Author: Andrew Parfitt / Editor: Steve Fordham / Reviewer: Shanthi Siva / Codes: HAP21 / Published: 18/09/2017 / Review Date: 18/09/2020
The adult body contains approximately 1 kg of Ca2+ (25,000 mmol). The vast majority, over 99%, is bound in the skeleton.
The 70 kg male contains only 9 mmol in his plasma, part of approximately 22.5 mmol in the extracellular fluid in total.
The normal range of calcium in plasma is 2.2-2.6 mmol/l. 40% is ionised and is the physiologically active component, whilst the remainder is complexed ( with citrate and phosphate) or protein bound mainly to albumin.
The measurement of ionised Ca2+ in plasma is difficult and not routine practice.
Total plasma Ca2+ is corrected for protein binding by adding or subtracting 0.02 mmol/l for every gram of albumin measured concurrently above or below 40 g/l.
Calcium samples are ideally taken when the patient is fasting but always without the tourniquet as this increases plasma protein measurement and alters values.
The therapeutic uses of calcium will be examined and the disturbances of hypo and hypercalcaemia will be discussed. Readers are referred to the unit on Hypercalcaemia in Malignancy.
Hypercalcaemia is said to be present when serum calcium is > 2.6 mmol/l.
Hypocalcaemia is said to be present when serum calcium is < 2.2 mmol/l.
Remember both of these values are subject to correction for albumin level.
For hypercalcaemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load.
Mild hypercalcaemia < 3 mmol/l is frequently asymptomatic as levels rise a number of features are often present.
Hypercalcaemia causes ECG changes
Hypercalcaemia may produce ECG abnormalities related to altered trans-membrane potentials that affect conduction time. QT interval shortening is common, and, in some cases, the PR interval is prolonged. At very high levels, the QRS interval may lengthen, T waves may flatten or invert, and a variable degree of heart block may develop. Digoxin effects are amplified.
- Tiredness, malaise, dehydration and depression
- Stone formation
- Polyuria loss concentrating ability nephron
- Bone Pain
- vomiting, constipation
- decreased appetite
- examination mimics peptic ulcer or pancreatitis
- Corneal calcification
- Ectopic calcification
Abdominal tenderness, constipation, weakness, cognitive difficulty, hypertension, bony pain and tenderness.
Causes of hypercalcaemia
This is a disease of bone characterised by low bone mass and micro-architectural deterioration of bone tissue. Bone is normally mineralised but deficient in quantity, quality and structural integrity. Oestrogen deficiency is a factor in both male and female. In the elderly Vitamin D insufficiency, and secondary hyperparathyroidism may cause. Dual energy absorptiometry is diagnostic. Lifestyle advice (exercise, diet) and alendronate (bisphosphonates inhibit osteoclast resorption) may be used to decrease the risk of hip and non vertebral fractures. Raloxifene has established efficacy in decreasing the risk of vertebral fractures. Calcium and vitamin D supplementation are also required.
Osteomalacia and Rickets
These disorders result from inadequate mineralisation of the bone matrix. Usually there is a defect in vitamin D metabolism. They can occur secondary to chronic renal failure.
Bone pain, tenderness and pathological fracture can occur. Proximal myopathy produces a waddling gait. Hypocalcaemic tetany is possible in severe cases.
A focal disorder of bone remodelling, initial excessive resorption is followed by excessive new bone formation. The new bone is structurally abnormal. The majority of cases defined by x-ray are asymptomatic. Common sites include the pelvis, skull, femur and spine. Cardiac hypertrophy and high output failure occur. Symptoms include bone pain, nerve compression and deformities with pathological fractures. Changes are shown in diagnostic section. Bisphosphonates are the mainstay of treatment.
