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

  1. List four likely aetiologies for the hypercalcaemia. (20% marks)
  1. List four other specific blood tests you would order to investigate the cause.

(20% marks)

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College answer

a)

  1. Primary hyperparathyroidism
  2. 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.

b)

  1. Albumin OR ionised calcium
  2. PTH
  3. Vitamin D metabolites
  4. PTH related protein
  5. 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

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.