What are the initial steps in investigating hyperparathyroidism?

Investigation of Hyperparathyroidism

Measure serum calcium (corrected for albumin) and intact parathyroid hormone (iPTH) simultaneously as the first diagnostic step—hypercalcemia with elevated or inappropriately normal PTH confirms primary hyperparathyroidism. 1, 2

Initial Biochemical Testing

The diagnostic cornerstone requires simultaneous measurement of three core laboratory values 2:

• Serum calcium (total calcium corrected for albumin): Hypercalcemia is the hallmark finding in primary hyperparathyroidism 1, 2
• Intact parathyroid hormone (iPTH): Elevated or inappropriately normal PTH in the setting of hypercalcemia confirms the diagnosis 1, 2
• Serum phosphorus: Typically low or low-normal in primary hyperparathyroidism 1, 2

Critical Technical Considerations for PTH Measurement

Use assay-specific reference ranges when interpreting PTH results, as different assay generations measure different PTH fragments and can yield significantly different values. 3, 2 The lack of standardization between PTH assays leads to remarkable differences in measured concentrations between laboratories, even when using the same assay generation 3, 2. Collect blood samples in EDTA tubes, as PTH is most stable in EDTA plasma 1, 2.

Be aware that biotin supplements can interfere with PTH assays, causing falsely elevated or decreased results depending on the assay design 1, 2. Additionally, PTH levels are influenced by race (higher in Black individuals), age (increases with age), and BMI (elevated in obese patients) 2.

Essential Complementary Tests

After establishing the calcium-PTH relationship, obtain these additional studies 1, 2:

• 25-hydroxyvitamin D: Vitamin D deficiency complicates PTH interpretation and can mask hypercalciuria in primary hyperparathyroidism patients 1, 2
• Serum creatinine: Essential to assess kidney function, as hypercalcemia can cause kidney damage and chronic kidney disease alters PTH interpretation 1, 2
• Serum chloride: Elevated chloride supports primary hyperparathyroidism in the differential diagnosis 2, 4
• Alkaline phosphatase: Serves as a marker of hyperparathyroid bone disease severity 2

Diagnostic Algorithm Based on Biochemical Pattern

Primary Hyperparathyroidism

Elevated serum calcium + elevated or inappropriately normal PTH + low/low-normal phosphorus = Primary hyperparathyroidism 2

Secondary Hyperparathyroidism

Normal or low serum calcium + elevated PTH = Secondary hyperparathyroidism, commonly from chronic kidney disease or vitamin D deficiency 1, 2

Tertiary Hyperparathyroidism

Hypercalcemia with elevated PTH in end-stage renal disease = Tertiary hyperparathyroidism 1

24-Hour Urine Collection

A 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine should be obtained to evaluate complications and metabolic abnormalities. 1, 2 This is particularly important because:

• Urine calcium >400 mg/day identifies patients at increased risk for kidney stone formation and bone complications, and represents a surgical indication 1
• Most primary hyperparathyroidism patients demonstrate hypercalciuria (>250-300 mg/day) due to increased filtered calcium load 1
• Vitamin D deficiency can suppress urine calcium excretion, potentially masking hypercalciuria 1

Special Diagnostic Considerations

Normocalcemic Hyperparathyroidism

Approximately 21% of primary hyperparathyroidism patients present with calcium ≤10.5 mg/dL and PTH ≥65 pg/dL 5. In these cases, ionized calcium measurement is superior to total calcium for diagnosis, as 95% of ionized calcium values are elevated even when total calcium is normal. 6

Chronic Kidney Disease Patients

In patients with CKD and GFR <60 mL/min/1.73 m², measure calcium, phosphorus, and intact PTH regularly to monitor for secondary hyperparathyroidism 2. When serum intact PTH levels are between 100 and 500 pg/mL (11.0 to 55.0 pmol/L) in CKD patients, there is insufficient sensitivity and specificity to reliably predict bone disease type 3. If unexplained hypercalcemia, bone pain, or increased bone alkaline phosphatase develops in this PTH range, bone biopsy may be useful 3.

Imaging Studies (After Biochemical Diagnosis)

Imaging has no utility in confirming or excluding the diagnosis of hyperparathyroidism—it is used only for localization after biochemical diagnosis is established. 3

When surgery is planned, obtain localization imaging 3, 1:

• Ultrasound of the neck: First-line localization study 1
• 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: Consider for reoperative cases, suspected ectopic glands, or when initial imaging is negative 3, 1

Common Pitfalls to Avoid

• Not assessing vitamin D status when interpreting PTH levels leads to misdiagnosis 1
• Screening patients with osteoporosis using only total calcium will miss cases with normocalcemic hyperparathyroidism—use ionized calcium and intact PTH 6
• Relying on a single calcium measurement is insufficient—primary hyperparathyroidism requires demonstration of persistent hypercalcemia or inappropriately normal/elevated PTH 4
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments results in inaccurate diagnoses 3, 1

When to Refer to Specialists

Refer patients with confirmed hyperparathyroidism to an endocrinologist for management, and when surgery is indicated, to a surgeon with specific experience in parathyroid disease. 7 For hereditary syndromes (MEN types 1 and 2A, hyperparathyroid-jaw tumor syndrome), patients should be followed at centers with expertise in genetic interpretation and long-term surveillance 7.