Hypercalcemia

Abstract

ImportanceHypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma.ObservationsApproximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival.Conclusions and RelevanceMild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

Calcium Carbonate (Tums)-Associated Milk-Alkali Syndrome as a Cause of Altered Mental Status in the Emergency Department: A Case Report

“…In patients with symptomatic hypercalcemic crisis (calcium level greater than 14 mg/dL or severe symptoms with calcium level greater than 12 mg/dl) (7), emergency physicians should consider the administration of calcitonin to more rapidly decrease the total calcium concentration. Calcitonin is a peptide hormone that lowers calcium levels by inhibiting bone calcium resorption and increasing renal calcium excretion.…”

Endocrine Society Hypercalcemia of Malignancy Guidelines

“…Symptoms range from fatigue, constipation, polyuria, and polydipsia with mild-to-moderate hypercalcemia (mild: serum calcium [SCa] level of 10.5 to <12 mg/dL; moderate: SCa level of 12 to Յ14 mg/dL) to cognitive dysfunction, kidney failure, and arrhythmias with rapidly rising calcium levels or severe hypercalcemia (SCa >14 mg/dL). 1 Pathophysiology followed by HCM can include (1) production of parathyroid hormone-related peptides, (2) bone metastases releasing osteoclast activating factors, and (3) excess production of calcitriol. 2 Treatment of HCM begins with intravenous (IV) hydration, potent antiresorptive agents (such as bisphosphonates [BPs] and denosumab [Dmab]), and calcitonin for severe hypercalcemia.…”

“…Hypercalcemia of malignancy (HCM) affects 2% to 30% of patients with cancer and is associated with high morbidity and mortality. Symptoms range from fatigue, constipation, polyuria, and polydipsia with mild-to-moderate hypercalcemia (mild: serum calcium [SCa] level of 10.5 to <12 mg/dL; moderate: SCa level of 12 to ≤14 mg/dL) to cognitive dysfunction, kidney failure, and arrhythmias with rapidly rising calcium levels or severe hypercalcemia (SCa >14 mg/dL) . Pathophysiology followed by HCM can include (1) production of parathyroid hormone–related peptides, (2) bone metastases releasing osteoclast activating factors, and (3) excess production of calcitriol .…”

Genetic determinants of pancreatitis: relevance in severe hypertriglyceridemia

“…Hypercalcemia is a risk state for pancreatitis although it is less common than gallstones, alcohol use or even hypertriglyceridemia. Primary hyperparathyroidism with hypercalcemia has been found in <0.5% of cases of pancreatitis [ 49 ], and about 90% of patients with hypercalcemia have either primary hyperparathyroidism or a malignancy [ 50 ]. General consideration of genetic etiologies for hypercalcemia is beyond the scope of this review; for instance, some cases of hyperparathyroidism are part of multiple endocrine neoplasia syndromes, which have a distinctive clinical presentation and genetic basis [ 51 ].…”