Mark Goodarzi, M.D.
Differential Diagnosis of Hypercalcemia
Primary hyperparathyroidism
Sporadic (adenoma, hyperplasia, or carcinoma)
Familial (isolated, cystic, MEN I, II)
Cancer
Parathyroid hormone-related protein
Ectopic production of 1,25-dihydroxyvitamin D
Other factors produced ectopically (cytokines, growth factors)
Lytic bone metastases
Disorders of vitamin D
Exogenous vitamin D toxicity (vitamin D, 25-OH-D, 1,25-OH-D)
Endogenous production of 25-OH-D: Williams syndrome
Endogenous production of 1,25-OH-D
Granulomatous diseases
Sarcoidosis
Tuberculosis
Histoplasmosis
Coccidioidomycosis
Leprosy
Others
Lymphoma
Nonparathyroid endocrine disorders
Thyrotoxicosis
Pheochromocytoma
Adrenal insufficiency
Vasoactive intestinal peptide hormone-producing tumor
Islet cell pancreatic tumors
Medications
Thiazide diuretics
Lithium
Estrogens, antiestrogens, testosterone, androgens
Milk-alkali syndrome
Vitamin A intoxication
Aluminum excess
Parenteral nutrition
Theophylline, aminophylline
8-chloro-cyclic AMP
Medications associated with hypercalcemia in case reports
Immobilization (with or without Paget's disease of bone)
Familial hypocalciuric hypercalcemia
Acute and chronic renal insufficiency
Humoral hypercalcemia of benignancy
Jansen's metaphyseal chondrodysplasia
Rare metabolic conditions: hypophosphatasia, primary oxalosis, Gaucher's disease
90% of all cases are caused by hyperparathyroidism (outpatients) and malignancy (inpatients).
Regulation of Serum Calcium
 | Calcium: 99% of total body (1000 g) calcium is extracellular, bound to phosphate salts in the skeleton (hydroxyapatite). 1% is intracellular and used for cellular functions and signaling; total serum calcium is about 0.1% of total body calcium. Average adult calcium ingestion is 1 g/d, with 10-20% absorbed. Generally, men excrete < 300 mg/d and women < 250 mg/d in urine. About 40% of serum calcium is protein bound (90% to albumin, which has 12 calcium binding sites [normally only 20% occupied], remainder to globulins); the unbound (50% ionized, 10% complex with citrate/phosphate) calcium is physiologically active. An increase in albumin of 1 g/dL over normal increases measured total calcium by 0.8 mg/dL. Very rarely, increased monoclonal proteins can increase measured total calcium. Acidemia increases ionized calcium, and alkalemia decreases it (altered protein binding) with no effect on total calcium. |
| Parathyroid hormone (PTH, 84 amino acids, initially synthesized as a 115 a.a. prohormone, prepro-PTH). PTH secretion is regulated by ionized calcium level; low or falling calcium leads to increased PTH secretion over seconds; over hours hypocalcemia leads to increased PTH mRNA, and over days to months, increased gland mass. PTH increases bone resorption, increasing calcium and phosphate. In the kidney, it decreases calcium excretion and increases phosphate excretion. It indirectly increases intestinal calcium absorption by stimulating the conversion of 25-hydroxyvitamin D3 (calcidiol) to 1,25-dihydroxyvitamin D3 (calcitriol). Magnesium is required both for PTH release and action on target tissues. PTH has a half-life of < 4 minutes due to rapid clearance (hepatic > renal), which generates longer-lasting inactive C-terminal fragments which are only renally cleared. |
| Vitamin D (either D2 or D3) must be converted to active metabolites (25-hydroxylation in the liver, 1a -hydroxylation in the renal proximal convoluted tubule) to have biologic effect. Calcitriol is 100 times more potent than calcidiol. It stimulates intestinal (duodenal) calcium and phosphate absorption and decreases renal calcium and phosphate excretion. With PTH present, calcitriol increases calcium and phosphate mobilization from bone. It also inhibits PTH secretion via a feedback loop (decreases PTH mRNA and gland mass). |
| In the epidermis, 7-dehydrocholesterol (provitamin D3) is transformed by nonenzymatic photoactivation to previtamin D3 by near ultraviolet light (wavelength 290-315 nm, UVB). Body temperature favors conversion of previtamin D3 to the lipid-soluble vitamin D3 (cholecalciferol), which is released into the circulation. The plant sterol, ergosterol, is transformed into vitamin D2 (ergocalciferol) by irradiation and is the source of vitamin D added to foods (e.g. milk); cod liver oil contains vitamin D3. In humans, the function of vitamins D2 and D3 are identical. Vitamin D3 is the largest steroid hormone. |
| Calcitonin (32 amino acids) is made by the parafollicular (C) cells of the thyroid. It inhibits bone resorption (stimulates osteoblasts, inhibits osteoclasts), increases renal calcium and phosphate excretion, and inhibits renal 1a -hydroxylase. At normal physiologic concentrations, calcitonin is less important than PTH in regulating serum calcium. Calcitonin release is stimulated by pentagastrin. |
Signs and Symptoms of Hypercalcemia
Severity of symptoms depends on magnitude and rapidity of rise in calcium.
