Causes of Secondary Hyperparathyroidism
Chronic kidney disease is the most common cause of secondary hyperparathyroidism, with nearly all patients developing parathyroid gland hyperplasia as kidney function declines, driven by phosphate retention, hypocalcemia, and deficiency of active vitamin D. 1
Primary Pathophysiological Mechanisms
Secondary hyperparathyroidism develops through three interconnected mechanisms that begin early in CKD progression:
Phosphate Retention and Hyperphosphatemia
- Phosphate retention occurs as renal excretion capacity diminishes, directly stimulating PTH secretion even when serum phosphorus appears normal 1
- High phosphate intake can independently provoke secondary hyperparathyroidism, as demonstrated in animal models 1
- Hyperphosphatemia lowers ionized calcium by forming calcium-phosphate complexes in serum, reducing bioavailable calcium 1
- Early in CKD, subtle increases in serum phosphorus decrease ionized calcium, stimulate PTH release, and increase phosphate excretion—normalizing phosphorus temporarily but at the cost of persistently elevated PTH 1
Vitamin D Deficiency and Impaired Activation
- Decreased levels of 1,25-dihydroxyvitamin D (calcitriol) occur in early CKD stages, reducing intestinal calcium absorption and impairing PTH suppression 2, 1
- Vitamin D insufficiency (25-hydroxyvitamin D <30 ng/mL) is extremely prevalent (80-90%) in CKD patients and common in the general population 1
- High serum phosphate directly interferes with production and secretion of calcitriol, creating a vicious cycle 1
- The diseased kidney cannot adequately convert 25-hydroxyvitamin D to its active form, resulting in PTH elevation 3
Hypocalcemia and Skeletal Resistance
- Reduced plasma 1,25(OH)₂D leads to decreased intestinal calcium absorption 2
- Skeletal resistance to PTH's calcemic action contributes to persistent hypocalcemia despite elevated PTH 1
- Calcium-phosphate complexes precipitate in soft tissues when the calcium-phosphate product exceeds 55 mg²/dL², further depleting serum calcium 1
Additional Contributing Causes
Insufficient Calcium Intake
- Inadequate oral calcium intake can cause secondary hyperparathyroidism even with normal kidney function (eGFR >60 mL/min/1.73 m²) and normal vitamin D levels (≥30 ng/mL) 4
- This cause is often overlooked but responds rapidly to calcium supplementation (600 mg twice daily), with PTH normalization within 2-3 weeks 4
Gastrointestinal Malabsorption
- Conditions impairing calcium absorption (inflammatory bowel disease, celiac disease, post-bariatric surgery) can trigger secondary hyperparathyroidism 5
Disease Progression and Complications
- A vicious cycle develops where hyperphosphatemia leads to hypocalcemia, which drives secondary hyperparathyroidism and further bone disease 1
- Untreated secondary hyperparathyroidism progresses to parathyroid gland hyperplasia, with approximately 10% of dialysis patients requiring parathyroidectomy after 10 years and 30% after more than 20 years 1
- Consequences extend beyond bone disease to include soft-tissue and vascular calcification, cardiovascular disease, calcific uremic arteriolopathy, neurological disturbances, hematological abnormalities, and endocrine dysfunction 6, 7
Critical Diagnostic Considerations
Begin laboratory monitoring when GFR falls below 60 mL/min/1.73 m², measuring serum calcium, phosphorus, and intact PTH, as PTH elevation and bone disease develop at this early stage. 2
- Intact PTH begins rising when GFR <60 mL/min/1.73 m² 2
- Alkaline phosphatase elevation suggests high bone turnover and increases the predictive power of PTH measurements 2
- Intact PTH assays overestimate biologically active PTH by detecting C-terminal fragments with potential inhibitory activity 2
Common Diagnostic Pitfalls
- Focusing only on PTH levels without evaluating calcium, phosphorus, and vitamin D status leads to misdiagnosis 1
- Overlooking vitamin D insufficiency (levels 16-30 ng/mL) as a contributor 1
- Ignoring alkaline phosphatase, which adds predictive value for assessing bone turnover 2
- Missing insufficient calcium intake as a reversible cause in patients with preserved kidney function 4