HyperCalcemia

Question 1

Causes of Hypercalcemia

Answer 1

Ingestions:

a. Calcium-containing products (calcium carbonate “TUMS,” → “milk-alkali syndrome,” Nicorette gum, calcium-supplemented bottled carbonated water, etc.)
b. Excessive vitamin D (recent report of over-the-counter vitamin supplement “Soladek” containing high dose of both vitamins D and A)

Question 2

Causes of Hypercalcemia

Answer 2

Malignancy:

a. Direct invasion (bone metastatic disease)
b. Osteoclastic activating factors: PTH-related peptides, calcitriol, transforming growth factors, prostaglandin E (PGE), tumor necrosis factor α, PTH (parathyroid malignancy)
c. Immobilization due to pain, deconditioning (increased bone resorption)

Question 3

Causes of Hypercalcemia

Primary hyperparathyroidism (hPTH):

Answer 3

Parathyroid adenoma (80%), diffuse hyperplasia (10% to 15%) or carcinoma (5%)

Multiple endocrine neoplasia type 1 (MEN-1):

a. Autosomal dominant, arises from inactivating germ line mutations of a tumor-suppressor gene (MEN-1 gene)
b. May involve parathyroid, anterior pituitary, enteropancreatic, and other endocrine tumors

Question 4

Causes of Hypercalcemia

Primary hyperparathyroidism (hPTH):

Answer 4

MEN-2A:

a. Autosomal dominant, arises from activating mutations of the RET proto-oncogene.
b. May involve thyroid medulla, adrenal medulla, parathyroid with associated increase in calcitonin, catecholamines, and PTH, respectively.

Question 5

Causes of Hypercalcemia

Primary hyperparathyroidism (hPTH):

Answer 5

Latent primary hPTH (diagnosis of exclusion):

a. May present as either normocalcemic hPTH (normal SCa, high PTH level) or normoparathyroid hypercalcemia (normal PTH level, high SCa)
b. High likelihood for eventual development of overt hPTH. Close monitoring recommended.

Question 6

Causes of Hypercalcemia

Answer 6

Granulomatous diseases (e.g., tuberculosis, sarcoid, berylliosis):

a. Due to increased 1α-hydroxylase activity in macrophages within granulomas
b. Sarcoid may increase plasma Ca2+ further with high sun exposure
c. Laboratory findings: low PTH, high 1,25 vitamin D

Question 7

Causes of Hypercalcemia

Answer 7

Medications: lithium (may lead to hPTH), thiazide diuretics, antacids (calcium carbonate—patients present with both hypercalcemia and metabolic alkalosis), vitamin A overload (due to increased bone resorption)

Question 8

Causes of Hypercalcemia

Familial Hypocalciuric Hypercalcemia (FHH):

Answer 8

Rare autosomal-dominant hereditary condition due to inactivating mutations of the gene encoding CaSR. Recall that normally CaSR senses hypercalcemia and inhibits ROMK in the thick ascending limb of Henle loop, which leads to the loss of the favorable positive luminal charge necessary for paracellular calcium reabsorption. Thus, normal activation of CaSR induces calciuria. In contrast, inactivating mutations of CaSR cannot sense the presence of ionized calcium/hypercalcemia to induce facilitated calciuria.

Question 9

Causes of Hypercalcemia

Familial Hypocalciuric Hypercalcemia (FHH):

Laboratory findings:

Answer 9

Moderate chronic hypercalcemia, normo- to hypophosphatemia, hyperma-gnesemia

Plasma PTH is normal to moderately high - thus association with hypophosphatemia (this is why FHH may be mistaken for primary hPTH). (Normal CaSR activity inhibits PTH secretion. Inactivating mutation of CaSR leads to uninhibited PTH secretion.)

Question 10

Causes of Hypercalcemia

Familial Hypocalciuric Hypercalcemia (FHH):

Laboratory findings:

Answer 10

1,25 vitamin D level may be high in response to elevated PTH levels.

