TOC | Lytes
Hypercalcemia SX | Diff-DX | RX
* Hospitalize patients with any degree of hyercalcemia and polyuria, polydipsia, dehydration, altered mental status, and all patients with serum levels greater than 13.0 mg/dL, regardless of clinical presentation.
EKG :decreased ST segment & QT interval, wide T waves ("wide QT interval"), 1st AV block, bradycardia.
GI : N/V, constipation, anorexia
Renal: polyuria, polydipsia
CNS :apathy, drowsiness, cognitive difficulty, stupor/coma.
A. Primary hyperparathyroidism: Sporadic or Clinical variants & familial syndromes
B. Neoplastic diseases: 1. Local osteolysis 2. Humoral hypercalcemia of malignancy 3. Other factors: prostaglandins, vit. D like sterols
C. Endocrinopathies: Thyrotoxicosis, Adrenal insufficiency, Pheochromocytoma
D. Medications: Thiazide diuretics, Vit. D & A, Milk alkali syndrome, Lithium
E. Sarcoidosis & other granulomatous diseases
F. Miscellaneous conditions
2. Acute renal failure
3. Idiopathic hypercalcemia of infancy; Familial hypocalciuric hypercalcemia
Differential Diagnosis of Hypercalcemia (REF: ACP - PIER 2002)
Most often seen as an incidental finding in the absence of obvious symptoms. Prevalence of symptoms depends on the intensity by which they are sought, particularly vague symptoms of being unwell. Infrequently shows as acute symptomatic hypercalcemia Calcium elevated.
PTH normal (20%) or elevated (80%).
Calcitriol normal or elevated.
Alkaline phosphatase normal or elevated.
Urine calcium normal or elevated
Humoral hypercalcemia of malignancy
The most common cause of hypercalcemia in patients with cancer, even in those with skeletal metastases Calcium is elevated.
Phosphate may be normal or low (elevated if GFR <35 mL/min).
PTHrP normal or elevated but infrequently needed for diagnosis.
Calcitriol normal or low.
Alkaline phosphatase may be normal or elevated.
Urine calcium increased
Metastatic bone disease
True prevalence uncertain. Hypercalciuria without hypercalcemia is much more prevalent but infrequently evaluated or monitored Calcium is elevated.
Phosphate may be normal or elevated.
Alkaline phosphatase usually elevated.
PTHrP may be low, normal, or elevated.
The most common cause of hypercalcemia in patients with hypercalcemia, decreased GFR, and anemia. Alkaline phosphatase is generally normal because there is only a limited osteoblastic response to myelomatous infiltrate in the marrow Calcium is elevated.
Phosphate is elevated.
Alkaline phosphatase is normal.
PTH is suppressed.
PTHrP is normal or low.
Serum protein immunoelectrophoresis is abnormal
Granulomatous disease (sarcoidosis and
tuberculosis are the most frequently considered but hypercalcemia has been
reported to complicate granulomatous disease from all etiologies)
Prevalence varies from region to region around the world. Felt by some to be related to vitamin nutritional status with hypercalcemia being more prevalent in countries with higher amounts of annual sunlight Calcium elevated.
Alkaline phosphatase elevated but may not be of skeletal origin.
Urine calcium elevated.
Calcitriol elevated (particularly in sarcoidosis)
Allegedly becoming more prevalent with increased use of calcium supplements. Should be considered in seemingly healthy people in whom primary hyperparathyroidism has been excluded Calcium elevated.
Alkaline phosphatase normal.
Calcitriol normal or low.
Urine calcium variable because of abnormal GFR
Benign familial hypocalciuric hypercalcemia
Constitutive overexpression of the calcium sensing receptor gene. Homozygote has fatal neonatal primary hyperparathyroidism. Heterozygote has benign familial hypocalciuric hypercalciuria Calcium elevated.
PTH normal (isolated reports of an elevated PTH exist).
Urine calcium <1 mg/kg body weight.
