• Information
  1. Mechanisms of Calcium Regulation
  2. Causes of Hypercalcemia
  3. Symptoms
  4. Evaluation
  5. Treatment

A. Mechanisms of Calcium Regulation [1]

1. Parathyroid Hormone (PTH) [2]
   1. 84-amino acid peptide released in response to decreased serum [Ca2+]
   2. Binds type 1 PTH receptors in bone, kidneys and intestines
   3. Causes osteoclast activity with release of Ca2+ and phosphate (HPO4(-2)) from bone
   4. Causes increased renal conversion of 25-OH Vitamin D to 1a,25 dihydroxy- Vitamin D
   5. Stimulates increased renal tubular Ca2+ resorption
   6. PTH related peptide (PTHRP), usually produced by tumors, has similar activity [11]
2. Dihydroxy-Vitamin D (DHVD)
   1. Vitamin D converted to 25-OH form in liver, then to dihydroxy form in kidney
   2. Stimulates gut absorption of Ca2+ and HPO4(-2)
   3. Maintaining adequate Vit D and calcium maintains serum PTH in the (low) normal range [22]
3. Calcitonin
   1. Produced by parafollicular (C-) cells in the thyroid
   2. Decrease bone resorption
   3. MInimal role in normal physiological regulation of Ca2+ in humans
   4. Patients with thyroidectomy (parathyroid sparing) have normal calcium homeostasis
4. Calcium Ion Sensor Receptor (CASR) [17]
   1. G-protein coupled receptor (GPCR) glycoprotein mainly found in parathyroid
   2. Couples extracellular ionized calcium level with intracellular responses
   3. Prominant on parathyroid, thyroid C (medullary), and kidney cells
   4. Heterozygous mutations in familial hypocalciuric hypercalcemia [5]
   5. Homozygous mutations in neonatal severe hyperparathyroidism [5]
   6. A986S genotype of sensor receptor accounts for ionized calcium variation in women [16]
   7. CASR agonist cinacalet can reduce PTH levels in 1° or 2° hyperparathyroidism [3]
5. Calcium Effects
   1. Calcium is bound primarily by albumin in the serum
   2. Ionized (not bound) calcium levels are sensed by the end organs
   3. High serum (ionized) calcium levels inhibit PTH and vitamin D, and stimulates diuresis
   4. Diuresis due to inhibition of proximal tubule resorption and anti-diuretic hormone action

B. Causes of Hypercalcemia [5,8,12]

1. Primary
   1. Primary Idiopathic Hyperparathyroidism [4]
   2. Renal Osteodystrophy (usually causes hypocalcemia and secondary hyperparathyroidism)
   3. Familial Benign Hypercalciumemia (Hypocalciuric Hypercalcemia)
   4. Parathyroid Carcinoma [20]
   5. Osteoporosis treatment with PTH derivative teriparatide can cause mild hypercalcemia [21]
2. Parathyroid Hormone-Related Protein (PTHRP) Hyperexcretion [8,11]
   1. Also called humoral hypercalcemia of malignancy
   2. Squamous > Small Cell Lung Cancers
   3. Squamous Cell Cancers: esophagus and others
   4. Renal Cell Carcinoma
   5. Ovarian Carcinoma
   6. Pancreatic Carcinoma
   7. Hepatoma
   8. Melanoma
   9. Hematologic Tumors: Non-Hodgkin's, Hodgkin's, others produce PTHRP [8]
   10. May be present with any of the islet cell carcinomas [13]
3. Malignancy with Bone Destruction (Osteolysis)
   1. Osteolysis: Multiple Myeloma, Breast CA
   2. Invasion of Bone: Prostate CA
   3. Increased Vitamin D Production: Lymphomas
4. Other Endocrine Disorders
   1. Hypervitaminosis D (Vitamin D Intoxication)
   2. Hyperthyroidism / Thyrotoxicosis (increased bone turnover) [11]
   3. Adrenal Insufficiency (Addison's Disease)
   4. Pheochromocytoma
   5. VIPoma
5. Granulomatous Diseases
   1. Granulomas often have increased dihydroxy-Vitamin D production
   2. Sarcoidosis
   3. Histoplasmosis and Coccidiomycosis
   4. Tuberculosis and Leprosy
   5. Syphilis
   6. Wegener's Granulomatosis [9]
   7. Cat-Scratch Disease (Bartonella henselae) [14]
6. Other Diseases
   1. Hyperproteinemic States - such as macroglobulinemia
   2. Paget's Disease
7. Medications
   1. Thiazide Diuretics - increase proximal tubule Ca2+ resorption
   2. Lithium - stimulates parathyroid hormone secretion
   3. Estrogens and Anti-estrogens
   4. Excessive Vitamin A or D intake
   5. Milk-Alkali Syndrome - overdose of calcium carbonate (TUMS®) ± bicarbonate [6]
8. Familial Hypocalciuric Hypercalcemia
   1. Abnormal calcium sensor primarily affecting the kidney
   2. Apparently leads to increased calcium resorption in the thick ascending limb (Henle)
   3. Reduced diuretic effects of calcium on the kidney
   4. Fairly benign disease mainly with laboratory abnormalities
9. Miscellaneous
   1. Immobilization
   2. Paget's Disease
   3. Chronic Renal Failure (usually hypocalcemia)

