Question 5.1

Highest mark

8.2

A 62-year-old female with a history of obstructive sleep apnoea (OSA) is admitted to your ICU for monitoring after an orthopaedic procedure. The results of her routine post-operative blood tests are given below:

Parameter	Patient Value	Adult Normal Range
Sodium	144 mmol/L	135 – 145
Potassium	4.0 mmol/L	3.5 – 4.5
Bicarbonate	24 mmol/L	22 – 26
Urea	8.7 mmol/L*	3.0 – 8.0
Creatinine	88 μmol/L	45 – 90
Total Calcium	3.00 mmol/L*	2.15 – 2.55

List four likely aetiologies for the hypercalcaemia. (20% marks)

List four other specific blood tests you would order to investigate the cause.

(20% marks)

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College answer

Primary hyperparathyroidism
Malignancy (including myeloma)

Note 1) and 2) are the two commonest causes accounting for 90% cases. 0.5 mark for each of these

For the two other causes, any of:

Vitamin D toxicity
Granulomatous disorders (e.g. sarcoid)
Medications (Thiazides, Lithium etc)
Factitious (high albumin, dehydration)
Hyperthyroidism
Acromegaly
Phaeochromocytoma
Adrenal Insufficiency

Or any other recognised cause consistent with the stem.

Albumin OR ionised calcium
PTH
Vitamin D metabolites
PTH related protein
Tests for a specific cause – e.g. Thyroid function tests, Serum ACE etc.

Discussion

What are the most likely causes of this hypercalcemia? What do we know about the patient?

Middle-aged
Female
OSA
Needed some sort of bone surgery
Totally normal bloods, apart from calcium

The OSA story begs the question, is a large thyroid gland or retrosternal goitre causing the obstruction? Even weirder is the association between OSA and raised PTH levels, thought to be due to Vitamin D deficiency (Krasimirova et al, 2017). Anyway: the college examiners, in a rare paroxysm of assessment transparency, offered us the marking rubric for this question, and they clearly wanted the trainees to unfocus from the question stem and just give the most common community-prevalent causes of hypercalcemia. In fact, in their 2003 article, Carroll & Schade specifically state that "primary hyperparathyroidism and malignancy account for more than 90 percent of hypercalcemia cases". Other possible causes are listed below:

Causes of Hypercalcemia, by Pathophysiology
Primary endocrine causes Primary hyperparathyroidism Thyrotoxicosis Adrenal insufficiency Paraneoplastic causes PTH-related protein carcinoma of lung oesophageal carcinoma head and neck SCC renal cell carcinoma Breast cancer Ovarian cancer Bladder cancer Ectopic 1,25-dihydroxyvitamin D Lymphoma Lytic bone lesions Multiple myeloma Breast cancer Hematological malignancies Phaeochromocytoma VIP-secreting gastric adenoma	Granulomatous disease Sarcoidosis HIV Tuberculosis Histoplasmosis Coccidioidomycosis Leprosy Drug-induced hypercalcemia Vitamin D oversupplementation Thiazide diuretics Lithium carbonate Oestrogens and HRT Androgens Theophylline and aminophylline Vitamin A Aluminum toxicity Total parenteral nutrition (TPN) Random miscellaneous causes Immobilization (eg. spinal injury) Chronic renal failure Milk alkali syndrome Rhabdomyolysis*

To order an ionised calcium level is reasonable, because this may reveal the true extent of the hypercalcemia (for instance, if the patient has little albumin on board, the majority of this "total" calcium will be in an ionised form, and the symptoms will be worse).

Additionally, the following investigations might be useful:

Alkaline phosphatase
Serum PTH level
CK
Parathyroid hormone related peptide (PTHrp)
Serum Vitamin D metabolite levels
CXR - or better yet, CT chest - to look for obvious malignancy and granulomatous disease.

References

UpToDate has a nice chapter on this topic, for the paying customer.

Krasimirova, Daniela, et al. "Parathyroid Hormone and Vitamin D Levels in Obstructive Sleep Apnea." (2017): PA2335.

Carroll, Marry F., and David S. Schade. "A practical approach to hypercalcemia." American family physician 67.9 (2003): 1959-1966.

Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.

Zawada Jr, E. T., D. B. Lee, and C. R. Kleeman. "Causes of hypercalcemia."Postgraduate medicine 66.4 (1979): 91-7.

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