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Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism
YAJEM-56514; No of Pages 3 American Journal of Emergency Medicine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism Myint Aung Win, MD a, Kyaw Zin Thein, MD a,b, Aiham Qdaisat, MD a, Sai-Ching Jim Yeung, MD, PhD a,c,⁎ a b c
Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Department of Hematology Oncology, Texas Tech University Health Sciences Center, Lubbock, TX, United States Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
a r t i c l e
i n f o
Article history: Received 10 February 2017 Accepted 25 February 2017 Available online xxxx Keywords: Hypoparathyroidism Hypocalcemia Thyroiditis Ipilimumab Nivolumab Melanoma
a b s t r a c t 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 1.5 months 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 4 months 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. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Immune checkpoints are inhibitory pathways that modulate the duration and severity of the immune system's responses to antigens or autoantigens. Cancer cells express immunosuppressive molecules that activate these pathways and enable the cells to escape from surveillance of the immune system [1]. Immune checkpoint therapies (ICTs) that target cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death receptor 1 (PD-1), and programmed cell death ligand 1 (PDL1) are now approved to treat a variety of malignancies, including melanoma, but may cause immune-related adverse effects (IRAEs). However, acute hypocalcemia due to acquired hypoparathyroidism has not been reported as an IRAE. We herein report the first case of ICT⁎ Corresponding author at: Department of Emergency Medicine, Unit 1468, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States. E-mail address: [email protected] (S.-C.J. Yeung).
induced primary hypoparathyroidism in a patient with metastatic melanoma treated with ipilimumab (a monoclonal antibody against CTLA4) and nivolumab (a humanized antibody against PD-1), who presented to the Emergency Department (ED) of a comprehensive cancer center with acute symptoms. 2. Case report A 73-year-old man with metastatic melanoma presented to the ED for the chief complaints of imbalance, general weakness and abdominal pain. He had numerous metastases in soft tissues, bones, and liver but not in the brain. He had begun ICT with concurrent ipilimumab and nivolumab 1.5 months earlier, and he had received the second cycle of ICT 10 days before his ED visit. He had increased difficulty with balance but denied having any weakness in the extremities or any other neurological symptoms. He had experienced paresthesia in the hands and feet for the past few days. He had abdominal cramping but no other no gastrointestinal symptoms.
http://dx.doi.org/10.1016/j.ajem.2017.02.048 0735-6757/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Win MA, et al, Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.02.048
2
M.A. Win et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx
In addition to melanoma, he had a medical history of prostate cancer, asthma, depression, and sporadic arrhythmia. His current medications were bupropion and metoprolol. He had no history of autoimmune diseases. His surgical history included a radical prostatectomy and a wide local excision of melanoma at his right temple. At the ED, his vital signs were stable. His physical examination was unremarkable except for marked ataxia. Laboratory testing showed hypocalcemia [calcium level of 5.0 mg/dL with normal albumin (4.1 g/dL) and ionized calcium of 0.67 mM] (Fig. 1), hypomagnesemia (1.5 mg/dL), and hyperphosphatemia (6.6 mg/dL). Electrocardiography showed a right bundle branch block and a slightly prolonged corrected QT interval (QTc; 481 ms). Abdominal radiography and magnetic resonance imaging of the brain with gadolinium contrast showed no abnormalities. He was diagnosed with acute severe symptomatic hypocalcemia, and he was hospitalized for further evaluation and treatment. His plasma intact parathyroid hormone (PTH) level was undetectable (b1 pg/mL; normal range, 9–80 pg/mL), his plasma 25-hydroxy vitamin D3 level was 18 ng/mL (normal range, 30–100 ng/mL), and his 1,25-dihydroxy vitamin D3 level was 29 pg/mL (normal range, 18–64 pg/mL). These laboratory results were consistent with a diagnosis of primary hypoparathyroidism. He was given calcium gluconate intravenously (a total of 3 g in divided doses) and then transitioned to oral treatment with ergocalciferol and calcium carbonate. His hypomagnesemia was treated with intravenous magnesium sulfate (32 mEq infused over 4 h). His ataxia and abdominal pain resolved after correction of the hypocalcemia. The QTc in subsequent electrocardiograms was normal. A 24-hour urine collection during the third day of hospitalization showed hypercalciuria (266 mg of calcium in 4300 mL of urine over 24 h; normal range, 50–150 mg/24 h), which was consistent with hypoparathyroidism. The patient's thyroid function was normal prior to initiation of ICT and was normal during at least the first 3 days of hospitalization (Fig. 2). However, 1 week after the ED presentation, he was anxious and tachycardic, and he was diagnosed with hyperthyroidism [thyrotropin (TSH), 0.03 mIU/L (normal range, 0.27–4.2 mIU/L); free thyroxine, 4.46 ng/dL (normal range, 0.9–1.7 ng/dL)]. His thyroperoxidase antibody level was 19 IU/mL (normal range, 0–35 IU/mL), and thyroidstimulating immunoglobulins and thyrotropin receptor antibodies were undetectable. These findings ruled out Graves disease. The clinical
Fig. 2. Time course of serum levels of thyroid hormones and thyrotropin in a melanoma patient who developed primary hypoparathyroidism and thyroiditis after two cycles of ipilimumab and nivolumab. Day 0 was the day on which the patient sought medical attention in the Emergency Department (ED). TSH: thyroid stimulating hormone.
