What does elevated Parathyroid Hormone (PTH) mean?

Elevated Parathyroid Hormone (PTH): Clinical Significance and Management

Elevated parathyroid hormone (PTH) primarily indicates a disorder of calcium homeostasis, most commonly primary hyperparathyroidism, which requires evaluation for hypercalcemia and end-organ damage to bones and kidneys. 1

Types of Hyperparathyroidism

Primary Hyperparathyroidism (PHPT)

• Defined as autonomous overproduction of PTH, typically resulting in hypercalcemia 1
• Most commonly caused by:
  • Single parathyroid adenoma (80%)
  • Multiple adenomas or hyperplasia (15-20%)
  • Parathyroid carcinoma (<1%) 1
• Clinical presentation:
  • Often asymptomatic in countries with routine biochemical screening
  • Can present with target organ involvement: bone demineralization, fractures, nephrolithiasis, muscle weakness 1

Secondary Hyperparathyroidism

• Physiologic response to low calcium levels or vitamin D deficiency 1
• Common causes:
  • Chronic kidney disease (CKD)
  • Vitamin D deficiency
  • Decreased intestinal calcium absorption 1
• In CKD, phosphate retention leads to decreased calcium levels, stimulating PTH secretion 1

Normocalcemic Primary Hyperparathyroidism (NPHPT)

• Elevated PTH with normal calcium levels
• Requires exclusion of secondary causes before diagnosis 2

Tertiary Hyperparathyroidism

• Occurs when hyperplastic parathyroid glands become autonomous
• Often seen after kidney transplantation in patients with longstanding secondary hyperparathyroidism 3

Factors Affecting PTH Measurement and Interpretation

• Preanalytical conditions: EDTA plasma preferred over serum for stability 1
• Biological variation: Within-subject variation of ~20% in healthy people, up to 30% in hemodialysis patients 1
• Demographic factors:
  • Race: Higher PTH in Black compared to White people
  • Age: PTH increases with age (related to declining GFR)
  • BMI: Higher PTH in obese patients 1
• Vitamin D status: Vitamin D deficiency increases PTH concentration 1
• Biotin supplements: Can interfere with PTH assays 1

Clinical Implications of Elevated PTH

Bone Health

• Elevated PTH promotes calcium release from bones, potentially leading to:
  • Osteoporosis
  • Increased fracture risk
  • Bone demineralization 1, 4

Kidney Function

• Can cause:
  • Nephrolithiasis (kidney stones)
  • Nephrocalcinosis
  • Hypercalciuria 1

Cardiovascular System

• Associated with:
  • Cardiomyopathy
  • Vascular calcification 4

Other Systems

• May contribute to:
  • Immunodeficiency
  • Impaired erythropoiesis
  • Increased energy expenditure
  • Muscle weakness 4

Diagnostic Approach

1. Confirm elevated PTH (accounting for assay-specific reference ranges) 1
2. Measure serum calcium:
   • If elevated: Likely primary hyperparathyroidism
   • If normal: Consider normocalcemic PHPT or secondary causes 2
3. Rule out secondary causes:
   • Vitamin D deficiency
   • Renal insufficiency
   • Medications affecting calcium metabolism
   • Gastrointestinal disorders affecting absorption 2
4. Evaluate for end-organ damage:
   • Bone mineral density testing
   • Kidney function and imaging for stones
   • Cardiovascular assessment 5

Management Considerations

Primary Hyperparathyroidism

• Surgical treatment (parathyroidectomy) is indicated for:
  • Symptomatic patients
  • Osteoporosis
  • Impaired kidney function (GFR < 60 mL/min/1.73 m²)
  • Kidney stones
  • Hypercalciuria
  • Age ≥ 50 years
  • Calcium > 0.25 mmol/L above upper limit of normal 1, 5
• Surgical approaches:
  • Bilateral neck exploration (BNE)
  • Minimally invasive parathyroidectomy (MIP) - preferred for single adenomas 1, 5

Secondary Hyperparathyroidism

• Treatment based on underlying cause:
  • Vitamin D supplementation for deficiency
  • Calcium supplementation if needed
  • In CKD: phosphate binders, active vitamin D, calcimimetics 1, 5
• Target PTH levels vary by CKD stage:
  • CKD G3: <70 pg/mL
  • CKD G4: <110 pg/mL
  • CKD G5: <300 pg/mL
  • CKD G5D (dialysis): 150-600 pg/mL 5

Clinical Pitfalls and Caveats

1. Underdiagnosis is common: Studies show that up to 72% of patients with hypercalcemia never have PTH levels checked 6
2. Assay variability: Different PTH assays may yield different results; use assay-specific reference ranges 1
3. Vitamin D status affects interpretation: Excluding vitamin D-deficient subjects leads to lower upper reference values for PTH 1
4. Post-transplant hyperparathyroidism: May persist in kidney transplant recipients, requiring monitoring and potential intervention 1
5. Normocalcemic PHPT: Can be easily missed but may still cause end-organ damage 2

By understanding the significance of elevated PTH and following a systematic diagnostic approach, clinicians can identify the underlying cause and implement appropriate management strategies to prevent complications related to bone health, kidney function, and cardiovascular disease.