44. Pathology of the parathyroid glands (hyperplasia, adenoma, causes of hypoparathyreoidism). Multiple endocrine neoplasms

Page created on April 16, 2019. Last updated on March 23, 2022 at 16:49


The parathyroid glands are four oval-shaped glands embedded in the posterior surface of the thyroid gland. They’re comprised of chief cells, pale cells that produce PTH, and oxyphil cells. The parathyroid glands produce parathyroid hormone or parathormon (PTH) in response to decreased levels of free (ionised) calcium in the blood. PTH has the following effects:

  • Increases the renal tubular reabsorption of calcium
  • Increases the urinary excretion of phosphate, lowering serum phosphate levels – phosphate binds to ionized calcium in the blood
  • Increases the production of vitamin D in the kidney, which increases calcium absorption from the GI tract
  • Enhances osteoclastic activity, causing bone resorption and liberation of calcium from bone

The net result of PTH is an increase in free calcium in the blood.



Hyperparathyroidism refers to the increased activity of the parathyroid glands, causing elevated levels of PTH. We distinguish primary, secondary, and tertiary hyperparathyroidism.

Primary hyperparathyroidism is caused by local parathyroid pathology, which is the most important cause in pathology. Secondary hyperparathyroidism occurs as a response to hypocalcaemia, causing the parathyroid glands to overproduce PTH. Tertiary hyperparathyroidism occurs due to long-standing secondary hyperparathyroidism, in which the parathyroid glands have been overstimulated for so long that they continue to overproduce PTH even if the original stimulus is removed.


Parathyroid adenoma is the most common cause of primary hyperparathyroidism, accounting for around 80% of cases. It’s a benign tumour of the parathyroid glands, always occurs in only one of the four parathyroid glands. The remaining glands are normal in size or slightly smaller, due to feedback inhibition.

Parathyroid hyperplasia affects more than one glands, often affecting all four glands equally. It can be idiopathic or associated with multiple endocrine neoplasia. It accounts for approximately 15% of cases of primary hyperparathyroidism.

Parathyroid carcinoma is very rare (0,5% of cases). It is impossible to distinguish an adenoma from a carcinoma by histology; the diagnosis of carcinoma is based on the presence of metastasis and local invasion.

Secondary hyperparathyroidism is caused by chronic kidney disease, malnutrition, vitamin D deficiency. Tertiary hyperparathyroidism is caused by long-standing secondary hyperparathyroidism.


Abnormalities in two specific genes are commonly associated with sporadic parathyroid adenoma, namely Cyclin D1 inversion and MEN1 mutations. 20-30% of parathyroid tumors not associated with MEN-1 syndrome have acquired/somatic mutations in both copies of MEN-1 gene.

Clinical features

The consequences of primary hyperparathyroidism are the following:

  • Abdominal pain
  • Acute pancreatitis
  • Nephrolithiasis
  • Gall stones
  • Metastatic calcification – most commonly of the kidney (nephrocalcinosis)
  • Osteitis fibrosa cystica generalisata – tumor-like lesions of bones due to increased osteoclast activity
  • Bone pain

Differential diagnosis for hypercalcaemia

We should know the differential diagnosis for hypercalcaemia:

  • Primary hyperparathyroidism
  • Paraneoplastic syndrome – tumor produced parathyroid hormone-related peptide (PTHrP)
  • Vitamin D toxicity
  • Thiazide diuretics
  • Metastasis into bone
  • Multiple myeloma
  • Immobilization – which increases osteoclast activity

In all cases except primary and secondary hyperparathyroidism the level of PTH is decreased.


Hypoparathyroidism is very rare. It’s most commonly due to surgical removal of the parathyroid glands during thyroid surgery, or due to autoimmune destruction. The result is hypocalcemia.

Multiple endocrine neoplasia

The multiple endocrine neoplasias (MEN) are autosomal dominant syndromes that increase the risk for certain hormone-producing neoplasias, to the point where they’re almost guaranteed to develop at least one of these neoplasms during their lifetime. They occur due to germ-line mutations in genes that are often involved in certain neoplasms. There are three types:

  • Multiple endocrine neoplasia type 1
    • Associated with mutations in the MEN1 gene
    • Increased risk for:
      • Pituitary adenoma
      • Pancreatic tumor
      • Parathyroid adenoma
  • Multiple endocrine neoplasia type 2a
    • Associated with mutations in the RET gene
    • Increased risk for:
      • Medullary thyroid carcinoma
      • Pheochromocytoma
      • Parathyroid adenoma
  • Multiple endocrine neoplasia type 2b
    • Associated with mutations in the RET gene
    • Increased risk for:
      • Medullary thyroid carcinoma
      • Pheochromocytoma
      • Marfanoid habitus – long limbs, tall stature

9 thoughts on “44. Pathology of the parathyroid glands (hyperplasia, adenoma, causes of hypoparathyreoidism). Multiple endocrine neoplasms”

  1. What do you mean by this sentence? Isn’t MEN 1 syndrome caused by MEN 1 gene mutation?
    “20-30% of parathyroid tumors not associated with MEN-1 syndrome have mutations in both copies of MEN-1 gene”

    1. These 20-30% of cases have acquired/somatic mutations in MEN1, not germline mutations. I.e., not all their cells have MEN1 mutations, only the tumour cells.

  2. hello greek doctor,
    in parathyriod abnormalities topic in pathophys, you mentioned that hypercalcaemia, never develops in secondary hyperparathyrioidism:
    ;In secondary hyperparathyroidism the calcium level is mostly normal.
    Hypercalcaemia does not develop.;
    then , how come secondary hayperparathyriodism , is DDx for hypercalcaemia in this topic?

    thanks alot.

  3. The title of the question says “causes of hypoparathyroidism” is there a reason why you don’t cover that at all?

    1. Whoops. You can study it in pathophys 2 topic 68 though. There’s not much to say about it so it shouldn’t be a big deal.

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