course of his thyroid disease instead fit the pattern of autoimmune thyroiditis, with a hyperthyroid phase followed by a hypothyroid phase (Fig. 2). When he became hypothyroid, thyroid hormone replacement therapy was started. After discharge from the hospital, he remained clinically stable and asymptomatic on thyroid hormone replacement (levothyroxine 88 mcg orally daily) and management of hypocalcemia using calcium carbonate (500 mg elemental calcium orally twice daily) and calcitriol (0.25 mcg orally twice daily). His parathyroid gland function did not recover during the 4 months after the diagnosis, based on measurements of PTH (Fig. 1).
3. Discussion
Fig. 1. Time course of serum levels of calcium and selected regulatory hormones in a melanoma patient who developed primary hypoparathyroidism and thyroiditis after two cycles of ipilimumab and nivolumab. Day 0 was the day on which the patient sought medical attention in the Emergency Department (ED). PTH: parathyroid hormone; 25-OH vit. D: 25-hydroxy vitamin D3.
The patient's acute-onset severe hypocalcemia manifested clinically as paresthesia, general muscle weakness, abdominal cramping, and ataxia. Primary hypoparathyroidism was diagnosed on the basis of hypocalcemia, hyperphosphatemia, and a low plasma PTH level [2]. Although hypomagnesemia can lead to functional hypoparathyroidism and hypocalcemia [3,4], PTH should not be undetectable in the plasma in the absence of primary dysfunction of the parathyroid glands. Other possible causes of primary hypoparathyroidism include damage to the parathyroid glands during thyroid surgery, DiGeorge syndrome (a genetic disorder due to 22q11.2 deletion), hemochromatosis, Wilson disease, metastatic infiltration of the parathyroid glands, and autoimmune destruction of the parathyroid glands [2,5,6]. Although this patient had dysfunction of two endocrine glands: parathyroid and thyroid, this case does not fit the clinical characteristics of the three known types of autoimmune polyglandular syndromes. Autoimmune diseases result from dysregulation of self-tolerance, and polymorphisms of immune checkpoint genes have been linked with various autoimmune diseases such as Hashimoto thyroiditis, Graves disease, myasthenia gravis, systemic and etc. [7-9]. Previously reported clinically significant IRAEs of ICT include colitis, pneumonitis, nephritis, and various endocrinopathies (e.g., hypophysitis, thyroid dysfunction, and primary adrenal insufficiency) [10]. Although thyroiditis is frequently seen after ICT, primary hypoparathyroidism has not been reported to result from ICT in the literature.
Please cite this article as: Win MA, et al, Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.02.048
M.A. Win et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx
In conclusion, although abundant endocrine complications have been reported as IRAEs of ICT, this is the first reported case of primary hypoparathyroidism caused by ICT presenting with acute symptomatic hypocalcemia. Emergency care providers should be aware of this new addition to ICT IRAEs in the new era of immuno-oncology since appropriate timely diagnosis and management are very important. Ethics, consent and permissions The retrospective review was conducted under a clinical research protocol (DR08-0066) approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. The patient consented to publication of this case report. Competing interests The authors declare that they have no competing interests. Funding
3
References [1] Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378):480–9. [2] Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008;359(4): 391–403. [3] Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984;310(19):1221–5. [4] Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005;20(1):3–17. [5] Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343(25):1863–75. [6] Thakker RV. Genetics of endocrine and metabolic disorders: parathyroid. Rev Endocr Metab Disord 2004;5(1):37–51. [7] Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423(6939):506–11. [8] Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002;32(4):666–9. [9] Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–48 (Oxford, England: 1990). [10] Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013;98(4):1361–75.
This report was not funded.
