Why does parathyroid hormone become elevated?

Why Parathyroid Hormone Becomes Elevated

Parathyroid hormone (PTH) becomes elevated primarily through three interconnected mechanisms: hypocalcemia triggering compensatory PTH secretion, hyperphosphatemia directly stimulating PTH production, and vitamin D deficiency reducing negative feedback on the parathyroid glands. 1

Primary Physiologic Mechanisms

Hypocalcemia-Driven PTH Elevation

• Low serum calcium is sensed by calcium-sensing receptors on parathyroid chief cells, which immediately triggers PTH release to restore calcium homeostasis. 1 This represents the most fundamental regulatory pathway.

• The parathyroid glands respond to even transient, undetectable increases in serum phosphorus by releasing PTH, which then increases urinary phosphate excretion to maintain normal phosphate levels—but at the expense of establishing a new steady state with chronically elevated PTH. 1

• In chronic kidney disease (CKD), PTH begins rising when GFR falls below 60 mL/min/1.73 m² due to the kidneys' inability to maintain calcium and phosphate balance. 1

Direct Phosphate Stimulation

• High extracellular phosphate levels directly stimulate both PTH secretion and prepro-PTH mRNA production in human parathyroid tissue, independent of calcium levels. 2 This mechanism is particularly important in renal failure.

• Phosphate retention occurs early in CKD with each decrement in kidney function, creating transient hyperphosphatemia that decreases ionized calcium and stimulates PTH release. 1

• Even when serum phosphorus appears normal or low-normal in early CKD (Stage 3), the parathyroid glands have already been stimulated by prior phosphate retention episodes. 1

Vitamin D Deficiency and Impaired Negative Feedback

• 1α,25-dihydroxyvitamin D normally suppresses PTH gene transcription by binding to vitamin D receptors that heterodimerize with retinoic acid X receptors; deficiency removes this brake on PTH production. 3

• Vitamin D deficiency is the most common cause of secondary hyperparathyroidism and must be evaluated first when encountering elevated PTH with normal calcium. 4, 5

• In CKD, declining kidney function reduces 1α-hydroxylase activity, decreasing conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D, which removes direct transcriptional suppression of the PTH gene. 1

Secondary Mechanisms in Chronic Disease States

Parathyroid Gland Remodeling in CKD

• Progressive loss of vitamin D receptors and calcium-sensing receptors occurs in parathyroid glands as CKD advances, rendering them increasingly resistant to both vitamin D and calcium suppression. 1

• Altered mRNA-binding protein activities within parathyroid cells increase PTH mRNA stability and translation, amplifying hormone production beyond what calcium and vitamin D changes alone would explain. 3

• Hyperphosphatemia directly affects parathyroid gland growth and function, promoting parathyroid hyperplasia that perpetuates elevated PTH even when other factors are corrected. 1

Skeletal Resistance to PTH

• In CKD, bones develop resistance to the calcemic action of PTH, requiring higher PTH levels to maintain serum calcium, which further drives compensatory PTH elevation. 1

Primary Hyperparathyroidism: Autonomous PTH Production

• In primary hyperparathyroidism, parathyroid adenomas or hyperplasia autonomously secrete PTH despite elevated calcium, representing a failure of normal calcium-sensing receptor feedback. 6, 5

• PTH secretion in primary hyperparathyroidism is not totally autonomous—calcium infusion can suppress PTH by 30-50% within 5-7.5 minutes—but the set-point for suppression is abnormally high. 7

• Normocalcemic primary hyperparathyroidism demonstrates that autonomous PTH elevation can occur even before hypercalcemia develops, indicating early parathyroid dysfunction. 4, 5

Critical Clinical Distinctions

Differentiating Primary from Secondary Causes

• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, whereas elevated PTH with normal or low calcium suggests secondary hyperparathyroidism. 6, 4

• The most common causes of secondary hyperparathyroidism are vitamin D deficiency (25-hydroxyvitamin D <30 ng/mL), early CKD (eGFR <60 mL/min/1.73 m²), and malabsorption disorders reducing calcium availability. 4

• Measuring 25-hydroxyvitamin D, serum creatinine/eGFR, serum phosphate, and 24-hour urine calcium distinguishes between normocalcemic primary hyperparathyroidism and secondary causes. 4

Important Measurement Considerations

PTH Assay Variability

• PTH assay results can vary by up to 47% between different assay generations because second-generation "intact" assays detect C-terminal fragments that overestimate biologically active PTH, while third-generation "whole" assays are more specific. 1, 4

• C-terminal PTH fragments accumulate in kidney disease (half-life 5-10 times longer than full-length PTH), causing assay-dependent differences in measured PTH concentrations even when using the same generation assay. 1

• PTH is most stable in EDTA plasma stored at 4°C, and biotin supplementation can interfere with immunoassays, leading to spurious results. 6, 4

Biological Factors Affecting PTH Levels

• PTH concentrations are influenced by age (increases with declining GFR in those >60 years), race (20% higher in Black individuals), BMI (positively correlated), and vitamin D status (20% lower reference values in vitamin D-replete individuals). 1, 6, 4

• Biological variation of PTH is substantial—approximately 20% in healthy individuals and up to 30% in hemodialysis patients—meaning changes must exceed 54% in healthy people or 72% in dialysis patients to be clinically meaningful. 6, 4