Question 5.1

A 27-year-old patient presents with the following laboratory results after a prolonged sub-acute illness.

Parameter	Patient Value	Adult Normal Range
Sodium	132 mmol/L*	135 – 150
Potassium	2.2 mmol/L*	3.5 – 5.5
Chloride	94 mmol/L*	100 – 110
Bicarbonate	28 mmol/L*	22 – 27
Urea	8.3 mmol/L*	3.0 – 8.0
Creatinine	236 μmol/L*	70 – 120
Total Calcium	5.04 mmol/L*	2.15 – 2.60
Ionised Calcium	2.6 mmol/L*	1.1 – 1.3
Magnesium	0.7 mmol/L	0.7 – 1.1
Phosphate	1.09 mmol/L	0.70 – 1.40
Albumin	37 g/L	35 – 47
Total Bilirubin	8 μmol/L	4 – 20
g-Glutamyl transferase	105 U/L*	0 – 50
Alkaline phosphatase	263 U/L*	40 – 110
Alanine transferase	76 U/L*	< 40
Aspartate transferase	48 U/L*	< 40

a) List the ECG changes associated with the most striking biochemical abnormalities. (10% marks)

b) List three differential diagnoses. (15% marks)

c) List three management strategies. (15% marks)

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College answer

Not available.

Discussion

The biochemical abnormalities which are the most "striking" here are the hypokalemia and hypercalcemia.

ECG changes of severe hypokalemia are:
- PR interval prolongation (>200 msec)
- P wave amplitude increased (>2.5 mm in limb leads, >1.5 mm in chest leads)
- P wave width increased (>120 msec)
- u-waves
- T-wave inversion
- Ectopics (ventricular and atrial)
ECG changes of hypercalcemia are:
- Shortened QT interval
- Osborn waves, notches in the end of the QRS complex (similar to those seen in hypothermia)
- Weird-looking QRS complexes

What could be happening here? And more importantly, what meaning can we scry from the decision to call this illness both "prolonged" and "sub-acute"? It sometimes helps to itemise the abnormalities. They are:

Mild hyponatremia
Severe hypokalemia
Hypochloraemia and alkalosis
Severe hypercalcemia
Renal failure, where the ratio of urea to creatinine suggests there is no problem with volume
Mildly deranged LFTs, with a mixed pattern leaning in the direction of cholestasis

So:

Malignancy is a strong differential:
- Hypercalcemia and LFT derangement are explained by cancer (ectopic PTH secretion, bony and liver metastases),
- Hypokalemia and metabolic alkalosis are explained by hypercalcemia, which has a frusemide-like effect on the loop of Henle (Riccardi & Brown, 2010)
Milk-alkali syndrome (hypercalcemia, metabolic alkalosis, acute kidney injury - assuming the creatinine is acutely elevated)
Tertiary hyperparathyroidism (but does not explain the LFT derangement, and the renal failure is really not severe enough, and you'd expect the phosphate to be more abnormal)
Something extra weird, like sarcoidosis, Vitamin D oversupplementation, or even Bartter or Gitleman syndrome combined with primary hyperparathyroidism (which can present in this exact way)

List three management strategies. But for which disorder? You have three differential diagnoses. Do they mean a management strategy for each of the differentials, or three management strategies for the most likely differential? In which case, what if you chose poorly? Reader, it is safest to assume that the severe hypercalcemia is what they were asking about here, considering that the management strategies for the hypokalemia will largely consist of potassium replacement, and to test this spinal reflex couldn't possibly have been the objective of a final-level exam question.

So, the management options for hypercalcemia are:

Dilute serum calcium
- Rehydration with IV fluids
Decrease calcium resportion from bone
- Calcitonin
- Bisphosphonates
- Gallium nitrate
- Mithramycin (for malignant disease)
Decrease calcium resportion from renal tubule
- Loop diuretics (this has fallen out of favour)
- Calcitonin
Decrease calcium absorption from the gut
- Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
Forcibly remove excess calcium from the circulation
- Haemodialysis
- EDTA administration (as chelating agent)

References

Riccardi, Daniela, and Edward M. Brown. "Physiology and pathophysiology of the calcium-sensing receptor in the kidney." American Journal of Physiology-Renal Physiology 298.3 (2010): F485-F499.

Beall, Douglas P., et al. "Milk-alkali syndrome: a historical review and description of the modern version of the syndrome." The American journal of the medical sciences 331.5 (2006): 233-242.

Van Der Plas, W. Y., et al. "Secondary and tertiary hyperparathyroidism: a narrative review." Scandinavian Journal of Surgery 109.4 (2020): 271-278.

Bukowczan, J., et al. "Gitelman’s syndrome presenting with hypercalcaemia due to severe primary hyperparathyroidism." Endocrine Abstracts. Vol. 29. Bioscientifica, 2012.

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