Clinical Anaesthesia

Hypercalcaemia

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By Adam George

 

 

 

 

 

 

 

 

 

 

 

 

Definition

  • Hypercalcaemia indicates a total serum calcium (Ca) concentration corrected for albumin of >2.6 mmol/L. hypercalcaemia can loosely be stratified as follows:
    • Mild/moderate (>2.6-2.9 mmol/L)
    • Severe (>3.0 mmol/L)
  • Approximately 99% of calcium in vivo is stored in bone as hydroxyapatite. Of the remaining 1%, 0.99% is extracellular, and 0.01% intracellular. This is necessitated by the fact that high intracellular calcium levels generate apoptosis – thus cells die if intracellular calcium levels rise excessively.
  • The serum concentration of calcium is monitored by the calcium-sensing receptors in parathyroid cells. This, in turn, determines how much parathyroid hormone (PTH) is released by the parathyroid gland. PTH is responsible for discharging calcium from bones, resorbing calcium at the kidneys, and synthesizing calcitriol (active vitamin D). Calcitriol successively boosts calcium absorption in the gastrointestinal tract. The net effect in homeostasis is maintenance of a total serum concentration between 2.1-2.6 mmol/L.
  • Pseudohypercalcaemia: is a situation where protein-bound calcium concentration increases (and therefore total calcium concentration is inflated), yet free ionized calcium concentration remains normal. The most common cause of pseudohypercalcaemia is dehydration, due to the ensuing high albumin concentration, which binds calcium. Paraprotein in multiple myeloma patients can also be a cause. Pseudohypercalcaemia is usually asymptomatic.

Causes

  • Hypercalcaemia can be divided into two pathophysiological pathways:
    • PTH-mediated hypercalcaemia, whereby excess PTH causes direct release of calcium from bones
    • Non-PTH-mediated hypercalcaemia

PTH-mediated causes of hypercalcaemia

  • Primary hyperparathyroidism: is usually generated by a primary adenoma or parathyroid hyperplasia. Here, a surfeit of PTH drives increased production of 1.25-dihydroxyvitamin D via stimulation of 1-alpha-hydroxylase in the kidneys. Primary hyperparathyroidism is usually asymptomatic.
  • Tertiary hyperparathyroidism: is caused by renal failure, which induces chronic secondary hyperparathyroidism and leads to autonomous activation of the parathyroid gland.
  • Familial hypocalciuric hypercalcemia (FHH): is a genetic mutation which deactivates the CaSR gene. This precipitates diminished sensitivity at the calcium-sensing receptors of the parathyroid gland and kidneys. As a result, greater levels of calcium are necessary to restrain PTH release, and more calcium is resorbed renally. This eventuates in hypercalciuria with mild hypercalcaemia and normal or elevated PTH.

Non-PTH-mediated causes of hypercalcaemia

  • Hypercalcemia of malignancy: most frequently engenders the paraneoplastic production of PTHrP. Commonly implicated cancers include SCC of the lung, breast cancer, bladder cancer, renal cancer, leukemia, and lymphoma. Other malignancies may involve osteolytic metastasis directly, such as multiple myeloma, leukemia, lymphoma, and breast cancer. In rarer cases, malignancies like lymphoma can provoke paraneoplastic production of 1.25-dihydroxyvitamin D rather than PTH. This increases the uptake of calcium in the gastrointestinal tract, generating hypercalcaemia.
  • Granulomatous disorders: such as Chron’s disease, primary biliary cirrhosis, and sarcoidosis can result in hydroxylase acting on mononuclear cells and the generation of 1.25-dihydroxyvitamin D extramural to the kidneys. The corollary is increased osteoclastic activity and release of calcium.
  • Medications/Drugs:
    • Excessive vitamin D enhances gastrointestinal calcium absorption
    • Thiazide diuretics decrease calcium excretion at the kidneys
    • Calcium supplements and antacids containing calcium carbonate can elevate total serum calcium concentrations
    • Lithium can cause increased resorption of calcium at the loop of Henle whilst simultaneously antagonizing CaSR, which heightens the set-point for the amount of calcium required to suppress PTH secretion at the parathyroid gland
    • Vitamin A can directly stimulate calcium release from bones
  • Thyrotoxicosis: leads to increased PTH secretion and consequently raised calcium uptake from bones.
  • Other causes: of hypercalcaemia include prolonged immobilization (eg: ICU stays leading to bone demineralization), adrenal insufficiency, and milk-alkali syndrome.
  • NB: Primary hyperparathyroidism and malignancy account for approximately 90% of all instances of hypercalcaemia.

