What are the causes of hyperparathyroidism?

Causes of Hyperparathyroidism

Hyperparathyroidism has three distinct forms with different etiologies: primary (autonomous parathyroid gland dysfunction), secondary (appropriate PTH response to hypocalcemia or hyperphosphatemia), and tertiary (autonomous PTH secretion after longstanding secondary disease). 1

Primary Hyperparathyroidism

Primary hyperparathyroidism results from intrinsic parathyroid gland pathology causing autonomous PTH overproduction and hypercalcemia. 1

Specific Causes:

• Single parathyroid adenoma is the most common cause, accounting for the majority of cases 2, 3
• Multiglandular hyperplasia occurs less frequently, particularly in younger patients (neonates and infants) 4
• Parathyroid carcinoma is a rare but important etiology 3
• Hereditary syndromes should be suspected in younger patients or those with family history 2

The pathophysiology involves autonomous overproduction of PTH from abnormal parathyroid tissue, leading to hypercalcemia and its metabolic consequences. 5

Secondary Hyperparathyroidism

Secondary hyperparathyroidism represents an appropriate compensatory response where PTH elevation occurs in response to hypocalcemia and/or hyperphosphatemia, with the serum calcium remaining normal or low. 1, 6

Chronic Kidney Disease (Most Common Cause):

The National Kidney Foundation identifies chronic kidney disease as the most common cause of secondary hyperparathyroidism, with nearly all CKD patients developing parathyroid gland hyperplasia as kidney function declines. 1

The pathophysiologic cascade in CKD involves multiple interrelated mechanisms:

• Phosphate retention is the fundamental initiating factor, triggering the cascade even before overt hyperphosphatemia develops 7, 1

  • Occurs early when GFR falls below 60 mL/min/1.73 m² 1
  • Transient increases in serum phosphorus directly lower ionized calcium by forming calcium-phosphate complexes 7
  • High phosphate levels interfere with 1,25-dihydroxyvitamin D production 7

• Decreased 1,25-dihydroxyvitamin D (calcitriol) production results from failing kidneys, reducing intestinal calcium absorption and causing hypocalcemia 2, 1

• Progressive parathyroid gland resistance develops as kidney function declines, with decreased vitamin D receptors (VDR) and calcium-sensing receptors (CaR) in parathyroid glands 2

Vitamin D Deficiency:

Vitamin D insufficiency is extremely prevalent and leads to reduced intestinal calcium absorption, hypocalcemia, and compensatory PTH elevation. 1

• Particularly common in elderly populations 8
• The Endocrine Society recommends vitamin D measurement in patients with secondary hyperparathyroidism 1
• Severe calcium or vitamin D deficiency causes secondary hyperparathyroidism managed with calcium and vitamin D replacement 3

Malabsorption Syndromes:

Malabsorption conditions cause secondary hyperparathyroidism through reduced calcium availability. 2

Specific causes include:

• Chronic intestinal malabsorption 4
• Post-bariatric surgery patients who develop impaired calcium and vitamin D absorption 1
• Hepatobiliary disease 4

Other Causes:

• Chronic metabolic acidosis can contribute to secondary hyperparathyroidism 2
• Vitamin D-dependent rickets (types I and II) 4
• Tubular acidosis or Fanconi's syndrome 4

Tertiary Hyperparathyroidism

Tertiary hyperparathyroidism results from long-standing, severe secondary hyperparathyroidism that has become autonomous, characterized by lack of PTH suppression despite rising serum calcium levels, manifesting as hypercalcemic hyperparathyroidism. 2, 6

Specific Clinical Contexts:

• Most commonly encountered following kidney transplantation in patients with long-standing chronic kidney disease 2
• The National Kidney Foundation reports approximately 10% of dialysis patients require parathyroidectomy after 10 years, increasing to 30% after more than 20 years 1
• After correction of CKD by renal transplant, hypertrophied parathyroid tissue fails to involute and continues to oversecrete PTH despite normal or elevated serum calcium 9
• Parathyroid glands may become resistant to calcimimetic treatment 9

Pathophysiology:

• Prolonged hypocalcemia causes parathyroid chief cell hyperplasia and nodular transformation 9, 4
• Hyperphosphatemia has direct stimulatory effects on parathyroid gland cells resulting in nodular hyperplasia 9
• The hypertrophied tissue becomes autonomous and fails to respond appropriately to calcium feedback 9

Iatrogenic Causes:

• Excessive intake of inorganic phosphates in familial hypophosphatemic rickets 4
• Chronic vitamin D deficiency 4

Important Clinical Pitfalls to Avoid

The National Kidney Foundation warns against focusing solely on PTH levels without evaluating calcium, phosphorus, and vitamin D status, as this leads to misdiagnosis. 1

• Overlooking vitamin D insufficiency is a common error that perpetuates secondary hyperparathyroidism 1
• Attempting to maintain PTH in the "normal" range in CKD patients can cause adynamic bone disease; KDIGO guidelines recommend stage-specific targets 1
• Normal or low PTH in ESRD may indicate adynamic bone disease, which requires different management 1
• PTH measurement can be influenced by biotin supplements, which may cause underestimation or overestimation depending on assay design 1

Demographic and Physiological Factors Affecting PTH

• PTH is higher in Black individuals compared to White individuals 1
• PTH increases with age, possibly due to steady decline in GFR, with higher concentrations in people over 60 years old 1
• PTH correlates positively with body mass index, with higher levels in obese patients 1