What are the causes of elevated parathyroid hormone (PTH) levels?

Causes of Elevated Parathyroid Hormone (PTH)

Elevated PTH results from either autonomous parathyroid overproduction (primary hyperparathyroidism) or appropriate physiologic compensation for calcium/vitamin D disturbances (secondary hyperparathyroidism), with chronic kidney disease and vitamin D deficiency being the most common secondary causes.

Primary Hyperparathyroidism (Autonomous PTH Production)

Primary hyperparathyroidism is characterized by hypercalcemia with elevated or inappropriately normal PTH levels, caused by autonomous parathyroid gland dysfunction. 1

Specific Etiologies:

• Solitary parathyroid adenoma: Accounts for 80-90% of all primary hyperparathyroidism cases 1, 2
• Multiglandular disease: Includes multiple adenomas or four-gland hyperplasia in 10-15% of cases 1
• Parathyroid carcinoma: Rare cause occurring in less than 1% of cases 1, 3
• Ectopic parathyroid adenomas: Result from abnormal embryological migration and can be difficult to localize 2

Risk Factors for Multiglandular Disease:

• Genetic syndromes (MEN1, MEN2A) 2
• Lithium therapy 2
• Previous radiotherapy 2

Secondary Hyperparathyroidism (Physiologic Compensation)

Secondary hyperparathyroidism is characterized by normal or low serum calcium with elevated PTH, representing appropriate parathyroid response to calcium homeostasis disturbances. 4, 1

Major Causes:

Chronic Kidney Disease:

• Declining kidney function disrupts calcium and phosphate homeostasis 4
• PTH increases in response to hyperphosphatemia, hypocalcemia, lowered 1,25-dihydroxy-vitamin D, and elevated FGF23 4
• C-terminal PTH fragments accumulate with progressive kidney disease 4
• Almost 90% of renal transplant recipients have elevated PTH at transplantation, with over 30% persisting up to 3 years post-transplant 4, 1

Vitamin D Deficiency:

• Most frequent cause of secondary hyperparathyroidism 5
• Vitamin D deficiency causes PTH elevation due to reduced calcium absorption 4
• PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status 4
• A 25-hydroxyvitamin D level >20 ng/mL (>50 nmol/L) is required to exclude vitamin D deficiency as the cause 5

Malabsorption Syndromes:

• Reduced calcium availability from gastrointestinal disorders 4

Dietary Calcium Deficiency:

• Inadequate calcium intake stimulates compensatory PTH secretion 5

Tertiary Hyperparathyroidism (Autonomous After Prolonged Secondary)

Tertiary hyperparathyroidism occurs when long-standing secondary hyperparathyroidism becomes autonomous, characterized by hypercalcemia with elevated PTH despite removal of the original stimulus. 4, 1

• Most commonly encountered following kidney transplantation in patients with long-standing chronic kidney disease 4
• Results from parathyroid glands that have become autonomous after prolonged stimulation 6
• Hypercalcemia occurs in 10-22% of renal transplant recipients 4

Normocalcemic Primary Hyperparathyroidism

This variant presents with persistently elevated PTH and consistently normal albumin-corrected serum calcium after exclusion of all secondary causes. 4, 5

• Patients remain at risk for complications associated with classic primary hyperparathyroidism despite normal calcium 4
• Diagnosis requires vitamin D level >20 ng/mL, adequate dietary calcium intake (1000-1200 mg/day), and normal kidney function (eGFR ≥60 mL/min/1.73 m²) 5

Critical Diagnostic Considerations

PTH Assay Variability:

• PTH assays differ by up to 47% between different generations due to varying antibody recognition of PTH fragments 4
• Always use assay-specific reference values 4
• EDTA plasma is preferred over serum for PTH measurement as PTH is most stable in EDTA plasma 4

Factors Influencing PTH Levels:

• Race: PTH is higher in Black compared to White individuals 4
• Age: PTH increases with age due to declining GFR 4
• BMI: PTH correlates positively with body mass index 4
• Vitamin D status: Vitamin D deficiency elevates PTH by 20% 4
• Biological variation: Within-subject PTH variation is ~20% in healthy people and up to 30% in hemodialysis patients 4

Common Pitfalls to Avoid:

• Not assessing vitamin D status before diagnosing primary hyperparathyroidism 5
• Vitamin D deficiency can suppress urine calcium excretion in primary hyperparathyroidism, potentially masking hypercalciuria 4
• Biotin supplements can interfere with PTH assays, causing under- or overestimation depending on assay design 4
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments 4