What causes hyperparathyroidism (overproduction of parathyroid hormone) in a patient with primary hyperparathyroidism?

What Causes Primary Hyperparathyroidism

Primary hyperparathyroidism is most commonly caused by a solitary parathyroid adenoma (85-90% of cases), with the remaining cases due to multiglandular disease including multiple adenomas or hyperplasia (10-15%), and rarely parathyroid carcinoma (<1%). 1, 2, 3

Primary Causes

Parathyroid Adenoma (Most Common)

• A single hyperfunctioning parathyroid adenoma accounts for 80-90% of all primary hyperparathyroidism cases 1, 2, 4
• These benign tumors consist of abnormal parathyroid cells that autonomously overproduce parathyroid hormone independent of normal calcium feedback mechanisms 5, 6
• Adenomas can occasionally develop in ectopic locations due to abnormal embryological migration of the parathyroid glands, making surgical localization challenging 2

Multiglandular Disease (Less Common)

• Multiple adenomas or parathyroid hyperplasia represent 10-15% of primary hyperparathyroidism 2, 3
• Risk factors for multiglandular disease include underlying genetic syndromes (MEN1 or MEN2A), lithium therapy, or previous neck radiotherapy 2
• Parathyroid hyperplasia involves enlargement of multiple parathyroid glands with excessive PTH production 3

Parathyroid Carcinoma (Rare)

• Parathyroid carcinoma accounts for approximately 1% of primary hyperparathyroidism cases 2

Distinguishing Features Between Adenoma and Hyperplasia

Parathyroid adenoma is more often a single-gland disease found in primary hyperparathyroidism with higher preoperative calcium levels compared to hyperplasia 3

• No significant differences exist between adenoma and hyperplasia regarding patient age, sex, clinical presentation, preoperative PTH levels, or gland size 3
• The distinction is clinically important because it affects surgical planning—single adenomas can be treated with focused parathyroidectomy while multiglandular disease may require more extensive exploration 2

Secondary and Tertiary Hyperparathyroidism (Different Entities)

While the question asks about primary hyperparathyroidism, it's important to distinguish these related conditions:

• Secondary hyperparathyroidism is characterized by normal or low serum calcium with elevated PTH, commonly caused by chronic kidney disease or vitamin D deficiency 7
• Tertiary hyperparathyroidism occurs in end-stage renal disease and is marked by hypercalcemia with elevated PTH due to autonomous parathyroid function after prolonged secondary hyperparathyroidism 7
• Almost 90% of renal transplant recipients have elevated PTH at transplantation, with over 30% persisting up to 3 years post-transplant 1

Clinical Pitfalls

• Consider multiglandular disease in all patients where preoperative localization fails to identify a target adenoma or following unsuccessful parathyroidectomy 2
• Screen for genetic syndromes (MEN1/2A) in younger patients or those with family history, as these increase risk of multiglandular disease 2
• Ectopic parathyroid adenomas should be suspected in patients requiring repeat parathyroid surgery 2