What is the diagnosis and recommended workup and treatment for a patient with high intact parathyroid hormone and elevated corrected serum calcium?

Primary Hyperparathyroidism: Diagnosis and Management

The combination of elevated parathyroid hormone (PTH) with elevated corrected serum calcium confirms primary hyperparathyroidism (PHPT), and the patient should be referred immediately to both an endocrinologist and an experienced parathyroid surgeon for evaluation and likely parathyroidectomy. 1

Confirm the Biochemical Diagnosis

Before proceeding, you must verify the diagnosis and exclude secondary causes:

• Measure serum phosphorus immediately – primary hyperparathyroidism typically shows low-normal phosphorus (PTH increases renal phosphate excretion), whereas CKD-related secondary hyperparathyroidism shows elevated phosphorus 2, 3

• Check serum creatinine and calculate eGFR – impaired kidney function (eGFR <60 mL/min/1.73 m²) can cause secondary hyperparathyroidism, but when combined with hypercalcemia suggests either primary hyperparathyroidism with renal impairment or tertiary hyperparathyroidism 1, 3

• Measure 25-hydroxyvitamin D levels – vitamin D deficiency is the most common cause of secondary hyperparathyroidism and must be excluded before confirming PHPT; aim for levels >20 ng/mL (>50 nmol/L) 4, 1

• Use EDTA plasma rather than serum for PTH measurement when possible, as PTH is most stable in EDTA plasma at 4°C, and always interpret results using assay-specific reference values since PTH measurements can vary up to 47% between different assay generations 1

• Verify corrected calcium – if albumin is abnormal, calculate corrected calcium or measure ionized calcium (normal 4.65–5.28 mg/dL) to avoid misleading total calcium values 1, 2

Diagnostic Pattern Recognition

The biochemical signature of primary hyperparathyroidism is:

• Elevated or inappropriately normal PTH (PTH fails to suppress below 20 pg/mL despite hypercalcemia) 1, 3
• Elevated corrected calcium (>10.2–10.3 mg/dL) 1, 2
• Low-normal serum phosphorus (PTH increases renal phosphate wasting) 1, 2
• Normal or elevated 1,25-dihydroxyvitamin D (PTH stimulates calcitriol production) 1

Critical pitfall: A small subset of patients with surgically confirmed parathyroid adenomas may have suppressed or low-normal PTH levels despite hypercalcemia; when clinical suspicion is high (persistent hypercalcemia, nephrolithiasis, bone disease), pursue the diagnosis despite atypical PTH values 5

Additional Diagnostic Workup

Once PHPT is biochemically confirmed, complete the following assessments:

• 24-hour urine calcium or spot urine calcium/creatinine ratio – to assess for hypercalciuria (>300 mg/24hr), which is a surgical indication 1, 2

• Renal ultrasonography – to evaluate for nephrolithiasis or nephrocalcinosis 1

• Bone density scan (DEXA) – to assess for osteoporosis (T-score ≤-2.5 at any site), which is a surgical indication 1, 2

• Do NOT order parathyroid imaging (ultrasound or sestamibi scan) until the biochemical diagnosis is confirmed and surgery is planned; imaging is for surgical localization only, not for diagnosis 1

Determine Surgical Candidacy

All patients meeting any of the following criteria should be referred for parathyroidectomy 1, 2:

• Corrected calcium >1 mg/dL above the upper limit of normal (approximately >11.2–11.3 mg/dL) 1
• Age <50 years 1, 3
• eGFR <60 mL/min/1.73 m² 1, 3
• Osteoporosis (T-score ≤-2.5 at lumbar spine, hip, or distal radius) 1, 2
• History of nephrolithiasis or nephrocalcinosis 1, 3
• Hypercalciuria (>300 mg/24hr) 2
• Symptomatic disease (kidney stones, bone pain, fractures, neurocognitive symptoms) 3
• Patient preference for definitive treatment 1

