How do you diagnose and manage primary hyperparathyroidism in an adult, including criteria for surgery and medical therapy options?

Primary Hyperparathyroidism: Diagnosis and Management

Diagnostic Approach

Diagnose primary hyperparathyroidism by simultaneously measuring serum calcium (corrected for albumin) and intact parathyroid hormone (iPTH), with the hallmark finding being hypercalcemia or high-normal calcium coupled with elevated or inappropriately normal PTH levels. 1

Essential Initial Laboratory Tests

• Serum calcium and intact PTH measured simultaneously are the cornerstone of diagnosis 1, 2
• Serum phosphate typically shows low or low-normal values in primary hyperparathyroidism 1, 2
• Assess 25-hydroxyvitamin D status before interpreting PTH levels, as vitamin D deficiency can cause secondary hyperparathyroidism and complicate diagnosis 1, 2
• Measure serum creatinine to evaluate kidney function (GFR), which impacts surgical decision-making 1

Critical Technical Considerations for PTH Measurement

• Use assay-specific reference values when interpreting PTH results, as different assay generations measure different PTH fragments and yield significantly different values between laboratories 1, 2
• Collect blood samples in EDTA tubes rather than serum, as PTH is most stable in EDTA plasma 1, 2
• Be aware that biotin supplements can interfere with PTH assays and cause under- or overestimation depending on assay design 1, 2
• Consider that PTH levels are influenced by race (20% higher in Black individuals), age (increases with declining GFR), and BMI (elevated BMI increases PTH) 1, 2

Confirmatory and Severity Assessment Testing

• 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
• Note that vitamin D deficiency can suppress urine calcium excretion and mask hypercalciuria 1

Differential Diagnosis

• Secondary hyperparathyroidism: normal or low serum calcium with elevated PTH, commonly from chronic kidney disease or vitamin D deficiency 1
• Tertiary hyperparathyroidism: hypercalcemia with elevated PTH, typically in end-stage renal disease 1
• Familial hypocalciuric hypercalcemia: requires urine calcium measurement to differentiate 3

Imaging for Surgical Localization

Imaging has no utility in confirming or excluding the diagnosis of hyperparathyroidism but is essential for localization when surgery is planned. 1

Recommended Imaging Studies

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

Surgical Management

Parathyroidectomy is the only curative treatment for primary hyperparathyroidism and should be performed in patients meeting specific surgical criteria. 4

Absolute Indications for Surgery

• Symptomatic disease including kidney stones, bone pain, fractures, and neuromuscular symptoms 4
• Osteoporosis on DEXA scan 4, 2
• Impaired kidney function (GFR <60 mL/min/1.73 m²) 4, 2
• Serum calcium >0.25 mmol/L (>1 mg/dL) above the upper limit of normal 1, 2
• 24-hour urine calcium >400 mg/day 1
• Age <50 years 1

Surgical Approach Options

• Minimally invasive parathyroidectomy (MIP) offers shorter operating times, faster recovery, and decreased perioperative costs compared to bilateral neck exploration 4
• MIP requires confident preoperative localization of a single parathyroid adenoma and intraoperative PTH monitoring 4
• For refractory cases with persistent iPTH >800 pg/mL with hypercalcemia and/or hyperphosphatemia despite medical therapy, total parathyroidectomy with or without autotransplantation is recommended 4, 2

Postoperative Monitoring

• Monitor ionized calcium every 4-6 hours for the first 48-72 hours after surgery, then twice daily until stable 2
• If calcium falls below normal, initiate calcium gluconate infusion 2

Medical Management for Non-Surgical Candidates

Medical management is reserved for asymptomatic patients who do not meet surgical criteria or have contraindications to surgery. 5

Medical Therapy Options

• Optimize calcium and vitamin D intake: ensure adequate dietary calcium and supplement vitamin D to achieve 25-OH vitamin D levels >20 ng/mL (50 nmol/L) 2
• Bisphosphonates may be used for skeletal protection, though no fracture outcome data currently exist 5
• Calcimimetics can be considered to lower serum calcium levels 5
• Hormone replacement therapy or raloxifene may be options for postmenopausal women 5

Monitoring for Non-Surgical Patients

• Regular monitoring of serum calcium, PTH, and kidney function is safe for asymptomatic patients not meeting surgical criteria 5
• Reassess surgical criteria periodically as disease may progress 6

Special Populations

Chronic Kidney Disease Patients

• For CKD patients on dialysis, parathyroidectomy is reserved for refractory and/or symptomatic hypercalcemia, refractory hyperphosphatemia, severe intractable pruritus, calcium × phosphorus product persistently exceeding 70-80 mg²/dL², and calciphylaxis 4
• Initial medical management includes dietary phosphate restriction, phosphate binders, calcium supplementation, and vitamin D sterols (calcitriol, paricalcitol, doxercalciferol) 4
• Cinacalcet may be considered for persistent secondary hyperparathyroidism despite initial therapy, starting at 30 mg once daily 4

Critical Pitfalls to Avoid

• Never interpret PTH levels without assessing vitamin D status, as deficiency causes secondary hyperparathyroidism and confounds diagnosis 1, 2
• Do not use PTH values from different laboratories or assay generations interchangeably without considering assay-specific reference ranges 1, 2
• Recognize that some patients with primary hyperparathyroidism may have PTH levels in the "normal" range that are inappropriately normal for the degree of hypercalcemia 7, 8
• In CKD patients, exclude aluminum-induced bone disease before proceeding to parathyroidectomy 4