMAT) are available in HypoPT. OBJECTIVE: To assess BMAT by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) in postmenopausal women with chronic postsurgical HypoPT. METHODS: This cross-sectional pilot study, conducted at an ambulatory referral center, included 29 postmenopausal women (mean age 66 ± 8.4 years) with postsurgical HypoPT and 31 healthy postmenopausal women (mean age 63 ± 8.5). Lumbar spine MRI was performed and BMAT was measured by applying PRESS sequences on the L3 body. Lumbar spine, femoral neck, and total hip BMD were measured by dual x-ray absorptiometry (DXA); site-matched spine trabecular bone score (TBS) was calculated by TBS iNsight (Medimaps, Switzerland); VF assessment was performed with lateral thoracic and lumbar spine DXA. RESULTS: Fat content (FC) and saturation level (SL%) were higher (P <.0001 and P <.001), while water content (W) was lower in HypoPT compared to controls (P <.0001). FC significantly correlated with years since menopause and body weight (P <.05) in HypoPT, while TBS negatively correlated with FC and SL% (P <.05) and positively with residual lipids (RL) and W (P <.05). CONCLUSION: We demonstrate for the first time that BMAT is increased in postmenopausal women with postsurgical hypoparathyroidism and negatively associated with trabecular microarchitecture.

Carbon Nanoparticles for Thyroidectomy and Central Lymph Node Dissection for Thyroid Cancer.

PURPOSE: To evaluate whether the application of carbon nanoparticles (CNs) in total or near-total thyroidectomy combined with central lymph node dissection (CLND) for thyroid cancer (TC) is beneficial to lymph node dissection, parathyroid, and recurrent laryngeal nerve (RLN) protection. METHODS: Relevant literatures were systematically searched on PubMed, EMBASE, and Cochrane Library Databases until March 31, 2021. All analyses were performed using Revman Manager 5.3 software. The main results were the number of central lymph nodes, the number of central metastatic lymph nodes, accidental parathyroidectomy, postoperative hypoparathyroidism, postoperative hypocalcemia, and postoperative transient RLN paralysis. RESULTS: This meta-analysis identified 4 randomized controlled trials and 8 non-randomized controlled trials comprising 1870 patients. Compared with the control, the use of CNs was helpful to dissect more central lymph nodes (weighted mean difference [WMD]: 3.55, 95% confidence interval [CI]: 2.12-4.98, P < .00001) and central metastatic lymph nodes (WMD: 1.69, 95% CI:1.31-2.08, P < .00001), lower rate of accidental parathyroidectomy (odds ratio [OR]: .33, 95% CI: .23-.47, P < .00001), lower rate of both postoperative transient hypoparathyroidism (OR: .40, 95% CI: .31-.51, P < .00001), and transient hypocalcemia (OR: .37, 95% CI: .27-.51, P < .00001). However, there were no statistical difference between the groups for postoperative permanent hypoparathyroidism (OR: .29, 95% CI: .06-1.28, P = .10), postoperative permanent hypocalcemia (OR: .94, 95% CI: .10-9.16, P = .96), and postoperative transient RLN paralysis (OR: .66, 95% CI: .40-1.12, P = .12). CONCLUSIONS: The application of CNs in total or near-total thyroidectomy combined with CLND for TC can better dissect the central lymph nodes and protect parathyroid glands (PGs) and their function.

Gauze blotting technique: a novel method to identify parathyroid glands during thyroid surgery without tissue damage.

Hypoparathyroidism is a major complication of thyroid surgery. To avoid this complication, visual identification of the parathyroid glands is essential. However, its effectiveness depends heavily on the surgeon's expertise. Here, we describe a novel method, the gauze blotting technique, to immunochemically identify the parathyroid glands during thyroid surgery. Twenty-three patients who underwent thyroid lobectomy were enrolled in this study; 16 and 7 had benign and malignant thyroid diseases, respectively. After visually identifying candidate nodules for the parathyroid gland, a piece of dry gauze (5 mm × 10 mm) was applied to each tissue until it was moistened by exudates from the tissue. Pieces of gauze were also applied to the thyroid gland and adipose tissue located away from the candidate nodules. The gauze was immersed in saline, and the intact PTH (i-PTH) level of the supernatant was measured. The median PTH level for the parathyroid glands was 1,060 pg/mL, which was significantly higher than that for the thyroid gland (34 pg/mL) and adipose tissue (28 pg/mL) (p < 0.001). The cut-off value to distinguish the parathyroid gland from other tissues was 68 pg/mL with a positive predictive value, negative predictive value, sensitivity, and specificity of 84.6%, 88.8%, 86.8%, and 86.7%, respectively. A value ≥250 pg/mL yielded a 100% positive predictive value. Our novel gauze blotting technique can identify the parathyroid glands without damaging tissues during thyroid surgery.

