What causes hyperparathyroidism?

Causes of Hyperparathyroidism

Primary hyperparathyroidism is most commonly caused by a single parathyroid adenoma (80%), with multiple adenomas, parathyroid hyperplasia, or rarely parathyroid carcinoma (<1%) accounting for the remaining cases. 1

Types of Hyperparathyroidism and Their Causes

Primary Hyperparathyroidism (PHPT)

• Occurs when parathyroid glands autonomously overproduce PTH, typically resulting in hypercalcemia 1
• Most common causes:
  • Single parathyroid adenoma (80% of cases) 1
  • Multiple adenomas or multigland hyperplasia (15-20% of cases) 1
  • Parathyroid carcinoma (less than 1% of cases) 1
• Most cases are sporadic, but hereditary causes exist 1
• Hereditary forms include:
  • Multiple Endocrine Neoplasia type 1 (MEN1) 1
  • Multiple Endocrine Neoplasia type 2A (MEN2A) 1
  • Familial isolated hyperparathyroidism 1
  • CDC73-related Hyperparathyroid-Jaw Tumor Syndrome 1

Secondary Hyperparathyroidism

• Occurs when an extrinsic abnormal change affects calcium homeostasis, stimulating production of PTH 2
• Main causes:
  • Chronic kidney disease (CKD) - most common cause 1
  • Vitamin D deficiency 1
  • Chronic intestinal malabsorption 3
  • Hepatobiliary disease 3
  • Types I and II vitamin D-dependent rickets 3
  • Tubular acidosis or Fanconi's syndrome 3
  • Phosphate retention in CKD leading to hypocalcemia 1

Tertiary Hyperparathyroidism

• Occurs when parathyroid glands become autonomous after longstanding secondary hyperparathyroidism 4
• Main causes:
  • Persistent hyperparathyroidism after successful renal transplantation 4
  • Long-standing chronic kidney disease with parathyroid gland hyperplasia that fails to resolve 4
  • Parathyroid glands become resistant to normal calcium feedback mechanisms 4

Pathophysiological Mechanisms

In Primary Hyperparathyroidism

• Autonomous overproduction of PTH from abnormal parathyroid tissue 1
• Genetic mutations in MEN1 gene (encoding Menin protein) in hereditary cases 1
• Pathogenic variants in CDC73 gene (encoding parafibromin) in HPT-JT syndrome 1
• Pathogenic variants in RET gene in MEN2A 1

In Secondary Hyperparathyroidism (particularly in CKD)

• Phosphate retention leads to transient hyperphosphatemia 1
• Hyperphosphatemia directly decreases blood levels of ionized calcium 1
• Low ionized calcium stimulates parathyroid glands to release more PTH 1
• Deficiency of 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] affects parathyroid gland function 1
• Progressive loss of kidney function causes decreased vitamin D receptors (VDR) and calcium-sensing receptors (CaR) in parathyroid glands 1
• Parathyroid glands become resistant to vitamin D and calcium 1

In Tertiary Hyperparathyroidism

• Prolonged hypocalcemia causes parathyroid chief cell hyperplasia 4
• Hyperphosphatemia has direct stimulatory effect on parathyroid gland cells 4
• Hypertrophied parathyroid tissue fails to resolve after correction of primary disorder 4
• Parathyroid glands continue to oversecrete PTH despite normal or elevated calcium levels 4

Special Considerations

• PHPT is more common in women, with an incidence of 66 per 100,000 person-years (vs. 25 per 100,000 in men) 1
• Prevalence of PHPT appears to be increasing significantly 1
• In countries with routine biochemical screening (US, Canada, Europe), PHPT predominantly presents as asymptomatic 1
• In countries without routine screening (China, India), PHPT predominantly presents with symptoms related to target organ involvement 1
• Vitamin D deficiency is a common cause of secondary hyperparathyroidism, particularly in elderly people 2
• Differential diagnosis must consider factors that disturb phospho-calcium parameters: vitamin D deficiency, renal insufficiency, malabsorption, insufficient calcium intake, and iatrogenic causes 5