I. Asymptomatic (up to 80% of patients with primary hyperparathyroidism).
II. Neuromuscular
-Apathy, drowsiness, decreased memory & concentration
-Depression, somatization, personality disturbances, psychosis
-Coma
-Proximal muscle weakness and atrophy of type II muscle fibers (very rare)
-Gait disturbance
-Hyperreflexia
III. Gastrointestinal
-Anorexia
-Abdominal pain
-Constipation
-Nausea and vomiting
-Peptic ulcer disease (seen with hypercalcemia and MEN I with gastrinoma)
-Acute pancreatitis (rare)
IV. Renal (stones mainly seen in hyperparathyroidism, occasionally in sarcoidosis)
-Polyuria, polydipsia (nephrogenic diabetes insipidus, if not matched by oral intake due to anorexia or vomiting, hypovolemia and decreased glomerular filtration impair calcium excretion, exacerbating hypercalcemia).
-Hypercalciuria (despite increased distal tubular resorption, overwhelmed by high filtered load; also, hypercalcemia inhibits calcium reabsorption in thick ascending limb of Henle)
-Nephrolithiasis (most frequent complication of primary hyperparathyroidism - 20%; of all patients presenting with calcium stones, up to 6% have primary hyperparathyroidism)
-Nephrocalcinosis (diffuse parenchymal calcification, can cause renal failure leading to phosphate retention and ectopic soft tissue calcification)
-Chronic pyelonephritis (stones serving as nidus for infection)
V. Skeletal (Rare - long term effects mainly of chronic hyperparathyroidism)
-Osteitis fibrosa cystica (rare now that hypercalcemia is detected earlier): "Salt and pepper" skull x-ray, subperiosteal resorption, phalangeal tuft resorption. Osteitis fibrosa cystica can impair response to erythropoietin.
-Brown tumors in long bones and pelvis, collections of osteoclasts intermixed with poorly mineralized woven bone. Brown tumors are usually accompanied by dramatic cortical thinning in the hands and symphysis pubis.
-Osteopenia: Preferential reduction of cortical bone mass (relative preservation of cancellous bone). Bone loss on DEXA: radius > hip > vertebrae. ? enhanced cancellous bone density.
-Nonspecific generalized skeletal demineralization
-Chondrocalcinosis/pseudogout
VI. Cardiovascular
-Decreased QT interval
-Hypertension if intravascular volume is maintained (tenuous association: rarely corrected after successful parathyroid surgery)
-Enhanced sensitivity to digitalis
-Bradyarrhythmias and first-degree heart block (rare)
-Reported higher incidence of valvular, myocardial and coronary artery calcification and LVH, especially with higher calcium levels
VII. Ectopic soft tissue calcification, especially when phosphorus is elevated (as in vitamin D toxic states or hyperparathyroidism complicated by renal damage, calcium phosphate product > 50-70). Abnormal deposits occur in aorta and major branches, heart (valve, myocardium), kidney, skin, joints, muscle (least resistant to calcification), respiratory tract, and the exposed area of the cornea (band keratopathy).
-Calciphylaxis is acute systemic medial calcification of arteries which results in tissue ischemia, purpuric plaques, and necrotic ulcers which often become infected. Calciphylaxis is rare (< 200 cases reported), precipitated by local tissue trauma, including injections, and has a poor prognosis. It is most commonly seen in end-stage renal disease, but also in some hypercalcemic states. Pathogenesis involves more than elevated calcium and phosphate, possibly related to elevated PTH levels or use of CaCO3, calcitriol, or prednisone.
VIII. Normochromic, normocytic anemia may be seen in severe hyperparathyroidism.
Hyperparathyroidism
I. Epidemiology
-Occurs at any age but very rare under age 15. More prevalent in those over age 40.
-Peak incidence is in fifth to sixth decade, with female:male of 3.5:1.
-100,000 new cases in U.S. per year; prevalence of 1 in 1000.
-Sporadic primary hyperparathyroidism is associated with external neck irradiation and lithium therapy.
-Parathyroid hyperplasia is more common in younger patients and concomitant hereditary disorders; adenoma usually sporadic and seen in older patients.
II. Etiology
-85% single adenoma; 15% multiple gland hyperfunction (hyperplasia, multiple adenomas); <0.5% carcinoma. In one series 8% had a mixture of adenoma & hyperplasia.
-Usually inferior glands; chief-cell hyperplasia; major histologic finding: disappearance of fat in parathyroid tissue
III. Modes of presentation
-80% are asymptomatic with mild hypercalcemia. In the remainder, nephrolithiasis is often the only symptom.
-Acute primary hyperparathyroidism: extremely severe hypercalcemia and very high PTH, must consider parathyroid carcinoma
-"Normocalcemic" hyperparathyroidism: usually hypoalbuminemic but in cases with true normocalcemia, the serum calcium tends to increase over time. May represent a secondary hyperparathyroidism in response to hypercalciuria induced by a high sodium diet and sodium excretion (sodium and calcium are excreted together).