Symptoms

Symptoms of hypercalcaemia generally correlate with the severity of increases in total serum calcium concentration. Mild hypercalcaemia can be asymptomatic, whereas severe hypercalcaemia can be a serious, life-threatening condition. Chronic symptoms are more consistent with hyperparathyroidism, while acute symptoms tend to suggest a malignant cause. Clinical features can include

    • Nephrolithiasis
    • Bone pain
    • Abdominal pain
    • Anorexia, nausea, vomiting
    • Constipation
    • Psychiatric symptoms (eg: anxiety, depression)
    • Neurologic symptoms (eg: fatigue, confusion, reduced concentration, coma)
    • Renal symptoms (eg: polyuria, polydipsia, nephrogenic DI, renal insufficiency)
    • Pancreatitis
    • Peptic ulcer disease
    • Muscle weakness, osteopenia, osteoporosis
    • Cardiac abnormalities (bradycardia, hypertension, shortened QT interval)

Investigations

Initial blood testing

    • Total serum calcium: generally adequate for the diagnosis of hypercalcaemia alone, unless a notably diminished plasma protein concentration is observed. Normal range is 2.1-2.6 mmol/L
    • Ionised calcium: is the physiologically significant form of calcium involved in cellular processes. Calcium, as a doubly positively charged ion (Ca2+) is repellent to albumin (the most abundant protein in the blood, accounting for 50% of plasma proteins). As such, protein concentration shifts can affect the ionised calcium concentration. If there is any protein concentration abnormality, then ionised calcium should be measured discretely. Normal range is 1.15-1.25 mmol/L
    • Serum PTH level: Distinguishing between primary hyperparathyroidism and malignancy (as they account for ~90% of cases of hypercalcaemia) is crucial. Elevated PTH despite high calcium levels indicates primary hyperparathyroidism. In cases of malignancy, PTH is likely to be very low to barely detectable due to the high calcium concentration inhibiting PTH secretion. Serum PTH is the principle initial investigation to determine confirmed hypercalcaemia of an unknown aetiology
    • Vitamin D levels: elevated 1.25-dihydroxyvitamin D is seen in lymphoma and granulomatous disorders. Increased 25-dihydroxyvitamin D can lead to vitamin D toxicity. This can be realised via excess vitamin D2, D3, or 25-OHD ingestion
    • PTHrP: production is the most frequent cause of hypercalcaemia of malignancy. Detectable PTHrP generally indicates a solid malignancy or neuroendocrine tumour

Additional blood testing

    • TSH, T3,T4: to investigate thyrotoxicosis
    • Cortisol & ACTH stimulation tests: to evaluate adrenal insufficiency
    • Vitamin A level: to examine vitamin A toxicity
    • Serum protein electrophoresis (SPEP): to assess for multiple myeloma

Urine

    • 24 hour urinary calcium excretion and/or
    • Urine Ca/Cr clearance ratio: In both cases, normal or increased urinary calcium (Ca/Cr >0.02, 24hr Ca >200mg) suggests primary hyperparathyroidism. Decreased urinary calcium (Ca/Cr <0.02, 24hr Ca <200mg) may suggest FHH or primary hyperparathyroidism

Imaging

    • X-rays: of painful areas to investigate metabolic bone disease
    • Skeletal survey: to scout for lytic bone lesions
    • Bone densitometry scan (DEXA): to determine fracture risk

Treatment

Supportive Care

  • Adequate hydration (6-8 standard glasses of water/day)
  • Decrease dietary calcium intake
  • Ensure medications that potentially contribute to hypercalcaemia are withdrawn/averted (eg: vitamin A, vitamin D >800 IU/day, calcium supplements, lithium carbonate, thiazide diuretics)
  • Avoid prolonged bed rest/inactivity

Mild/moderate (<3.0 mmol/L albumin-corrected) hypercalcaemia

  • In patients with total serum calcium corrected for albumin <3 mmol/L immediate therapy beyond supportive measures may not be necessary. Any acute elevation in calcium concentration should be treated as severe hypercalcaemia.

