What are the causes of hyperparathyroidism?

Causes of Hyperparathyroidism

Hyperparathyroidism is classified into three distinct types: primary, secondary, and tertiary, each with specific underlying causes related to abnormal parathyroid hormone (PTH) secretion and calcium homeostasis. 1

Primary Hyperparathyroidism

Primary hyperparathyroidism occurs when there is an intrinsic abnormality in the parathyroid glands leading to autonomous overproduction of PTH:

• Parathyroid adenoma (most common cause, 80-85% of cases)
• Parathyroid hyperplasia (10-15% of cases)
• Parathyroid carcinoma (rare, <1% of cases)
• Multiple endocrine neoplasia (MEN) syndromes (MEN type 1 and 2A) 2

Primary hyperparathyroidism is characterized by elevated PTH levels with hypercalcemia and is the third most common endocrine disorder, with highest incidence in postmenopausal women 3.

Secondary Hyperparathyroidism

Secondary hyperparathyroidism develops as an appropriate physiological response to conditions that cause chronic hypocalcemia, leading to increased PTH secretion:

• Chronic kidney disease (CKD) - most common cause 1

  • Involves multiple mechanisms:
    • Phosphate retention
    • Decreased calcitriol (1,25-dihydroxyvitamin D) production
    • Receptor abnormalities in parathyroid glands

• Vitamin D deficiency (80-90% prevalent in CKD patients) 1

  • Causes include:
    • Sedentary lifestyle
    • Limited intake of vitamin D-rich foods
    • Reduced endogenous synthesis with uremia
    • Urinary losses of 25(OH)D in nephrotic syndrome

• Other causes:

  • Chronic intestinal malabsorption
  • Hepatobiliary disease
  • Vitamin D-dependent rickets (types I and II)
  • Renal tubular acidosis
  • Fanconi's syndrome 4

In secondary hyperparathyroidism, serum calcium is typically normal or low, while PTH is elevated 5.

Tertiary Hyperparathyroidism

Tertiary hyperparathyroidism develops when long-standing secondary hyperparathyroidism progresses to autonomous PTH secretion:

• Parathyroid gland hyperplasia becoming autonomous after prolonged stimulation
• Post-kidney transplantation (common timing for manifestation) 1, 6
• Prolonged untreated secondary hyperparathyroidism 6

In tertiary hyperparathyroidism, the hypertrophied parathyroid tissue fails to resolve and continues to oversecrete PTH despite normal or elevated serum calcium levels 6.

Pathophysiological Mechanisms

In Chronic Kidney Disease:

1. Phosphate retention - directly stimulates PTH secretion, even in early CKD (Stage 3)
2. Decreased calcitriol production - reduces intestinal calcium absorption
3. Receptor abnormalities - decreased vitamin D receptor and calcium-sensing receptor expression in parathyroid glands 1

In Tertiary Hyperparathyroidism:

1. Nodular transformation of parathyroid glands
2. Autonomous function resistant to normal regulatory mechanisms
3. Resistance to calcimimetic treatment may develop 1, 6

Clinical Pearls and Pitfalls

• Diagnostic pitfall: In primary hyperparathyroidism, focus on the inappropriately elevated PTH despite hypercalcemia, not just the calcium level alone 1

• Treatment consideration: While primary hyperparathyroidism is often managed surgically, secondary hyperparathyroidism typically requires addressing the underlying cause (vitamin D deficiency, CKD) 2

• Monitoring caveat: Regular assessment of serum calcium, phosphorus, PTH levels, and bone mineral density is essential for all forms of hyperparathyroidism 1

• Post-transplant consideration: Even after successful kidney transplantation, tertiary hyperparathyroidism may persist and require surgical intervention 6