Calcium Disorders.

This article provides a comprehensive overview of calcium physiology, clinical presentation with physical examination findings, laboratory assessment, differential diagnosis, and management of hypocalcemia and hypercalcemia for the primary care provider.

Endocrine Emergencies.

Endocrine emergencies encompass a group of conditions that occur when hormonal deficiency or excess results in acute presentation. If these endocrine disorders are not rapidly identified or if specific treatment is delayed, significant complications or even death may occur. This article outlines the basics of endocrine emergencies involving the thyroid, parathyroid, pituitary, pancreas, and adrenal glands. It discusses various causative factors, diagnostic approaches, and treatment modalities, emphasizing the significance of preventive measures. This article is aimed at guiding health care professionals, and this overview seeks to enhance understanding and improve patient outcomes in managing endocrine emergencies.

The Safety Profile of Vitamin D Supplements Using Real-World Data from 445,493 Participants of the UK Biobank: Slightly Higher Hypercalcemia Prevalence but Neither Increased Risks of Kidney Stones nor Atherosclerosis.

Background: Potential calcium-related adverse events of vitamin D supplement use have not been addressed in large-scale, real-world data so far. Methods: Leveraging data from the UK Biobank, encompassing 445,493 individuals aged 40-69, we examined associations of high 25-hydroxyvitamin (25(OH)D) levels ≥ 100 nmol/L and vitamin D supplementation with hypercalcemia (serum calcium > 2.6 mmol/L), kidney stones, and atherosclerosis assessments (pulse wave arterial stiffness index and carotid intima-medial thickness). Regression models were comprehensively adjusted for 49 covariates. Results: Approximately 1.5% of the participants had high 25(OH)D levels, 4.3% regularly used vitamin D supplements, and 20.4% reported regular multivitamin use. At baseline, the hypercalcemia prevalence was 1.6%, and 1.1% was diagnosed with kidney stones during follow-up. High 25(OH)D levels were neither associated with calcium-related adverse events nor atherosclerosis assessments. Vitamin D and multivitamin supplementation were associated with an increased prevalence of hypercalcemia (odds ratios and 95% confidence intervals: 1.46 [1.32-1.62] and 1.11 [1.04-1.18], respectively) but were neither associated with atherosclerosis nor future kidney stones. Conclusions: High 25(OH)D levels observable in routine care were not associated with any adverse outcome. Vitamin D users have a slightly higher prevalence of hypercalcemia, possibly due to co-supplementation with calcium, but without a higher atherosclerosis prevalence or risk of kidney stones.

Persisting Hypercalcemia and Hyperparathyroidism after Kidney Transplantation Have a Negative Impact on Graft and Patient Survival.

Hyperparathyroidism (HPT) with hypercalcemia, often deemed irreversible and detrimental to graft survival post-kidney transplantation (KT), prompts pre-transplant parathyroidectomy in hypercalcemic patients. In this retrospective analysis of 1212 kidney transplant recipients (KTRs) between 2006 and 2019, the incidence and effect of persistent HPT and hypercalcemia on graft and patient survival, and risk factors for persistence were analyzed until 60 months of follow up (FU). At KT, 5.7% (n = 69) had no HPT, 32.7% (n = 396) had HPT without hypercalcemia and 37.0% (n = 448) had HPT with hypercalcemia. At 2 years FU, 26.4% (n = 320) of patients had no HPT and 6% (n = 73) had HPT with hypercalcemia. Dialysis and dialysis duration were linked to HPT development, while dialysis, KT waiting time and donor type correlated with persisting hypercalcemia after KT. KTRs with normalized PTH and recovered hypercalcemia had improved death-censored graft survival (p < 0.001) and overall patient survival (p < 0.001). HPT with hypercalcemia is frequent at time of KT with normalization of PTH and calcium in a substantial proportion of patients after a KT. These findings question the routine pre-KT parathyroidectomy for suspected parathyroid autonomy. Persisting HPT, especially with hypercalcemia, adversely affects graft and patient survival, suggesting the need for more aggressive treatment of HPT, especially in cases of persisting hypercalcemia.