C. Symptoms

1. Common Presentation: asymptomatic; polydipsia, polyuria
2. Renal: Polyuria, Nephrolithiasis, Nephrocalcinosis; Diabetes insipidus may occur
3. Cardiovascular: Hypertension, Shortened QT interval on ECG
4. Gastrointestinal: Anorexia, Nausea, Vomiting, Constipation, Pancreatitis
5. Musculoskeletal: Myalgias, Weakness
6. CNS: Apathy, Lethargy, Confusion, Delirium
7. Mnemonic: "Bones, Stones and Groans (delirium)"
8. Soft Tissue Calcium Deposition
   1. A rise in serum calcium X phosphate product >70 leads to soft tissue deposition
   2. Calcium phosphate salts are deposited in soft tissues
   3. This leads to hypocalcemia and potentially organ damage

D. Evaluation

1. Underlying causes should always be assessed (see above)
2. Calcium and/or vitamin D supplementation is most common cause
   1. Normal Serum Calcium Level 2.07-2.59 mmol/L (8.2-10.4 mg/dL)
   2. Urine calcium to urine creatinine ratio normal: <0.16
   3. Higher levels in urine are called hypercalcuria and associated with renal stones
   4. 25-hydroxyvitamin D normal levels: 22-125 nmol/L
   5. 1,25-dyhydroxyvitamin D normal levels: 36-144 pmol/L
3. Hyperparathyroidism is fairly common
   1. Measure serum Parathyroid Hormone (PTH) concentrations
   2. Normal levels immunoreactive PTH 1.1-6.8 pM
   3. Consider measurement of PTH-like hormone
4. Search for malignancy may be warrented
5. Osteoporosis evaluation in all hypercalcemic persons

