What is the appropriate workup and treatment for a patient suspected of having primary hyperparathyroidism (PHPT)?

Workup for Primary Hyperparathyroidism

Initial Biochemical Diagnosis

The diagnosis of primary hyperparathyroidism requires simultaneous measurement of serum calcium (corrected for albumin) and intact parathyroid hormone (iPTH), with the hallmark finding being hypercalcemia or high-normal calcium alongside elevated or inappropriately normal PTH levels. 1

Essential First-Line Laboratory Tests

• Serum calcium (total, corrected for albumin) and intact PTH must be measured simultaneously—this is the cornerstone of diagnosis 1, 2
• Serum phosphate should be checked, as it is typically low or low-normal in PHPT 1
• 25-hydroxyvitamin D measurement is crucial because vitamin D deficiency can complicate PTH interpretation and lead to misdiagnosis 1, 2
• Serum creatinine to assess kidney function (calculate eGFR) is essential 1
• Serum chloride and uric acid may help identify underlying conditions associated with stone disease 1

Critical Technical Considerations for PTH Measurement

• Blood samples for PTH should be collected in EDTA tubes rather than serum, as PTH is most stable in EDTA plasma 1
• Use assay-specific reference values for PTH interpretation, as different assay generations measure different PTH fragments and can yield significantly different results 1
• PTH should be measured at least 12 hours after any cinacalcet dose if the patient is on this medication 1
• Biotin supplements can interfere with PTH assays and cause under- or overestimation depending on assay design 1

Confirmatory and Complication Assessment

24-Hour Urine Collection

• A 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine helps evaluate complications and metabolic abnormalities 1
• Urine calcium >400 mg/day identifies patients at increased risk for kidney stones and bone complications, and serves as a surgical indication 1
• Most PHPT patients demonstrate hypercalciuria (>250-300 mg/day) due to increased filtered calcium load 1
• Important caveat: Vitamin D deficiency can suppress urine calcium excretion, potentially masking hypercalciuria 1

Differential Diagnosis Exclusions

Before confirming PHPT, exclude these conditions:

• Secondary hyperparathyroidism: Normal or low serum calcium with elevated PTH (seen in CKD or vitamin D deficiency) 1
• Tertiary hyperparathyroidism: Hypercalcemia with elevated PTH in end-stage renal disease 1
• Familial hypocalciuric hypercalcemia (FHH): Check calcium-to-creatinine clearance ratio; if <0.01, consider FHH rather than PHPT 3
• Hypercalcemia with suppressed PTH: Suggests malignancy, granulomatous disease, vitamin D intoxication, or other non-parathyroid causes 3, 4

Imaging Studies (Only After Biochemical Diagnosis)

Imaging has no utility in confirming or excluding the diagnosis of hyperparathyroidism—it is used only for surgical localization after biochemical diagnosis is established. 1

Preoperative Localization (When Surgery is Planned)

• Neck ultrasound is the recommended first-line localization study 1, 2
• Dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT provides high sensitivity for localizing parathyroid adenomas 1
• Combination of ultrasound and sestamibi scan offers the highest sensitivity for localization 1
• 4D-CT or MRI may be considered if initial imaging is negative or for reoperative cases/suspected ectopic glands 1, 2

Assessment of Target Organ Damage

Skeletal Evaluation

• Dual-energy X-ray absorptiometry (DEXA) scan to assess for osteoporosis is essential, as bone disease is a key surgical indication 5, 6

Renal Evaluation

• Renal imaging (ultrasound or CT) to detect nephrolithiasis or nephrocalcinosis should be performed 6, 7

Common Pitfalls to Avoid

• Not assessing vitamin D status when interpreting PTH levels is a frequent cause of misdiagnosis 1, 2
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments can result in inaccurate diagnoses 1
• Attributing symptoms solely to PHPT without excluding other causes, particularly in elderly patients with multiple comorbidities 2
• Ordering imaging before biochemical confirmation wastes resources and does not aid diagnosis 1

Special Population Considerations

• For patients with CKD and GFR <60 mL/min/1.73 m², different diagnostic criteria apply, and imaging prior to parathyroidectomy is essential 1
• For patients with multiple endocrine neoplasia (MEN) syndromes, screening should begin at age 11 for high-risk variants and age 16 for moderate-risk variants 1
• Post-kidney transplant patients may have persistent hyperparathyroidism requiring close monitoring 5

Surgical Indications Assessment

Once PHPT is confirmed, evaluate for surgical criteria:

• Age <50 years 1, 6
• Serum calcium >1 mg/dL (0.25 mmol/L) above upper limit of normal 1, 2
• eGFR <60 mL/min/1.73 m² 1, 6
• Nephrolithiasis or nephrocalcinosis 1, 6
• Osteoporosis on DEXA scan (T-score ≤-2.5) 1, 6
• 24-hour urine calcium >400 mg/day 1

Medical Management Consideration (Non-Surgical Candidates Only)

• Cinacalcet is FDA-approved for hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated based on serum calcium levels, but who are unable to undergo surgery 8
• Starting dose is 30 mg twice daily, titrated every 2-4 weeks to normalize serum calcium 8
• Monitor serum calcium within 1 week after initiation or dose adjustment, then every 2 months once stable 2, 8
• Cinacalcet effectively lowers serum calcium but does not cure the disease and has significant side effects including nausea (63%), vomiting (46%), and hypocalcemia 2, 8