Hypercalcemia

Calcium Homeostasis

Calcium

Calcium is the most abundant mineral in the human body, with 99% found in bone alone. Calcium in blood exists in 3 forms:

• 15% of calcium is bound to small anions (citrate, phosphate).
• 45% of calcium is protein bound (mostly with albumin).
• 40% of calcium is ionized or in the free form (metabolically active or can be transported into cells)

Levels:

• Normal serum total calcium: 8.5–10.5 mg/dL (2.12–2.62 mmol/L)
• Normal ionized calcium: 4.65–5.25 mg/dL (1.16–1.31 mmol/L)

Importance of calcium:

• Bone mineralization
• Cofactor of enzymes
• Cardiac and nerve function
• Muscle contraction
• Regulation of clotting mechanisms
• Effective intracellular messenger for several molecules such as insulin

Calcium regulation

Bone, intestine, and kidneys are involved in homeostasis.

Key elements of calcium regulation:

• Parathyroid hormone (PTH) from parathyroid glands:
  • ↑ Vitamin D production in the kidneys, ↑ reabsorption of calcium in the distal tubules
  • ↑ Calcium absorption in the intestines
  • ↑ Bone resorption (release of calcium and phosphate from bones)
• Vitamin D:
  • In the presence of sunlight, 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) in the skin. 
  • Vitamin D3 is converted to 25-hydroxyvitamin D (calcidiol) in the liver. 
  • In the kidney, calcidiol is converted into the active form, 1,25-dihydroxy vitamin D (calcitriol).
  • Effects: activation of osteoclasts to release calcium and phosphorus, and the absorption of intestinal calcium and phosphate
• pH: 
  • ↑ pH (alkalosis) will ↑ the binding of calcium to albumin = ↓ ionized calcium
  • ↓ pH (acidosis) will ↓ the binding of calcium to albumin = ↑ ionized calcium
• Albumin:
  • ↓ Serum protein/albumin (i.e., nephrotic syndrome) = ↓ serum calcium (pseudohypocalcemia)
  • ↑ Serum protein/albumin (i.e., multiple myeloma) = ↑ serum calcium (pseudohypercalcemia)
  • Levels of ionized calcium are normal in the above cases.
  • Every 1 g/dL ↓ in albumin → ↓ in calcium by 0.8 mg/dL
  • Corrected calcium (mg/dL) = measured total calcium (mg/dL) + [0.8 x (4.0 – albumin concentration (g/dL))]
• Other factors:
  • Calcitonin from the thyroid gland opposes the effects of PTH → ↓ calcium
  • Hyperphosphatemia (↑ phosphate binding, ↓ ionized calcium)
  • Hypomagnesemia (↓ PTH release → ↓ calcium)

Epidemiology and Etiology

Epidemiology

• Hypercalcemia is often detected incidentally.
• Prevalence in the general population: 1%–2%
• Primary hyperparathyroidism and malignancy account for 90% of the causes.
• Malignancy is likely associated with calcium levels > 13 mg/dL.

Mechanisms

Hypercalcemia is characterized by elevated calcium levels and generally results from any 1 of these factors or a combination:

• Increased bone resorption
• Increased calcium absorption in the GI tract
• Increased renal tubular reabsorption of calcium
• Decreased renal excretion of calcium

Etiology

Increased bone resorption:

• Hyperparathyroidism:
  • ↑ PTH → bone resorption from osteoclast activation (also with ↑ intestinal calcium absorption)
  • Primary (frequently from parathyroid adenoma)
  • Secondary and tertiary (frequently from CKD)
• Thyrotoxicosis: Thyroid hormone mediates bone resorption.
• Malignancy increases bone resorption by:
  • Secretion of PTH-related protein (PTHrP) from solid tumors
  • Metastasis: ↑ osteoclastic activity → ↑ bone resorption
  • ↑ Osteoclast-activating factors, such as interleukin-6 and lymphotoxin (in multiple myeloma)
  • Production of calcitriol from macrophages (in lymphoma)
• Others:
  • Immobilization
  • Paget disease of the bone
  • Estrogen or antiestrogen (tamoxifen) in patients with breast cancer
  • Hypervitaminosis A: dose-dependent increase in bone resorption

Increased calcium absorption:

• CKD:
  • Patients are given calcium carbonate as phosphate binder and calcitriol for secondary hypoparathyroidism.
  • The above combination increases the risk of hypercalcemia.
• Milk-alkali syndrome:
  • Results from ↑ intake of milk or calcium carbonate (when treating dyspepsia or osteoporosis)
  • Syndrome of hypercalcemia + alkalosis (which further ↑ calcium reabsorption) + renal insufficiency
• Vitamin D toxicity:
  • Often due to ingestion of calcitriol to treat hypoparathyroidism or hypocalcemia
  • May result from over-the-counter supplements

Others:

• Adrenal insufficiency: ↑ bone resorption, ↑ renal calcium reabsorption
• Pheochromocytoma: from PTHrP or as part of MEN syndrome
• Lithium: ↑ PTH
• Thiazide diuretics: ↓ renal calcium excretion
• Metabolic effect of theophylline toxicity
• Chronic granulomatous disease (sarcoidosis, TB): ectopic vitamin D production
• Familial hypocalciuric hypercalcemia (FHH): mutation in the calcium-sensing receptor gene
• Williams syndrome: de novo mutations

Clinical Presentation

Manifestations depend on the level and onset of hypercalcemia.

