What is primary hyperparathyroidism?

What is Primary Hyperparathyroidism?

Primary hyperparathyroidism (PHPT) is a disorder in which one or more parathyroid glands autonomously overproduce parathyroid hormone (PTH), typically resulting in hypercalcemia. 1

Pathophysiology and Etiology

• PHPT occurs when parathyroid glands excessively secrete PTH independent of normal regulatory feedback mechanisms, leading to elevated serum calcium levels 1, 2
• A single benign parathyroid adenoma causes approximately 80% of all PHPT cases 1, 3
• Multigland disease (multiple adenomas or hyperplasia) accounts for 15-20% of cases 1
• Parathyroid carcinoma is rare, occurring in less than 1% of cases 1
• Most cases are sporadic, though hereditary forms exist including multiple endocrine neoplasia types 1 and 2A, as well as familial hyperparathyroidism 1

Biochemical Hallmark and Diagnosis

The diagnosis of PHPT is established biochemically by demonstrating hypercalcemia (or high-normal calcium) with elevated or inappropriately normal PTH levels. 4, 5

Diagnostic Criteria:

• Measure serum calcium (corrected for albumin) and intact PTH simultaneously 4
• Hypercalcemia with normal or elevated PTH is diagnostic 3
• Serum phosphate is typically low or low-normal 4
• Imaging has no utility in confirming or excluding the diagnosis of PHPT—it is used solely for preoperative localization 1, 3

Important Diagnostic Considerations:

• Assess 25-hydroxyvitamin D levels, as vitamin D deficiency can complicate PTH interpretation 3, 4
• Measure serum creatinine to evaluate kidney function 4
• A 24-hour urine collection for calcium and other metabolites helps evaluate complications 4

Clinical Presentation Spectrum

Geographic Variation in Presentation:

• In countries with routine biochemical screening (United States, Canada, most of Europe), PHPT predominantly presents as asymptomatic hypercalcemia 1, 2
• In countries without routine screening (China, India), PHPT typically presents with symptomatic target organ involvement 1

Symptomatic Manifestations:

• Bone demineralization and pathologic fractures 1
• Nephrolithiasis and nephrocalcinosis 1, 6
• Muscle weakness 1
• Neurocognitive disorders 1
• Pancreatitis (less common) 6

Normocalcemic Variant:

• A forme fruste variant exists where serum calcium remains persistently normal but PTH is consistently elevated without an obvious secondary cause 2, 7

Epidemiology

• PHPT is more common in women, with an incidence of 66 per 100,000 person-years compared to 25 per 100,000 person-years in men 1
• The prevalence appears to be increasing significantly 1
• PHPT is uncommon in children, with an estimated incidence of 2-5 cases per 100,000 persons 6

Clinical Significance and Complications

• PHPT is recognized as a secondary cause of hypertension in major cardiovascular guidelines 8, 3
• Long-term hypercalcemia can lead to persistent hypertension, kidney stones, bone disease, and other complications 8, 3
• Patients with 24-hour urine calcium >400 mg/day are at increased risk for kidney stone formation and bone complications 4

Treatment Approach

Surgical excision of the abnormally functioning parathyroid tissue is the definitive curative treatment and is typically indicated even when asymptomatic, given the potential negative effects of long-term hypercalcemia. 1, 8, 3

Surgical Options:

• Minimally invasive parathyroidectomy (MIP) requires confident preoperative localization of a single adenoma and offers shorter operating times, faster recovery, and decreased costs 1
• Bilateral neck exploration (BNE) remains necessary for discordant/nonlocalizing imaging or high suspicion for multigland disease 1

Preoperative Localization Imaging:

• First-line imaging includes ultrasound and 99mTc-sestamibi scintigraphy with SPECT/CT 3, 4
• 4D-CT (noncontrast, arterial, and venous phases) may be useful for reoperative cases or suspected ectopic glands 3, 4
• Remember: imaging is performed solely for surgical planning, not for diagnosis 3, 4

Common Pitfalls to Avoid

• Do not use imaging to diagnose PHPT—diagnosis is biochemical only 1, 3
• Always assess vitamin D status before interpreting PTH levels, as deficiency can mask the diagnosis 4
• Be aware that different PTH assay generations measure different PTH fragments and lack standardization between laboratories 4
• Biotin supplements can interfere with PTH assays 4