-In MEN syndromes, hyperparathyroidism tends to involve multiple glands. MEN I (parathyroid (onset age ~25 years), pituitary, pancreatic tumors; autosomal dominant, mutation of menin tumor suppressor gene) or IIA (medullary CA thyroid, pheochromocytoma, parathyroid [84% hyperplasia, 16% adenomatosis]; autosomal dominant, activating mutation of RET proto-oncogene).
-Familial primary hyperparathyroidism
-Familial cystic parathyroid adenomatosis
-Neonatal severe primary hyperparathyroidism: autosomal recessive, homozygous inactivating mutations of calcium-sensing receptor, all glands enlarged, Ca > 16 mg/dL, very high PTH levels
-Hyperparathyroidism-jaw tumor syndrome: rare, hyperparathyroidism, cemento-ossifying jaw fibromas, renal cysts, Wilms’ tumor, renal hamartomas. Autosomal dominant (chr. 1q24), often multiple adenomas, 10% develop parathyroid carcinoma.
IV. Laboratory findings
-Hypercalcemia: bone resorption, ¯ renal clearance
-Hypophosphatemia (1/3 of patients): renal clearance
-Elevated PTH relative to serum calcium: inappropriately high/normal (hypercalcemia should suppress PTH; N versus C terminal Intact PTH IRMA most sensitive and specific). In very mild cases, ingestion of a meal containing a significant amount of Ca can suppress PTH levels to normal range. Ideally, PTH levels should be drawn after a week of low-calcium diet (no milk, yogurt, ice cream, cheese), and in the fasting state.
-Low-normal 25-OH-D, high normal or elevated (30%) 1,25-OH-D
-Urinary calcium excretion high normal to elevated (30-40% of cases)
urinary cAMP: cAMP is second messenger in kidney for PTH action
serum Cl (Cl/PO4 > 30): exchange of Cl for PO4 produces metabolic hyperchloremic acidosis
¯ serum HCO3: mild hyperchloremic metabolic acidosis
serum alkaline phosphatase, osteocalcin: with significant bone disease (reflects osteoblast stimulation)
urinary hydroxyproline, pyridinoline, deoxypyridinoline, N-telopeptide: with significant bone disease (reflects osteoclast stimulation)
V. Surgical Guidelines
-In one series, all patients (n=61) undergoing surgery had normalization of serum and urinary calcium, PTH levels, and a sustained increase in lumbar & femoral neck (cancellous) bone density but no change in radius (cortical) bone density. There were no cases of recurrent nephrolithiasis.
-Indications for surgery (up to 50% of patients will meet one of these):
- Serum calcium > 12 mg/dl
- Marked hypercalciuria > 400 mg/d
- Any overt manifestation of hyperparathyroidism (eg. nephrolithiasis)
- Markedly reduced cortical bone density (distal radial density > 2 SD below nl [z < -2])
- Reduced creatinine clearance with no other identifiable cause (<70% of nl)
- Age < 50
- Episode of acute primary hyperparathyroidism (parathyroid crisis)
-Cure rate for those without previous neck surgery is over 90%.
-Best localization test is an experienced parathyroid surgeon.
-Preoperative localization tests (99mTc-sestamibi imaging (77% sensitive, 96% specific for adenoma detection), MRI (77% sensitive), ultrasound (57% sensitive), CT (42% sensitive), arteriography (60% sensitive, 95% specific), selective venous sampling for PTH (80% sensitive)) are not indicated (do not decrease operative time or morbidity) except in cases of surgical failure or previous neck surgery or to identify the rare mediastinal parathyroid (extended field sestamibi scan). Sestamibi is taken up by highly metabolically active tissue (heart, thyroid, parathyroid, salivary gland) and washes out most slowly from the parathyroids, scan done 1.5-3 hours after administration to best distinguish parathyroids from the thyroid. Even though it is the most accurate parathyroid imaging, sestamibi scanning can be nonlocalizing in 15% of adenomas and can be blank, show a single or multiple foci of uptake in multiglandular disease.
-At surgery, all four parathyroids must be identified.
-If an adenoma is present, that gland is removed and other glands biopsied (controversial); some surgeons elect not to biopsy if other glands are very small (from suppression)
-In hyperplasia, either remove three and 1/2 glands (subtotal) or do total parathyroidectomy followed by autotransplantation of gland fragments in nondominant forearm (potential for graft-mediated recurrence).
-In the new technique, minimally invasive radio-guided parathyroidectomy, a 99mTc-sestamibi scan is done immediately preop. If only a single adenoma is seen then a small incision is made (under local anesthesia, outpatient surgery) and a small gamma probe used to guide and confirm removal. If the scan suggests hyperplasia, then a traditional open procedure is done.
-Rapid intraoperative PTH measurement can increase the success of parathyroidectomy.
-Deep ectopic lesions can be managed with angiographic embolization (70-85% success rate).