Hypercalcemia Secondary to Calcitriol Production From Dual Combination Immunotherapy in Pulmonary Metastatic Melanoma.

Nivolumab and ipilimumab are immunotherapy agents recommended for the treatment of metastatic melanoma. A rare adverse effect of these agents is hypercalcemia. The mechanism of immunotherapy-mediated hypercalcemia is thought to be due to ectopic calcitriol production from activated macrophages, similar to sarcoidosis. We present a case of a 76-year-old female with metastatic melanoma who developed severe hypercalcemia after completing a cycle of combined nivolumab and ipilimumab therapy. After other common causes of hypercalcemia in malignancy were ruled out, the decision was made to aggressively treat her hypercalcemia while inpatient and hold immunotherapy at discharge. Since holding immunotherapy, she has not had a repeat occurrence of hypercalcemia. This case stresses the importance of including immunotherapy adverse effects in the differential diagnosis for hypercalcemia in malignancy.

Hypercalcemia in children induced by denosumab: a case report and an analysis of the FDA adverse event reporting system database.

BACKGROUND: The potential risks of denosumab on pediatric patients have raised concerns about its safety. This article aims to analyze the adverse effects of denosumab in minors, with a specific focus on hypercalcemia. RESEARCH DESIGN AND METHODS: A case study involving a child was analyzed. The OpenVigil 2.1 was utilized to extract adverse event data from the FAERS database, focusing on denosumab as the primary suspect drug in pediatric patients. The study also reviewed published cases of children developing hypercalcemia after discontinuing denosumab. RESULTS: The incidence of denosumab induced hypercalcemia in individuals under 18 years old is significantly higher than the overall incidence. The signal value for hypercalcemia was higher in the male group and was highest in the adolescent group. Hypercalcemia usually appeared approximately 4 months after denosumab discontinuation. Males had a higher peak blood calcium level. Patients aged 0-11 years had a higher average peak serum calcium compared to aged 12-17 years. CONCLUSIONS: This study highlights the risk of hypercalcemia after discontinuation of denosumab in minors, with young age and male gender identified as potential high-risk factors. These findings offer valuable safety warnings and preventative measures for the secure administration of this drug in pediatric populations.

Clinical and epidemiologic characteristics of hospitalized oncological patients with hypercalcemia: a longitudinal, multicenter study.

BACKGROUND: There are few studies that have analyzed the characteristics of hypercalcemia in hospitalized oncological patients. Our objectives were to describe the clinical characteristics of hospitalized patients with paraneoplastic hypercalcemia and to identify prognostic variables for mortality. METHODS: This was an observational, longitudinal, retrospective, and bicentric study. It included adult patients admitted to two hospitals in Málaga, Spain (2014-2018). The minimum follow-up period was 2 years or until death. RESULTS: A total of 154 patients were included; the majority (71.4%) were admitted to the internal medicine department. The median follow-up was 3.5 weeks (interquartile range [IQR] 1.1-11.5). The mean (standard deviation) age was 67.6 (12.3) years, with a predominance of males (58.4%). The median (IQR) serum calcium at admission was 13.2 (11.8-14.6) mg/dl. The most common neoplasms were pulmonary (27.3%), hematologic (23.4%), urological (13%), and breast (12.3%). Furthermore, 56.5% of cases had a known history of neoplasia at the time of diagnosis. The parathyroid hormone (PTH) level was determined in 24%; of these, 10.8% had elevated levels. In all, 95.5% of patients died during follow-up. The median survival was 3.4 weeks (95% confidence interval 2.6-4.3). Factors associated with higher mortality were age, serum calcium at admission, previous history of neoplasia, etiology other than multiple myeloma, and noncorrection of hypercalcemia. CONCLUSIONS: In hospitalized patients, paraneoplastic hypercalcemia was associated with high short-term mortality. Several factors associated with a worse prognosis were identified in these patients.

