Endocrine Abstracts

Case: We report a 79-year-old female who was referred to our Endocrine Bone Unit with osteoporosis, which was initially treated with Alendronate (but poorly tolerated due to dyspepsia) followed by annual Zoledronate infusions. Her bone history was significant for a proximal humeral fragility fracture 30-years previously. She was an ex-smoker, had limited dietary calcium intake, and had a brother with osteoporosis. DEXA demonstrated T scores at lumbar spine -1.8, total hip -2.0 and distal radius -2.8, corresponding to 4.6% reduction in lumbar spine BMD from the assessment two years earlier. Thoracolumbar X-rays revealed multiple silent vertebral fractures. However, serial measurements revealed persistent PTH-dependent hypercalcaemia (adjusted calcium range 2.73-2.84mmol/l, PTH 15.7-21.8 pmol/l, 25 OH vitamin D 69.1nmol/land eGFR 79). 24-hour urinary calcium to creatinine clearance ratio (CCCR) was 0.0056, suggesting that Familial Hypocalciuric Hypercalcaemia (FHH) should be considered. However, genetic testing for FHH did not identify known pathogenic variants of the AP2S1, GNa11 or CASR genes. Repeat 24-hour urinary CCCR was slightly higher at 0.012, raising a suspicion for Primary Hyperparathyroidism (PHPT). Parathyroid USS revealed a possible 5mm left inferior parathyroid adenoma (also noted on 4D CT), but without strong evidence of uptake on sestamibi. Renal USS demonstrated a 4mm non-obstructing renal cortical calculus of the left kidney.

Outcome: Owing to non-concordant localisation studies, she underwent a four-gland exploration of the parathyroids, with the left inferior gland removed. Post-operative histology was consistent with an adenoma, and she is now cured with corrected calcium values 2.27-2.39mmol/l. Repeat DEXA at 24-months post-parathyroidectomy has been arranged to re-assess her BMD.

Discussion: Differentiating between FHH and PHPT is essential for correct management, as FHH usually necessitates no intervention, whereas PHPT may require parathyroidectomy. Discrimination is usually based on a 24-hour urinary CCCR with values <0.01 suggestive of FHH. This is based on data highlighting that 80% of individuals with FHH will have a CCCR of <0.01, while 20% have values between 0.01-0.02 and so can overlap with PHPT. However, as noted in this case, a falsely low CCCR can be observed in PHPT with concurrent use of medications that affect calcium metabolism or renal calcium handling, such as bisphosphonates (as in our patient), lithium and thiazide diuretics, as well as vitamin D deficiency/insufficiency, low dietary calcium intake, Afro-Caribbean ethnicity, and chronic kidney disease. As shown here, a combination of clinical suspicion, biochemical testing and genetic analysis may be required to differentiate PHPT from FHH.