What is the presentation of hypercalcemia?

From the Guidelines

Hypercalcemia is a life-threatening condition that requires immediate attention, and its management should prioritize hydration, loop diuretics, and bisphosphonates to reduce morbidity and mortality. For a presentation on hypercalcemia, I recommend organizing it around five key sections: definition and pathophysiology, causes, clinical manifestations, diagnostic approach, and management strategies.

Definition and Pathophysiology

Hypercalcemia occurs in 10% to 25% of patients with lung cancer, and is most commonly seen in patients with squamous cell lung cancer 1. The common etiologic mechanisms of hypercalcemia of malignancy are parathyroid hormone-related protein (PTHrP) production, increased active metabolite of vitamin D (calcitriol, also called 1,25-dihydroxyvitamin D), and localized osteolytic hypercalcemia 1.

Causes

The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, followed by less common causes like granulomatous diseases, medications, vitamin D toxicity, and endocrine disorders.

Clinical Manifestations

Clinical symptoms of hypercalcemia depend on severity and acuity of onset, and include:

• Polyuria
• Polydipsia
• Nausea
• Confusion
• Vomiting
• Abdominal pain
• Myalgia Patients may present with severe dehydration and acute renal failure, and when hypercalcemia is severe (> 14.0 mg/dL), patients may develop mental status changes, bradycardia, and hypotension 1.

Diagnostic Approach

The diagnostic evaluation includes measuring serum concentrations of:

• Intact parathyroid hormone (iPTH)
• PTHrP
• 1,25-dihydroxyvitamin D
• 25-hydroxyvitamin D
• Calcium
• Albumin
• Magnesium
• Phosphorus

Management Strategies

Management of hypercalcemia should include oral hydration for mild cases, and rehydrating with IV crystalloid fluids not containing calcium, loop diuretics, and bisphosphonates for moderate to severe cases. Additional therapeutic options such as glucocorticoids, gallium nitrate, and salmon calcitonin may be considered 1. It is essential to note that the median survival after discovery of hypercalcemia of malignancy in patients with lung cancer is about 1 month, highlighting the need for prompt and effective management to improve quality of life and reduce morbidity and mortality 1.

From the FDA Drug Label

Hypercalcemia may produce a spectrum of signs and symptoms including: anorexia, lethargy, fatigue, nausea, vomiting, constipation, dehydration, renal insufficiency, impaired mental status, coma and cardiac arrest. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i. e., saline hydration, with or without diuretics). In patients who have an underlying cancer type that may be sensitive to corticosteroids (e.g., hematologic cancers), the use or addition of corticosteroid therapy may be indicated.

Presentation of Hypercalcemia:

• Signs and Symptoms: anorexia, lethargy, fatigue, nausea, vomiting, constipation, dehydration, renal insufficiency, impaired mental status, coma, and cardiac arrest
• Treatment:
  • Conservative measures: saline hydration, with or without diuretics
  • Corticosteroid therapy may be indicated in patients with underlying cancer types sensitive to corticosteroids (e.g., hematologic cancers) 2

From the Research

Definition and Prevalence of Hypercalcemia

• Hypercalcemia affects approximately 1% of the worldwide population 3
• It is 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) for mild cases, and 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) for severe cases 3

Causes of Hypercalcemia

• Primary hyperparathyroidism (PHPT) and malignancy are responsible for greater than 90% of all cases of hypercalcemia 3, 4
• Other causes include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements like calcium, vitamin D, or vitamin A 3
• Hypercalcemia has also 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 3

Symptoms of Hypercalcemia

• Mild hypercalcemia is usually asymptomatic, but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 3
• Severe hypercalcemia can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 3, 4

Diagnosis of Hypercalcemia

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 3
• An elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level indicates another cause 3

Treatment of Hypercalcemia

• Mild hypercalcemia usually does not need acute intervention, but may require observation or parathyroidectomy depending on age, serum calcium level, and kidney or skeletal involvement 3
• Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 3, 4, 5, 6
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas) 3, 4
• Dialysis may be indicated in patients with kidney failure 3, 4, 6

Management of Severe Hypercalcemia

• Severe hypercalcemia is a life-threatening condition that should be managed urgently 5, 6
• The aim of treatment is to reduce serum calcium levels and improve symptoms, at least transiently 3, 4, 5, 6
• Normal saline hydration, furosemide, and zoledronic acid may be used in the management of severe hypercalcemia secondary to primary hyperparathyroidism (PHPT) 5
• Bisphosphonates are the drugs of choice in most patients after adequate hydration, while non-bisphosphonates drugs, such as calcitonin, gallium nitrate, and mithramycin, are now rarely used 6

Safety of Intravenous Bisphosphonates

• Intravenous bisphosphonates, such as pamidronate and zoledronic acid, are first-line medications for the management of hypercalcemia, but their use in patients with preexisting renal dysfunction is limited 7
• The safety and efficacy of pamidronate and zoledronic acid in the treatment of hypercalcemia in patients with baseline renal dysfunction have been evaluated, with results suggesting an association between IV bisphosphonates and increased rates of serum creatinine elevations among patients with preexisting renal dysfunction 7