Parathyroid hormone-related peptide induced hypercalcemia of pregnancy due to mammary hyperplasia.

Maternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy.

Dietary magnesium supplementation in cats with chronic kidney disease: A prospective double-blind randomized controlled trial.

BACKGROUND: Plasma total magnesium concentration (tMg) is a prognostic indicator in cats with chronic kidney disease (CKD), shorter survival time being associated with hypomagnesemia. Whether this risk factor is modifiable with dietary magnesium supplementation remains unexplored. OBJECTIVES: Evaluate effects of a magnesium-enriched phosphate-restricted diet (PRD) on CKD-mineral bone disorder (CKD-MBD) variables. ANIMALS: Sixty euthyroid client-owned cats with azotemic CKD, with 27 and 33 allocated to magnesium-enriched PRD or control PRD, respectively. METHODS: Prospective double-blind, parallel-group randomized trial. Cats with CKD, stabilized on a PRD, without hypermagnesemia (tMg >2.43 mg/dL) or hypercalcemia (plasma ionized calcium concentration, (iCa) >6 mg/dL), were recruited. Both intention-to-treat and per-protocol (eating ≥50% of study diet) analyses were performed; effects of dietary magnesium supplementation on clinicopathological variables were evaluated using linear mixed effects models. RESULTS: In the per-protocol analysis, tMg increased in cats consuming a magnesium-enriched PRD (ß, 0.25 ± .07 mg/dL/month; P < .001). Five magnesium supplemented cats had tMg >2.92 mg/dL, but none experienced adverse effects. Rate of change in iCa differed between groups (P = .01), with decreasing and increasing trends observed in cats fed magnesium-enriched PRD and control PRD, respectively. Four control cats developed ionized hypercalcemia versus none in the magnesium supplemented group. Log-transformed plasma fibroblast growth factor-23 concentration (FGF23) increased significantly in controls (ß, 0.14 ± .05 pg/mL/month; P = .01), but remained stable in the magnesium supplemented group (ß, 0.05±.06 pg/mL/month; P =.37). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnesium-enriched PRD is a novel therapeutic strategy for managing feline CKD-MBD in cats, further stabilizing plasma FGF23 and preventing hypercalcemia.

Use of Cinacalcet for the Management of Primary Hyperparathyroidism in Pregnancy.

Primary hyperparathyroidism in pregnancy is uncommon. Consequently, there are no randomized controlled studies that address treatment of primary hyperparathyroidism in pregnancy, and the efficacy and safety of medical management with cinacalcet in this setting is unknown. We report a case of a 28-year-old woman with primary hyperparathyroidism and hypercalcemia that worsened during her third trimester of pregnancy. Cinacalcet led to achievement of normocalcemia, allowing the delay of parathyroidectomy until after delivery of the baby. We also review the published literature on cinacalcet use in the management of primary hyperparathyroidism during pregnancy. Cinacalcet is typically reserved for pregnant patients with severe and symptomatic hypercalcemia, primarily serving as a last resort to delay parathyroidectomy until either the second trimester or the postpartum period.

Refractory Hypercalcemia Secondary to Metastatic Parathyroid Carcinoma Treated With Immunotherapy.

Parathyroid carcinoma (PC) is a rare endocrine malignancy and an uncommon cause of primary hyperparathyroidism. Metastatic disease confers a guarded prognosis with limited systemic treatment options available. We describe a case of a 64-year-old woman with primary hyperparathyroidism secondary to PC. Despite initial surgical resection, the patient relapsed within 6 months with widespread cerebral and skeletal metastatic disease. She developed worsening parathyroid hormone-mediated hypercalcemia that was refractory to escalating doses of cinacalcet and antiresorptive therapy. Molecular genomics identified high tumor mutation burden within the malignant tissue and single-agent nivolumab immunotherapy was administered. After one dose, there was resolution of her refractory hypercalcemia and primary hyperparathyroidism. The patient has tolerated ongoing treatment with 3 weekly cycles of nivolumab. She remains in biochemical remission as of June 2024, which is now 12 months after commencement of nivolumab.