NOTE: Fractional calcium excretion is low (e.g., <0.01) in FHH but HIGH in primary hPTH. This is the differentiating point for FHH versus primary hPTH. Do not perform parathyroidectomy if hypercalcemia is due to FHH.

Question 11

Causes of Hypercalcemia

Familial Hypocalciuric Hypercalcemia (FHH):

Laboratory findings:

Answer 11

Fractional excretion of calcium may be calculated based on 24-hour clearance and referred to as “calcium-to-creatinine-clearance ratio” (CCCR):

CCCR = [(24-hour urine calcium) × (SCr)]/[(24-hour urine creatinine) × (SCa)]

CCCR < 0.010 indicates FHH, whereas a CCCR > 0.020 is likely consistent with primary hPTH.

Question 12

Causes of Hypercalcemia

Answer 12

Activating mutation of the PTH/PTHrP receptor gene (Jansen disease):

a. Laboratory findings are similar to those with primary hPTH.
b. Clinical manifestations: short-limbed dwarfism, severe hypercalcemia, hypophosphatemia, and metaphyseal chondrodysplasia

Question 13

Causes of Hypercalcemia

Answer 13

Loss of function mutation of vitamin D-24-hydroxylase:

a. Loss of function mutation of vitamin D-24-hydroxylase leads to high levels of 1,25 vitamin D and hypercalcemia (both of which suppress PTH).
b. Resultant phenotype: hypercalcemia with associated nephrocalcinosis and/or nephrolithiasis
c. Treatment: ketoconazole (inhibitor of vitamin D-1α-hydroxylase) corrects hypercalcemia.

Question 14

Causes of Hypercalcemia

Answer 14

NOTE

Corticosteroids ameliorate hypercalcemia in patients with high 1,25 vitamin D level due to ingestion and granulomatous disease, but not in those with inactivating mutation of vitamin D-24-hydroxylase.

Question 15

Causes of Hypercalcemia

Sunitinib

Answer 15

Sunitinib and imatinib may induce secondary hPTH, presumably by inducing bone resistance to PTH.

Question 16

Causes of Hypercalcemia

Sunitinib

Answer 16

Sunitinib (Sutent) and imatinib (Gleevac) are tyrosine kinase inhibitors that inhibit the actions of vascular endothelial growth factors. These agents are used in the treatment of various malignancies including pancreatic neuroendocrine tumors, gastrointestinal stromal tumors, and advanced renal cell carcinoma, and Philadelphia chromosome-positive chronic myelogenous leukemia.

Question 17

Causes of Hypercalcemia

Sunitinib

Answer 17

Affected patients typically have marked hypocalciuria and normal to high SCa, hypophosphatemia, elevated 1,25 vitamin D.

Reversal of this form of secondary hPTH is possible with drug discontinuation.

Question 18

Causes of Hypercalcemia

Answer 18

Other cause of hypercalcemia: Paget disease

Question 19

Clinical Manifestations, Complications of Hypercalcemia

Answer 19

Fatigue, poor concentration, headaches, depression, anxiety

Ocular: conjunctivitis, band keratopathy

Question 20

Clinical Manifestations, Complications of Hypercalcemia

Answer 20

Cardiac: shortened QT, arrhythmias

Gastrointestinal: constipation, nausea, vomiting, peptic ulcer disease, pancreatitis

Question 21

Clinical Manifestations, Complications of Hypercalcemia

Answer 21

Kidney-related complications: polyuria, nephrogenic diabetes insipidus, kidney stones, medullary and cortical calcium depositions (nephrocalcinosis).

Question 22

Management of Hypercalcemia

Answer 22

Volume repletion with normal saline as tolerated

Loop diuretics may be added once euvolemic or hypervolemic to enhance paracellular Ca2+ excretion from thick ascending loop of Henle.

