Hypoparathyroidism pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Hypoparathyroidism is a decrease in serum parathyroid hormone. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedback for secretion of parathyroid hormone. Deficiency of parathyroid hormone causes body to decrease reabsorption of calcium from bone, excretion of phosphate, reabsorbtion of calcium from distal tubules, and vitamin D mediated absorption of calcium from intestine leading to hypocalcemia. Many genetic conditions are associated with hypoparathyroidism. Hypoparathyroidism associated with genetic defects may be either autoimmune hypoparathyroidism, isolated hypoparathyroidism, associated with congenital multisystem syndromes, or a part of metabolic disorders.

Pathophysiology

Parathyroid, Vitamin D, and Mineral Homeostasis

The effect of parathyroid hormone on mineral metabolism is as follows:[1][2]

Effect of minerals and vitamin D on parathyroid hormone:







The Sequence of Events in Parathyroid, Vitamin D, and Mineral Homeostasis


 
 
 
 
 
 
 
 
 
 
 
Parathyroid hormone
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kidney
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decreased excretion of magnesium
 
 
 
Increasead conversion of inactive 25-hydroyx vitamin D to the active 1,25-dihydroy xvitamin 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


Pathogenesis




 
 
 
 
 
 
 
 
 
Hypoparathyroidism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deficiency of parathyroid hormone
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decrease reabsorption of calcium from bone
 
 
Decrease excretion of phosphate
 
 
 
Decrease reabsorbtion of calcium from distal tubules
 
 
Decrease vitamin D mediated absorption of calcium from intestine
 


Post-surgical Hypoparathyroidism

  • Anterior neck surgery most commonly causes hypoparathyroidism. Majority of time this hypoparathyroidism is transient i.e. it resolves within 6 months.[5][6][7]
  • The features of hypoparathyroidism should persist for atleast 6 month after surgery to be diagnosed as chronic hypoparathyroidism.
  • 30–60% Patients undergoing total thyroidectomy develops hypocalcaemia within 24 hours as an initial manifestation of postoperative parathyroid failure. About 60%-70% of these cases resolve within 4–6 weeks after surgery. Remaining cases progress to develop protracted hypoparathyroidism requiring continuous treatment. Around 15–25% of patients with protracted hypoparathyroidism progress to chronic hypoparathyroidism.[8]
  • Factors favorring recovery from protracted hypoparathyroidism include:
    • Number of parathyroid glands remaining in situ.
    • Serum calcium level at this stage : There is high rate of recovery in individuals whose calcium levels are normal to elevated one month postoperatively.

Genetics

Genetics of Hypoparathyroidism
Hypoparathyroidism Inheritance Gene mutation Clinical features
Autoimmune Autoimmune polyglandular hypoparathyroidism Autoimmune polyendocrine syndrome type 1[9] Autosomal recessive Mutation in AIRE gene
Isolated Familial Isolated hypoparathyroidism Autosomal dominant PTH gene[10]
Glial cells missing GCM2 gene[11]
Autosomal recessive PTH gene[12]
Glial cells missing 2 (GCM2) gene[11][13]
X-linked FHL1 gene (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27[14]
Autosomal dominant hypercalcemia[15] Autosomal dominant hypocalcemia type 1 Autosomal dominant Calcium-sensing receptor gene mutation
NOTE: Calcium-sensing receptor gene activating mutation can also cause mild Bartter syndrome type 5. This mutation cause the inhibition of apical potassium channel in the thick ascending limb of the loop of Henle in the kidney.[16][17]
Autosomal dominant hypocalcemia type 2 Autosomal dominant G protein G11 (GNA11) mutation
Congenital multisystem syndromes DiGeorge syndrome[18] Autosomal dominant 22q11.2 deletion
CHARGE syndrome[19] Autosomal dominant CHD7 G744S missense mutation
Kenny-Caffey syndrome type 1[20] Autosomal recessive Deletion of the TBCE gene
Kenny-Caffey syndrome type 2[21] Autosomal dominant Mutation of “family with sequence similarity 111, member A″ (FAM111A) gene located on chromosome locus 11q12.1
Sanjad-Sakati syndrome[22] Autosomal recessive Mutation in TBCE gene
Barakat syndrome[23][24] Autosomal recessive Mutations in the GATA3 gene
Metabolic diseases Mitochondiral polyneuropathies[25] Kearns–Sayre syndrome Mitochondrial inheritence mtDNA deletion
Maternally inherited diabetes and deafness (MIDD) Mitochondrial inheritence MT‑TL1 defect
Mitochondrial enzyme deficiencies Mitochondrial trifunctional protein deficiency (MTP deficiency)[26][27] Autosomal recessive HADHA or HADHB gene mutation
Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)[28] Autosomal recessive G1528C gene mutation
Heavy metal storage disorders Hemochromatosis[29][30] Autosomal recessive HFE gene mutation
Wilson's disease[31][32] Autosomal recessive ATP7B gene mutation

Associated Conditions

Conditions associated with hypoparathyroidism include:[9][15][16][17][18][19][20][21][22][23][24][25][26][28][29][31]

Gross Pathology

  • There is no gross pathology findings for hypoparathyroidism.

Microscopic Pathology

  • There is no microscopic pathology findings for hypoparathyroidism.

References

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