What does elevated Parathyroid Hormone (PTH) mean?

Understanding Elevated Parathyroid Hormone (PTH)

Elevated PTH indicates a disruption in calcium homeostasis, most commonly representing primary hyperparathyroidism, secondary hyperparathyroidism due to chronic kidney disease, or vitamin D deficiency. The clinical significance and management depend on identifying the underlying cause.

Primary Causes of Elevated PTH

Primary Hyperparathyroidism (PHPT)

• Characterized by autonomous overproduction of PTH, typically from a parathyroid adenoma
• Diagnostic features:
  • Hypercalcemia with elevated or inappropriately normal PTH levels 1
  • May present as:
    1. Symptomatic disease with target organ involvement
    2. Mild asymptomatic hypercalcemia (most common in countries with routine biochemical screening)
    3. Normocalcemic variant (normal serum calcium with elevated PTH) 2, 1
• Clinical implications:
  • Increased risk of cardiovascular disease, osteoporosis, psychiatric disturbances, and renal complications 3
  • Preferential bone loss in cortical bone (distal radius) while cancellous bone (lumbar spine) is relatively preserved 2
  • Renal stones remain the most common overt complication 2

Secondary Hyperparathyroidism

Chronic Kidney Disease (CKD)

• Pathophysiology:
  • Declining kidney function leads to disturbances in calcium and phosphate homeostasis
  • Hyperphosphatemia, hypocalcemia, reduced 1,25-dihydroxy-vitamin D, and elevated FGF23 stimulate PTH secretion 4
• Clinical implications:
  • Contributes to CKD-mineral and bone disorder (CKD-MBD)
  • Associated with increased risk of fractures, cardiovascular events, and mortality 4
  • Can lead to parathyroid gland hyperplasia that may persist even after kidney transplantation 4

Vitamin D Deficiency

• Low vitamin D status leads to compensatory increase in PTH
• Reference values for PTH are approximately 20% lower when established in vitamin D-sufficient individuals 5
• Essential to assess vitamin D status when interpreting elevated PTH results 5

Factors Affecting PTH Measurement and Interpretation

• Assay variability: Different PTH assays can yield results varying by up to 47% 5
• Demographic factors:
  • PTH levels are higher in Black compared to White individuals
  • Positively correlated with BMI
  • Increase with age, particularly in people over 60 years 5
• Sample handling: PTH is more stable in EDTA plasma than in serum 5
• Biotin supplements can interfere with PTH assays 5
• Within-subject variation: Approximately 20% in healthy individuals and up to 30% in hemodialysis patients 5

Clinical Consequences of Persistent Hyperparathyroidism

Skeletal Effects

• Increased bone turnover leading to bone loss and fracture risk
• In CKD patients, PTH is associated with fracture risk (HR 1.04,95% CI 1.01-1.08) 4
• Contributes to renal osteodystrophy in CKD patients 4

Cardiovascular Effects

• PTH acts as a uremic toxin in CKD patients 6
• Associated with vascular calcification and increased cardiovascular mortality 6

Metabolic Effects

• Hypercalcemia (in primary hyperparathyroidism)
• Hypophosphatemia (especially in CKD patients post-transplant) 4
• Increased energy expenditure 6

Management Considerations

In Primary Hyperparathyroidism

• Parathyroidectomy is the only definitive treatment 3
• Early detection may allow for medical and lifestyle interventions before complications develop 3

In CKD-Related Secondary Hyperparathyroidism

• Optimal PTH level in CKD patients differs from normal reference range
• For CKD G5D patients, PTH target range is 2-9 times the upper limit of normal 4
• Treatment options include:
  1. Phosphate binders to control hyperphosphatemia
  2. Vitamin D supplementation for deficiency
  3. Calcitriol for management of secondary hyperparathyroidism in moderate to severe CKD 7
  4. Calcimimetics (e.g., cinacalcet) for PTH reduction in dialysis patients 8
  5. Parathyroidectomy for severe, refractory cases 4

Common Pitfalls in PTH Interpretation

1. Failing to check PTH levels in patients with hypercalcemia (72.3% of hypercalcemic patients in one study never had PTH levels measured) 3
2. Not considering vitamin D status when interpreting PTH levels
3. Overlooking normocalcemic hyperparathyroidism as a clinical entity
4. Applying normal reference ranges to CKD patients (may lead to adynamic bone disease) 5
5. Not accounting for assay variability and pre-analytical factors

Conclusion

Elevated PTH requires a systematic approach to diagnosis that includes assessment of calcium, phosphate, vitamin D status, and kidney function. The clinical significance varies widely from an incidental laboratory finding to a marker of significant metabolic bone disease requiring surgical intervention.