Question 23

Management of Hypercalcemia

Answer 23

Bisphosphonates:

Inhibit bone resorption

Preferred agents for hypercalcemia associated with cancer

Commonly used agents:

a. Intravenous pamidronate, oral alendronate
b. Calcitonin: rapid onset of action (within hours), but only short-term benefit due to tachyphylaxis

Question 24

Management of Hypercalcemia

Answer 24

Mithramycin: cytostatic drug

a. Potent inhibitor of bone resorption
b. Rapid onset of action, effect lasts days, but high adverse effects (transaminitis, thrombocytopenia)
c. Reserved for malignant hypercalcemia. Prostaglandin antagonists (e.g., aspirin, indomethacin) may also be considered in malignant hypercalcemia.

Question 25

Management of Hypercalcemia

Answer 25

Corticosteroids: (0.5 to 1.0 mg/kg prednisone daily)

a. Reduces GI absorption of calcium
b. May be used in hypervitaminosis D (either endogenous source such as sarcoid/granulomatous diseases or exogenous vitamin D ingestion)
c. Corticosteroid is ineffective in patients with vitamin D-24-hydroxylase mutations. Ketoconazole is used instead (see Ketoconazole).
4. May be considered in lymphoproliferative malignancies such as lymphoma, multiple myeloma, or even solid organ malignancy such as breast CA.

Question 26

Management of Hypercalcemia

Answer 26

Ketoconazole:

a. Inhibits calcitriol synthesis via inhibition of 1-α hydroxylase
b. May be used for patients with vitamin D-24-hydroxylase loss of function mutation

Question 27

Management of Hypercalcemia

Answer 27

Others:

a. Propranolol for thyrotoxicosis-induced hypercalcemia
b. Estrogens in women with primary hPTH to reduce bone resorption.
c. Calcimimetics (CaSR agonists such as cinacalcet) for hPTH (primary, secondary, or even parathyroid carcinoma), particularly for nonsurgical patients

Question 28

Management of Hypercalcemia

Answer 28

Parathyroidectomy for primary hPTH (National Institute of Health Consensus Guidelines):

Indications:

a. SCa level > 1.0 mg/dL above upper limit of normal
b. Hypercalciuria > 400 mg/d or kidney stones
c. Creatinine clearance < 30% of normal
d. Marked bone density reduction with T-score < −2.5 at any site
e. Age < 50 due to eventual significant complications if left untreated
f. Patient surgical preference due to difficult/impossible follow-up

Question 29

Management of Hypercalcemia

Answer 29

Presurgical considerations for hPTH:

a. Localization with imaging studies to allow minimal invasive surgery is now preferred over four-gland exploration without presurgical imaging.
b. Localization studies: combination 99mTc-sestamibi scintigraphy ± single-photon emission computed tomography (SPECT) and ultrasound
1. If positive for adenoma → focused surgery
2. Otherwise, consider 4D-computed tomography, exploratory surgery

Question 30

Management of Hypercalcemia

Hungry bone syndrome:

Answer 30

Hungry bone syndrome:

a. Definition: profound (SCa < 6 mg/dL) and prolonged (>4 days postoperative) hypocalcemia following parathyroidectomy for severe hPTH.
b. Risks: severe hPTH with associated skeletal manifestations, preoperative indices of high bone turnover, osteitis fibrosa cystica, and/or “brown tumors”

Question 31

Management of Hypercalcemia

Hungry bone syndrome:

Answer 31

c. Pathogenesis:

Continuing high skeletal calcium uptake from plasma without the opposing calcium leaking back into plasma from bone resorption due to acute fall in PTH with parathyroidectomy

Question 32

Management of Hypercalcemia

Hungry bone syndrome:

Answer 32

d. Management:
1. Intravenous calcium supplement (6 to 12 g/d), followed by oral therapy when safe, plus
2. Calcitriol (2 to 4 mcg/d), plus
3. Correction of hypomagnesemia if present