Please cite this article as: Win MA, et al, Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.02.048
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism Myint Aung Win, MD a, Kyaw Zin Thein, MD a,b, Aiham Qdaisat, MD a, Sai-Ching Jim Yeung, MD, PhD a,c,⁎ a b c
Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Department of Hematology Oncology, Texas Tech University Health Sciences Center, Lubbock, TX, United States Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
a r t i c l e
i n f o
Article history: Received 10 February 2017 Accepted 25 February 2017 Available online xxxx Keywords: Hypoparathyroidism Hypocalcemia Thyroiditis Ipilimumab Nivolumab Melanoma
a b s t r a c t 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 1.5 months 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 4 months 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. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Immune checkpoints are inhibitory pathways that modulate the duration and severity of the immune system's responses to antigens or autoantigens. Cancer cells express immunosuppressive molecules that activate these pathways and enable the cells to escape from surveillance of the immune system [1]. Immune checkpoint therapies (ICTs) that target cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death receptor 1 (PD-1), and programmed cell death ligand 1 (PDL1) are now approved to treat a variety of malignancies, including melanoma, but may cause immune-related adverse effects (IRAEs). However, acute hypocalcemia due to acquired hypoparathyroidism has not been reported as an IRAE. We herein report the first case of ICT⁎ Corresponding author at: Department of Emergency Medicine, Unit 1468, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States. E-mail address: [email protected] (S.-C.J. Yeung).
induced primary hypoparathyroidism in a patient with metastatic melanoma treated with ipilimumab (a monoclonal antibody against CTLA4) and nivolumab (a humanized antibody against PD-1), who presented to the Emergency Department (ED) of a comprehensive cancer center with acute symptoms. 2. Case report A 73-year-old man with metastatic melanoma presented to the ED for the chief complaints of imbalance, general weakness and abdominal pain. He had numerous metastases in soft tissues, bones, and liver but not in the brain. He had begun ICT with concurrent ipilimumab and nivolumab 1.5 months earlier, and he had received the second cycle of ICT 10 days before his ED visit. He had increased difficulty with balance but denied having any weakness in the extremities or any other neurological symptoms. He had experienced paresthesia in the hands and feet for the past few days. He had abdominal cramping but no other no gastrointestinal symptoms.
http://dx.doi.org/10.1016/j.ajem.2017.02.048 0735-6757/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Win MA, et al, Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.02.048
2
M.A. Win et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx
In addition to melanoma, he had a medical history of prostate cancer, asthma, depression, and sporadic arrhythmia. His current medications were bupropion and metoprolol. He had no history of autoimmune diseases. His surgical history included a radical prostatectomy and a wide local excision of melanoma at his right temple. At the ED, his vital signs were stable. His physical examination was unremarkable except for marked ataxia. Laboratory testing showed hypocalcemia [calcium level of 5.0 mg/dL with normal albumin (4.1 g/dL) and ionized calcium of 0.67 mM] (Fig. 1), hypomagnesemia (1.5 mg/dL), and hyperphosphatemia (6.6 mg/dL). Electrocardiography showed a right bundle branch block and a slightly prolonged corrected QT interval (QTc; 481 ms). Abdominal radiography and magnetic resonance imaging of the brain with gadolinium contrast showed no abnormalities. He was diagnosed with acute severe symptomatic hypocalcemia, and he was hospitalized for further evaluation and treatment. His plasma intact parathyroid hormone (PTH) level was undetectable (b1 pg/mL; normal range, 9–80 pg/mL), his plasma 25-hydroxy vitamin D3 level was 18 ng/mL (normal range, 30–100 ng/mL), and his 1,25-dihydroxy vitamin D3 level was 29 pg/mL (normal range, 18–64 pg/mL). These laboratory results were consistent with a diagnosis of primary hypoparathyroidism. He was given calcium gluconate intravenously (a total of 3 g in divided doses) and then transitioned to oral treatment with ergocalciferol and calcium carbonate. His hypomagnesemia was treated with intravenous magnesium sulfate (32 mEq infused over 4 h). His ataxia and abdominal pain resolved after correction of the hypocalcemia. The QTc in subsequent electrocardiograms was normal. A 24-hour urine collection during the third day of hospitalization showed hypercalciuria (266 mg of calcium in 4300 mL of urine over 24 h; normal range, 50–150 mg/24 h), which was consistent with hypoparathyroidism. The patient's thyroid function was normal prior to initiation of ICT and was normal during at least the first 3 days of hospitalization (Fig. 2). However, 1 week after the ED presentation, he was anxious and tachycardic, and he was diagnosed with hyperthyroidism [thyrotropin (TSH), 0.03 mIU/L (normal range, 0.27–4.2 mIU/L); free thyroxine, 4.46 ng/dL (normal range, 0.9–1.7 ng/dL)]. His thyroperoxidase antibody level was 19 IU/mL (normal range, 0–35 IU/mL), and thyroidstimulating immunoglobulins and thyrotropin receptor antibodies were undetectable. These findings ruled out Graves disease. The clinical
Fig. 2. Time course of serum levels of thyroid hormones and thyrotropin in a melanoma patient who developed primary hypoparathyroidism and thyroiditis after two cycles of ipilimumab and nivolumab. Day 0 was the day on which the patient sought medical attention in the Emergency Department (ED). TSH: thyroid stimulating hormone.