Hypercalcemia without elevated PTH in other family members
Diuretic phase of acute renal failure
Most often seen when acute renal failure resulted from rhabdomyolysis. Felt to be mobilization of extra-cellular calcium-phosphate deposits released into the circulation during acute phase of rhabdomyolysis Calcium elevated.
Prevalence uncertain. Generally only occurs in persons with high bone turnover before immobilizing event (growing children, untreated primary hyperparathyroidism, hyperthyroidism, Paget's disease of bone) Calcium elevated.
Alkaline phosphatase elevated.
Urine calcium elevated
A frequent, but usually incidental finding in hyperthyroidism. Results from direct action of thyroxine or tri-iodothyronine to stimulate osteoclasts. In those rare patients where the hypercalcemia is severe, usual symptoms and signs of hyperthyroidism are masked Calcium elevated.
Alkaline phosphatase elevated.
Urine calcium elevated
A rare cause of hypercalcemia. Mechanism unclear Calcium elevated.
Phosphate normal or low.
PTH normal or elevated
Causes of Hypercalcemia, by age:
From birth to age 20 years:
From older adolescence to age 40 years
From age 40 years and older
Consider the need for treatment of dehydration and altering of exogenous calcium intake in patients with hypercalcemia, depending on the underlying etiology.
Understand that the initial therapy for acute hypercalcemia is rehydration with IV saline fluid.
Recognize that curtailing intake of calcium and alkali is indicated in patients with milk-alkali syndrome and vitamin D intoxication but not in other hypercalcemic states.
Consider parathyroidectomy in patients with primary hyperparathyroidism.
Acute Rx of Hypercalcemia : Drug Therapy
Consider drug therapy, in addition to rehydration, to lower serum calcium in patients with hypercalcemia.
Consider treatment with an intravenous bisphosphonate once rehydration has been initiated.
Consider administering other drugs in patients critically ill with hypercalcemia.
Recognize that drug therapy for patients with chronic hypercalcemia depends on the underlying etiology and its clinical manifestations.
1. IV Hydration 2 - 4 liters of normal saline
Furosemide (Lasix) 20-100 mg IV or PO as needed to prevent fluid overload of IV hydration.
Normal saline - Promotes calcium diuresis - 200 mg/h, IV, per hour
Benefits: Corrects dehydration. Lowers serum calcium rapidly (hour) but incompletely
Side effects: May promote fluid overload, particularly in the elderly with preexistent cardiac dysfunction
NOTE: Fluid status should be carefully monitored preferably in an ICU. Serum calcium should be monitored every 6 hours during therapy for acute hypercalcemia. Furosemide therapy should only be used to correct fluid overload, not to prevent it. Such therapy may contribute to negative sodium balance that would hinder a calcium diuresis. Furosemide is not therapy for hypercalcemia per se.
2. Specific Rx of Hypercalcemia:
4. Phosphate as IV Na phosphate can lower
Calcium rapidly & profoundly.
This Rx is very dangerous because of the risk that cal phosphate complexes
will be deposited in blood vessels, lungs, & kidneys.
5. Dialysis for severe or symptomatic hypercalcemia !
Mild, chronic hypercalcemia 11 to 12 mg/dL
(2.8 to 3 mmol/L)
In general, patients with even mild, asymptomatic hypercalcemia who have serum calcium concentrations in the range of 11 to 12 mg/dL (2.8 to 3 mmol/L) should be treated when there is associated hypercalciuria because of the risk of nephrolithiasis and nephrocalcinosis. The most effective therapy depends mostly upon the cause of the hypercalcemia:
More severe or symptomatic hypercalcemia
>12 mg/dL (3 mmol/L)
Acute therapy consists of a three-pronged approach:
The calcitonin plus saline-furosemide regimen should result substantial reduction in serum calcium concentrations within 12 to 48 hours, whatever the cause of the hypercalcemia.
The bisphosphonate will be effective by the second to fourth day, thereby maintaining control of the hypercalcemia. Follow-up therapy is aimed at preventing recurrence of hypercalcemia.