An Atypical Case of Extrapulmonary Sarcoidosis with Severe Hypercalcemia as Initial Presentation, Successfully Treated with Glucocorticoids.

BACKGROUND: Sarcoidosis is a multisystemic disease that is histologically characterized by non-caseating granulomas in one or more organs. Although hypercalcemia is commonly seen in sarcoidosis, clinically significant hypercalcemia as the initial presentation of sarcoidosis is exceedingly rare. Long-standing hypercalcemia can lead to several complications and needs to be adequately managed to prevent irreversible damage. Currently, there are no standard treatment guidelines for sarcoidosis-induced hypercalcemia, although glucocorticoids have often been used as first-line therapy. CASE REPORT: We describe a 55-year-old male patient who presented with dull right upper quadrant abdominal pain and a 30-pound weight loss over one month. He was found to have severe hypercalcemia, which was treated with intravenous (IV) normal saline and intramuscular calcitonin. Imaging studies revealed hypodense lesions throughout the bilateral hepatic lobes, spleen, and bilateral kidneys, with no pathologic mediastinal, hilar, supraclavicular, or axillary lymphadenopathy or pulmonary parenchymal disease. A splenic biopsy confirmed extrapulmonary sarcoidosis. After initial discharge, the patient was re-admitted weeks later for severe hypercalcemia, which was successfully treated with the initiation of prednisone. CONCLUSIONS: In this report, we present an atypical case of isolated extrapulmonary sarcoidosis with severe hypercalcemia as the initial presentation, successfully treated with steroids.

Patient Characteristics, Management, and Outcomes in a Novel Cohort of Primary Hyperparathyroidism.

Context: Primary hyperparathyroidism (PHPT) increases the risk of bone loss, debilitating fractures, kidney stones, impaired renal function, and neurocognitive symptoms. Studies describing the natural history of PHPT have been limited to small samples, single institutions, or specific populations. Objective: We assessed the natural history of PHPT through a large, diverse national cohort from an electronic health record dataset representing more than 100 million patients. Methods: The TriNetX database was queried for adult patients with PHPT. We extracted demographics, comorbidities, and longitudinal biochemistries. Primary outcomes included major osteoporotic fracture (MOF) and chronic kidney disease (CKD). Outcomes were stratified by treatment strategy (surgical parathyroidectomy [PTX] vs nonsurgical) and age. Results: Among 50 958 patients with PHPT, 26.5% were treated surgically at a median of 0.3 years postdiagnosis. At diagnosis, median age was 65 years, 74.0% were female, and median calcium level was 10.9 mg/dL. Black and older patients underwent PTX less frequently than White and younger patients. MOF 10-year incidence was 5.20% (PTX) and 7.91% (nonsurgical), with median 1.7-year delay with PTX compared to nonsurgical. PTX-associated MOF absolute risk reduction was 0.83% (age < 65 years) and 3.33% (age ≥ 65 years). CKD 10-year incidence was 21.2% (PTX) and 33.6% (nonsurgical), with median 1.9-year delay with PTX. PTX-associated CKD absolute risk reduction was 12.2% (age < 65 years) and 9.5% (age ≥ 65 years). Conclusion: We report 1 of the largest, representative, population-based natural histories of PHPT with different management strategies. A minority of patients underwent PTX, especially in older age. Patients managed surgically had lower incidence of fracture and CKD, and older patients experienced differential benefit.

Intentional vomiting as a rare cause of hypercalcemia and consequent acute renal failure: a case report.

Two most common causes of elevated serum calcium levels, which together account for nearly 90% of all cases, are primary hyperparathyroidism and malignancy. Thus, it is necessary to consider other disorders in the diagnostic evaluation of patients with hypercalcemia. We report the case of a 40-year-old female patient with an intellectual disability who was admitted to the Emergency Department with severe symptomatic hypercalcemia and acute renal failure, caused by recurrent intentional vomiting. The aim of this report is to help clinicians make an accurate diagnosis by considering recurrent vomiting habits as a potential cause of hypercalcemia and acute renal failure. Our case provides a comprehensive diagnostic work-up and multidisciplinary treatment strategies for patients with symptomatic hypercalcemia.