Acute severe (>3.0 mmol/L albumin-corrected) or symptomatic moderate hypercalcaemia

  • Initial rehydration: is NaCl 0.9% 4-6 litres IV over 24 hours.
    • Cardiac function must be monitored until calcium levels are within normal range
    • If fluid overload occurs, IV furosemide can be used to redress this (under specialist supervision)
    • Rehydration in children is determined by weight and degree of dehydration.
  • IV bisphosphonates: to lower serum calcium concentration may be considered in cases of severe hypercalcaemia in adults if patient is not responsive to rehydration. PTH should be measured prior to initiation to assist in determining the cause of hypercalcaemia. IV bisphosphonate treatment is IV zoledronic acid 4 mg over minimum of 15 minutes OR IV pamidronate 60-90 mg over 4 hours (initiating dose depends on albumin-corrected serum calcium concentration).
    • Paracetamol should be taken before and after IV bisphosphonate treatment to reduce the severity of potential flu-like symptoms that may be caused
    • In cases of acute life-threatening hypercalcaemia, parenteral calcitonin salmon (salcatonin) may used in addition to IV bisphosphonates for more rapid calcium concentration correction. Salcatonin is diminishingly effective and generally ineffectual after several days of use. Salcatonin treatment is calcitonin salmon (salcatonin) 100 IU SC, IM or IV, every 8 to 12 hours
  • Glucocorticoids: may be needed in cases of refractory hypercalcaemia caused by malignancy, sarcoidosis, or vitamin D toxicity.

Vitamin D toxicity-mediated hypercalcaemia

  • Glucocorticoids: may be required conjointly with rehydration to treat severe or protracted vitamin D toxicity. Treatment is oral prednisone/prednisolone 30-60 mg/day (initiating dose depends on albumin-corrected serum calcium concentration).
    • Therapy should be continued until calcium levels are within normal range and hypercalciuria is substantially decreased. Dose must be tapered at withdrawal to avoid adrenal insufficiency

Granulomatous disorder-mediated hypercalcaemia

  • Glucocorticoids: are generally required in cases of hypercalcaemia caused by granulomatous disorders. This is to address inappropriate extramural production of 1.25-dihydroxyvitamin D. Treatment is oral prednisone/prednisolone 15-30 mg/day (initiating dose depends on albumin-corrected serum calcium concentration).
    • Therapy should be continued until calcium levels are within normal range and hypercalciuria is substantially decreased. Dose must be tapered at withdrawal to avoid adrenal insufficiency

References

Amboss. (2022, September 19). Hypercalcemia – Knowledge @ amboss. Amboss. Retrieved February 28, 2023, from https://www.amboss.com/us/knowledge/Hypercalcemia/

Assessment of hypercalcaemia. Assessment of hypercalcaemia – Differential diagnosis of symptoms | BMJ Best Practice. (n.d.). Retrieved March 3, 2023, from https://bestpractice.bmj.com/topics/en-gb/159

Bertero, E., & Maack, C. (2018). Calcium signaling and reactive oxygen species in mitochondria. Circulation Research, 122(10), 1460–1478. https://doi.org/10.1161/circresaha.118.310082

Desai, R., & Marshall, T. (n.d.). Hypercalcemia | Osmosis. Osmosis. Retrieved February 28, 2023, from https://www.osmosis.org/learn/Hypercalcemia

eTG. (n.d.). Therapeutic guidelines > therapeutic guidelines: Therapeutic guidelines. Therapeutic guidelines > Therapeutic Guidelines | Therapeutic Guidelines. Retrieved February 28, 2023, from https://tgldcdp.tg.org.au/searchAction?appendedinputbuttons=electrolyte+abnormalities

Hypercalcaemia of Malignancy (HCM). eviQ. (2022, December 15). Retrieved March 3, 2023, from https://www.eviq.org.au/clinical-resources/oncological-emergencies/486-hypercalcaemia-of-malignancy-hcm

Shane, E., Rosen, C. J., & Mulder, J. E. (2022, November 10). Diagnostic approach to hypercalcemia . UpToDate. Retrieved March 3, 2023, from https://www.uptodate.com/contents/diagnostic-approach-to-hypercalcemia

Shane, E., Rosen, C. J., & Mulder, J. E. (2022, April 8). Treatment of hypercalcemia. UpToDate. Retrieved March 3, 2023, from https://www.uptodate.com/contents/treatment-of-hypercalcemia

 

 

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