Calcium Metabolism

The adult body contains approximately 1kg of Ca2+ ions (Ca2+) (25,000mmol) with over 99% bound in the skeleton. The 70 kg male contains approximately 22.5mmol of Ca2+ in extracellular fluid, of this only 9% is in plasma.

Normal range

 

 

 

 

 

 

Measurement

The measurement of ionised Ca2+ in plasma is difficult and not routine practice.

Formula

Total plasma Ca2+ is corrected for protein binding by adding or subtracting 0.02mmol/l for every gram of albumin measured concurrently above or below 40g/l. Formula: [Ca] +/- 0.02 (40 – albumin)

Corrected calcium (mmol/L) = measured total calcium (mmol/L) + 0.02 (40 – serum albumin [g/L]), where 40 represents the average albumin level in g/L.

In other words, each 1 g/L decrease of albumin, will raise 0.02 mmol/L in serum Ca.

When there is hypoalbuminemia (a lower than normal albumin), the corrected calcium level is higher than the total calcium. The formula is shown below:

[Ca] + 0.02 (40 – albumin)

Thus, when there is a higher than normal albumin, the corrected calcium level is lower than the total calcium. The formula is shown below:

[Ca] – 0.02 (40 – albumin)

Learning Bite:

Calcium samples are ideally taken when the patient is fasting. Samples should always be taken without the tourniquet as this increases plasma protein measurement and alters values.

Definition

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.

Systemic:

• Tiredness, malaise, dehydration and depression

Renal:

• Stone formation
• Polyuria loss concentrating ability nephron
• Nocturia
• Haematuria
• Hypertension

Bone:

• Bone Pain

Abdomen :

• pain
• vomiting, constipation
• decreased appetite
• examination mimics peptic ulcer or pancreatitis

Calcification:

• Corneal calcification
• Chondrocalcinosis
• Ectopic calcification

Signs

Abdominal tenderness, constipation, weakness, cognitive difficulty, hypertension, bony pain and tenderness.

Risk stratification

Causes of hypercalcaemia

Associated diseases

Osteoporosis

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.

Pagets disease

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

Plasma phosphate

• 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

Urinary calcium

• 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

25-hydroxyvitamin D

• 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

Plain radiography

• Used to visualise fractures and can reveal specific metabolic disorders of calcium e.g. Pagets, osteoporosis

Technetium scanning

• Can reveal increased bone activity in fracture, infection, metastatic bone disease

MRI

• 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.

Treatment

Rehydrate

• 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.

Bisphosphonates

• 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

Calcitonin

• 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

Prednisolone

• Usually only slightly helpful in myeloma and sarcoid but is not of great use most often

Oral phosphate

• Can be used but intravenous is dangerous

Furosemide

• 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

• 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

1. Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ. 2008 Jun 7;336(7656):1298-302. doi: 10.1136/bmj.39582.589433.BE. Erratum in: BMJ. 2008 Jun 28;336(7659).
2. Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med. 2004 Apr;32(4 Suppl):S146-54.
3. Marshall WJ Bangert S Clinical Chemistry Fifth Edition London Mosby 2004.
4. Inzucchi SE Understanding Hypercalcaemia Postgraduate Medicine Volume 115 No 4 April 2004.
5. Sarko J. Bone and mineral metabolism. Emerg Med Clin North Am. 2005 Aug;23(3):703-21, viii.
6. Shepard MM and Smith JS Hypercalcaemia American Journal Medical Sciences November 2007 Volume 334 Number 5 382-385.
7. Taneigra ED Hyperparathyroidism American Family Physician January 15 2004 Volume 69 No 2 p 333-337.
8. Uptodate.com Treatment of hypercalcemia Authors – Elizabeth Shane, MD James R Berenson, MD