What is the recommended workup for a patient presenting with potential parathyroid issues?

Workup for Parathyroid Disease

The initial workup for suspected parathyroid disease requires simultaneous measurement of serum calcium and PTH to differentiate PTH-dependent from PTH-independent hypercalcemia, followed by targeted evaluation based on this critical distinction. 1, 2

Initial Laboratory Assessment

Obtain these tests simultaneously:

• Serum calcium (total and ionized) – the cornerstone measurement that determines urgency and direction of workup 1, 2
• Intact PTH (iPTH) – distinguishes primary hyperparathyroidism (elevated or inappropriately normal PTH with hypercalcemia) from PTH-independent causes (suppressed PTH) 1, 2, 3
• Serum phosphorus – typically low in primary hyperparathyroidism and PTHrP-mediated hypercalcemia; helps differentiate from other causes 1, 3
• Serum albumin – necessary to correct total calcium if ionized calcium unavailable 1
• 25-hydroxyvitamin D – vitamin D deficiency can mask severity of hyperparathyroidism and must be assessed before surgical decisions 2, 4
• Serum creatinine and eGFR – essential to distinguish primary from secondary hyperparathyroidism related to chronic kidney disease 5, 3

Interpretation Algorithm

If Calcium is Elevated with Elevated or Inappropriately Normal PTH:

This indicates primary hyperparathyroidism 2, 3, 6

Additional workup includes:

• Confirm vitamin D status – measure 25-hydroxyvitamin D, as deficiency should be repleted before surgical decision-making (target ≥50 nmol/L or 20 ng/mL minimum, though ≥75 nmol/L or 30 ng/mL is reasonable) 2, 4
• 24-hour urine calcium – to exclude familial hypocalciuric hypercalcemia (low urinary calcium excretion) 3
• Assess for symptoms – bone disease, kidney stones, neurocognitive symptoms, or cardiovascular manifestations determine surgical candidacy 3, 4

Localization studies (only if surgery is planned):

• Neck ultrasonography – first-line imaging with 76.6% sensitivity for adenoma localization 7
• 99mTc-MIBI (sestamibi) scintigraphy – 83.3% sensitivity; combination with ultrasound does not significantly improve accuracy 7
• Consider additional imaging (4D-CT, MRI) only if initial studies are negative or ectopic adenoma suspected 6

If Calcium is Elevated with Low/Suppressed PTH:

This indicates PTH-independent hypercalcemia – fundamentally different pathophysiology 1

Critical additional tests:

• PTH-related protein (PTHrP) – elevated in malignancy-associated hypercalcemia (most commonly squamous cell lung cancer, occurring in 10-25% of lung cancer patients) 1
• 1,25-dihydroxyvitamin D – elevated in granulomatous disease or lymphoma 1
• 25-hydroxyvitamin D – if markedly elevated (>150 ng/mL), indicates exogenous vitamin D toxicity 1

If Calcium is Low or Normal with Elevated PTH:

This suggests secondary hyperparathyroidism 5, 3

Determine the underlying cause:

• In chronic kidney disease (CKD): PTH elevation is compensatory response to hypocalcemia, hyperphosphatemia, or vitamin D deficiency; measure serum phosphorus and assess CKD stage 5, 3
• In vitamin D deficiency: Measure 25-hydroxyvitamin D; severe deficiency causes secondary hyperparathyroidism managed with calcium and vitamin D replacement 3, 4
• Post-bariatric surgery: Consider malabsorption-related secondary hyperparathyroidism 8

For CKD patients with secondary hyperparathyroidism:

• Bone biopsy may be necessary to accurately diagnose the type of renal osteodystrophy (hyperparathyroid bone disease, adynamic bone disease, osteomalacia, or mixed), as PTH levels between 100-500 pg/mL do not reliably predict underlying bone disease 5

Additional Workup for Specific Scenarios

For Medullary Thyroid Cancer Screening (if MEN syndrome suspected):

• Basal serum calcitonin – elevated in medullary thyroid carcinoma 8
• Serum CEA – tumor marker for MTC 8
• Plasma metanephrines and normetanephrines – to exclude pheochromocytoma in hereditary forms 8

For Genetic Hypophosphatemic Disorders (if hypophosphatemia with renal phosphate wasting):

• Plasma intact FGF23 – non-suppressed levels with hypophosphatemia support X-linked hypophosphatemia (XLH) or other FGF23-mediated disorders 8
• Exclude metabolic acidosis, hypercalciuria, and Fanconi syndrome by measuring serum bicarbonate, urinary calcium, amino acids, glucose, and low-molecular-weight proteins 8
• Genetic testing – confirm diagnosis of XLH by PHEX gene analysis if available 8

Critical Pitfalls to Avoid

• Do not assume "low PTH" means hypoparathyroidism – true hypoparathyroidism presents with hypocalcemia and low PTH, not hypercalcemia; hypercalcemia with low PTH indicates PTH-independent causes requiring malignancy workup 1
• Do not start aggressive vitamin D supplementation in primary hyperparathyroidism before addressing hypercalcemia, as this worsens calcium levels 2
• Do not confuse primary with secondary hyperparathyroidism – secondary occurs in CKD with hypocalcemia or normal calcium, not hypercalcemia 2, 5
• Do not order localization studies (ultrasound, sestamibi) unless surgery is already planned; these do not aid in diagnosis, only surgical planning 7, 6
• Do not delay malignancy workup if PTHrP is elevated – this indicates advanced malignancy with median survival of approximately 1 month in lung cancer patients 1
• Do not restrict calcium intake in patients with primary hyperparathyroidism; recommended calcium intake should follow general population guidelines 4

Assay Considerations

Be aware that PTH assay generation matters: Second- and third-generation PTH assays measure different PTH fragments to varying extents due to lack of standardization 8. For diagnostic purposes in classic primary hyperparathyroidism, the precise PTH concentration is less relevant as diagnosis relies on the PTH-calcium relationship 8. However, in CKD-related secondary hyperparathyroidism, guidelines recommend treating above a twofold to ninefold PTH increase, which will result in different clinical decisions depending on the assay used 8.