What does a high intact Parathyroid Hormone (PTH) level indicate?

High Intact PTH: Clinical Significance and Interpretation

An elevated intact PTH level indicates either primary hyperparathyroidism (autonomous PTH secretion with hypercalcemia) or secondary hyperparathyroidism (physiologic PTH elevation in response to hypocalcemia, hyperphosphatemia, vitamin D deficiency, or chronic kidney disease). 1

Primary Diagnostic Framework

The interpretation of high intact PTH depends critically on the serum calcium level:

High PTH with Hypercalcemia or High-Normal Calcium

• This pattern indicates primary hyperparathyroidism (PHPT), characterized by autonomous parathyroid hormone production 2, 3
• PTH levels are either frankly elevated or "inappropriately normal" (within reference range despite hypercalcemia) 2, 4
• PHPT is the third most common endocrine disease and typically presents asymptomatically with incidental hypercalcemia 5
• The intact PTH assay is superior to measurement of PTH fragments for diagnosing PHPT 6

High PTH with Normal Calcium (Normocalcemic)

• This requires careful differentiation between normocalcemic primary hyperparathyroidism (NPHPT) and secondary hyperparathyroidism (SHPT) 4
• NPHPT represents autonomous parathyroid function without overt hypercalcemia, while SHPT is a physiologic response to metabolic disturbances 4
• The diagnosis of NPHPT should only be made after excluding all causes of SHPT, including vitamin D deficiency, renal insufficiency, medications, and malabsorption 4

High PTH with Low or Low-Normal Calcium

• This definitively indicates secondary hyperparathyroidism 1
• Common causes include chronic kidney disease, vitamin D deficiency, hyperphosphatemia, and malabsorption 1, 7

Secondary Hyperparathyroidism in Chronic Kidney Disease

In CKD patients, PTH elevation is a compensatory response to maintain mineral homeostasis:

• PTH levels begin rising when GFR falls below 60 mL/min/1.73 m² (CKD Stage 3) 7
• The phosphaturic effect of PTH helps maintain normal serum phosphate levels as kidney function declines 7
• When creatinine clearance falls below 20-30 mL/min/1.73 m² (CKD Stage 4), the maximum phosphaturic effect is reached and serum phosphorus rises despite elevated PTH 7

Stage-Specific PTH Targets in CKD (K/DOQI Guidelines):

• CKD Stage 3: PTH >70 pg/mL warrants dietary phosphate restriction and possible vitamin D therapy 1
• CKD Stage 4: PTH >110 pg/mL requires intervention 1
• CKD Stage 5 (dialysis): PTH >300 pg/mL requires active vitamin D sterols or analogs to prevent high-turnover bone disease 1
• Target PTH range for dialysis patients is 150-300 pg/mL 7, 8

Clinical Consequences of Elevated PTH

Bone Disease

• High PTH levels (typically >400 pg/mL) are associated with high-turnover bone disease (osteitis fibrosa and mixed uremic osteodystrophy) 1
• This manifests as increased osteoclasts, osteoblasts, abnormal bone resorption and formation, and marrow fibrosis 1
• In PHPT, complications include nephrolithiasis, nephrocalcinosis, osseous pain, subperiosteal resorption, pathologic fractures, and osteoporosis 2, 5

Cardiovascular and Renal Effects

• Elevated PTH contributes to hyperphosphatemia, which drives vascular calcification and increases cardiovascular mortality 1
• PHPT is associated with reduced kidney function, hypercalciuria, asymptomatic kidney stones, and increased cardiovascular morbidity and mortality 5

Mineral Metabolism Disturbances

• High PTH increases phosphate excretion (phosphaturic effect) but also stimulates 1,25-dihydroxyvitamin D production 7
• In advanced CKD, this compensatory mechanism fails, leading to hyperphosphatemia despite elevated PTH 7

Critical Assay Considerations

Intact PTH assays have important limitations:

• Second-generation "intact PTH" assays detect both active PTH (1-84) and biologically inactive fragments (particularly 7-84 PTH) 7
• This leads to overestimation of biologically active PTH, especially in CKD patients 1, 7
• Attempting to maintain intact PTH in the "normal" range (<65 pg/mL) in CKD patients can cause adynamic bone disease (low bone turnover) 1, 7
• Third-generation assays are more specific, measuring only full-length PTH, but measurements can vary up to 47% between assay generations 7

Common Pitfalls to Avoid

• Do not assume normal calcium excludes PHPT: Normocalcemic PHPT exists but requires exclusion of all SHPT causes first 4
• Do not target "normal" PTH ranges in CKD: This causes adynamic bone disease; use stage-specific targets 1, 7
• Do not ignore vitamin D status: Vitamin D deficiency is a common and reversible cause of secondary hyperparathyroidism 7
• Do not overlook medications: Various drugs can increase PTH secretion and must be considered 4
• Know which PTH assay is being used: Different generations yield different results affecting clinical decisions 7