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:

• 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-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone 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 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

• Calcium-sensing 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 ionized calcium.

Pathogenesis

• There is deficiency of parathyroid hormone in hypoparathyroidism.
• Deficiency of parathyroid hormone causes body to decrease:
  • Reabsorption of calcium from bone.
  • Excretion of phosphate.
  • Reabsorbtion of calcium from distal tubules.
  • Vitamin D mediated absorption of calcium from intestine.
• This leads to hypocalcemia.

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.
• 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.
• 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	Autosomal recessive	Mutation in AIRE gene	Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) Presents with a variable combination of: Failure of the parathyroid glands, adrenal cortex, gonads, pancreatic beta cells, gastric parietal cells, thyroid gland, and hepatitis Chronic mucocutaneous candidiasis Dystrophy of dental enamel and nails, alopecia, vitiligo, and keratopathy
Isolated		Familial Isolated hypoparathyroidism		Autosomal dominant	PTH gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness
					Glial cells missing GCM2 gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness Dominant negative mutation
				Autosomal recessive	PTH gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness
					Glial cells missing 2 (GCM2) gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness
				X-linked	FHL1 gene (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness
		Autosomal dominant hypercalcemia	Autosomal dominant hypocalcemia type 1	Autosomal dominant	Calcium-sensing receptor gene mutation	Calcium-sensing receptor gene activating mutation Most common genetic form of hypoparathyroidism Also known as familial hypercalciuric hypocalcemia The activating mutation results in gain in function 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.
			Autosomal dominant hypocalcemia type 2	Autosomal dominant	G protein G11 (GNA11) mutation	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness
Congenital multisystem syndromes		DiGeorge syndrome		Autosomal dominant	22q11.2 deletion	Presents with: Thymus dysfunction Cardiac defects Immunodeficiency Hypocalcemia Other clinical problems Also known as: 22q11.2DS or deletion 22q11.2 syndrome CATCH 22 syndrome Cayler cardiofacial syndrome Conotruncal anomaly face syndrome (CTAF) Sedlackova syndrome Shprintzen syndrome VCFS or velocardiofacial syndrome or velo-cardio-facial syndrome CATCH 22 stands for: Cardiac defects Abnormal facies Thymic aplasia Cleft palate Hypocalcemia with 22q11.2 deletion
		CHARGE syndrome		Autosomal dominant	CHD7 G744S missense mutation	Presents with: Coloboma Cardiac defects Atresia choanae Retarded growth and development Genitourinary abnormalities Ear anomalies and/or deafness
		Kenny-Caffey syndrome type 1		Autosomal recessive	Deletion of the TBCE gene	Presents with hypoparathyroidism due to: Absent parathyroid tissue Growth retardation Medullary stenosis of tubular bones
		Kenny-Caffey syndrome type 2		Autosomal dominant	Mutation of “family with sequence similarity 111, member A″ (FAM111A) gene located on chromosome locus 11q12.1	Similar clinical features as Kenny-Caffey syndrome type 1 Except for mental retardation
		Sanjad-Sakati syndrome		Autosomal recessive	Mutation in TBCE gene	Exclusively found in arabian descent population Presents with: Hypoparathyroidism Intellectual disability Dysmorphism
		Barakat syndrome		Autosomal recessive	Mutations in the GATA3 gene	Also known as hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. Presents with: Primary hypoparathyroidism Nerve deafness Steroid-resistant nephrosis
Metabolic diseases	Mitochondiral polyneuropathies	Kearns–Sayre syndrome		Mitochondrial inheritence	mtDNA deletion	Presents with: Progressive external ophthalmoplegia Retinitis pigmentosa Cardiomyopathy Heart block
		Maternally inherited diabetes and deafness (MIDD)		Mitochondrial inheritence	MT‑TL1 defect	Presents with: Diabetes mellitus Deafness
	Mitochondrial enzyme deficiencies	Mitochondrial trifunctional protein deficiency (MTP deficiency)		Autosomal recessive	HADHA or HADHB gene mutation	Clinical features of mitochondrial trifunctional protein deficiency occurring: During infancy include: Feeding difficulties Lethargy Hypoglycemia Hypotonia Liver problems After infancy include: Hypotonia Muscle pain Breakdown of muscle tissue Peripheral neuropathy Infants with mitochondrial trifunctional protein deficiency are also at increased risk for: Serious heart problems Breathing difficulties Coma Sudden death
		Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)		Autosomal recessive	G1528C gene mutation	Clinical features of LCHAD deficiency include: Hypoglycemia Hepatopathy Hypotonia Cardiomyopathy Retinopathy
	Heavy metal storage disorders	Hemochromatosis		Autosomal recessive	HFE gene mutation	Early symptoms of hereditary hemochromatosis are nonspecific and may include: Fatigue Joint pain Abdominal pain Decreased libido Late stage clinical features may include: Arthritis Liver disease Diabetes Heart abnormalities Skin discoloration
		Wilson's disease		Autosomal recessive	ATP7B gene mutation	Clinical features of Wilson's disease include: Initial feature Children and young adults:Liver disease Adults: Nervous system disorders and psychiatric disorders Other clinical features include: Clumsiness Tremors Difficulty walking Speech problems Impaired thinking ability Depression Anxiety Mood swings

Associated Conditions

Conditions associated with hypoparathyroidism include:

• Autoimmune polyendocrine syndrome type 1
• Autosomal dominant hypocalcemia type 1
• Autosomal dominant hypocalcemia type 2
• Bartter syndrome type 5
• DiGeorge syndrome
• CHARGE syndrome
• Kenny-Caffey syndrome type 1
• Kenny-Caffey syndrome type 2
• Sanjad-Sakati syndrome
• Barakat syndrome
• Kearns–Sayre syndrome
• Maternally inherited diabetes and deafness (MIDD)
• Mitochondrial trifunctional protein deficiency (MTP deficiency)
• Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)
• Hemochromatosis
• Wilson's disease

Gross Pathology

• There is no gross pathology findings for hypoparathyroidism.

Microscopic Pathology

• There is no microscopic pathology findings for hypoparathyroidism.