Hyperparathyroidism pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief:

Overview

• The exact pathogenesis of [disease name] is not fully understood.

OR

• It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathohysiology

Parathyroid, Vitamin D, and mineral homeostasis

The effect of Parathyroid hormone on mineral metabolism is as follows:

• Effect of parathyroid hormone on inorganic phosphate metabolism:
  • Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
• Effect on parathyroid hormone on calcium metabolism:
  • Direct effect:
    • Increased resorption of bones.
    • Decreases excretion from kidney.
  • Indirect effect:
    • Increases conversion of inactive 25-hydroyxvitamin D to the active 1,25-dihydroyxvitamin D which increases absorption of calcium from gut.Decreased phosphate concentration also increases this conversion process. Vitamin D also synergizes with parathyroid action on bone.
    • Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
  • Both these direct and indirect mechanism results in an increased serum calcium concentration.
• Effect of parathyroid hormone on magnesium concentration:
  • Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

Effect of minerals and vitamin D on parathyroid hormone:

• Decrease in serum calcium concentration stimulates parathyroid hormone.
• Calcium provides negative feedback on parathyroid hormone.
• Magnesium provides negative feedback on parathyroid hormone.
• Vitamin D decreases the concentration of parathyroid hormone.

The sequence of events is shown in the algorithm below:

Parathyroid hormone

Kidney

Bone

Decreased excretion of magnesium

Increasead conversion of inactive 25-hydroyxvitamin D to the active 1,25-dihydroyxvitamin D

Increase excretion of inorganic phosphate

Decrease excretion of calcium

Increased resorption of bone

Increased serum concentration of magnesium

Increased absorption of calcium from gut

Decreased serum concentration of inorganic phosphate

Prevents precipitation of calcium phosphate in bones

Increased serum concentration of calcium

Calcium-sensing receptors

• Calcium -ensing receptors are present on parathyroid glands. They are a type of 7-transmembrane receptors in G-protein coupled receptors superfamily of receptors.
• Calcium-sensing receptors sense change in extracellular concentration of inonised calcium.
• Calcium-sensing receptor expression in reduced in primary hyperparathyroidism (parathyroid adenomas) and secondary hyperparathyroidism.
• This reduced expression of receptor causes an increases in calcium sensing set point.
• This in turn leads to increase in secretion of parathyroid hormone in presence on normal serum concentration of extracellular ionized calcium.

Pathogenesis of primary hyperparathyroidism

• Primary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a primary process in parathyroid gland.
• Majority of times, increase in secretion of parathyroid hormone is the result of parathyroid adenoma. Other causes of increase in secretion of parathyroid hormone includes parathyroid hyperplasia and parathyroid carcinoma.
• Calcium sensing receptor expression in reduced in parathyroid adenomas resulting in an increase in calcium sensing set point.
• In parathyroid hyperplasia, an increase in cell number causes increased secretion of parathyroid hormone.

Pathogenesis of secondary hyperparathyroidism

• Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process, most commonly due chronic renal failure. Other causes include vitamin D deficiency, severe calcium deficiency.
• Chronic renal failure leads to high serum inorganic phosphate and low serum calcium and deficiency of active form of vitamin D(1,25-dihydroxy vitamin D, calcitirol)
• This leads to continuous stimulation of parathyroid glands resulting downregulation of parathyroid vitamin D receptors and calcium sensing receptors.
• Fibroblast growth factor 23 (FGF-23) concentration increases in chronic renal failure which plays a central role in regulation of phosphate vitamin D homeostasis.
• Elevated FGF-23 expression downregulates remaining 25(OH)-1-hydroxylase enzyme. 25(OH)-1-hydroxylase enzyme is responsible for conversion of inactive 1-hydroxy vitamin D into active 1,25-dihydroxy vitamin D(calcitirol). This leads to aggravates the deficiency of active vitamin D.
• These all factors leads to hyperplasia of parathyroid gland.

Chronic renal failure

Elevated serum inorganic phosphate concentration

Elevated FGF-23

Decreased Calcitriol

Decreaed serum calcium concentration

Continuous stimulation of parathyroid gland

Downregulation of parathyroid vitaminn D receptors and calcium-sensing receptors

Parathyroid hyperplasia

Increased secretion of parathyroid hormone

Mechanism of fibroblast growth factor 23 (FGF-23)

• FGF-23 is a hormone produced in the osteocytes and osteoblasts.
• Its production is increased due to high serum phosphate and high calcitriol.
• FGF-23 binds and activates a receptor called fibroblast growth factor receptor 1 (FGFR1).
• FGFR1 is functional when coexpressed with the Klotho transmembrane protein, as a Klotho-FGF receptor complex.
• FGF-23 reduces the expression of type II sodium phosphate cotransporters (NaPi-2a and NaPi-2c) decreasing phosphate reabsorption in proximal tubules.
• In chronic renal failure, as a result, phosphate absorption is increased in proximal tubules due to effect of FGF-23 as well as increased parathyroid hormone. This is responsible for normal serum phosphate levels in majority of patients until the GFR falls below 20 ml/min.
• As chronic renal failure progresses, these negative feedback loops are impaired leading to deranged phosphate homeostasis.
• FGF-23 have direct and indirect effect on parathyroid hormone.
  • Direct effect: In normal parathyroid gland,FGF-23 decreases synthesis of parathyroid hormone through the mitogen-activated protein kinase (MAPK) pathway. FGF-23 increased expression of the parathyroid calcium-sensing receptor and the vitamin D receptor, and reducing cellular proliferation.
  • Indirect effect: Increased synthesis of parathyroid hormone by decreasing synthesis of calcitriol.
• FGF-23 fails to activate mitogen-activated protein kinase pathway in hyperplastic parathyroid gland secondary to chronic renal failure.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].