Approach to a patient with hypercalcemia

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Introduction

  • Hypercalcemia is a relatively common clinical problem. Among all causes of hypercalcemia, primary hyperparathyroidism and malignancy are the most common, accounting for greater than 90 percent of cases.[1] [2] [3]
  • Hypercalcemia : Serum total calcium above 10.6 mg/dl.[4]
  • This topic card will discuss how to approach a hypercalcemic patient.

History and physical examination :

  • Signs and symptoms related to the Hypercalcemia itself :
1. Polyuria and polydipsia : Chronic Hypercalcemia cause nephrogenic diabetes insipidus.
2. Gastrointestinal symptoms, such as constipation, anorexia, and nausea.
3. Palpitations and chest pain : due to cardiac arrhythmias from severe hypercalcemia.[5]
4. lethargy, confusion, stupor, and coma : with severe hypercalcemia (calcium >14 mg/dL [3.5 mmol/L]) from any cause.[6]
5. Band keratopathy[*] : very rare finding.[7]
  • Signs and symptoms related to the cause of Hypercalcemia.
1. For suspected Primary hyperparathyroidism: Remember “bones, stones, abdominal moans and psychic groans.”
o Bone pain : due to Bone disease “Osteitis fibrosa cystica”.[8]
o Renal colic : from nephrolithiasis.[8]
o Muscle weakness and fatigue.[9] [10]
o lethargy, depressed mood, psychosis, decreased social interaction and cognitive dysfunction : neuropsychiatric abnormalities.[11]
o History of recurrent bone fractures especially vertebral,pelvic and distal forearm fractures.[12] [13] [14] [15] [16] [17]
2. History of solid or hematologic tumors especially breast , lung , multiple myeloma :For suspected malignancy .[18]
3. Warm moist skin,lid lag, heat intolerance, weight loss despite normal appetite and other signs and symptoms of hyperthyroidism:For suspected thyrotoxicosis.
4. History of immobilization.[19] [20] [21]
5. History of bone pain and pathological femoral fractures : For suspected paget disease of bone.
6. History of estrogen or estrogen antagonist intake (tamoxefin).[22] [23]
7. History of calcium carbonate and calcium acetate intake for chronic kidney disease and prolonged intake of milk : for suspected excessive calcium intake and milk-alkali syndrome.[24]
8. History of Vitamin D ingestion : for vitamin D intoxication.[25]
9. History of lithium or thiazide diuretics intake.
10. History of pheochromocytoma : due to the disease itself or associated hyperparathyroidism in MEN type 2.[26] [27] [28]
11. History of myalgias and brown to red urine : for suspected rhabdomyalysis and acute renal failure.[29] [30]
12. History of thyophilline intake : for suspected thyophilline toxicity. [31]

Diagnostic approach : See algorithm.

Diagnostic approach to hypercalcemia.jpg
  • Step one: Serum total calcium level.
  • Step two : Correction of serum calcium level for albumin level to exclude pseudohypercalcemia (facticious Hypercalcemia) by the following equation :
corrected Ca = SerumCa + 0.8 * (NormalAlbumin - PatientAlbumin)[†]
  • Step three : Serum parathyroid hormone level(PTH) : To distinguish PTH-dependent from PTH-independent Hypercalcemia.
Elevated or high normal PTH indicates PTH-dependent Hypercalcemia, while decreased levels (<20 pg/ml) indicates PTH-independent causes.
  • Step four (A) : In PTH-dependent cases do the following :
1. Urinary execration of Ca+2  : to discriminate primary hyper-PTH from Familial hypocalciuric Hypercalcemia (FHH).
Urinary execration of Ca+2 is elevated in primary hyper-PTH and decreased in FHH.
2. Consider tertiary hyper-PTH from prolonged secondary hyper-PTH. [32] [33]
3. Consider lithium and thyophilline toxicity.
  • Step four (B) : In PTH-independent cases do serum phosphate level.
  • Step five (A): If serum phosphate level is low, do Parathyroid-hormone related peptide (PhRP) level : to assess for Hypercalcemia of malignancy.[34]
  • Step five (B) : If serum phosphate level is high do the following :
1. Chest x-ray : for suspected granulomatous disease.
2. Vitamin D metabolites, 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D (calcitriol) level : for vitamin D intoxication.[35]
3. TSH and T4 : for suspected hyperthyroidism.[36]
4. serum and urinary protein electrophoresis : for suspected multiple myeloma.[36]
5. Serum Chloride level and arterial blood gases : a low serum chloride concentration and metabolic alkalosis are characteristic of the milk-alkali syndrome.
6. Bone scan : for suspected metastatic bone disease.
7. Vitamin A : for suspected hypervitaminosis A.[36]
8. Consider immobilization.

