Hypercalcemia

Diagnosis

Indications for Testing

• Fatigue, muscle weakness, recurrent nephrolithiasis, bone pain, constipation, changes in mental status
• Elevated calcium on laboratory testing

Laboratory Testing

• Initial testing – comprehensive metabolic panel (CMP)
  • Abnormalities in other lab results may provide clues to underlying pathology
  • Chronic kidney disease with metabolic bone disease results in abnormalities of calcium, phosphorus, PTH, and bone turnover
• Calcium
  • Calculate corrected calcium
    • Corrected calcium = serum calcium + [0.8 x (normal albumin - serum albumin)]
    • Normal albumin is usually 4-4.5 g/dL, depending on testing lab
  • Consider ionized calcium if albumin is low
  • Total serum calcium
    • In asymptomatic patient with concentration >10.3 but <11.0 mg/dL, repeat with albumin measurement or ionized calcium
    • In symptomatic patient and/or patient with concentration >11.0 mg/dL – order PTH
• PTH (intact)
  • Elevated or normal – indicates primary hyperparathyroidism; order urine calcium, 24-hour collection
    • High urine calcium (≥100 pg/mL) – primary hyperparathyroidism
    • Low urine calcium (<100 pg/mL) – familial benign hypercalcemia
  • Low – order PTH-related peptide (PTHrP)
    • High PTHrP – consider cancer
    • Low or normal PTHrP – order vitamin D, 1,25-dihydroxy [1,25-(OH)₂-D]
      • High 1,25-(OH)₂-D – consider lymphoma or granulomatous disease
      • Low or normal 1,25-(OH)₂-D – consider vitamin D excess, cancer, milk-alkali syndrome, or hyperthyroidism
• Other testing
  • Thyroid-stimulating hormone (TSH) – rarely, hyperthyroidism can cause hypercalcemia

Differential Diagnosis

See Etiology in Background

Background

Epidemiology

• Incidence – 8/100,000
• Age – 40s-50s; mean is 55 years
• Sex – M<F for primary hyperparathyroidism

Etiology

• Hyperparathyroidism
• Drugs/supplements
  • Thiazides
  • Lithium
  • Vitamin excess – D and A
  • Calcium and alkali (milk-alkali syndrome)
  • Parathyroid hormone
• Cancer
  • Usually metastatic disease
  • Osteolysis due to bone metastases
  • Humoral-mediated PTHrP (ectopic production)
  • Most common malignancies
    • Squamous cell – lung, head and neck
    • Breast
    • Multiple myeloma
    • Lymphomas – T/NK cell most common
    • Renal cell
    • Ovarian
• Immobilization
• Chronic kidney disease with metabolic bone disease
• Endocrine disorders
  • Thyrotoxicosis
  • ​Adrenal insufficiency
  • Pheochromocytoma
• Granulomatous disease
  • Sarcoidosis
  • Mycobacterium leprae
  • Granulomatosis with polyangiitis
  • Mycobacterium tuberculosis
  • Histoplasma spp
  • Coccidioides immitis
  • Berylliosis
• Syndromic diseases
  • Multiple endocrine neoplasias (MEN)
  • Hypocalciuric hypercalcemia
  • Hyperparathyroidism – jaw tumor syndrome
  • Neonatal severe hyperparathyroidism

Pathophysiology

• ~90% of hypercalcemia is caused by hyperparathyroidism or malignancy (Minisola, 2015)
• Hyperparathyroidism – usually causes mild hypercalcemia
  • Four parathyroid glands found within the thyroid gland secrete PTH
  • PTH acts directly on bone and kidneys and induces calcium resorption with a tight negative feedback loop
  • Pathology for hyperparathyroidism and excess secretion of PTH
    • Adenoma
    • Hyperplasia
    • Carcinoma (rare)
  • Due to frequent use of screening chemistries, most patients are asymptomatic when hypercalcemia is discovered
• Cancer – may cause severe hypercalcemia; there are several etiologies for hypercalcemia in malignancy
  • Presence of humoral factors that mimic PTH action
    • Secretion of PTHrP by tumor tissue or tumor metastasis
  • Osteolytic or nonosteolytic activity related to bone metastases
  • Ectopic secretion of 1-alpha hydroxylase (calcitriol) by tumor tissue
    • Stimulates gastrointestinal calcium absorption
  • Impaired renal function caused by tumor or treatment
• Calcium is bound to plasma proteins
  • ~45% is free and active (this is measured by ionized calcium)
  • Total calcium measures are highly dependent on albumin level
  • Also influenced by pH changes

Clinical Presentation

• Clinical symptoms progress slowly in hyperparathyroid-related disease
  •  Rate of increase related to presence of symptoms
•  Symptoms
  • Renal – nephrolithiasis, nephrocalcinosis, polyuria
  • Cardiovascular – arrhythmias, bradycardia, short QT interval with prolonged PR and QRS intervals
    • Atrioventricular block or complete heart block can develop with severe hypercalcemia
  • Skeletal – bone pain, arthralgias; classic finding is osteitis fibrosa (rare)
  • Neurologic – easy fatigability, proximal muscle weakness, muscle atrophy, lethargy, confusion
    • Can progress to seizures, coma
  • Gastrointestinal – nausea, bloating, constipation, anorexia
• Syndromic diseases associated with hypercalcemia
  • MEN
    • MEN1 (Werner Syndrome) – hyperparathyroidism, tumors of the anterior pituitary and enterohepatic tumors such as Zollinger-Ellison syndrome
    • MEN2A – medullary carcinoma of the thyroid, pheochromocytoma, and mild hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
    • Hypercalcemia with subnormal urine calcium excretion; removal of parathyroids does not correct hypercalcemia
  • Neonatal severe primary hyperparathyroidism
    • Enlargement of all four parathyroids with very high PTH; rare and potentially lethal
  • Hyperparathyroidism – jaw tumor syndrome
    • Hyperparathyroidism with cemento-ossifying tumors of the jaw, Wilms tumor, and renal cysts