Parathyroid Allotransplantation: A Systematic Review.

Background: To date, there is no satisfactory treatment for patients with calcium and vitamin D supplementation refractive hypoparathyroidism. Parathyroid allotransplantation by design is a one-time cure through its restoration of the parathyroid function and, therefore, could be the solution. A systematic literature review is conducted in the present paper, with the aim of outlining the possibilities of parathyroid allotransplantation and to calculate its efficacy. Additionally, various transplantation characteristics are linked to success. Methods: This review is carried out according to the PRISMA statement and checklist. Relevant articles were searched for in medical databases with the most recent literature search performed on 9 December 2021. Results: In total, 24 articles involving 22 unique patient cohorts were identified with 203 transplantations performed on 148 patients. Numerous types of (exploratory) interventions were carried out with virtually no protocols that were alike: there was the use of (non-) cryopreserved parathyroid tissue combined with direct transplantation or pretreatment using in vitro techniques, such as culturing cells and macro-/microencapsulation. The variability increased further when considering immunosuppression, graft histology, and donor-recipient compatibility, but this was found to be reported in its entirety by exception. As a result of the large heterogeneity among studies, we constructed our own criterium for transplantation success. With only the studies eligible for our assessment, the pooled success rate for parathyroid allotransplantation emerged to be 46% (13/28 transplantations) with a median follow-up duration of 12 months (Q1-Q3: 8-24 months). Conclusions: Manifold possibilities have been explored around parathyroid allotransplantation but are presented as a double-edged sword due to high clinical diverseness, low expertise in carrying out the procedure, and unsatisfactory study quality. Transplantations carried out with permanent immunosuppression seem to be the most promising, but, in its current state, little could be said about the treatment efficacy with a high quality of evidence. Of foremost importance in pursuing the answer whether parathyroid allotransplantation is a suitable treatment for hypoparathyroidism, a standardized definition of transplantation success must be established with a high-quality trial.

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors.

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.

Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome.

Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.

Changes in Serum Calcium and Treatment of Hypoparathyroidism During Pregnancy and Lactation: A Single-center Case Series.

BACKGROUND: Hypoparathyroidism (hypo-PT) is rare, and studies on hypo-PT, especially during pregnancy and lactation, are limited. DESIGN AND SETTING: This was a retrospective study on a relatively large case series in a single center from mainland China. METHODS: A total of 19 patients with 25 pregnancies, diagnosed with hypo-PT before pregnancy, were enrolled. Data on clinical characteristics and treatment strategies at onset time and around pregnancy period were collected. RESULTS: During pregnancy, except for 2 patients with missing data, 5 patients with 6 pregnancies (6/23, 26.1%) experienced improved hypo-PT condition, defined as an increased serum calcium level; 4 patients with 4 pregnancies (4/23, 17.4%) experienced worsened hypo-PT condition, defined as a more than 0.2 mmol/L decline in the serum calcium level; and 3 patients with 3 pregnancies (3/23, 13.0%) remained in stable hypo-PT condition. The prevalence of adverse pregnancy outcomes was 30.4% (4/23 for preterm delivery; 3/23 for miscarriage). The serum calcium and 24-hour urine calcium levels significantly increased during lactation compared with pregnancy (2.57 ± 0.34 vs 1.99 ± 0.11 mmol/L, P < 0.001; 12.28 ± 5.41 vs 8.63 ± 3.22 mmol/L, P = 0.013), and 5 patients with 5 lactations (5/12, 41.7%) developed hypercalcemia in the first 2 months after delivery. CONCLUSIONS: Female patients with hypo-PT had different changes in calcium homeostasis and a high prevalence of adverse outcomes during pregnancy. Thus, they should be monitored closely to maintain the optimal serum calcium level. Decreasing drug dosage during the lactation period should be considered to avoid hypercalcemia.

