In an adult with suspected hyperparathyroidism (e.g., bone pain, kidney stones, gastrointestinal or neurocognitive symptoms, or incidentally elevated serum calcium), what initial laboratory tests, criteria for parathyroidectomy, and medical treatment options are recommended?

Hyperparathyroidism: Diagnosis and Management

Initial Laboratory Evaluation

In an adult with suspected hyperparathyroidism, simultaneously measure serum calcium (corrected for albumin) and intact parathyroid hormone (PTH) as the cornerstone diagnostic tests. 1, 2

Essential First-Line Tests

• Serum calcium (corrected for albumin) and intact PTH measured simultaneously establish the diagnosis—hypercalcemia with elevated or inappropriately normal PTH (failure to suppress below 20 pg/mL) confirms primary hyperparathyroidism. 1, 2
• 25-hydroxyvitamin D must be measured because vitamin D deficiency (levels <20 ng/mL) causes secondary hyperparathyroidism and will falsely elevate PTH; this is the most common diagnostic pitfall. 1, 2
• Serum phosphorus is typically low or low-normal in primary hyperparathyroidism due to PTH-mediated renal phosphate wasting. 1, 2
• Serum creatinine and eGFR are essential because impaired kidney function (eGFR <60 mL/min/1.73 m²) is itself a surgical indication and changes the differential diagnosis toward secondary hyperparathyroidism. 1, 2

Critical Technical Considerations

• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma stored at 4°C. 1, 2
• PTH assays vary by up to 47% between different generations—always use assay-specific reference values and recognize that lack of standardization between laboratories can produce significantly different results. 1, 3, 2
• PTH concentrations are influenced by race (higher in Black individuals), age (increases with declining GFR), BMI (higher with obesity), and vitamin D status (20% lower when vitamin D-replete). 1, 2

Confirmatory and Severity Assessment Tests

• 24-hour urine calcium (or spot urine calcium/creatinine ratio) identifies severe hypercalciuria (>400 mg/24hr), which is a surgical indication and signals high risk for nephrocalcinosis and progressive renal calcifications. 1, 2
• Ionized calcium (normal 4.65–5.28 mg/dL) provides definitive assessment when albumin is abnormal or total calcium is equivocal. 1
• Bone density scan (DEXA) is recommended if chronic hyperparathyroidism is suspected, as osteoporosis (T-score ≤-2.5 at any site) is a surgical indication. 1
• Renal ultrasonography assesses for nephrocalcinosis or kidney stones, both of which are surgical indications. 1

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Diagnostic Interpretation Algorithm

Primary Hyperparathyroidism (Most Common)

Elevated or inappropriately normal PTH + hypercalcemia confirms primary hyperparathyroidism after excluding vitamin D deficiency. 1, 2

• Corrected calcium >1 mg/dL above the upper limit of normal (approximately >11.3 mg/dL) indicates more severe disease and is a surgical indication. 1
• Even patients with normocalcemic primary hyperparathyroidism (persistently elevated PTH with consistently normal calcium after excluding all secondary causes) carry comparable risk to hypercalcemic disease and warrant surgical evaluation if they have target-organ involvement. 1

Secondary Hyperparathyroidism

Elevated PTH + normal or low calcium suggests secondary hyperparathyroidism. 2, 4

• Most commonly caused by chronic kidney disease (eGFR <60 mL/min/1.73 m²) or vitamin D deficiency (<20 ng/mL). 2, 5
• Vitamin D deficiency must be corrected and calcium normalized before diagnosing primary hyperparathyroidism. 1

Tertiary Hyperparathyroidism

Elevated PTH + hypercalcemia in the setting of longstanding chronic kidney disease (especially post-renal transplant) indicates tertiary hyperparathyroidism—autonomous parathyroid function that persists despite correction of the original stimulus. 6, 4

Malignancy-Associated Hypercalcemia

Hypercalcemia + suppressed PTH (<20 pg/mL) + elevated PTHrP defines humoral hypercalcemia of malignancy, which carries a median survival of approximately 1 month and requires immediate comprehensive imaging (chest/abdominal/pelvic CT, PET-CT if available) to identify squamous cell carcinoma of lung, head-and-neck, renal cell carcinoma, or breast carcinoma. 1

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Criteria for Parathyroidectomy

Parathyroidectomy is the only curative treatment for primary hyperparathyroidism and should be performed in patients meeting any of the following criteria: 1, 3

Absolute Surgical Indications

• Age <50 years 1, 3
• Corrected calcium >1 mg/dL above upper limit of normal (approximately >11.3 mg/dL) 1, 3
• Impaired kidney function (eGFR <60 mL/min/1.73 m²) 1, 3
• Osteoporosis on DEXA scan (T-score ≤-2.5 at any site) 1, 3
• History of nephrolithiasis or nephrocalcinosis 1, 3
• Severe hypercalciuria (>400 mg/24hr) due to high risk of irreversible renal calcifications 1