-Postoperative hypocalcemia due to either hypoparathyroidism (low PTH, normal to high phosphate, more likely if all glands were biopsied, may be transient as suppressed glands recover or permanent [4%, or 10-20% in patient with previous neck surgery or subtotal parathyroidectomy]) or hungry bone syndrome (normal PTH, low phosphate, rapid deposition of calcium and phosphate into bone)
-Hoarseness due to damage to recurrent laryngeal nerve (<1%)
-Postoperative persistent hypercalcemia: operative failure (2-8%): operator inexperience, unrecognized parathyroid hyperplasia, supernumerary or unrecognized ectopic parathyroid tissue, which can be found anywhere from the lower mandible to posterior mediastinum to diaphragm (28% paraesophageal, 26% mediastinal, 24% intrathyroidal, 9% carotid sheath, 2% cervical).
-Postoperative recurrent hyperparathyroidism: arises in unresected hyperplastic glands, especially in familial parathyroid hyperplasia (MEN I).
VI. Non-surgical management
-Encourage ambulation and adequate hydration
-Avoid thiazides
-Moderate dietary calcium intake (< 1000 mg/d). Low intake can aggravate hyperparathyroidism and bone loss.
-Twice yearly calcium, creatinine, PTH measurements. Yearly urinary calcium, sodium, creatinine clearance and bone densitometry
-Oral phosphate: controversial
-Estrogen in post-menopausal women (increases bone density and may slightly decrease calcium levels and decrease urinary hydroxyproline excretion)
| In a study of 52 asymptomatic patients not undergoing surgery (10-year follow up), there was no overall change in serum or urinary calcium, PTH levels, or bone mineral density. No patient developed symptoms; however, 14/52 (27%) of patients developed an indication for surgery (increased serum or urinary calcium level, or development of osteopenia). Patients entering menopause during the study were at higher risk of losing bone density. |
| Patients with primary hyperparathyroidism have been found to have an increased risk of death from cardiovascular diseases. Calcium levels have been found to correlate with long-term cardiovascular morbidity and mortality and increased risk of premature death. PTH has direct positive chronotropic and mediated inotropic effects on the heart; elevated PTH levels have been associated with LVH and increased vascular stiffness on pulse wave analysis. An association of elevated PTH with insulin resistance has been observed. These are arguments for surgery even in asymptomatic patients. It remains to be clearly documented that the increased risk of death is prevented by early parathyroid surgery. |
| Others argue that, considering non-specific physical (fatigue, constipation) and neuropsychological (poor memory, malaise) features, most patients are actually symptomatic and should have surgery since surgery has been shown to improve these subjective symptoms in addition to objective signs. |
Hypercalcemia in Malignancy
| Hypercalcemia complicates 5-10% of advanced malignancy. Direct bone invasion with concomitant mechanical release of calcium is no longer thought to be a cause of malignancy-related hypercalcemia. All hypercalcemia is likely due to elaboration of some factor which acts either locally or systemically. |
| PTH related protein (synonyms: humoral hypercalcemic factor, hypercalcemia of malignancy factor, PTH related peptide, PTH-like protein): PTH-rp is a factor immunologically distinct yet related biochemically to PTH (84 amino acids). Single PTH-rp gene produces one peptide of varying length (139, 141, or 173 amino acids). Homology to PTH in the first 13 amino acids of the N-terminal, thereafter unique sequence. Does not cross react with C-terminal of intact PTH (IRMA) assays. Can be measured in reference laboratories by two-site IRMA (frozen plasma). Most commonly associated with squamous cell carcinomas (lung, esophagus, cervix, vulva, skin, head & neck), also adenocarcinomas and others (breast, renal, transitional cell, ovarian, pancreatic, thymic, islet cell tumors, pheochromocytoma, carcinoid, sclerosing hepatic carcinoma), and HTLV-1 associated adult T cell leukemia/lymphoma. |
| Osteoclastic activating factors: Responsible for hypercalcemia associated with local osteolysis and also the 20% of cases (usually leukemia or lymphoma) of humoral hypercalcemia not associated with elevated levels of PTH-rp. Factors of multiple sizes from 1,000 to 25,000 described. Myeloma and other tumor cells and mononuclear cells (host cells activated by nearby malignant cells) have been found to secrete a wide variety of proteins that can stimulate osteoclastic activity (lymphotoxin, epidermal growth factor, interleukin-1, interleukin-6, TGF-b , TNF-a , calcitriol, authentic PTH). Usually associated with widespread bone metastases, particularly breast cancer. A case of hypercalcemia in juvenile rheumatoid arthritis was attributed to IL-1b with no known malignancy. |
| Calcitriol humoral hypercalcemia. Lymphoma tissue (Hodgkin’s more commonly than NHL; almost all hypercalcemia in Hodgkin’s due to calcitriol, while only 30-40% of hypercalcemic NHL due to calcitriol) may contain the enzyme 1a -hydroxylase and lead to increased levels of biologically active 1,25-OH-D, thus causing hypercalcemia. It is unclear whether the lymphoma cells or infiltrating host monocytes/macrophages are the primary source of calcitriol. As in sarcoidosis, interferon-g production by lymphocytes stimulating monocyte/macrophage 1a -hydroxylase activity (macrophages are one of the few extra-renal cell types with such activity) and enhancing vitamin D activation may be an initiating event. Process may involve complex cytokine interactions (for example, IL-1 and TNF have been found to increase expression of IFN-g receptors on macrophages, potentially enhancing cellular responsiveness to IFN-g ). In NHL, hypercalcemia occurs most commonly in high-grade histologic subtypes, which correlates with higher degree of host macrophage infiltration of lymphomatous tissue ("starry sky"). |
| Coexistent primary hyperparathyroidism is common, with some estimates up to 55% in malignancy, may be the cause of hypercalcemia. |
| Prostaglandins: PGE2 has powerful osteolytic effects in vitro. Best evidence is in animals, scant evidence in man, or type of tumor. Patient response to indomethacin is the best diagnostic-therapeutic test. (Secreted by breast CA?, but not exclusively). |
| Ectopic secretion of intact PTH by tumors is very rare but has been documented in isolated cases in small cell lung carcinoma, squamous cell lung carcinoma, ovarian carcinoma, thymoma, papillary thyroid carcinoma, hepatocellular carcinoma, undifferentiated neuroendocrine tumor. |
| Humoral hypercalcemia of malignancy compared with hyperparathyroidism: |
-Hypercalcemia more severe and sudden in onset.
