What are the causes of secondary hyperparathyroidism?

Causes of Secondary Hyperparathyroidism

Secondary hyperparathyroidism is primarily caused by chronic kidney disease, vitamin D deficiency, and disorders that affect calcium absorption, all of which lead to compensatory parathyroid gland hyperplasia and elevated PTH levels. 1

Main Causes of Secondary Hyperparathyroidism

Chronic Kidney Disease (CKD)

• CKD is the most common cause of secondary hyperparathyroidism, with nearly all patients developing parathyroid gland hyperplasia as kidney function declines 1
• Three interrelated mechanisms contribute to secondary hyperparathyroidism in CKD:
  • Phosphate retention: Even transient increases in serum phosphorus directly decrease ionized calcium, stimulating PTH release 1
  • Hypocalcemia: Develops during the course of kidney disease due to multiple factors 1
  • Deficiency of 1,25-dihydroxycholecalciferol (active vitamin D): Reduced kidney function impairs conversion of 25-hydroxyvitamin D to its active form 1
• With progressive loss of kidney function, parathyroid glands develop decreased vitamin D receptors (VDR) and calcium-sensing receptors (CaR), making them resistant to vitamin D and calcium 1

Vitamin D Deficiency

• Vitamin D insufficiency (25-hydroxyvitamin D levels <30 ng/mL) is common in the general population and extremely prevalent (80-90%) in CKD patients 1
• Inadequate vitamin D leads to reduced intestinal calcium absorption and subsequent hypocalcemia, triggering PTH elevation 1
• Causes of vitamin D deficiency include:
  • Limited sun exposure (sedentary lifestyle) 1
  • Poor dietary intake of vitamin D-rich foods 1
  • Impaired endogenous synthesis in uremia 1
  • Urinary losses of vitamin D-binding protein in nephrotic syndrome 1

Disorders of Calcium Absorption

• Gastrointestinal conditions that impair calcium absorption can cause secondary hyperparathyroidism 2
• Insufficient dietary calcium intake or absorption can lead to secondary hyperparathyroidism even with normal vitamin D levels and kidney function 3

Phosphate Loading

• High phosphate intake can directly provoke secondary hyperparathyroidism, as demonstrated in animal studies 1
• Phosphate retention leads to hypocalcemia, stimulating parathyroid gland hyperplasia 1

Pathophysiological Mechanisms

• Early in CKD, even subtle increases in serum phosphorus (sometimes undetectable) can:
  • Decrease ionized calcium levels 1
  • Stimulate parathyroid glands to release more PTH 1
  • Increase phosphate excretion, normalizing phosphorus levels but at the cost of elevated PTH 1
• Skeletal resistance to the calcemic action of PTH contributes to hypocalcemia in CKD 1
• Hyperphosphatemia directly affects parathyroid gland function and growth, worsening secondary hyperparathyroidism 1

Clinical Significance

• Untreated secondary hyperparathyroidism leads to:
  • Bone disease with increased turnover and resorption 4
  • Soft-tissue and vascular calcification 4
  • Increased cardiovascular morbidity and mortality 4
  • Neurological disturbances and endocrine dysfunction 4
• Secondary hyperparathyroidism in CKD patients can progress to require surgical intervention if medical management fails 1

Common Pitfalls in Diagnosis

• Focusing only on PTH levels without evaluating calcium, phosphorus, and vitamin D status 1
• Failing to consider secondary hyperparathyroidism in patients with normal serum calcium (mid to low-normal range) 3
• Not recognizing that secondary hyperparathyroidism can occur with normal kidney function if calcium intake is insufficient 3
• Overlooking vitamin D insufficiency (levels between 16-30 ng/mL) which can contribute to secondary hyperparathyroidism 1

Early identification and management of these underlying causes can prevent the progression of secondary hyperparathyroidism and its complications, particularly in patients with CKD where the condition is most prevalent and impactful on morbidity and mortality.