Acute pancreatitis and refractory hypercalcemia in the third trimester caused by parathyroid carcinoma.

BACKGROUND: Hypercalcemia can be a rare contributor to acute pancreatitis (AP) in pregnancy. This is primarily due to primary hyperparathyroidism (PHPT), resulting from parathyroid carcinoma. We exhibited a case report to analyze the diagnosis and treatment during the onset of hypercalcemia-induced AP. CASE PRESENTATION: A 32-year-old primigravida presented with acute pancreatitis near full-term gestation. Following a cesarean delivery, there was a reduction in serum amylase and peripancreatic exudate, but her serum calcium concentrations persistently elevated over 4.0 mmol/L. Interventions to lower the hypercalcemia were only temporarily effective, until a high serum parathyroid hormone (PTH) concentration of 1404 pg/mL was detected. Ultrasound revealed a 31 mm × 24 mm hypoechoic oval nodule in the left lower lobe of the thyroid gland. She underwent a parathyroidectomy, resulting in a dramatic decrease in serum PTH level, from preoperative levels of 2051 pg/mL to 299 pg/mL just 20 minutes after removal. Similarly, her serum calcium declined from 3.82 mmol/L to 1.73 mmol/L within 24 hours postoperatively. The final histopathology suggested parathyroid carcinoma. CONCLUSION: When refractory hypercalcemia is present, serum PTH levels should be measured to determine PHPT. Parathyroidectomy is the optimal strategy for alleviating hypercalcemia and clarifying the underlying pathology.

Endocrine Shades of Silicone Fillers: A Case of Calcitriol-mediated Hypercalcemia.

Background: The inflammatory reaction of foreign body granulomas (FBG) may be so vast that it leads to severe systemic effects. Case report: A 42-year-old woman was referred to the ED with severe recurrent symptomatic hypercalcemia associated with worsening kidney function. She had presented multiple times with similar complaints. Severe hypercalcemia (13.8 mg/dL) was noted, with appropriately low PTH, elevated PTHrP, low 25-hydroxyvitamin D, and normal 1,25-dihydroxyvitamin D levels. She admitted having significant subcutaneous silicone filler injections in the hips six years prior. Admission workup revealed a normal 25-hydroxyvitamin D, but a marked elevation of 1,25-dihydroxyvitamin D (138 pg/mL). Whole-body PET-CT demonstrated moderate 2-18F-fluoro-2-deoxy-d-glucose (FDG) uptake within the subcutaneous adipose tissue of the lateral aspects of the gluteal regions. She was diagnosed with silicone filler injection-induced hypercalcemia, secondary to granulomatous inflammation. Her calcium level normalized a month after the initiation of prednisone. Discussion: FBG may occur years after filler injection. In rare cases, a significant granulomatous immune response leads to uncontrolled production of calcitriol. Pro-inflammatory cytokines can also upregulate PTHrP expression in macrophages, further contributing to hypercalcemia. Treatment focuses on general hypercalcemia management and FBG remission, most effectively achieved with anti-inflammatory corticosteroid doses. Nevertheless, further studies are needed to evaluate its long-term treatment efficacy. Conclusion: Granulomatous inflammation from silicone filler injection can cause hypercalcemia by uncontrolled production of calcitriol and increased PTHrP production by macrophages and giant cells.

Exploring the relationship between calcitonin, ionized calcium, and bone turnover in cats with and without naturally occurring hypercalcemia.