-Increased bone resorption and suppressed bone formation (in hyperparathyroidism, both are increased).
-Calcitriol level normal or suppressed (in hyperparathyroidism, calcitriol level tends to be in upper range of normal).
-Hypercalcemia in malignancy associated with mild hypochloremic alkalosis; hyperparathyroidism associated with mild hyperchloremic acidosis.
-Treatment with glucocorticoid may decrease calcium.
Less Common Causes of Hypercalcemia
A. Thyrotoxicosis
-Incidence of 5-10%
-Hypercalcemia rarely exceeds 11.5 mg/dl.
-Etiology: excessive osteoclastic activity in thyrotoxic state, perhaps via beta receptors, since propranolol will decrease calcium.
-PTH is appropriately suppressed. Urinary cAMP is normal or low.
B. Pheochromocytoma
Hypercalcemia usually occurs with coexisting hyperparathyroidism in MEN II, but occasional remission of hypercalcemia after removal of pheochromocytoma suggests possible secretion of hypercalcemic factor.
C. Adrenal insufficiency
Thought due to loss of antagonistic properties of glucocorticoids on calcium absorption and on bone mobilization and to dehydration.
D. VIP-oma
Benign and malignant islet cell tumors that secrete vasoactive intestinal peptide present with watery diarrhea, hypokalemia and achlorhydria. 50% of these patients have hypercalcemia. Hypercalcemia may be due to associated MEN I hyperparathyroidism, but there are cases where hypercalcemia remitted after resection of the pancreatic tumor.
E. Vitamin D intoxication
-Excess intake of vitamin D, calcidiol, or calcitriol, or oral or topical vitamin D analogs.
-Excess vitamin D particularly problematic due to lipid solubility leading to long half life (20 days to months, compare with 25-OH-D half life 15 days, 1,25-OH-D half life 15 hours). Slow release from fat depots can prolong vitamin D toxicity for up to 18 months.
-PTH is appropriately suppressed.
-Elevated 25-hydroxyvitamin D level with a normal 1,25-OH-D level is indicative of vitamin D, or 25-OH-D toxicity (25-hydroxylation by the liver is not tightly regulated).
-Elevated 1,25-OH-D level indicative of 1,25-OH-D or 1-a -OH-D toxicity (or dysregulated production in granulomatous diseases or lymphoma).
-Increased calcium and phosphorus may lead to soft tissue calcification, band keratopathy.
-Increase in both intestinal calcium absorption and bone resorption.
F. Granulomatous diseases
-Sarcoidosis: most common granulomatous disease associated with hypercalcemia. Incidence of hypercalcemia 10-20%. Patients with sarcoidosis should avoid vitamin D and sun exposure.
-Other: tuberculosis, histoplasmosis, coccidioidomycosis, leprosy, candidiasis, eosinophilic granuloma, berylliosis, silicone-induced granuloma, Wegener’s granulomatosis, cat scratch disease, paraffin-induced granuloma.
-Hypercalcemia is usually mild but may be severe.
-Etiology: dysregulated 1a -hydroxylation of 25-OH-D by granulomatous cells, therefore, disease is of vitamin D intoxication.
G. Familial hypocalciuric hypercalcemia
Familial, autosomal dominant disease with a high degree of penetrance. Characterized by hypocalciuria and hypercalcemia (usually mild); generally benign asymptomatic course (no treatment required), no renal or bone disease; fractional excretion of divalent cations (Ca, Mg) is impaired. PTH level is usually normal but has been elevated in several cases. Diagnose with low 24-hour calcium excretion, with ratio of calcium to creatinine clearance < 0.01, or FECa < 1%. Gene for calcium-sensing receptor is responsible for FHH (heterozygous mutation). Homozygous mutation results in neonatal severe primary hyperparathyroidism.