Immediate Management Considerations

If Calcium is Severely Elevated (≥12 mg/dL or symptomatic):

• Initiate aggressive IV crystalloid hydration with isotonic normal saline to restore intravascular volume and promote calciuresis 1, 2
• Add loop diuretics only after adequate volume repletion 1
• Consider IV bisphosphonates (zoledronic acid or pamidronate) for severe hypercalcemia; they inhibit osteoclast-mediated bone resorption and achieve calcium reduction within 2–4 days 1
• Refer urgently for surgical evaluation – do not delay surgical referral for persistent severe hypercalcemia, as this leads to progressive renal damage, nephrocalcinosis, and bone disease 2

If Calcium is Mildly Elevated (10.2–12 mg/dL):

• Ensure adequate oral hydration and discontinue any calcium supplements, vitamin D supplements, or thiazide diuretics 1
• Maintain normal dietary calcium intake (1,000–1,200 mg/day); avoid both high and low calcium diets, as calcium restriction paradoxically worsens PTH secretion 1, 2
• Total elemental calcium intake should not exceed 2,000 mg/day 1

Medical Management for Non-Surgical Candidates

For patients who decline surgery or have contraindications:

• Maintain 25-hydroxyvitamin D levels >20 ng/mL using cholecalciferol or ergocalciferol supplementation to support bone health, but monitor calcium closely during repletion 1
• Monitor serum calcium every 3 months for patients with eGFR >30 mL/min/1.73 m² 1
• Reassess surgical candidacy annually, as disease may progress 3

Do NOT use calcitriol or active vitamin D analogs in primary hyperparathyroidism, as they will worsen hypercalcemia by increasing intestinal calcium absorption 4, 2

Special Considerations: Distinguishing Primary from Secondary/Tertiary Hyperparathyroidism

Secondary Hyperparathyroidism:

• Presents with hypocalcemia or normal calcium, NOT hypercalcemia 2, 6
• Elevated PTH is an appropriate physiologic response to low calcium, vitamin D deficiency, or CKD 3, 6
• Serum phosphorus is typically elevated in CKD-related secondary hyperparathyroidism 2

Tertiary Hyperparathyroidism:

• Occurs after longstanding secondary hyperparathyroidism (usually from CKD), where autonomous parathyroid hyperplasia persists despite correction of the primary disorder (e.g., after renal transplant) 7, 6
• Presents with elevated PTH and hypercalcemia, but in the context of prior CKD and often after transplantation 7
• May require parathyroidectomy if PTH remains >800 pg/mL with refractory hypercalcemia after 3–6 months of optimized medical therapy 2

Referral Pathway

Refer to endocrinology for:

• Confirmation of biochemical diagnosis
• Exclusion of secondary causes (vitamin D deficiency, CKD, familial hypocalciuric hypercalcemia)
• Assessment of surgical candidacy
• Medical optimization before surgery 1

Refer to an experienced, high-volume parathyroid surgeon for:

• Preoperative localization imaging (ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT) 1
• Surgical planning and parathyroidectomy 1
• Outcomes are significantly better with specialized surgical expertise 1

Common Pitfalls to Avoid

• Never order parathyroid imaging before confirming the biochemical diagnosis – imaging is for surgical planning, not diagnosis 1, 2

• Never delay surgical referral for persistent hypercalcemia >12 mg/dL – this leads to progressive renal damage, nephrocalcinosis, and bone disease 2

• Never supplement with vitamin D until hypercalcemia is resolved – discontinue all forms of vitamin D therapy if serum calcium exceeds 10.2 mg/dL 1, 2

• Never assume normal PTH excludes primary hyperparathyroidism – in the setting of hypercalcemia, a PTH in the "normal" range is inappropriately elevated and confirms PHPT 1, 3

• Never restrict dietary calcium in PHPT – low calcium intake paradoxically worsens PTH secretion; maintain normal intake of 1,000–1,200 mg/day 1, 2