Objectives: This case-control study aimed to evaluate calcitonin response in naturally occurring hypercalcemia in cats and assess the relationships between calcitonin and ionized calcium (iCa) and examine relationships between calcitonin, iCa and bone turnover. Methods: Hypercalcemic cats (persistently increased iCa concentration [>1.40 mmol/l]) were identified retrospectively via a medical database search; additional hypercalcemic and normocalcemic cats were recruited prospectively. Data regarding routine biochemical and urine testing, diagnostic imaging and additional blood testing were obtained. Serum alkaline phosphatase (ALP) activity was used as a marker of bone turnover. Serum calcitonin concentration was analyzed using a previously validated immunoradiometric assay. Hypercalcemic cats with an increased calcitonin concentration (>0.9 ng/L) were termed responders. Group comparisons were performed using a Mann-Whitney test for continuous variables and a χ2 test for categorical variables. Spearman's correlation coefficient was used to examine the relationships between calcitonin, iCa and ALP. Results: Twenty-six hypercalcemic and 25 normocalcemic cats were recruited. Only 5/26 (19.2%) of the hypercalcemic cats were identified as responders, and all were diagnosed with idiopathic hypercalcemia. There was no significant correlation between the concentrations of calcitonin and iCa (p = 0.929), calcitonin and ALP (p = 0.917) or iCa and ALP (p = 0.678) in hypercalcemic cats, however, a significant negative correlation was observed between calcitonin and ALP (p = 0.037) when normocalcemic and hypercalcemic cats with an elevated calcitonin concentration were analyzed together. Discussion: The expected increase in calcitonin concentration was present in only a small subset of hypercalcemic cats; no correlation was found between iCa and calcitonin concentration. The inverse relationship between calcitonin and ALP in cats with increased calcitonin concentrations suggests that the ability of calcitonin to correct hypercalcemia may be related to the degree of bone turnover.

Random Occurrence or Real Association? Primary Hyperparathyroidism in a Young Man With Sickle Cell Disease.

A 32-year-old man with sickle cell disease (SCD) was admitted to the hospital for sickle cell crisis, during which laboratory workup revealed primary hyperparathyroidism. His treatment regimen included hydration, calcitonin, and calcimimetics. A parathyroid nuclear scan revealed anomalous parathyroid tissue. The precise relationship between primary hyperparathyroidism (PHPT) and SCD remains incompletely understood but may involve factors such as vitamin D deficiency, elevated erythropoietin levels, and the influence of growth factors on the development of parathyroid adenomas. Furthermore, the concurrent occurrence of both PHPT and SCD at an earlier age may potentiate adverse long-term outcomes. Effective management of PHPT in SCD entails addressing hypercalcemia and treating the underlying cause of hyperparathyroidism. While a potential association between PHPT and SCD exists, further research is essential to better elucidate their interaction, prevalence, clinical presentations, and outcomes.

Systemic sarcoidosis presenting with hypercalcemia, sinusitis and hypothalamic-pituitary dysfunction.

OBJECTIVES: Sarcoidosis is a multi-system granulomatous disease of unknown origin. It is mainly thought of as a lung disease but it can affect any organ system. Sinus and endocrine dysfunctions are described but are rare and seldomly linked with sarcoidosis. METHODS: Here we describe a case of a young Caucasian man who already visited multiple care givers for sinusitis, erectile dysfunction and anorexia. He presented at the emergency department with fever and emaciation, polyuria and polydipsia. The results of the blood sampling revealed a hypercalcaemia as well as abnormal thyroid function. RESULTS: After biochemical, radiological and histopathological workup, he was diagnosed with pulmonary sarcoidosis. Treatment with corticosteroids resulted in resolution of the sinusitis and normalisation of the calcemia, as well as the thyroid function while the impotence, polydipsia and polyuria remained. Elaboration revealed extra-pulmonary involvement of the sarcoidosis with dysfunction of the hypothalamic-pituitary axis with hypogonadotropic hypogonadism and diabetes insipidus due to a sellar mass. CONCLUSION: This is a rare case of systemic sarcoidosis with both thoracic and extra thoracic manifestations, with pituitary and sinus involvement. It shows that sarcoidosis can affect any organ system and diagnosis can be difficult in case of extrapulmonary manifestations.