Normocalcemic primary hyperparathyroidism (PHPT) is characterized by elevated serum parathyroid hormone (PTH) with a normal albumin-corrected serum calcium and normal ionized serum calcium after exclusion of secondary causes of hyperparathyroidism. It is most often recognized during the diagnostic workup of patients with osteoporosis or nephrolithiasis; PTH is not routinely measured in eucalcemic patients without these disorders. Normocalcemic PHPT is a diagnosis of exclusion, after ruling out causes of secondary hyperparathyroidism such as gastrointestinal calcium malabsorption, vitamin D deficiency, and chronic kidney disease.1 For classical PHPT, characterized by hypercalcemia, there are clear management guidelines. However, less is known about the optimal management of normocalcemic PHPT, including the impact of parathyroidectomy on clinical outcomes such as bone density. Thus, further research is needed to guide clinicians in evaluating and managing the eucalcemic patient with elevated PTH levels. This is a case report of a diagnostic dilemma in a patient with normal serum calcium and high serum PTH, presented and discussed at a session of Bone Health Extension for Community Healthcare Outcomes (ECHO).

A 74-year-old female with a history of rheumatoid arthritis, osteoporosis, and hyperparathyroidism with past one-gland parathyroidectomy in 2011, was referred to endocrinology for bone health evaluation prior to spine surgery. The patient’s operative report from her prior parathyroidectomy at an outside hospital was unavailable. The patient had no known history of fractures, nephrolithiasis, chronic kidney disease, or gastrointestinal malabsorptive conditions. She denied symptoms of hypercalcemia, including bone pain, constipation, or neuropsychiatric changes. She reported minimal calcium intake given lactose intolerance and was not on calcium or vitamin D supplementation. She was not taking medications known to affect calcium levels. Notably, her mother and sister had nephrolithiasis of unknown composition. Another sister had hyperparathyroidism and underwent one-gland parathyroidectomy at age 69, with reportedly benign pathology, after she was found to have elevated parathyroid hormone level and elevated calcium levels over 11 up to 13 mg/dL.

The patient’s laboratory data revealed elevated PTH levels ranging from 116 to 309 pg/mL across nine years, with a recent PTH level of 151 pg/mL (Fig. 1). Her calcium levels were consistently normal, with a recent calcium of 9.7 mg/dL (Fig. 2) with normal albumin 4 g/dL, and ionized calcium 1.19 mMol/L. Her 25-hydroxyvitamin D level was 30 ng/mL. Her kidney function was normal, with glomerular filtration rate (GFR) over 60 mL/min (Table 1). Her creatinine clearance was 88.6 mL/min based on 24-hour urine. Twenty-four-hour urine calcium was 112 mg, with a urine calcium/creatinine clearance ratio of 0.00986. Medical records with laboratory data prior to her parathyroidectomy in 2011 were unavailable. She had negative CASR gene duplication/deletion test. The Invitae Hereditary Hyperparathyroidism Panel resulted negative for eight tested genes including AP2S1, CASR, CDC73, CDKN1B, GNA11, MEN1, RET, and TRPV6. Her dual-energy X-ray absorptiometry (DXA) study showed T-scores of -1.5 at right femoral neck, -1.4 at left femoral neck, with invalid lumbar spine bone density given hardware present. A DXA of the 33% radius from one year prior revealed an osteoporosis-range T-score of -3.0.

The patient was advised to start calcium carbonate 500mg three times daily and vitamin D3 5000 international units daily with plan for repeat labs afterwards, given her limited dietary calcium intake and low-normal 24-hour urine calcium, which suggested possible secondary hyperparathyroidism due to calcium deficiency. However, after taking calcium and vitamin D supplementation for over four months, the patient’s repeat labs revealed persistent normocalcemic hyperparathyroidism with a calcium level of 9.6 mg/dL, normal albumin of 3.8 g/dL, and elevated parathyroid hormone level of 153 pg/mL. Her 25-hydroxyvitamin D level increased to 60 ng/mL, from 30 ng/mL over a year prior. Her kidney function based on creatinine remained stable at 0.64 mg/dL with GFR >60 mL/min, though her GFR based on cystatin C was mildly reduced at 58 mL/min with no prior for comparison. Based on this data, there is lower suspicion for secondary hyperparathyroidism.

There was consideration of familial hypocalciuric hypercalemia (FHH) because of the low urine calcium/creatinine clearance ratio; however, this diagnosis was dismissed because of persistently normal calcium levels and normal genetic tests. A neck soft tissue ultrasound revealed a 1.6 cm left thyroid gland lesion and a 9 mm lesion in or subjacent to the right thyroid gland, which could be an abnormal parathyroid. Fine needle aspiration of the 1.6 cm left thyroid lesion revealed a benign thyroid adenoma (Bethesda II). She was referred for a parathyroid sestamibi scan, and her osteoporosis treatment and spine surgery were delayed pending further evaluation. Subsequent to the case discussion on Bone Health ECHO, a parathyroid sestamibi scan and neck CT both failed to localize a parathyroid adenoma.