Hypercalcemia with total albumin-corrected calcium < 12 mg/dL:

• Usually asymptomatic
• Can manifest with vague symptoms:
  • Depression
  • Fatigue
  • Constipation

Hypercalcemia with total albumin-corrected calcium > 12 mg/dL:

• Acute presentation:
  • GI: anorexia, nausea, vomiting, constipation, abdominal pain
  • Neurologic: confusion, lethargy, hyporeflexia, altered mental status, coma (especially if > 14 mg/dL)
  • Cardiovascular: hypertension, bradycardia, ECG changes (1st-degree heart block, shortened QT interval, J waves, T wave inversions)
  • Renal: polyuria or nocturia, polydipsia
  • Musculoskeletal: weakness, bone pain
• Chronic presentation:
  • Osteoporosis with bone pain
  • Nephrocalcinosis
  • Band keratopathy (corneal degeneration due to calcium deposition)
  • Chondrocalcinosis
  • Pancreatitis
  • Hypertension

Hypercalcemic crisis/severe hypercalcemia:

• Life-threatening condition occurring when total calcium > 14 mg/dL 
• Symptoms: dehydration, nausea, vomiting, fever, psychosis, coma

Mnemonic:

To recall the common clinical symptoms of hypercalcemia, remember “groans, bones, stones, moans, thrones, and psychic overtones”:

• Groans: abdominal pain, nausea, vomiting, gastric and duodenal ulcers, pancreatitis
• Bones: osteopenia, osteoporosis, bone pain
• Stones: nephrolithiasis (calcium phosphate or calcium oxalate stones)
• Moans: fatigue, malaise
• Thrones: polyuria, polydipsia, constipation
• Psychic overtones: confusion, depression, memory loss

Diagnosis

Diagnostic approach

• Review clinical history/manifestations.
• Laboratory tests:
  • Serum calcium levels
  • Confirm true hypercalcemia:
    • Repeat test.
    • Determine serum albumin level and calculate corrected calcium level (mg/dL). 
    • Ionized calcium level
• PTH levels:
  • Increased PTH: primary hyperparathyroidism
  • Normal/slightly increased PTH:
    • Low 24-hour urinary calcium levels → FHH
    • Otherwise, primary hyperparathyroidism likely
  • Decreased PTH (not PTHrP): obtain additional tests 
    • ↑ PTHrP: malignancy
    • ↑ 1,25-Dihydroxyvitamin D3: lymphoma, granulomatous disease
    • ↑ 25-Hydroxyvitamin D: vitamin D toxicity

Additional tests

• Further testing in the case of decreased PTH:
  • SPEP and UPEP to exclude myeloma
  • Serum thyroid-stimulating hormone (TSH) to exclude hyperthyroidism
  • Vitamin A to determine toxicity
• Disease-specific work-up when diagnosis has been narrowed down:
  • Additional tests (i.e., cortisol, adrenocorticotropic hormone (ACTH) in adrenal insufficiency)
  • Imaging:
    • Chest X-ray for lung cancer and sarcoidosis
    • Mammogram for breast cancer
    • CT to evaluate nephrolithiasis

Management

Mild hypercalcemia (total albumin-corrected calcium < 12 mg/dL)

• Patients who are asymptomatic or mildly symptomatic do not require immediate treatment.
• Low calcium diet
• Avoid thiazide diuretics (and other calcium-increasing medications), immobilization, and dehydration.

Moderate hypercalcemia (total albumin-corrected calcium = 12–14 mg/dL)

• An acute increase in calcium levels is treated with:
  •  IV isotonic saline hydration
  • Bisphosphonate
• Recommend precautions similar to those used for mild hypercalcemia.