Duration of Parathyroid Function Recovery in Patients With Protracted Hypoparathyroidism After Total Thyroidectomy for Papillary Thyroid Carcinoma.

Purpose: The aim of the present study is to investigate the time to recovery of parathyroid function in patients with protracted hypoparathyroidism at 1 month after total thyroidectomy of papillary thyroid carcinoma. Materials and Methods: Adult patients who underwent total thyroidectomy for papillary thyroid cancer were included. Cases of long-term hypoparathyroidism were studied for recovery of parathyroid function during the follow-up. The duration of recovery and associated variables were recorded. Results: Out of the 964 patients, 128 (13.28%) developed protracted hypoparathyroidism and of these, 23 (2.39%) developed permanent hypoparathyroidism and 105 (10.89%) recovered: 86 (8.92%) before 6 months, 11 (1.14%) within 6 and 12 months and 8 (0.83%) after 1 year follow-up. Variables significantly associated with the time to parathyroid function recovery were number of autotransplanted parathyroid glands (HR, 1.399; 95% CI, 1.060 - 1.846; P = 0.018), serum calcium concentration >2.07 mmol/L (Hazard ratio [HR], 1.628; 95% confidence interval [CI], 1.009 - 2.628; P = 0.046) and PTH level > 1.2 pmol/L (HR, 1.702; 95% CI, 1.083 - 2.628; P = 0.021) at 1 month postoperatively. Conclusion: Permanent hypoparathyroidism should not be diagnosed easily by time, since up to one-fifth of the patients will experience recovery after a period of 6 months and a few patients even beyond one year. The number of autotransplanted parathyroid glands is positively associated with the time to parathyroid function recovery.

Parathyroid hormone.

Parathyroid hormone is an essential regulator of extracellular calcium and phosphate. PTH enhances calcium reabsorption while inhibiting phosphate reabsorption in the kidneys, increases the synthesis of 1,25-dihydroxyvitamin D, which then increases gastrointestinal absorption of calcium, and increases bone resorption to increase calcium and phosphate. Parathyroid disease can be an isolated endocrine disorder or part of a complex syndrome. Genetic mutations can account for diseases of parathyroid gland formulation, dysregulation of parathyroid hormone synthesis or secretion, and destruction of the parathyroid glands. Over the years, a number of different options are available for the treatment of different types of parathyroid disease. Therapeutic options include surgical removal of hypersecreting parathyroid tissue, administration of parathyroid hormone, vitamin D, activated vitamin D, calcium, phosphate binders, calcium-sensing receptor, and vitamin D receptor activators to name a few. The accurate assessment of parathyroid hormone also provides essential biochemical information to properly diagnose parathyroid disease. Currently available immunoassays may overestimate or underestimate bioactive parathyroid hormone because of interferences from truncated parathyroid hormone fragments, phosphorylation of parathyroid hormone, and oxidation of amino acids of parathyroid hormone.

Burden of illness in patients with chronic hypoparathyroidism not adequately controlled with conventional therapy: a Belgium and the Netherlands survey.

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.

The Calcium-Sensing Receptor Is Essential for Calcium and Bicarbonate Sensitivity in Human Spermatozoa.

CONTEXT: The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown. OBJECTIVE: This work aimed to investigate the role of CaSR in human spermatozoa. METHODS: We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and 3',5'-cyclic adenosine 5'-monophosphate (cAMP) in spermatozoa from men with either loss-of-function or gain-of-function mutations in CASR and healthy donors. RESULTS: CaSR is expressed in human spermatozoa and is essential for sensing extracellular free ionized calcium (Ca2+) and Mg2+. Activators of CaSR augmented the effect of sperm-activating signals such as the response to HCO3- and the acrosome reaction, whereas spermatozoa from men with a loss-of-function mutation in CASR had a diminished response to HCO3-, lower progesterone-mediated calcium influx, and were less likely to undergo the acrosome reaction in response to progesterone or Ca2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca2+ or Mg2+ was indispensable for HCO3- activation of sAC. Two male patients with a CASR loss-of-function mutation in exon 3 presented with normal sperm counts and motility, whereas a patient with a loss-of-function mutation in exon 7 had low sperm count, motility, and morphology. CONCLUSION: CaSR is important for the sensing of Ca2+, Mg2+, and HCO3- in spermatozoa, and loss-of-function may impair male sperm function.