H. Medications
| Vitamin A (retinol) toxicity (> 5000 IU/d): If causing hypercalcemia, will also see dry skin/dermatitis, pruritus, headache from pseudotumor cerebri, bone pain, alopecia, hepatic dysfunction, dementia and weight loss. Mechanism is osteoclast stimulation. Diagnose by measuring vitamin A level or percentage of vitamin A in retinyl ester form (more specific). Hypercalcemia may also be caused by ingestion of vitamin A derivatives: isotretinoin (13-cis-retinoic acid) or tretinoin (all-trans-retinoic acid). |
| Thiazides (increased tubular resorption of calcium) and lithium carbonate (?altered set point for calcium in parathyroid cell, reduction in renal calcium clearance, increase in parathyroid cell mass with long term therapy) tend to be associated with elevated serum PTH in the face of hypercalcemia, thus hyperparathyroidism cannot be diagnosed until drug is withdrawn and hypercalcemia and elevated PTH are shown to persist after 2-3 months. Mild hyperparathyroidism occurs in ~5% of those on long-term lithium and often persists after lithium is stopped. Thiazides usually unmask, not cause, hypercalcemia. |
| Aluminum toxicity leads to a mineralization defect, osteomalacia, and osteoblast suppression, inability to incorporate circulating calcium into bone. Renal bone disease may be due to aluminum toxicity when aluminum compounds have been given chronically as phosphate binders. Aluminum toxicity may complicate antacid administration or parenteral nutrition (aluminum present in amino acid hydrolysates). |
| Milk-alkali syndrome (triad: hypercalcemia, metabolic alkalosis, renal failure): Now rare since the advent of nonabsorbable antacids. Ingestion of large quantities of milk and absorbable alkali (milk + sodium bicarbonate, once a treatment for peptic ulcer disease). Toxic syndrome consisting of headache, nausea, neuromuscular irritability, pruritus, lethargy, hypercalcemia, hypocalciuria, metabolic alkalosis, azotemia. Increased pH and increased phos/Ca ratio leads to soft tissue calcification (band keratopathy), nephrocalcinosis (and renal failure), and pruritus. Much of the renal function can be regained and pruritus relieved by reducing the calcium and alkali intake, if structural damage has not occurred. Recent increase in cases may be due to use of calcium carbonate for osteoporosis or as a phosphate binder. |
| Parenteral nutrition can result in hypercalcemia if too much calcium (> 300 mg/day) is given, especially in the setting of renal impairment. |
| 8-chloro-cyclic AMP is an anticancer agent which has been found to increase renal 1,25-OH-D production. |
| Isolated case reports have seen hypercalcemia with use of ganciclovir, foscarnet (usually associated with hypocalcemia), recombinant growth hormone therapy in AIDS patients, manganese intoxication, and recent hepatitis B vaccination. |
I. Immobilization
Prolonged immobilization or weightlessness (space flight) promotes negative calcium balance, but frank hypercalcemia occurs only in young patients or those with an underlying disorder of accelerated bone turnover (Paget’s disease, malignancy ± overt skeletal metastases, primary or secondary hyperparathyroidism, spinal cord injury, prolonged bed rest). Osteoclast activity is enhanced and osteoblast activity diminished due to loss of gravitational biomechanical effects on the skeleton.
J. Renal failure
| Hypercalcemia occasionally seen in recovery phase of acute renal failure, due to rebound effect of elevated PTH and calcitriol level induced by early hypocalcemic period of acute renal failure. |
| Hypercalcemia may be observed in the recovery phase of rhabdomyolysis-induced renal insufficiency as calcium recently deposited in muscle and soft tissue is mobilized. |
| Secondary hyperparathyroidism occurs in chronic renal failure (prolonged hypocalcemia, phosphate retention, altered vitamin D metabolism inducing gland hyperplasia (reversible) and increased PTH, PTH secretion still controlled by serum calcium, but at any calcium level, secretion is higher than normal). Tertiary hyperparathyroidism occurs when these hyperplastic glands lose inhibition by calcium, resulting in hypercalcemia (often an adenoma develops in background of hyperplasia) and extremely elevated PTH levels. Control secondary hyperparathyroidism with low phosphate diet (avoid milk, dairy, cola), phosphate binder (CaCO3 or calcium acetate [PhosLo] or sevelamer; avoid calcium citrate which can increase aluminum absorption) and calcitriol (Rocaltrol, Calcijex) 0.25-1 µg PO qd or 0.5-3 µg IV 3x/week with HD or paricalcitol (Zemplar) 0.1 µg/kg IV 3x/wk with HD. If severe hyperparathyroidism, refractory bone disease or metastatic calcification are present, parathyroidectomy is indicated. |
| Hypercalcemia (usually transient) occurs in up to 30% of patients after renal transplantation, due to restoration of calcitriol production by allograft and amelioration of end-organ resistance to PTH during slow involution of hypersecreting parathyroids (6-12 months). After transplantation, regression of secondary hyperparathyroidism occurs over 1-10 years and may be incomplete. 1-3% require parathyroidectomy ~3 years after transplant due to persistent hypercalcemia. |
K. Humoral hypercalcemia of benignancy
A recently described syndrome of hypercalcemia induced by PTH-rp produced by benign tumors. Five reported cases: ovarian dermoid cyst, uterine fibroid, intestinal leiomyoma, mammary hyperplasia, pheochromocytoma. A case of symptomatic hypercalcemia due to elevated PTH-rp was reported in a lactating woman; the source of the PTH-rp was the breast, where it may normally play a paracrine (local) role. A case of hypercalcemia in systemic lupus was attributed to PTH-rp secretion from non-malignant lymph nodes.