Total plasma calcium
- Reference range is 2.2-2.6 mmol/l
- Reference range is 0.8-1.4 mmol/l
- Essential to biological systems
- Levels are low in primary hyperparathyroidism
- High levels are found in renal failure and hypoparathyroidism
- Normal range 2.5-7.5 mmol/24h
- Clearly increased in hypercalcaemia and where renal absorption is decreased
- In familial hypocalciuric hypercalcaemia, urinary Ca2+ is inappropriately low with high serum calcium levels
- In clinical practice the relevance of urinary calcium collection is in the investigation of renal colic patients
Parathyroid hormone measurement (PTH)
- Raised levels of PTH are found in:
- Primary, secondary and tertiary hyperparathyroidism
- Familial hypocalciuric hypercalcaemia
- Lithium toxicity
- PTH levels should be decreased in hypercalcaemia due to other causes
- Serum 25-OHD levels allow determination of vitamin D status in the body
- Vitamin D insufficiency or deficiency is usually associated with increase in serum PTH
- Used to visualise fractures and can reveal specific metabolic disorders of calcium e.g. Pagets, osteoporosis
- Can reveal increased bone activity in fracture, infection, metastatic bone disease
- Allows detailed subchondral bone assessment
- Acute hypercalcaemia is a medical emergency.
- Hypercalcaemia in the malignant patient is described in a separate article.
- Immediate treatment is mandatory above a serum level of 3.5 mmol/l.
- Coexistent diseases should clearly be treated.
- Rehydration, even orally, enhances calcium excretion
- Several litres of normal saline may be required. Pay strict attention to balance and consider CVP monitoring. Continuous ECG monitoring and regular 12 leads will be required.
- Useful in malignancy and other aetiologies Pamidronate is the most commonly used. Commonly they take 2-4 days to take effect. Zolendronic acid,ibandronate with pamedronate
- Reduces serum calcium by increasing renal calcium excretion and by decreasing bone resorption with osteoclast formation. It works rapidly by decreasing serum calcium within 4-6 hrs. Its efficacy is limited to first 48 hrs. It works well in combination with bisphosphonates and hydration
- Usually only slightly helpful in myeloma and sarcoid but is not of great use most often
- Can be used but intravenous is dangerous
- Can be used to increase renal excretion of calcium and, rarely, dialysis is required to remove calcium. Renal and cardiac failure patients will require dialysis as they are unable to cope with the large volumes required
Safety pearls and Pitfalls
- Remember the diagnosis of hypercalcaemia is most often made on asymptomatic patients during routine analysis
- Remember to remove the tourniquet prior to venesection to avoid elevation of calcium
- Urgent rehydration is required in acute hypercalcaemia which is an emergency
- Hypercalcaemia in 90% cases is due to hyperparathyroidism or malignancy; these must be ruled out early in a work up
- Severe dehydration can elevate albumin and hence calcium levels. Remember to correct for albumin elevation
- Never prescribe corticosteroids prior to proper evaluation of hypercalcaemia
- Never prescribe furosemide without ensuring adequate hydration
- Symptomatic hypocalcaemia requires immediate treatment. Established tetany and seizures will require intravenous replacement
- Remember iv calcium chloride causes problems when extravasation occurs. Slow infusion is necessary owing to the small serum pool of calcium and hypercalcaemia is easily caused
- Parenteral calcium therapy is contraindicated in patients receiving cardiac glycosides. Give cautiously to patients with impaired renal function, cardiac disease, or sarcoidosis
- Consider hypercalcaemia in patients with multiple nonspecific complaints and an associated lung mass
- Severe elevations in calcium levels may cause coma
- Elderly patients are more likely to be symptomatic from moderate elevations of calcium levels
- Hypercalcaemia of malignancy may lack many of the features commonly associated with hypercalcaemia caused by hyperparathyroidism. In addition, the symptoms of elevated calcium level may overlap with the symptoms of the patients malignancy
- Hypercalcaemia associated with renal calculi, joint complaints and ulcer disease is more likely to be caused by hyperparathyroidism
- Cooper S, Gittoes N. Diagnosis and management of hypocalcaemia. BMJ 2008;336:1298-1302.
- Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med 2004;32(4):S146-S157.
- Marshall WJ, Bangert S. Clinical Chemistry. 5th edn. London: Mosby, 2004.
- Inzucchi SE. Understanding hypercalcemia. Its metabolic basis, signs, and symptoms. Postgrad Med 2004;115(4):69-70.
- Sarko J. Bone and mineral metabolism. Emerg Med Clin North Am 2005;23:703-721.
- Shepard MM, Smith JS. Hypercalcaemia. Am J Med Sci 2007;334(5):382-385.
- Taneigra ED. Hyperparathyroidism. Am Fam Physician 2004;69(2):333-337.
- Uptodate.com Treatment of hypercalcemia Authors – Elizabeth Shane, MD James R Berenson, MD