E. Treatment [1,10,15,18]

1. Severe Hypercalcemia is defined as Serum [Ca2+] >14mg/dL (3.5mmol/L)
   1. However, ionized (free) Ca2+ is the crucial determinant of symptoms
   2. Since Ca2+ binds proteins, one must correct for serum protein (albumin)
   3. Rule: Correct 0.8mg/dL up or down for each 1g/dL albumin down or up from baseline value of 4.0g/dL
2. Diagnosis and treatment of underlying disease is essential
3. Initial Measures
   1. Good Hydration: all patients with hypercalcemia are hypovolemic
   2. Hydration initially to euvolemia followed with loop (non-thiazide) diuretic therapy such as furosemide to increase calcium excretion
4. Calcitonin
   1. Requires sc or im injection, 4-8U/kg q12 hours up to 3 days (then tachyphylaxis occurs)
   2. Relatively weak agent but exerts its effects rapidly (within 12 hours)
   3. Use in combination with other agents in severe (symptomatic) hypercalcemia
5. Glucocorticoids
   1. May potentiate effects of calcitonin and other agents
   2. May decrease Ca2+ alone
   3. Reduces production of PTH-rP in many neoplastic cell types
   4. Potent anti-lymphocyte activity will lower Ca2+ in myeloma, lymphoma, sarcoid
6. Bisphosphonates
   1. Responses begin 2-4 days after initial dose
   2. Intravenous and oral agents are available
   3. Highly effective, with long term activity
   4. Likely prevent osteoporosis (due to aging) as well
   5. Specific agents discussed below
7. Zoledronate (Zometa®) [19]
   1. More effective than pamidronate for hypercalcemia of malignancy
   2. Reduces need for bone irradiation in patients with cancers
   3. Given as IV 4mg or 8mg in 100mL saline over 15 minutes
   4. Similar side effects as pamidronate
   5. Ease of use and improved efficacy should prompt use of zoledronate
8. Pamidronate (Aredia®) [17]
   1. More specific for blocking bone destruction than formation (compared with etidronate)
   2. Oral and intravenous formulations are available
   3. Single slow (over 2 hours) IV infusion of 60-90mg monthly or q 6 months
   4. Highest dose gave 100% normalization of calcium in cancer patients
   5. Side effects: low grade fever, hypomagnesemia, low phosphate, transient leukopenia
   6. Oral agent 1200mg po for up to 5 days
   7. Monthly 90mg infusions reduced pathologic fractures and bone pain in breast Ca [7]
9. Etidronate (Didronel®)
   1. Oral and iv formulations of this bisphosphonate available
   2. Blocks bone formation as well as bone destruction
   3. 7.5mg/kg iv over 4 hours for 3-7 days (follow serum calcium)
   4. Decreases will be 1-2 mg/dL over first 3 days
   5. Oral agent: 400-1600mg po qd maintenance may prevent re-occurrence
   6. Affects both bone destruction and bone formation, nearly equally
10. Aldendronate (Fosamax®)
    1. Highly specific for blocking bone destruction (minimal effects on bone formation)
    2. FDA approved for treatment of osteoporosis and Paget's Disease
    3. Oral formulation only
    4. Consider use in hypercalcemia from other causes
11. Gallium Nitrate
    1. Appears to inhibit bone resorption by reducing hydroxyapatite solubility
    2. IV infusion 200mg/m2 in 1 liter fluid daily x 5 days
    3. Nephrotoxic - avoid in patients with renal insufficiency and concomitant nephrotoxins
    4. Highly effective (~2X more so than etidronate)
12. Plicamycin (Mithramycin®)
    1. Inhibitor of RNA synthesis; particularly effective against osteoclasts
    2. Nephrotoxicity and Neutropenia have limited its use

References

1. Bushinsky DA and Monk RD. 1998. Lancet. 352(9124):306
2. Mark SJ. 2000. NEJM. 343(25):1863
3. Block GA, Martin KJ, de Rancisco ALM, et al. 2004. NEJM. 350(15):1516
4. Bilezikian JP and Silverberg Shonni. 2004. NEJM. 350(17):1746
5. Strewler GJ. 2005. JAMA. 293(14):1773
6. Bagriely I, Leu JP, Barzel US. 2008. NEJM. 358(18):1952 (Case Discussion)
7. Hortobagyi GN, Theriault RL, Porter L, et al. 1996. NEJM. 335(24):1785
8. Erban JK and Tang Z. 2002. NEJM. 347(24):1952 (Case Record)
9. Bosch X, Lopez-Soto A, Morello A, et al. 1997. Mayo Clin Proc. 72:440
10. Stewart AF. 2005. NEJM. 352(4):373
11. Diamond T, Vine J, Smart R, Butler P. 1994. Ann Intern Med. 120:(1)8
12. Mundy GR and Guise TA. 1997. Am J Med. 103(2):134
13. Wu TJ, Lin CL, Taylor RL, et al. 1997. Mayo Clin Proc. 72(12):1111
14. Bosch X. 1998. JAMA. 279(7):532
15. Bilezikian JP. 1992. NEJM. 326(18):1196
16. Cole DEC, Peltekova VD, Rubin LA, et al. 1999. Lancet. 353(9147):112
17. Brown EM. 1999. Am J Med. 106(2):238
18. Treatment of Hypercalcemia. 1992. Med. Let. 34(861):1
19. Zoledronate. 2001. Med Let. 43(1120):110
20. Broadus AE and Braaten KM. 2002. NEJM. 346(9):694 (Case Record)
21. Teriparatide. 2003. Med Let. 45(1149):9
22. Steingrimsdottir L, Gunnarsson O, Indridason OS, et al. 2005. JAMA. 294(18):2336