The  blood  results  of a 75 year  old who  presents  with  lethargy,  confusion  and weight loss are shown below:

Patient value

Normal range

Sodium

141 mmol/L

135 – 145

Potassium

3.8 mmol/L

3.5 – 5.0

Chloride

100 mmol/L

97 – 109

Bicarbonate

29 mmol/L

24 – 32

Urea

11.5 mmol/L

3.0 – 8.0

Creatinine

150 µmol/L

70 – 110

Calcium

4.69 mmol/L

2.10 – 2.60

Phosphate

0.4 mmol/L

0.8 – 1.5

Albumin

44 G/L

38 – 48

a) What is the likely diagnosis?

b) What other biochemistry would you request and why?

c) Briefly explain the pathogenesis of the biochemical abnormalities.

d) Outline your management of this patient.

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College Answer

a) What is the likely diagnosis?
Underlying malignancy

b) What other biochemistry would you request and why?
PTH to exclude primary hyperPTH – very high calcium indicates malignancy but patients with  malignancy  have  higher  incidence  of  hyperPTH  than  general  population  so  both conditions can co-exist

c) Briefly explain the pathogenesis of the biochemical abnormalities.

Hypercalcaemia:

Malignancy:

  • PTH rp (Parathyroid related peptide)
  • Ectopic PTH
  • Bone lysis

Increased PTH:

  • Leading to increased osteoclast activity leads to hypercalcaemia by bone reabsorption. It also acts at renal tubule to reabsorb Ca++ and increases conversion 25-OHD to 1,25 (OH)2D increases intestinal absorption of Ca++

Elevated urea and creatinine:

  • Secondary to hypovolaemia

d) Outline your management of this patient.

•    Fluid replacement with NS
•     Biphosphonates
•    Calcitonin
•    Steroids act by decreasing calcitriol
•    Dialysis
•    Treat underlying malignancy
•    Parathyroidectomy if raised PTH
•    (Diuretics no longer recommended)

Discussion

As for the diagnosis- the clue is in the age and the weight loss, and the college does sound as if they are asking for the one most likely diagnosis. But if one were to approach this on classical footing, one would be expected to regurgitate a small pool of differentials.

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

One may wish to launch the following investigations:

  • 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.

As for management, one would be well served to organise the response by the physiological aims of one's therapy:

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
  • 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)