L. Jansen's metaphyseal chondrodysplasia. Autosomal dominant, activating mutation of type 1 PTH/PTH-rp receptor leading to mild hypercalcemia, low PTH levels, short limbs.
Treatment of Hypercalcemia
| Therapeutic goals: 1. Correct dehydration; 2. Enhance renal excretion of calcium; 3. Inhibit accelerated bone resorption; 4. Decrease intestinal absorption of calcium; 5. Treat the underlying disorder. |
| Hydration: Anorexia, vomiting and inability to concentrate urine (hypercalcemia causes nephrogenic diabetes insipidus) results in dehydration. Correction of intravascular volume corrects the serum calcium at least by the degree to which dehydration raised it (1.5 to 3.0 mg/dl) and facilitates renal calcium clearance by increasing GFR and decreasing proximal sodium and water reabsorption (calcium is reabsorbed passively with sodium). Tailor infusion to clinical status (severity of hypercalcemia, degree of dehydration, cardiovascular disease). Typically 2.5 to 4 liters of NS daily. |
| Loop diuretic agents: After volume expansion, furosemide may be used to facilitate urinary excretion of calcium by inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle. Loop diuretic use is also useful to guard against volume overload during saline administration, especially in elderly patients. For severe hypercalcemia, intensive administration of lasix (80 to 100 mg IV every 1-2 hours) with fluid and electrolyte replacement based on urinary losses is labor intensive (and often complicated by hypokalemia, hypomagnasemia) but effective. |
| Dialysis: In the setting of renal failure, attempts to increase renal calcium excretion are often ineffective, in which case peritoneal or hemodialysis (hemodialysis more effective) with a low calcium dialysate may be indicated. |
| Bisphosphonates: Compounds related to pyrophosphate, but resistant to phosphatases, bind to hydroxyapatite in bone and inhibit crystal dissolution. Have very long half life in bone. Inhibit osteoclasts and can also decrease osteoclast viability. Serum calcium begins to decrease by 24-48 hours, reaches its nadir within 7 days, and may last for weeks. Decreased urinary hydroxyproline and calcium reflect decreased bone resorption. Poorly absorbed orally; renally excreted. Must be well hydrated before use and infuse drug in large volume of fluid because precipitated calcium bisphosphonate is nephrotoxic (renal insufficiency is a relative contraindication). |
| Etidronate (Didronel) is given at 7.5 mg/kg/day [over 4 hours] x 3-5 days. Adverse effects include transient increases in creatinine and phosphorus. Unlike other bisphosphonates, etidronate given long-term can cause osteomalacia. |
| Pamidronate (Aredia) is more effective, 30-90 mg IV infused over 4-24 hr., in lowering serum calcium. May also be given orally (1.2 g qd over 5 days) but this is less well tolerated. Adverse effects of IV administration include a mild, transient increase in temperature, transient leukopenia, overshoot hypocalcemia and a small reduction in serum phosphate. |
| Alendronate (Fosamax) may be considered as oral therapy for mild hypercalcemia, but it is not approved for this indication. |
| New third generation bisphosphonates (ibandronate, risedronate [Actonel], zoledronate) have been found to be more potent than pamidronate but have not yet found their way into routine clinical use. |
| Plicamycin (Mithramycin): An inhibitor of DNA-dependent RNA synthesis which inhibits osteoclast function and generation. Given IV at 25 m g/kg over 4-6 hours, and can, if needed, be repeated at intervals of 24-48 hours. Calcium begins to decrease as early as 12 hours after infusion, and maximal reduction occurs in 48-72 hours, persisting for several days to weeks. Adverse effects (dose dependent) include nausea, hepatotoxicity (transaminitis in 20% of patients), nephrotoxicity, proteinuria and thrombocytopenia. Extravasation causes irritation and cellulitis. Contraindications to use are overt hepatic or renal dysfunction, thrombocytopenia or coagulopathy. |
| Calcitonin: After a 1 U skin test, salmon (more potent than human) calcitonin is given SC or IM 4 U/kg every 12 hours (can go up to 8 U/kg every 6 hours). Less potent compared to bisphosphonates or plicamycin but most rapid onset of action (most likely due to hypercalciuric action); calcium starts to fall in a few hours, with nadir reached within 12-24 hours, but often rebounds despite continued administration due to development of resistance. Since this agent’s effect is weak and short-lived but rapid, consider it for use in very high calcium levels or when vigorous hydration is not possible or in combination therapy. Calcitonin is safe; adverse effects include nausea, abdominal cramps, flushing; allergic reactions are unusual. Calcitonin has potent analgesic properties, useful when the patient has painful bony metastases. |