Tumors may respond to chemotherapy or radiation therapy leading to resolution of the hypercalcemia. In patients whose primary disease cannot be cured, oral etidronate, oral phosphates, low-dose glucocorticoids and aggressive oral hydration may be tried. These therapies are rarely effective for very long. In these situations, hypercalcemia can be prevented with infusions of pamidronate at two to three week intervals, administered on an outpatient basis.
Severe hypercalcemia 18 to 20 mg/dL (4.5 to 5 mmol/L)
Additional, more aggressive measures are necessary in the rare patient with severe, symptomatic hypercalcemia.
Hemodialysis should be considered, in addition to the above treatments, in patients who have serum calcium concentrations in the range of 18 to 20 mg/dL (4.5 to 5 mmol/L) and neurologic symptoms but a stable circulation.
REF: Uptodate Medicine 08-2001
Laboratory and Other Studies for Hypercalcemia (REF: ACP - PIER 2002)
Serum inorganic phosphate -Low value might suggest PTH excess. Normal or high value has limited differential diagnostic value. Even with PTH excess value may be normal if renal function impaired
Serum albumin - An essential component of ongoing hypercalcemia evaluation
Serum globulin - Elevated value seen in multiple myeloma but also in chronic disease such as TB, sarcoidosis
Serum creatinine - Should decrease with adequate hydration. Elevated creatinine has limited differential diagnostic value
Serum alkaline phosphatase - Normal in multiple myeloma complicated by hypercalcemia. Limited differential diagnostic value from an elevated value that may occur with PTH excess, PTHrP, metastases
Serum intact PTH - Suppressed value diagnostic for nonparathyroid hypercalcemia. Value may be normal or high (80% of the time) in primary hyperparathyroidism
Complete blood count - Limited differential diagnostic value, but may provide information about hematologic and other malignancies
Serum PTHrP - May be elevated in some patients with humoral hypercalcemia of malignancy. Not correlated with severity of hypercalcemia. Levels decrease with removal of primary tumor but not necessarily with drug correction of the hypercalcemia
Serum calcediol (25-hydroxyvitamin D) - Elevated only with exogenous vitamin D intoxication
Serum calcitriol (1,25-dihydroxyvitamin D) - Elevated in granulomatous disease (most often in sarcoidosis, less often in other granulomatous diseases) exogenous calcitriol intoxication. May be modestly elevated in primary hyperparathyroidism
24-hour urine calcium, creatinine, sodium - Should always be measured together. Creatinine assesses adequacy of collection. High urine sodium promotes calcium diuresis and increases urine calcium. Normal urine calcium is <4 mg/kg·24 h. If renal function is normal, absence of hypercalciuria suggests PTH excess. If urine calcium low (<50 mg/24 h) consider benign familial hypocalciuric hypercalcemia. Hypercalciuria has limited differential diagnostic value
Biochemical markers of bone resorption (serum or urine N-telopeptide of collagen cross-links; serum or urine C-telopeptide of collagen cross-links; urine pyridinoline; urine deoxypyridinoline) - Reflect ongoing bone resorption. Of limited differential diagnostic value. May prove useful in monitoring progression or regression of disease
Hand radiographs - A very low-yield study in all but those patients with the most severe primary hyperparathyroidism
Skull radiographs - May demonstrate "salt and pepper" appearance of severe primary hyperparathyroidism. A low-yield procedure. May demonstrate "punched out" lytic lesions of multiple myeloma
Radiographic skeletal survey - May be helpful if skeletal metastases suspected
Radiographs of skeletal regions associated with clinical findings such as pain or deformity - A high-yield procedure if skeletal metastases expected
Skeletal scintigraphy (Bone Scan) - A high-yield procedure if skeletal metastases expected. Radiographic confirmation should be obtained for identified "hot spots." Metastatic disease may be so diffuse that "super" scan with generalized increased isotope uptake may be developed, obscuring discrete metastases. "Super" scan may be seen with severe primary hyperparathyroidism
Bone mineral densitometry - Limited differential diagnostic value. Of importance in deciding management in primary hyperparathyroidism. Important for monitoring progression or regression of primary hyperparathyroidism
PTH = parathyroid hormone; PTHrP = parathyroid hormone-related protein; TB = tuberculosis.