Hypercalcaemia
Hypercalcaemia is a disorder of calcium homeostasis characterised by high levels of calcium (free calcium > 1,30 mmol/L). It's a relatively common electrolyte abnormality and is the opposite of hypocalcaemia.
| Hypercalcaemi | |
|---|---|
| Definition | Free calcium > 1,30 mmol/L |
| Symptoms | Gastrointestinal symptoms, non-specific symptoms, polyuria, altered mental status |
| Complications | Acute pancreatitis, nephrocalcinosis, diabetes insipidus, peptic ulcer |
| Causes | Parathyroid adenoma, malignancy |
| Treatment | IV hydration, bisphosphonates, calcitonin |
A free calcium level of > 2,00 is sometimes called a hypercalcaemic crisis.
99% of the body's calcium is in the bones. The remaining 1% is in the blood. 40% of calcium in the serum is bound to albumin, 10% is bound to other anions (lactate and citrate), and the remaining 50% exists as free calcium ions (Ca2+) in the serum. It is the free calcium which is biologically active and therefore is used to diagnose hypercalcaemia. Bound calcium is inactive.
Grading of severity
Hypercalcaemia isn't really graded into "mild", "moderate", and "severe" in most sources, instead only using 1,30 mmol/L as the border between normal and abnormal. However, here is one source's grading:
| Free calcium level | Total calcium level | Severity |
|---|---|---|
| 1,30 - 1,50 | 2,5 - 3,00 | Mild |
| 1,50 - 1,70 | 3,00 - 3,50 | Moderate |
| 1,70 - 2,00 | > 3,50 | Severe |
| > 2,00 | Hypercalcaemic crisis |
Etiology
Hypercalcaemia can be secondary to hyperparathyroidism or it can be secondary to other causes. The most common causes (90% of cases) are primary hyperparathyroidism (causes mild hypercalcaemia) and malignancy (causes more severe hypercalcaemia).
- Hyperparathyroidism
- Primary hyperparathyroidism (due to parathyroid adenoma)
- Tertiary hyperparathyroidism (due to long-standing chronic kidney disease)
- Unrelated to hyperparathyroidism
- Malignancy (paraneoplastic syndrome)
- Vitamin D intoxication
- Granulomatous disorder (sarcoidosis)
- Drugs (lithium, thiazides)
In chronic kidney disease, calcium is lost during diuresis, causing hypocalcaemia or normocalcaemia with a compensatory parathyroid hyperplasia causing secondary hyperparathyroidism. However, in some long-standing cases of CKD, the parathyroid hyperplasia may progress regardless of calcium levels. This is called tertiary hyperparathyroidism.
Many malignancies are associated with hypercalcaemia, through multiple mechanisms. The most common mechanism is paraneoplastic syndrome due to secretion parathyroid hormone-related protein (PTHrP) by the tumour. Lytic bone metastases can also release calcium from bone. In multiple myeloma, other osteoclast-stimulating factors than PTHrP are secreted.
Vitamin D intoxication is usually accidental, but certain malignancies and granulomatous disorders like sarcoidosis can cause hypercalcaemia by increased production of 1,25-dihydroxyvitamin D.
Drugs are a rare cause of hypercalcaemia alone, but use of lithium or thiazides, which increase PTH secretion and inhibit urinary excretion respectively, may be the sole etiology in mild cases.
Pathomechanism
Hypercalcaemia decreases neuromuscular excitability and inhibits myocardial depolarisation. It also impairs the kidney's ability to concentrate urine, by reducing the kidney's response to vasopressin.
Clinical features
The symptoms of hypercalcaemia have long been remembered by the phrase "groans, bones, moans, thrones, and psychiatric overtones".
Groans refer to abdominal pain, which can be accompanied by nausea and vomiting.
Bones refer to bone pain.
Stones refer to kidney stones, which may cause renal colic.
Moans refer to fatigue and malaise.
Thrones, as in sitting on a toilet throne (it wasn't me who came up with these I swear) refer to polyuria and constipation. There may also be polydipsia.
Psychiatric overtones refers to symptoms of encephalopathy, including lethargy and confusion.
Diagnosis and evaluation
Different ways to report calcium levels
There are three different ways the laboratory can report a patient's calcium levels.
| Advantage | Disadvantage | Reference range | |
|---|---|---|---|
| Total calcium | Easy to measure | Inaccurate estimate of free calcium in case of abnormal albumin levels, abnormal parathyroid levels, surgery, blood tranfusion, multiple organ failure, acid-base disorder | 2.1 - 2.5 mmol/L |
| Albumin-corrected calcium | Easy to measure and calculate | Even more inaccurate estimate of free calcium in case of abnormal albumin levels | 2.18 - 2.45 mmol/L |
| Free calcium | The gold standard | Requires special sample taking, sample must be cooled, must be processed quickly after sample taking, expensive | 1.15 - 1.28 mmol/L |
As already stated, only the free calcium matters, and this is therefore the gold standard for diagnosis of calcium disorders. However, measuring the free serum calcium is more difficult (see the table) and more expensive than measuring total calcium.
Because 50% of calcium in the serum is free, one would assume one could simply halve the total calcium value to get the free value. However, as evident from the table, this relationship can change in many cases, most notably in case of hypoalbuminaemia. As such, total calcium levels does not always provide an accurate estimate of the free calcium level. In the absence of the aforementioned complicating factors, total calcium is good enough to evaluate the calcium level.
A formula was developed to "correct" the total calcium level in case of hypoalbuminaemia. This formula, which the lab often calculates for you and reports as a separate, "albumin-corrected" calcium, unfortunately performs poorly clinically and has actually been shown to be a worse estimator of free calcium level than the uncorrected total calcium level. This formula overestimates the total calcium level and may therefore give a false diagnosis of hypercalcaemia or mask hypocalcaemia. Its use should therefore be avoided and free calcium should be measured instead.
Checking the heart
Hypercalcaemia can cause QT shortening, so ECG is indicated.
Determining the cause
Measurement of PTH is obligatory as it can help determine the cause. The presence of hyperparathyroidism means a diagnosis of primary hyperparathyroidism is most likely. If the PTH is low, malignancy is the most likely cause and must be ruled out. PTHrP and 1,25-dihydroxyvitamin D should be measured. If PTHrP is elevated, the patient should undergo evaluation for malignancy. If it's negative and 1,25-dihydroxyvitamin D is elevated, granulomatous disease should be ruled out.
Management
Asymptomatic or mildly symptomatic hypercalcaemia does not require treatment. Severe hypercalcaemia or hypercalcaemia with severe symptoms requires treatment.
IV fluids help normalise hypercalcaemia, as it corrects any concomitant hypovolaemia and increases renal excretion of calcium. Calcitonin and a bisphosphonate may also be administered in more severe cases. Bisphosphonates has a long-lasting inhibitory effect on osteoclast activity but takes 2-3 days to kick in. Calcitonin works within 6 hours but the effect is transient. In the most severe cases, renal replacement therapy is required.
Complications
Hypercalcaemia, especially chronic, can cause many complications:
- Acute pancreatitis
- Peptic ulcer disease
- Nephrogenic diabetes insipidus (by impairing the kidney's response to vasopressin)
- Nephrocalcinosis
- Deposition of calcium in the heart
Arrhythmias are not typical for hypercalcaemia but may occur in severe cases.