Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism.

BACKGROUND: Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. CASE DESCRIPTION: A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. CONCLUSIONS: Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology.

Hypocalcemia Secondary to Zoledronate Therapy in a Patient With Low Vitamin D Level.

Zoledronate (ZDA) is a bisphosphonate used to treat hypercalcemia that commonly occurs with malignancy, multiple myeloma, and bone metastases from solid tumors. It acts primarily by decreasing osteoclastic activity, thereby slowing the release of skeletal calcium. However, a potential adverse effect of ZDA is hypocalcemia that can be symptomatic, especially in patients with risk factors such as hypomagnesemia, hypoparathyroidism, renal failure, and vitamin D deficiency. We report the case of a patient with extensive stage small cell lung cancer with multiple osseous and visceral metastases who developed symptomatic hypocalcemia following ZDA administration. Significant clinical improvement occurred following administration of calcium and vitamin D, and his calcium levels returned to normal within a few days. Due to the high incidence of vitamin D deficiency and the low accuracy of clinical risk factors to predict vitamin D deficiency, screening for vitamin D deficiency before administration of ZDA may be appropriate.

Calcium Citrate Versus Calcium Carbonate in the Management of Chronic Hypoparathyroidism: A Randomized, Double-Blind, Crossover Clinical Trial.

In hypoparathyroidism (HypoPT), calcium supplementation is virtually always required, although the disease is likely to be associated with an increased risk of nephrolithiasis. The use of calcium citrate (Ca-Cit) theoretically could have a positive impact on the nephrolithiasis risk because citrate salts are used to reduce this risk. Our objective was to evaluate the potential therapeutic advantage of Ca-Cit in comparison with calcium carbonate (CaCO3 ) in HypoPT, on nephrolithiasis risk factors, as well as to their ability to maintain desirable serum calcium levels. We also evaluated these preparations on quality of life (QOL). This randomized, double-blind, crossover trial recruited 24 adults with postsurgical chronic hypoparathyroidism at Campus Bio-Medico University of Rome. Participants were randomized 1:1 to Ca-Cit or CaCO3 for 1 month and then crossed over to the other treatment for another month. The primary outcomes were changes in albumin-adjusted serum calcium and in ion activity product of calcium oxalate levels (AP[CaOx] index). Secondary efficacy outcomes included changes in SF-36 survey score, fatigue score, constipation, and adverse events. No difference in terms of AP(CaOx) index was observed between the two groups. However, Ca-Cit was associated with a significant reduction in the oxalate/creatinine ratio compared with CaCO3 (-2.46 mmol/mol [SD 11.93] versus 7.42 mmol/mol [SD 17.63], p = 0.029). Serum calcium and phosphorus concentration was not different between the two calcium preparations. Ca-Cit was associated with less constipation (p = 0.047). No difference was found in QOL scores. Although Ca-Cit did not modify the AP(CaOx) index when compared with CaCO3, it was associated with a reduction in urinary oxalate excretion that could have a potential beneficial effect on nephrolithiasis risk. These results are likely to have clinical implications in HypoPT, particularly those who do not tolerate CaCO3 and those affected by nephrolithiasis. A longer-term experience is needed to confirm these findings. © 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).

Lenvatinib-induced hypocalcaemia due to transient primary hypoparathyroidism.

CONTEXT: Radioiodine refractory differentiated thyroid cancer can be effectively treated with multi-tyrosine-kinase inhibitors (MKIs). Hypocalcaemia has been reported among the side effects of these drugs, but little is known about its pathophysiology and clinical relevance. CASE REPORT: We report the case of a 78-years-old woman with an aggressive papillary thyroid cancer infiltrating perithyroidal structures. The extent of surgery was limited to hemithyroidectomy, RAI treatment could not be performed, and she started lenvatinib treatment. After 4 months of therapy, the patient accessed the Emergency Department for a grade III hypocalcaemia (corrected serum calcium: 6.6 mg/dL, n.v. 8.1-10.4 mg/dL), due to primary hypoparathyroidism (serum PTH: 12.6 ng/L, n.v. 13-64 ng/L). The patient was treated with intravenous calcium infusions and vitamin D supplementation. After discharge, the oral dose of carbonate calcium (CaCO3) was of 6 g/day, and was titrated according to blood exams. Two weeks after discharge, while taking CaCO3 at the dose of 3 g/day, the patient experienced symptomatic grade II hypercalcemia (corrected serum calcium: 11.6 mg/dL), associated to the spontaneous reprise of PTH secretion, and leading to oral calcium withdrawal. During the subsequent follow-up, the patient remained eucalcemic without calcium supplementation. CONCLUSIONS: Though hypocalcaemia has been described as potential side effect of MKI treatment, this is the first report of a lenvatinib-induced primary hypoparathyroidism, in a patient with a documented normal parathyroid function after surgery. The periodical assessment of calcium-phosphorus metabolism is thus warranted to prevent this potentially lethal side effect, in both post-surgical hypoparathyroid and euparathyroid patients.

