Hypocalcemia

Created on Thu, 06/25/2015 - 17:55
Last updated on Thu, 06/15/2017 - 18:44

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This has come up many times in the exam:

  • Question 7.1 from the first paper of 2014 (guess that the post-op patient's problems are all due to parathyroid surgery)
  • Question 9 from the second paper of 2013 (list four causes)
  • Question 25.1 from the second paper of 2010 (the parathyroid surgery patient again - identical to Question 7.1 from the first paper of 2014)
  • Question 25 from the second paper of 2006 (list five causes and three clinical manifestations)

Oh's Manual has dedicated a small paragraph to hypocalcemia, which is inadequate for CICM SAQ preparation. As the SAQs generally trend towards the "list six kinds of something" questions, the following summary is in the form of easily memorised lists. It has been derived largely from two good articles from the BMJ, one by Cooper and Gittoes (2008) and the other by Hannan and Thakker (2013). Both are too long even for the casual reader; the time-poor exam candidate may wish to limit themselves to the excellent summary from LITFL.

Causes of hypocalcemia

The causes of hypocalcemia can be divided into those which are caused by a low parathyroid hormone, and those which feature a normal parathyroid hormone level.

Causes of Hypocalcemia

Low  Parathyroid Hormone

  • Primary hypoparathyroidism (i.e. destruction of the parathyroid glands)
    • Surgical: post-operative hypoparathyroidism
    • Autoimmune
    • Storage disease, eg. haemochromatosis or Wilsons'\
    • HIV infection
  • Dysregulation of PTH secretion
    • Congenital
    • Hypomagnesemia
    • Sepsis

 

High or normal Parathyroid hormone

Vitamin D deficiency

  • "True" deficiency (i.e. malabsorption or inadequate UV light)
  • Insufficient synthesis (eg. renal failure)

Altered protein binding

  • Alkalosis

PTH resistance

  • Hypomagnesemia

Chelation or depletion

  • Hyperphosphataemia
  • Tumour lysis syndrome (which causes hyperphosphataemia)
  • Acute pancreatitis
  • Depletion in coagulopathy
  • Consumption by osteoclastic bone metastases

Drugs

  • Phenytoin
  • Fluoride toxicity
  • Foscarnet
  • EDTA
  • Citrate
  • Phosphate
  • Bisphosphonates

Question 9 from the second paper of 2013 asked specifically for four causes of ionised  hypocalcemia, which may have led some of the candidates to discuss situations where ionised calcium is low in the presence of a normal total calcium. Of course, that would be a very short list. Ionised hypocalcemia in isolation is rare. It is seen in only one scenario: citrate toxicity. When citrate is used to chelate calcium, the total calcium is normal, but the ionised fraction is low. This is because measurement instruments which detect calcium will also measure citrate-calcium complexes in the serum, but the electrode which measures ionised calcium will only measure the free fraction, which decreases with citrate chelation.

Investigations for hypocalcemia

If one goes by the table above, parathyroid hormone measurement is central to the diagnosis. However, other tests are also helpful. The following list of tests needs to be regurgitated if the college ever ask to "suggest a list of investigations":

  • PTH
  • Serum 25-hydroxyvitamin D
  • Magnesium level
  • Phosphate level
  • Urea and creatinine
  • Amylase and lipase

Serum PTH helps discriminate where the disorder is coming from. Low parathyroid levels are the opposite of what is supposed to happen in hypocalcemia: PTH is supposed to be secreted in response to hypocalcemia, to increase bone resorption and decrease renal excretion (among other things). Ergo, if the patient is hypocalcemic and the PTH is low, something is horribly wrong with the way the PTH is being excreted. This could be due to a number of causes. For instance, there may have been some sort of surgical destruction of the parathyroid glands, as in the favoured CICM SAQ. Alternatively, PTH secretion may have been suppressed,  as in sepsis where the parathyroid glands are suppressed by inflammatory cytokines, or in the case of low magnesium levels (the serum magnesium needs to be below 0.4mmol/L). Lastly, the secretion of PTH may be dysregulated by some sort orf congential mutation of the PTH regulatory pathway.

A raised PTH is a normal reaction to low calcium, which assures you that the parathyroid glands are intact and functioning normally. The question then is, why is the calcium still low?

Serum 25-hydroxyvitamin D  should be the next investigation. Vitamin D deficiency is a very common cause of hypocalcemia. In turn, the commonest causes of Vitamin D deficiency are renal failure, dietary deficiency and lack of UV light. For this reason, urea and creatinine should be tested. Realistically, in the ICU you will be aware of renal function long before the vitamin D levels are available.

Hypomagnesemia can cause both depressed PTH secretion and impaired tissue response to PTH; the sustained level required for this effect is below 0.4mmol/L

Hyperphosphataemia can be associated with low calcium; generally speaking primary hypoparathyroid disorders are associated with a raised serum phosphate. In turn, secondary hyperparathyroidism (eg. in Vitamin D deficiency) are associated with a low phosphate. High phosphate will also chelate calcium, forming insoluble calcium phosphate, but because it is insoluble it is not measurable by normal means and therefore is unlikely to show up in the tests.

Clinical features of hypocalcemia

Clinical Manifestations of Hypocalcemia

Mild hypocalcemia

  • Generalised myalgia
  • Twitching, fasciculations
  • QT prolongation
  • Chvostek’s sign
  • Confusion, delirium, psychosis

Severe hypocalcemia

  • Carpopedal spasm (Trousseau’s sign)
  • Tetany and seizures
  • Papilloedema, raised intracranial pressure
  • Cardiac arrhythmias, esp. Torsades
  • Hypotension

 

References

UpToDate has a nice summary of this topic for the paying customer.

Cooper, Mark S., and Neil JL Gittoes. "Diagnosis and management of hypocalcaemia." BMJ: British Medical Journal 336.7656 (2008): 1298.

Tohme, J. F., and J. P. Bilezikian. "Hypocalcemic emergencies." Endocrinology and metabolism clinics of North America 22.2 (1993): 363-375.

Diercks, Deborah B., et al. "Electrocardiographic manifestations: electrolyte abnormalities." The Journal of emergency medicine 27.2 (2004): 153-160.

Hannan, Fadil M., and Rajesh V. Thakker. "Investigating hypocalcaemia." BMJ 346 (2013): f2213.