Have seen a few patients with hypercalcemia recently and it has gotten me thinking. It is one of those areas of medicine where the complex endocrine physiology and diseases can seem a bit overwhelming. When we approach it in a practical sense it is much simpler than the head-spinning Med school lectures left us believing!
So lets break it down.
How high is high? The normal range for calcium in plasma is 2.2 – 2.6 mmol/l, however it is common to find “asymptomatic” mild hypercalcemia. I put asymptomatic in parentheses as the symptoms of early hypercalcemia can be very subtle, vague or easily mistaken for other diseases.
Generally hypercalcemic patients are consistently symptomatic at levels > 3.0 mol/l. Once one gets up above 3.5 mmol/l the more severe symptoms occur – this is an emergent situation.
Symptoms of hypercalcemia:
Increased gastrin output can lead to peptic ulcer disease.
Causes of hypercalcemia
Pick up any medical textbook and you will find a long list of causes of hypercalcemia (same with pancreatitis).
However, in reality the list is pretty simple. There are 2 big causes, one lesser and then daylight until the small print causes.
Very rarely a malignant parathyroid tumour.
Adenomas may occur in the context of MEN-1 syndrome (pituitary, gastric (ZE) and pancreatic neoplasia.
Parathyroid tumours also form part of MEN2a (phaeo, thyroid medullary carcinoma)
Tumours with humoral-mediation via a PTH-related peptide include lung and renal cancers
Haematological malignancy: multiple myeloma, leukemias and lymphomas.
Hypercalcemia in the setting of known malignancy is usually easier to diagnose, though on occasion can be the presenting symptom of a malignancy
Lithium toxicity results in excessive PTH – hence a picture more like primary hyperPTH.
Thiazide diuretics and excessive thyroxine replacement can increase bone turnover and hence lead to high Ca.
Sarcoidosis also causes hypercalcemia through excessive Vit D activity
Severe secondary hyperparathyroidism can occur in chronic renal failure – as Hildy has reminded me – it is the tertiary hyperPTH that causes the hypercalcemia in chronic renal failure
Aluminum intoxication can cause raised Ca in dialysis
Management of Hyperclacemia
The management of hypercalcemia does to some extent depend on the underlying cause, however most of the causes are not readily remediable in the acute sense – hence we have treatments which can be applied to get the calcium down until the smart docs arrive and work out what is going on! Often the cause is readily apparent on the previous history – cancer, known endocrine disease, renal failure etc. So here is a quick skim through the management of hypercalcemia in the acute setting.
Normal saline has been he traditional fluid used in this setting. Not much evidence to confirm or repute this practice and I imagine other IV fluids would also work – one needs to replace the lost electrolytes also – and this requires individualised monitoring. Fluid resuscitation alone will not likely reduce the calcium level much – so this is really a resuscitative measure.
Largely this is because frusemide has little or no evidence base to show it helps and the introduction of newer, proven effective agents mean there is little role for this potentially harmful intervention. So in my practice I think I would prefer to use a drug that works, rather than one that might or might not be effective.
The main agents used are pamidronate and zoledronic acid – they are pretty safe and well tolerated – the one big risk is the development of osteonecrosis of the jaw in ongoing use. They are usually given as an infusion – ZA quickly, pamidronate slower.
So I think this one fits in as a front line agent in severe hypercalcemia where you want to get it down fast.
Hydrocortisone can be given IV in the acute setting
There are really only 2 indications for this drug:
(1) secondary PTH in renal failure and
(2) in primary PTH adenomas where surgery is not an option or malignant adenocarcinoma is responsible for the excess PTH.