Severe hypercalcemia (total albumin-corrected calcium > 14 mg/dL)

• Acute management:
  • IV fluids for volume expansion and prevention of dehydration
  • Loop diuretics are not routinely used but considered judiciously (i.e., to prevent fluid overload in heart failure).
  • Calcitonin is used to increase renal excretion of calcium and inhibit bone resorption.
  • IV bisphosphonates (zoledronic acid or pamidronate) are used to suppress bone resorption.
  • Denosumab is used if bisphosphonates are contraindicated.
  • Consider hemodialysis for calcium > 18 mg/dL, or in the case of heart failure or renal insufficiency.
• Prevention of recurrence:
  • Bisphosphonates
  • Denosumab

Cause-specific treatment

• Parathyroidectomy for hyperparathyroidism
• Glucocorticoids for granulomatous diseases and vitamin D toxicity

Clinical Relevance

• Hyperparathyroidism: a condition associated with elevated PTH levels. Primary hyperparathyroidism is an inherent disease of the parathyroid glands that causes abnormal PTH secretion. Secondary hyperparathyroidism results from abnormalities of calcium metabolism, which, if untreated, can progress to tertiary hyperparathyroidism, which is characterized by hypertrophy of the parathyroid gland and PTH oversecretion, even if the primary cause is eliminated. Diagnosis is based on laboratory tests (levels of PTH, calcium, phosphate, and urinary calcium). Management of primary and tertiary hyperparathyroidism involves surgical parathyroidectomy. Management of secondary hyperparathyroidism is by treating the underlying disease.
• Thyrotoxicosis: the manifestation of excess thyroid hormones. Clinical features are mostly due to an increase in the metabolic rate and overactivity of the sympathetic nervous system. Diagnosis is by measuring the levels of TSH, unbound T4, and T3. Depending on the etiology and clinical presentation, thyrotoxicosis may be treated pharmacologically, surgically, or using radioiodine.
• FHH: an autosomal dominant syndrome that involves inactivating mutations in the calcium-sensor receptors. Urine calcium levels are reduced due to excessive renal calcium reabsorption. Serum calcium levels are elevated and PTH levels are usually normal or mildly elevated. Most patients have mild hypercalcemia and do not require treatment.
• Williams syndrome: results from microdeletion in region q11.23 of chromosome 7. Williams syndrome mostly results from de novo mutations but is also seen with an autosomal dominant pattern. Affected individuals have features that include characteristic elfin facies, cardiovascular anomalies, cognitive deficits, short stature, and endocrine abnormalities (hypercalcemia and hypothyroidism). Patients exhibit a mild elevation in calcium levels and are asymptomatic. The cause of hypercalcemia is generally unclear.
• Paget disease of bone (osteitis deformans): a disorder in bone metabolism characterized by accelerated bone remodeling that results in overgrowth of bones that are weak and fragile. Commonly affected areas include the skull, spine, pelvis, and long bones of the lower extremity. The main clinical manifestations of Paget disease are bone pain and the consequences of bone deformities, such as fractures, osteoarthritis, and nerve impingement. Treatment is with bisphosphonates and calcitonin, and surgery is indicated for the management of fractures, deformities, and other complications. 
• Adrenal insufficiency: the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary adrenal insufficiency, or Addison’s disease, is caused by an adrenal gland disorder (i.e., autoimmune disease). The secondary type is caused by the decreased production of ACTH from the pituitary gland, whereas the tertiary type is due to hypothalamic disorders and prolonged glucocorticoid therapy. Diagnosis is by demonstrating hypocortisolism and determining the etiology (adrenal autoantibodies, imaging). Management involves glucocorticoid replacement. Mineralocorticoids are also used in primary adrenal insufficiency.
• Pheochromocytoma: a catecholamine-secreting tumor derived from chromaffin cells. Although the majority of pheochromocytomas originate in the adrenal medulla, they can also originate from the sympathetic ganglia (also referred to as paragangliomas). The symptoms are similar to those observed in the case of excessive catecholamine production and include hypertension, tachycardia, headache, and sweating. Classical MEN2A syndrome is characterized by pheochromocytoma, along with primary hyperparathyroidism and medullary thyroid carcinoma. Treatment is by surgical resection. The prognosis is generally good for completely resected benign sporadic tumors but is associated with higher recurrence rates and a potential for malignancy in the familial forms.
• Sarcoidosis: a multisystem disease usually affecting the lungs and thoracic lymph nodes (also involves the skin, heart, and eyes). Acute sarcoidosis presents with lymphadenopathy, fever, malaise, joint pains, panniculitis on the shins (erythema nodosum), occasional cough, and shortness of breath. Chronic pulmonary sarcoidosis presents with an insidious onset of dyspnea, cough, and chest pain, and includes other symptoms depending on the systems involved. Diagnosis often requires a biopsy of the granulomas. Management includes observation, glucocorticoids, and, potentially, a steroid-sparing agent. 
• TB: a disease caused by Mycobacterium tuberculosis. These acid-fast bacteria usually affect the lungs; however, they can also affect other organs. Tuberculosis spreads through the air when an individual with an active pulmonary infection coughs or sneezes. M. tuberculosis is a slow-growing bacterium that can survive in macrophages; thus, there is a possibility of a latent infection that can remain asymptomatic for decades and pose a challenge to diagnose, treat, or prevent. The diagnosis is established based on the tuberculin skin test, sputum culture, and lung imaging. The mainstay of management is antimycobacterial drugs.