A 65-year-old man is brought to A&E with progressive confusion over the past week, lethargy and sleepiness. He is disoriented and reports occasional palpitations. He has a 60-pack-year smoking history and was diagnosed with non-small cell lung cancer nine months ago, and has completed multiple cycles of chemotherapy and radiotherapy, with the last cycle four weeks ago.


He is tachycardic, apyrexial, and has dry mucous membranes. His chest is clear, abdomen is soft and non-tender, with no focal neurology.  


ECG shows new 1st degree heart block; urine dip is clear. Chest X-ray shows a known left hilar mass.



Bloods tests:


|Serum|Result|Reference Range|
|---------------------------|------|-----------------------------|
|Haemoglobin|82|130 - 170 mg/dL|
|White Cell Count|4.1|3.0 - 10.0 x 10⁹ /L|
|Platelets|180|150 - 400 x 10⁹/L|
|Mean Cell Volume|71|80 - 96 fL|
|Urea|10.1|2.5 - 7.8 mmol/L|
|Creatinine|170|60 - 120 µmol/L|
|eGFR|37|≥ 60 mL/min/1.73m<sup>2</sup>|
|Iron|5.6|14 - 31 μmol/L|
|Total Iron Binding Capacity|35|54 - 75 μmol/L|
|Corrected Calcium|3.6|2.2 - 2.6 mmol/L|
|Magnesium|0.65|0.7 - 1.0 mmol/L|
|Phosphate|0.4|0.8 - 1.5|
|Parathyroid Hormone|0.1|1.6 - 8.5 pmol/L|


What is the most likely cause of this patient's symptoms?

Options:
explanation: Tumour lysis syndrome (TLS) is a potentially fatal complication from chemotherapy. It is more likely seen in cancers with high cell turnover rates, particularly haematological malignancies, e.g. lymphomas and leukaemias, but other solid tumours have also been associated with TLS. It is caused by tumour cells being lysed during treatment and releasing their contents into the blood, producing similar electrolyte abnormalities as rhabdomyolysis. It results in hyperkalaemia, hyperphosphataemia, hypocalcaemia, and hyperuricaemia (high blood uric acid). The patient has presented with symptoms that could be consistent with TLS, although it has been four weeks since his last cycle of chemotherapy and so this is very unlikely. His blood markers are also not consistent with TLS, and so this would be an unlikely cause for this patient's symptoms
name: Tumour lysis syndrome
label: c
answer: no
explanation: In primary hypoparathyroidism, PTH is low, calcium is low, and phosphate is high. This is because of reduced osteoclastic activity in bone and so reduced serum calcium produced from bone reabsorption. Low PTH would also result in reduced reabsorption of calcium in the distal tubules and collecting ducts (reduces serum calcium), and reduced inhibition of reabsorption of phosphate from tubular fluid (increases serum phosphate)
name: Primary hypoparathyroidism
label: b
answer: no
explanation: The patient's symptoms are most likely caused by his hypercalcaemia. It rarely presents with _all_ of "stones, moans, groans, and psychic overtones" and often presents solely as lethargy or confusion. Non-small cell lung cancers often can cause hypercalcaemia due to tumour secretion of parathyroid-related protein (PTHrP). This acts in the same way as parathyroid hormone (PTH), activating parathyroid hormone receptors in tissue which results in increased osteoclastic bone resorption (with or without bone metastases), increased renal tubular absorption of calcium, and decreased reabsorption of phosphate in the kidney. The body's normal homeostatic mechanisms are still intact, and so secretion of PTH from the parathyroid gland is reduced to combat the patient's hypercalcaemia. Alkaline phosphatase is increased because of increased osteoclastic bone resorption. This patient's palpitations and new ECG findings can also be explained by hypercalcaemia. ECG findings found in hypercalcaemia are short QT interval, prolonged PR-interval (1st degree heart block), and Osborn waves.
 

 This patient has likely also developed an acute kidney injury (AKI) secondary to dehydration from hypercalcaemia - driven by forced diuresis and reduced oral intake from nausea/confusion. NB: The patient may not volunteer polyuria unless asked directly. While the patient does have raised urea, likely from pre-renal AKI, this would not usually elicit cognitive dysfunction at this concentration.
 

 This patient does have iron-deficiency anaemia, although this is very common in patients with cancer. There is no evidence of acute haemorrhage to cause this patient's confusion and a mildly increased urea gives further evidence against having had an upper gastrointestinal haemorrhage
name: Hypercalcaemia of Malignancy
label: a
answer: yes
explanation: In primary hypoparathyroidism, PTH is low, calcium is low, and phosphate is high. This is because of reduced osteoclastic activity in bone and so reduced serum calcium produced from bone reabsorption. Low PTH would also result in reduced reabsorption of calcium in the distal tubules and collecting ducts (reduces serum calcium), and reduced inhibition of reabsorption of phosphate from tubular fluid (increases serum phosphate)
name: Uraemia
label: d
answer: no
explanation: This patient does have iron-deficiency anaemia, although this is very common in patients with cancer. There is no evidence of acute haemorrhage to cause this patient's confusion and a mildly increased urea gives further evidence against having had an upper gastrointestinal haemorrhage. Patients often compensate very well with chronic anaemia and may have few or no symptoms. They may complain of general lethargy and shortness of breath on exertion with haemoglobin (Hb) in the 80s, but without signs of acute haemorrhage, this is unlikely to cause confusion
name: Microcytic iron deficiency anaemia
label: e
answer: no

Correct answer: a

Hypercalcaemia of Malignancy

Learning point: Hypercalcaemia of malignancy can cause confusion and lethargy, often due to parathyroid hormone-related peptide secretion from tumours.