Parathyroid hormone resistance from severe hypomagnesaemia caused by cisplatin.

Not required for Clinical Vignette.

Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism.

CONTEXT: Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. OBJECTIVES: The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. METHODS: Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. RESULTS: The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. CONCLUSION: The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.

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.

Immune Checkpoint Inhibitor-Induced Hypoparathyroidism Associated With Calcium-Sensing Receptor-Activating Autoantibodies.

Context: Whereas therapy with immune checkpoint inhibitors (ICIs), such as nivolumab, have substantially improved survival in several types of cancer, increased attention has been given to adverse immune events associated with their use, including the development of endocrine autoimmunity. Objectives: First, to describe a patient with a 2-year history of metastatic small cell lung cancer who had been treated with nivolumab a few months before presentation with the signs and symptoms of severe hypocalcemia and hypoparathyroidism. Second, to investigate the etiology of the patient's hypoparathyroidism, including the presence of activating autoantibodies against the calcium-sensing receptor (CaSR), as humoral and cellular immune responses against the CaSR have been reported in patients with autoimmune hypoparathyroidism. Participants: A 61-year-old female was admitted with persistent nausea, vomiting, epigastric pain, constipation, and generalized weakness. Laboratory analyses showed low total serum calcium, ionized calcium, and parathyroid hormone (PTH). The patient was diagnosed with severe hypocalcemia as a result of autoimmune hypoparathyroidism after testing positive for CaSR-activating autoantibodies. Interventions: She was treated with intravenous calcium gluconate infusions, followed by a transition to oral calcium carbonate, plus calcitriol, which normalized her serum calcium. Results: Her serum PTH remained low during her hospitalization and initial outpatient follow-up, despite adequate repletion of magnesium. Conclusions: This case illustrates autoimmune hypoparathyroidism induced by ICI blockade. As ICIs are now used to treat many cancers, clinicians should be aware of the potential risk for hypocalcemia that may be associated with their use.

Inflammation-induced hypoparathyroidism triggered by combination immune checkpoint blockade for melanoma.

BACKGROUND: Treatment with a combination of PD-1 and CTLA-4 targeted checkpoint inhibition has improved outcome of melanoma patients and led to durable remissions but is also associated with significant toxicities. Endocrinopathies such as thyroiditis and hypophysitis are often seen, but other, rarer disturbances have also been described. Endocrinopathies affecting the parathyroid gland are rarely reported and no clear pathomechanism has been proposed. CASE PRESENTATION: Here, we report a case of severe hypocalcemia due to an antibody-mediated hypoparathyroidism as an immune-related adverse event (irAE) in a patient who was treated with the anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab. Hypocalcemia was rapidly corrected by substitution, but the endogenous serum parathyroid hormone (PTH) remained low. The patient demonstrated a rapid and profound tumor response to the combination immune checkpoint blockade, but developed a severe colitis that required high-dose intravenous corticosteroid and anti-TNFα therapy. During this strong immunosuppression the PTH level normalized and the calcium levels were stable without substitution. However, during tapering of immunosuppressants, the PTH and calcium levels decreased again to a level requiring calcium substitution. CONCLUSION: Our report demonstrates a rare endocrinopathy as a complication of combined PD-1 and CTLA-4 blockade. In addition, it provides evidence from the course of the disease that inflammation within the parathyroid gland is involved in the mechanism.

Cinacalcet in the management of tumor-induced osteomalacia.

