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Arab Board IM Final Written study materials
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A 28-Year-Old Woman with Recurrent Hypercalcaemia and a Normal PTH

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A 28-Year-Old Woman with Recurrent Hypercalcaemia and a Normal PTH

A 28-year-old woman is referred with fatigue, constipation and recurrent renal stones. Corrected calcium is 3.05 mmol/L (2.15-2.55), phosphate 0.75 mmol/L (0.8-1.45), albumin 38 g/L. Intact PTH is 1.2 pmol/L (1.6-6.9), i.e. suppressed. 25-hydroxyvitamin D is 62 nmol/L, 1,25-dihydroxyvitamin D is 210 pmol/L (48-190). She takes no calcium or vitamin D supplements. She has a strong family history of hypercalcaemia in her mother and maternal uncle; her mother had a parathyroidectomy in her 30s. Serum creatinine is 78 micromol/L. A 24-hour urine calcium is 9.8 mmol/24h (2.5-7.5).

1. Construct a differential diagnosis and explain the biochemical pattern.

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The pattern is hypercalcaemia with a suppressed PTH, which excludes primary hyperparathyroidism and points to a PTH-independent cause.

Differential:

  1. Malignancy - myeloma, bony metastases, PTHrP-secreting tumours (squamous cell lung, renal, ovarian). The young age and family history make this less likely but it must be excluded.
  2. Granulomatous disease - sarcoidosis, tuberculosis: extra-renal 1-alpha-hydroxylation produces high 1,25-(OH)2D. Her 1,25-(OH)2D is elevated, which fits.
  3. Familial hypocalciuric hypercalcaemia (FHH) - but her 24-hour urine calcium is high (9.8 mmol), which argues strongly against FHH (FHH has low urinary calcium, typically <2.5 mmol/24h).
  4. Vitamin D intoxication - excluded (no supplements, 25-OHD normal).
  5. Thyrotoxicosis, immobilisation, milk-alkali - less likely.
  6. Familial hyperparathyroidism / MEN - but PTH is suppressed, so this does not fit.

The key discriminator is the elevated 1,25-(OH)2D with suppressed PTH and high urinary calcium. In sarcoidosis, macrophages express 1-alpha-hydroxylase, generating calcitriol independent of PTH, which drives intestinal calcium absorption and hypercalciuria. The family history of hypercalcaemia should prompt consideration of a familial syndrome, but FHH is excluded by the high urine calcium - so the family history may be coincidental or reflect a separate familial trait. Malignancy must still be excluded with a myeloma screen and imaging.

2. What investigations would you order, and how would you manage the hypercalcaemia acutely if she becomes symptomatic with confusion?

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Investigations:

  • Confirm and characterise: repeat corrected calcium, ionised calcium, PTH, phosphate, magnesium, ALP, creatinine, 24-hour urinary calcium and creatinine clearance.
  • Exclude malignancy: FBC, film, ESR, serum protein electrophoresis with immunofixation, free light chains, LDH, chest X-ray/CT, and age-appropriate imaging; PTHrP if malignancy suspected.
  • Granulomatous disease: serum ACE (supportive only), chest CT, and consider biopsy of any mediastinal nodes.
  • Endocrine: TSH, cortisol if relevant.
  • Renal: stone imaging, 24-hour urine for stone risk factors.

Acute management of symptomatic hypercalcaemia (confusion):

  1. IV 0.9% saline - restore volume first; aim for urine output 100-150 mL/h. This is the single most important initial step.
  2. IV bisphosphonate - zoledronic acid 4 mg (adjusted for renal function) or pamidronate; effect takes 24-48 h, so it complements fluids.
  3. Calcitonin - 4 IU/kg SC/IM 12-hourly for rapid (hours) but transient effect while bisphosphonate works.
  4. Loop diuretic only after volume repletion and if there is fluid overload - never as first-line.
  5. Treat the cause - if sarcoidosis is confirmed, corticosteroids are the definitive treatment (they suppress macrophage 1-alpha-hydroxylase); hydroxychloroquine or ketoconazole are alternatives.
  6. Avoid thiazides, lithium, and calcium/vitamin D; monitor K+ and Mg2+.

3. Her chest CT shows bilateral hilar lymphadenopathy and she is diagnosed with sarcoidosis. What is the long-term plan?

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Diagnosis: sarcoidosis with hypercalcaemia due to extra-renal 1-alpha-hydroxylation. Bilateral hilar lymphadenopathy in a young woman is classic; biopsy (endobronchial ultrasound-guided) confirms non-caseating granulomas and excludes lymphoma/infection.

Long-term plan:

  • Corticosteroids are first-line for symptomatic sarcoidosis with hypercalcaemia: prednisolone 20-40 mg/day, then taper to the lowest effective dose. Monitor calcium, renal function and 1,25-(OH)2D.
  • Steroid-sparing agents if relapse on tapering: methotrexate, azathioprine, hydroxychloroquine (particularly for calcium/hypercalciuria), or anti-TNF agents in refractory disease.
  • Monitor for organ involvement: pulmonary function tests, ECG (cardiac sarcoid), ophthalmology review (uveitis), and neurological assessment.
  • Renal protection: high urinary calcium causes nephrocalcinosis and stones; maintain hydration, consider potassium citrate, and monitor eGFR.
  • Patient education: avoid calcium and vitamin D supplements; avoid excessive sun exposure (which can worsen hypercalcaemia via cutaneous vitamin D synthesis).
  • Prognosis: many patients remit; a minority have chronic progressive disease. Long-term follow-up with a respiratory/rheumatology team is required.