Symptomatic Disease (Target-Organ Involvement)

• Bone pain, pathological fractures 3, 5
• Kidney stones 3, 5
• Neurocognitive symptoms: refractory depression, emotional lability, impaired cognition, "brain fog," memory loss, or profound functional impairment that prevents occupational tasks 1
• Gastrointestinal symptoms: nausea, vomiting, abdominal pain, constipation 1
• Severe hypercalcemia (>14 mg/dL or ionized calcium ≥5.9 mg/dL) with mental status changes, bradycardia, hypotension, severe dehydration, or acute renal failure 1

Patient Preference

Patient preference for definitive treatment is a valid indication for surgical referral even in asymptomatic disease, as prolonged hyperparathyroidism produces adverse metabolic effects. 1

Surgical Approach and Referral

• Refer all surgical candidates to both an endocrinologist and a high-volume, experienced parathyroid surgeon, as outcomes (cure rates, complication profiles) are significantly better with specialized expertise. 1, 3
• Preoperative localization imaging (ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT) is performed only after biochemical diagnosis is confirmed and only when surgery is planned—imaging is for surgical planning, not diagnosis. 1, 2
• Minimally invasive parathyroidectomy is preferred when a single adenoma is confidently localized preoperatively, offering shorter operative times, faster recovery, and lower costs. 3

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Medical Treatment Options

For Non-Surgical Candidates or While Awaiting Surgery

Medical management is reserved for patients who cannot undergo surgery, decline surgery, or are awaiting parathyroidectomy. 1, 3

Dietary and Lifestyle Measures

• Maintain normal calcium intake (1000–1200 mg/day)—avoid both high and low calcium diets, as extremes worsen disease. 1
• Total elemental calcium intake should not exceed 2000 mg/day. 1
• Ensure adequate oral hydration and discontinue thiazide diuretics, which worsen hypercalcemia. 1

Vitamin D Management

• Correct vitamin D deficiency (target 25-hydroxyvitamin D >20 ng/mL) using cholecalciferol or ergocalciferol to support bone health and mitigate secondary hyperparathyroidism. 1
• Avoid calcitriol or active vitamin D analogs in primary hyperparathyroidism, as they increase intestinal calcium absorption and exacerbate hypercalcemia. 1
• Monitor serum calcium and phosphorus at least every 3 months during vitamin D supplementation; discontinue immediately if calcium exceeds 10.2 mg/dL. 1

Monitoring for Non-Surgical Patients

• Measure serum calcium every 3 months for patients with eGFR >30 mL/min/1.73 m². 1
• Reassess renal function regularly (creatinine, eGFR), as hypercalcemia can cause acute kidney injury and worsen chronic kidney disease. 1
• Repeat bone density scans to monitor for progressive osteoporosis. 1

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Management of Acute Severe Hypercalcemia

Severe hypercalcemia (>14 mg/dL or ionized calcium ≥5.9 mg/dL) is a medical emergency requiring immediate intervention. 1

Immediate Actions

• Aggressive intravenous hydration with isotonic normal saline to restore intravascular volume and promote calciuresis—this is the cornerstone of acute therapy. 1
• Intravenous bisphosphonates (zoledronic acid or pamidronate) are first-line pharmacologic agents, inhibiting osteoclast-mediated bone resorption with calcium reduction within 2–4 days. 1
• Loop diuretics only after volume restoration to enhance calciuresis. 1
• Measure ionized calcium every 4–6 hours during initial treatment to assess response. 1

Post-Parathyroidectomy Monitoring

• Measure ionized calcium every 4–6 hours for the first 48–72 hours after surgery to detect "hungry bone syndrome"—rapid calcium decline as bone avidly takes up calcium. 1
• If ionized calcium drops below 0.9 mmol/L (≈3.6 mg/dL), start intravenous calcium gluconate infusion at 1–2 mg elemental calcium/kg/hr. 1
• Transition to oral calcium carbonate 1–2 g three times daily plus calcitriol up to 2 µg/day once oral intake is feasible. 1

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Common Pitfalls and How to Avoid Them

• Never order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning, not diagnosis. 1
• Always measure 25-hydroxyvitamin D before diagnosing primary hyperparathyroidism—vitamin D deficiency is the most common cause of secondary hyperparathyroidism and will falsely elevate PTH. 1, 2
• Do not supplement vitamin D until hypercalcemia resolves if calcium exceeds 10.2 mg/dL. 1
• Recognize that PTH in the "normal range" does not exclude primary hyperparathyroidism—inappropriately normal PTH in the setting of hypercalcemia is diagnostic, as PTH should be suppressed. 1
• Avoid calcium-based phosphate binders in CKD patients with hypercalcemia, as they worsen hypercalcemia. 1
• Biological variation of PTH is substantial (20% in healthy individuals)—differences must exceed 54% to be clinically significant. 1