What are the primary causes of secondary hyperparathyroidism?

Primary Causes of Secondary Hyperparathyroidism

The primary causes of secondary hyperparathyroidism are chronic kidney disease, vitamin D deficiency, phosphate retention, and insufficient calcium intake or absorption. 1, 2

Chronic Kidney Disease (CKD)

CKD is the most common cause of secondary hyperparathyroidism through several interrelated mechanisms:

• Phosphate retention: As kidney function declines, the ability to excrete phosphate decreases, leading to hyperphosphatemia 1

  • Even in early CKD (Stage 3), transient increases in serum phosphorus can stimulate PTH secretion
  • The elevated PTH increases phosphate excretion, often normalizing serum phosphorus levels but at the expense of elevated PTH

• Decreased calcitriol (1,25(OH)₂D₃) production: 1, 2

  • Impaired kidney function reduces the conversion of 25(OH)D to active 1,25(OH)₂D₃
  • Decreased calcitriol leads to reduced intestinal calcium absorption and hypocalcemia
  • Low calcitriol directly affects parathyroid gland function

• Receptor abnormalities in parathyroid glands: 1, 2

  • Decreased vitamin D receptor (VDR) expression
  • Reduced calcium-sensing receptor (CaR) expression
  • These changes make parathyroid glands more resistant to vitamin D and calcium

Vitamin D Deficiency

• Vitamin D insufficiency/deficiency is highly prevalent (80-90%) in CKD patients 1

• Causes of vitamin D deficiency in CKD include:

  • Sedentary lifestyle with reduced sun exposure
  • Limited intake of vitamin D-rich foods
  • Reduced endogenous synthesis with uremia
  • Urinary losses of 25(OH)D and vitamin D-binding protein in nephrotic syndrome 1

• Even in patients with normal kidney function, vitamin D deficiency can lead to secondary hyperparathyroidism 3

Calcium Deficiency

• Insufficient calcium intake or absorption can cause secondary hyperparathyroidism even with normal kidney function and vitamin D levels 3
• Low serum calcium directly stimulates PTH secretion
• This form of secondary hyperparathyroidism can be diagnosed through a "calcium challenge" - providing calcium supplementation and observing normalization of PTH levels 3

Other Causes

• Malabsorption syndromes affecting calcium and vitamin D absorption
• Medications that affect calcium, phosphorus, or vitamin D metabolism
• Phosphate loading (high phosphate diet) 1

Pathophysiological Cascade

1. Initial trigger (kidney dysfunction, vitamin D deficiency, or calcium deficiency)
2. Decreased serum calcium and/or increased serum phosphorus
3. Increased PTH secretion (initially adaptive)
4. Parathyroid gland hyperplasia
5. Progressive resistance to normal regulatory mechanisms
6. Persistent elevation of PTH despite treatment

Clinical Implications

Uncontrolled secondary hyperparathyroidism can lead to:

• Renal osteodystrophy and bone disease
• Vascular and soft tissue calcification
• Increased cardiovascular morbidity and mortality
• Neurological disturbances
• Hematological abnormalities 2, 4

Understanding the underlying cause is essential for appropriate management, which may include dietary modifications, phosphate binders, vitamin D supplementation, calcimimetics, and in severe cases, parathyroidectomy 2, 5.