Clinical Clues :

  • The degree of hypercalcemia also may be useful diagnostically.
o Primary hyperparathyroidism is often associated with borderline or mild hypercalcemia (serum calcium concentration often below 11 mg/dL [2.75 mmol/L]).
o Values above 13 mg/dL (3.25 mmol/L) are more common in patients with malignancy-associated Hypercalcemia.
  • PhRP is usually not necessary for diagnosis since most patients have clinically apparent malignancy at the time of Hypercalcemia.
  • There appears to be a higher incidence of primary hyperparathyroidism in patients with malignancy than in the general population [2][3]. Thus, despite the increased cost, it is reasonable to order an intact PTH assay as part of the routine evaluation for hypercalcemia even in a patient with known malignant disease.
  • Vitamin D metabolites :
o elevated 25-hydroxyvitamin D (25OHD) is indicative of vitamin D intoxication due to the ingestion of either vitamin D or calcidiol itself.[37] [38]
o elevated 1,25-dihydroxyvitamin D may be induced by
1. direct intake of this metabolite.
2. extrarenal production in granulomatous diseases or lymphoma.
3. increased renal production that can be induced by primary hyperparathyroidism but not by PTHrp.[39]
  • Other tests that can be helpful :
o Urinary execretion of calcium.
• Elevated or high normal in hyperparathyroidism and hypercalcemia of malignancy.
• Decreased in The milk-alkali syndrome, Thiazide diuretics and FHH.
o Chloride level :
• elevated chloride level (associated with a mild fall in the serum bicarbonate concentration) is consistent with primary hyperparathyroidism.
• Remember a low serum chloride concentration and metabolic alkalosis are characteristic of the milk-alkali syndrome.
o Bone x-ray : evidence of osteitis fibrosa on bone films is very specific for primary hyperparathyroidism .

References

[*] a reflection of subepithelial calcium phosphate deposits in the cornea
[†] some authorities prefer to measure the serum ionized calcium.
[1] Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res 1991; 6 Suppl 2:S51.
[2] Burtis WJ, Wu TL, Insogna KL, Stewart AF. Humoral hypercalcemia of malignancy. Ann Intern Med 1988; 108:454.
[3] Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG. Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Lancet 1992; 339:164.
[4] Blood Test Results - Normal Ranges
[5] Rosenqvist M, Nordenström J, Andersson M, Edhag OK. Cardiac conduction in patients with hypercalcaemia due to primary hyperparathyroidism. Clin Endocrinol (Oxf) 1992; 37:29.
[6] Shane, E, Dinaz, I. Hypercalcemia: Pathogenesis, clinical manifestations, differential diagnosis, and managment. In: Favus, MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. Sixth ed. Philadelphia: Lippincott, Williams, and Wilkins. 2006; 26:176.
[7] Wilson KS, Alexander S, Chisholm IA. Band keratopathy in hypercalcemia of myeloma. Can Med Assoc J 1982; 126:1314.
[8] Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:2036.
[9] Lundgren E, Ljunghall S, Akerström G, et al. Case-control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism. Surgery 1998; 124:980.
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