| Corticosteroids: Glucocorticoids antagonize the effects of vitamin D on calcium absorption in the gastrointestinal tract, and inhibit extrarenal 1a -hydroxylation (thus effective for granulomatous diseases, lymphoma, vitamin D intoxication) and inhibits growth of neoplastic lymphoid tissue (thus effective in multiple myeloma, lymphoma). Also inhibit secretion of potentially important mediators by lymphocytes (IFN-g , IL-1, IL-10). May also alter hepatic metabolism of vitamin D to favor production of inactive metabolites, and may inhibit osteoclast action. Generally not effective for nonhematologic tumors or primary hyperparathyroidism. Dose is 40-100 mg PO qd of prednisone or 200 mg to 300 mg IV of hydrocortisone qd for 3-5 days. Should not be used prior to obtaining adequate tissue sampling if malignancy suspected (one dose will alter histopathology, i.e. lymphoma). Hypocalcemic response is variable (may be rapid or take 7-10 days). |
| Gallium nitrate: Inhibits bone resorption by adsorbing to and reducing the solubility of hydroxyapatite crystals (no direct effect on osteoclasts). Given as a continuous infusion (200 mg/m2 in 1 liter qd) for five days. IV infusion takes about 3 days to reach the calcium lowering effect of calcitonin alone, but then exceeds it significantly (up to 3 fold), serum calcium reaches nadir 3 days after infusion. Use is limited by nephrotoxicity (make sure patient is well hydrated), hypophosphatemia, decreased red blood cell mass. |
| Chloroquine and hydroxychloroquine can reduce calcitriol and calcium concentrations in sarcoidosis. Possibly efffect is mediated by inhibition of macrophage IL-1 production or by a reduced responsiveness to stimulatory cytokines. |
| Ketoconazole in high dose can inhibit mitochondrial P450-linked 1a -hydroxylase regardless of whether it is renal or extrarenal as in sarcoidosis or tuberculosis. |
| Mobilization: Immobilization (loss of weight bearing) accelerates mobilization of skeletal calcium, so ambulation should be encouraged if possible. |
| Indomethacin: Given at 25 mg q 6 h or aspirin are effective for tumors producing prostaglandins (rare). |
| Phosphate: IV sodium phosphate can rapidly lower calcium, but with great risk of precipitation in blood vessels, lungs, kidneys which can lead to severe organ damage or fatal hypotension. Less effective is oral phosphate, given at 0.5 g bid to 1.0 g tid (interferes with absorption of dietary calcium, inhibits bone resorption, inhibits renal calcitriol production). Minimal risk for renal stones or metastatic calcification if normal renal function and normal (or low) serum phosphorus. Best for chronic therapy. Side effect is diarrhea (over 2 g qd). Hyperphosphatemia and azotemia are contraindications. |
| Antagonists of PTH and the various humoral factors are being synthesized and tested in hopes of developing specific therapy. Calcimimetic agents (which alter the function of the extracellular calcium-sensing receptor) are in development. R-568, a calcium receptor agonist, caused dose dependent inhibition of PTH secretion and lowered calcium levels at higher doses in primary hyperparathyroidism. Also being developed are agents to mimic vitamin D’s inhibition of PTH synthesis and possible inhibition of growth of parathyroid tissue. |
References (v1.2.8)
- Baskin HJ. Primary hyperparathyroidism: new options for surgical management. Endocr Pract 2001;7:313-317.
- Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992;326:1196-1202.
- Body JJ. Clinical research update: zoledronate. Cancer 1997;80:1699-1701.
- Buchinsky DA, Monk RD. Calcium. Lancet 1998;352:306-311.
- Chan FK, Koberle LM, Thys-Jacobs S, Bilezikian JP. Differential diagnosis, causes, and management of hypercalcemia. Curr Prob Surg 1997;34:444-523.
- Clarke BL. Hypercalcemia. MTP Handouts, 82nd Annual Meeting of the Endocrine Society, June 21-24, 2000:58-61.
- Dooley M, Balfour JA. Ibandronate. Drugs 1999;57:101-108.
- Lepre F, Grill V, Ho PWM, Martin TJ. Hypercalcemia in pregnancy and lactation associated with parathyroid hormone-related protein. N Engl J Med 1993;328:666.
- Marx SJ. Hyperparathyroid and hypoparathyroid disorders. NEJM 2000;343:1863-1875.
- Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for PTH. N Engl J Med 1990;323:1324-8.
- Ravakhah K, Gover A, Mukunda BN. Humoral hypercalcemia associated with a uterine fibroid. Ann Int Med 1999;130:702.
- Raue F. Increased incidence of cardiovascular diseases in primary hyperparathyroidism - a cause for more aggressive treatment? Eur J Clin Inv 1998;28:277-278.
- Saky MT, Hasinski S, Rose LI. Ectopic primary hyperparathyroidism. Endocr Pract 2001;7:272-274.
- Seymour JF, Gagel RF. Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 82;1383-1394.
- Silverberg SJ. Editorial: cardiovascular disease in primary hyperparathyroidism. J Clin Endocrinol Metabol 2000;85:3513-4.
- Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249-55.