Overlapping phenotype comprising Kenny-Caffey type 2 and Sanjad-Sakati syndromes: The first case report.

Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum.

A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.

Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.

Physical Activity-Dependent Regulation of Parathyroid Hormone and Calcium-Phosphorous Metabolism.

Exercise perturbs homeostasis, alters the levels of circulating mediators and hormones, and increases the demand by skeletal muscles and other vital organs for energy substrates. Exercise also affects bone and mineral metabolism, particularly calcium and phosphate, both of which are essential for muscle contraction, neuromuscular signaling, biosynthesis of adenosine triphosphate (ATP), and other energy substrates. Parathyroid hormone (PTH) is involved in the regulation of calcium and phosphate homeostasis. Understanding the effects of exercise on PTH secretion is fundamental for appreciating how the body adapts to exercise. Altered PTH metabolism underlies hyperparathyroidism and hypoparathyroidism, the complications of which affect the organs involved in calcium and phosphorous metabolism (bone and kidney) and other body systems as well. Exercise affects PTH expression and secretion by altering the circulating levels of calcium and phosphate. In turn, PTH responds directly to exercise and exercise-induced myokines. Here, we review the main concepts of the regulation of PTH expression and secretion under physiological conditions, in acute and chronic exercise, and in relation to PTH-related disorders.

Severe Hypocalcemia and Transient Hypoparathyroidism After Hyperthermic Intraperitoneal Chemotherapy.

Dear Editors,Hypocalcemia is not unusual in patients hospitalized for critical illness and has also been described after general surgery in addition to head and neck surgical procedures 1 2 3. Hypocalcemic events commonly occur in the setting of massive blood transfusion, albumin deficiency, vitamin D deficiency, and/or hypomagnesemia. In the absence of these factors, only slight decreases in calcium levels within the normal range have been reported during surgical procedures 1. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) causing asymptomatic hypocalcemia has only been reported in two previous studies 4 5. The etiology is unclear. We here report a patient who developed severe symptomatic hypocalcemia likely as a result of a profound inflammatory reaction with transient hypoparathyroidism after HIPEC.

A New Therapeutic Approach Using a Calcilytic (AXT914) for Postsurgical Hypoparathyroidism in Female Rats.

Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues.

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented. CASE AND METHODS: A 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively. RESULTS: The patient's symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient's hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient's clinical course of hypoparathyroidism. CaSR antibodies purified from the patient's serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1. CONCLUSION: The etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.

Hypoparathyroidism.

BACKGROUND: Hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia and low or undetectable levels of parathyroid hormone. METHODS: This review is an evidence-based summary of hypoparathyroidism in terms of relevant pathophysiological, clinical, and therapeutic concepts. RESULTS: Many clinical manifestations of hypoparathyroidism are due to the lack of the physiological actions of parathyroid hormone on its 2 major target organs: the skeleton and the kidney. The skeleton is inactive, accruing bone without remodeling it. The kidneys lose the calcium-conserving actions of parathyroid hormone and, thus, excrete a greater fraction of calcium. Biochemical manifestations, besides hypocalcemia and low or undetectable levels of parathyroid hormone, include hyperphosphatemia and low levels of 1,25-dihydroxyvitamin D. Calcifications in the kidney, brain, and other soft tissues are common. Removal of, or damage to, the parathyroid glands at the time of anterior neck surgery is, by far, the most likely etiology. Autoimmune destruction of the parathyroid glands and other genetic causes represent most of the other etiologies. Conventional treatment with calcium and active vitamin D can maintain the serum calcium level but high doses may be required, adding to the risk of long-term soft tissue calcifications. The advent of replacement therapy with recombinant human PTH(1-84) represents a major step in the therapeutics of this disease. CONCLUSIONS: Advances in our knowledge of hypoparathyroidism have led to greater understanding of the disease itself and our approach to it.