UNLABELLED: Both FGF-23 and PTH inhibit renal phosphate reabsorption. We treated two patients with TIO and FGF-23-mediated hypophosphatemia with cinacalcet to test the hypothesis that medicinally induced hypoparathyroidism would decrease renal phosphate wasting. Cinacalcet treatment resulted in increased renal phosphate reabsorption, allowed for a decrease in phosphate supplementation, and showed evidence of bone healing in one of the two patients. INTRODUCTION: Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting, which results in hypophosphatemia and osteomalacia. It is caused by mesenchymal tumors that produce the phosphate and vitamin D-regulating hormone, fibroblast growth factor (FGF)-23. Removal of the tumor is curative, but the tumors are often difficult to locate. Medical treatment involves high doses of oral phosphate and calcitriol, but the phosphate is often poorly tolerated and leads to diarrhea. Because PTH also promotes phosphaturia, and patients with hypoparathyroidism are hyperphosphatemic in the setting of elevated serum FGF-23, we postulated that the calcium-sensing receptor agonist, cinacalcet, which can induce hypoparathyroidism, would be an effective adjuvant in the treatment of TIO. MATERIALS AND METHODS: Two subjects with presumed TIO in whom the tumor was not located after extensive testing and who did not tolerate medical therapy with phosphorus and calcitriol were treated with cinacalcet. RESULTS: Neither treatment with phosphorus nor combined treatment with phosphorus and calcitriol had an effect on serum FGF-23 levels. Treatment with cinacalcet resulted in increased renal phosphate reabsorption and serum phosphorus and allowed for a decrease in phosphate supplementation to a dose that was tolerated. On this regimen, one patient showed significant bone healing as shown by resolution of activity on bone scan and lack of osteomalacia as assessed by histomorphometry. CONCLUSIONS: These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic option for disorders of FGF-23-mediated hypophosphatemia and that, in the absence of PTH, the phosphaturic effect of FGF-23 is decreased.

Neonatal hypocalcemic seizures in siblings exposed to topiramate in utero.

We describe two siblings with neonatal hypocalcemic seizures whose mother took topiramate during both pregnancies. Apart from hypocalcemia, the patients had no identifiable etiology for their seizures. Although biochemical data suggested that the hypocalcemia was caused by hypoparathyroidism, no disorders typically associated with this condition were identified in the patients. We propose that topiramate exposure in utero led to hypoparathyroidism and subsequent hypocalcemia via effects on protein kinase A signaling, resulting in hypocalcemic seizures. Neonates exposed to topiramate in utero should be monitored for hypocalcemic seizures.

Proton pump inhibitors and symptomatic hypomagnesemic hypoparathyroidism.

Hypomagnesemia is a common but often overlooked problem in hospitalized patients. Unrecognized hypomagnesemia can cause serious complications. The association of hypokalemia and hypocalcemia is strongly evocative of a magnesium deficiency. Research into the causes of hypomagnesemia is imperative, as it will definitely change the approach, treatment and prognosis. We report the case of a 65-year-old man with chronic hypocalcemia and hypokalemia associated with cerebellar syndrome, a solitary seizure and cerebellar hyperintensities on magnetic resonance imaging. After the detection and treatment of hypomagnesemia with oral supplements of magnesium and the replacement of pantoprazole with ranitidine, we observed immediate relief of the symptoms. In conclusion, in clinical practice, magnesium depletion should be investigated in elderly patients with hypocalcemia treated with proton pump inhibitors for many years, in particular in the presence of neurological disorders.

Diphtheria Toxin- and GFP-Based Mouse Models of Acquired Hypoparathyroidism and Treatment With a Long-Acting Parathyroid Hormone Analog.

Hypoparathyroidism (HP) arises most commonly from parathyroid (PT) gland damage associated with neck surgery, and is typically treated with oral calcium and active vitamin D. Such treatment effectively increases levels of serum calcium (sCa), but also brings risk of hypercalciuria and renal damage. There is thus considerable interest in using PTH or PTH analogs to treat HP. To facilitate study of this disease and the assessment of new treatment options, we developed two mouse models of acquired HP, and used them to assess efficacy of PTH(1-34) as well as a long-acting PTH analog (LA-PTH) in regulating blood calcium levels. In one model, we used PTHcre-iDTR mice in which the diphtheria toxin (DT) receptor (DTR) is selectively expressed in PT glands, such that systemic DT administration selectively ablates parathyroid cells. For the second model, we generated GFP-PT mice in which green fluorescent protein (GFP) is selectively expressed in PT cells, such that parathyroidectomy (PTX) is facilitated by green fluorescence of the PT glands. In the PTHcre-iDTR mice, DT injection (2 × 5 µg/kg, i.p.) resulted in moderate yet consistent reductions in serum PTH and sCa levels. The more severe hypoparathyroid phenotype was observed in GFP-PT mice following GFP-guided PTX surgery. In each model, a single subcutaneous injection of LA-PTH increased sCa levels more effectively and for a longer duration (>24 hours) than did a 10-fold higher dose of PTH(1-34), without causing excessive urinary calcium excretion. These new mouse models thus faithfully replicate two degrees of acquired HP, moderate and severe, and may be useful for assessing potential new modes of therapy. © 2015 American Society for Bone and Mineral Research.