course of his thyroid disease instead fit the pattern of autoimmune thyroiditis, with a hyperthyroid phase followed by a hypothyroid phase (Fig. 2). When he became hypothyroid, thyroid hormone replacement therapy was started. After discharge from the hospital, he remained clinically stable and asymptomatic on thyroid hormone replacement (levothyroxine 88 mcg orally daily) and management of hypocalcemia using calcium carbonate (500 mg elemental calcium orally twice daily) and calcitriol (0.25 mcg orally twice daily). His parathyroid gland function did not recover during the 4 months after the diagnosis, based on measurements of PTH (Fig. 1).
3. Discussion
Fig. 1. Time course of serum levels of calcium and selected regulatory hormones in a melanoma patient who developed primary hypoparathyroidism and thyroiditis after two cycles of ipilimumab and nivolumab. Day 0 was the day on which the patient sought medical attention in the Emergency Department (ED). PTH: parathyroid hormone; 25-OH vit. D: 25-hydroxy vitamin D3.
The patient's acute-onset severe hypocalcemia manifested clinically as paresthesia, general muscle weakness, abdominal cramping, and ataxia. Primary hypoparathyroidism was diagnosed on the basis of hypocalcemia, hyperphosphatemia, and a low plasma PTH level [2]. Although hypomagnesemia can lead to functional hypoparathyroidism and hypocalcemia [3,4], PTH should not be undetectable in the plasma in the absence of primary dysfunction of the parathyroid glands. Other possible causes of primary hypoparathyroidism include damage to the parathyroid glands during thyroid surgery, DiGeorge syndrome (a genetic disorder due to 22q11.2 deletion), hemochromatosis, Wilson disease, metastatic infiltration of the parathyroid glands, and autoimmune destruction of the parathyroid glands [2,5,6]. Although this patient had dysfunction of two endocrine glands: parathyroid and thyroid, this case does not fit the clinical characteristics of the three known types of autoimmune polyglandular syndromes. Autoimmune diseases result from dysregulation of self-tolerance, and polymorphisms of immune checkpoint genes have been linked with various autoimmune diseases such as Hashimoto thyroiditis, Graves disease, myasthenia gravis, systemic and etc. [7-9]. Previously reported clinically significant IRAEs of ICT include colitis, pneumonitis, nephritis, and various endocrinopathies (e.g., hypophysitis, thyroid dysfunction, and primary adrenal insufficiency) [10]. Although thyroiditis is frequently seen after ICT, primary hypoparathyroidism has not been reported to result from ICT in the literature.
Please cite this article as: Win MA, et al, Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.02.048
M.A. Win et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx
In conclusion, although abundant endocrine complications have been reported as IRAEs of ICT, this is the first reported case of primary hypoparathyroidism caused by ICT presenting with acute symptomatic hypocalcemia. Emergency care providers should be aware of this new addition to ICT IRAEs in the new era of immuno-oncology since appropriate timely diagnosis and management are very important. Ethics, consent and permissions The retrospective review was conducted under a clinical research protocol (DR08-0066) approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. The patient consented to publication of this case report. Competing interests The authors declare that they have no competing interests. Funding
3
References [1] Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378):480–9. [2] Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008;359(4): 391–403. [3] Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984;310(19):1221–5. [4] Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005;20(1):3–17. [5] Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343(25):1863–75. [6] Thakker RV. Genetics of endocrine and metabolic disorders: parathyroid. Rev Endocr Metab Disord 2004;5(1):37–51. [7] Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423(6939):506–11. [8] Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002;32(4):666–9. [9] Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–48 (Oxford, England: 1990). [10] Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013;98(4):1361–75.
This report was not funded.
Please cite this article as: Win MA, et al, Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.02.048