Hypocalcemia, hypomagnesemia, and transient hypoparathyroidism during therapy with potassium phosphate in diabetic ketoacidosis.

The effects of intravenous administration of potassium phosphate in the treatment of diabetic ketoacidosis were studied in nine children, ages 9 9/12 to 17 10/12 yr. During phosphate infusion (20--40 meq/L of fluid), all children maintained normal serum concentrations of phosphorus. Transient hypocalcemia occurred in six and transient hypomagnesemia in five patients. One child developed carpopedal spasms refractory to intravenous infusion of calcium gluconate but responsive to intramuscular injection of magnesium sulfate. In three patients, serum levels of intact parathyroid hormone were low at the time of hypocalcemia, an observation that suggests transient hypoparathyroidism. This study indicates that the use of potassium phosphate as the sole source of potassium replacement might potentiate ketoacidosis-induced hypocalcemia through multiple mechanisms.

Proton pump inhibitor-induced hypomagnesemic hypoparathyroidism.

Proton pump inhibitors are the one of the most widely used drugs in the world. Hypomagnesemic hypoparathyroidism has been reported with different proton pump inhibitors with prolonged oral use. We report the first reported case of possible such effect with intravenous preparation of proton pump inhibitor. This case report raises awareness among physicians worldwide of this often unknown association, as life-threatening cardiac and neuromuscular complications can arise with unrecognized hypocalcemia and hypomagnesemia with proton pump inhibitors.

An approach to the diagnosis and management of a case presenting with recurrent hypomagnesemia secondary to the chronic use of a proton pump inhibitor.

PURPOSE: Magnesium is an important electrolyte for very many cell functions and its deficiency may lead to a wide spectrum of diseases. We report a clinical case of hypomagnesemia resulting from the chronic use of a proton pump inhibitor (PPI). PPIs are drugs widely used in medical practice, and a growing number of cases of PPIs causing hypomagnesemia have been described. Our aim was to monitor the clinical and electrolyte findings during recovery from hypomagnesemia caused by long-term PPI use. RESULTS: A 65-year old female who had been using omeprazole for 10 years, presented with arrhythmia and paresthesia of the lower and upper limbs that had been attributed to severe hypomagnesemia, hypocalcemia, and hypoparathyroidism. Her laboratory tests revealed the following results: magnesium 0.6 mg/dL (NR: 1.5 to 2.5 mg/dL), calcium 7.3 mg/dL (NR: 8.5 to 10.2 mg/dL), parathyroid hormone (PTH) 13.3 pg/mL (NR: 15 to 65 pg/mL), and low urinary calcium and magnesium excretion. Her electrocardiogram disclosed typical, prolonged QT interval, ST depression, and U waves. We discuss the differential diagnoses, pathophysiology, and reversibility of symptoms after effective treatment of the hypomagnesemia. CONCLUSION: this report emphasizes that even if long-term PPI users appear largely asymptomatic, life-threatening arrhythmias can present very suddenly. Long-term PPI users should be monitored for otherwise unexplained hypomagnesemia, hypocalcemia, functional hypoparathyroidism and associated symptoms.

Permanent hypoparathyroidism following radioiodine treatment for hyperthyroidism.

Persistent hypoparathyroidism following 131I treatment is a rare but recognized complication. A case is presented, where a relatively small dose of 131I produced persistent hypocalcaemia.

Transient hypoparathyroidism following successful treatment of hypercalcaemia of malignancy in a dog.

A 4-year-old, entire female, English Cocker Spaniel was presented for treatment of lymphosarcoma and secondary hypercalcaemia. After induction chemotherapy the dog became severely hypocalcaemic and showed signs of weakness, muscle fasciculation and facial pruritus. Hormone analysis confirmed inadequate production of parathyroid hormone. Although hypocalcaemia has been previously reported as a component of tumour lysis syndrome, it has not been associated with transient parathyroid hormone deficiency.