Hypoparathyroidism

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]

Hypoparathyroidism is a disorder characterized by hypocalcemia due to insufficient secretion of parathyroid hormone. Hypoparathyroidism may be classified according to etiology into following groups including post-surgical hypoparathyroidism, autoimmune hypoparathyroidism, hypoparathyroidism associated with genetic defects, and functional hypoparathyroidism. 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. Most common cause for hypoparathyroidism is post-surgical including thyroidectomy, parathyroidectomy, and radical neck dissection. Hypoparathyroidism should be differentiated from other causes of hypocalcemia. Causes of hypocalcemia other than hypoparathyroidism include pseudohypoparathyroidism, hypomagnesemia, hypovitaminosis D, chronic kidney disease, and relative hypocalcemia due to hypoalbuminemia. The symptoms and complications of hypoparathyroidism usually develop due to hypocalcemia. There is an increased risk of renal complications due to hypercalciuria in patients treated with calcium and vitamin D analogs. Majority of post-surgical patients have transient hypoparathyroidism. The prognosis of post-surgical hypoparathyroidism is usually good as it is transient and serum calcium levels becomes normal within 6 months of surgery. The diagnosis of hypoparathyroidism is made when the following diagnostic criteria are met: Hypocalcemia (albumin-adjusted) confirmed on at least two occasions separated by at least 2 weeks, parathyroid hormone (PTH) concentration, by second- or third-generation immunoassay, that is undetectable or inappropriately low (ie, <20 pg/mL) in the presence of hypocalcemia on at least two occasions, phosphate levels in the upper normal or frankly elevated range (helpful but not mandatory), and chronic hypoparathyroidism is established only after 6 months after neck surgery. The hallmark of acute hypocalcemia due to hypoparathyroidism is tetany. The presence of Chvostek’s sign and Trousseau’s sign on physical examination is highly suggestive of hypocalcemia which is commonly caused by hypoparathyroidism. Diagnosis of hypoparathyroidism is made by measurement of serum calcium (total and ionized), serum albumin (for correction), phosphate, intact parathyroid hormone (PTH), and 25-hydroxy vitamin D levels. Normal or inappropriately low serum intact parathyroid hormone (PTH) concentration in patients with subnormal serum albumin corrected total or ionized calcium concentration diagnostic of hypoparathyroidism. Pharmacologic medical therapies for hypoparathyroidism include calcium and Vitamin D3 supplementation. Severe hypocalcemia, a potentially life-threatening condition, is treated as soon as possible with intravenous calcium (e.g. as calcium gluconate). Generally, a central venous catheter is recommended, as the calcium can irritate peripheral veins and cause phlebitis. Natpara (rhPTH) is a synthetic recombinant human parathyroid hormone approved by U.S. FDA in 2015 for treatment of hypoparathyroidism.

In 1909, William George MacCallum and Carl Voegtlin, demonstrated association between parathyroid gland, calcium, and tetany. In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone. In 1925, James Bertram Collip along with Douglous B Leitch treated tetany with the help of parathyroid extract. In 2015, use of recombinant human parathyroid hormone 1-84 (rhPTH 1-84) for the management of hypoparathyroidism was approved by the U.S. Food and Drug Administration (FDA).

Hypoparathyroidism may be classified according to etiology into following groups including post-surgical hypoparathyroidism, autoimmune hypoparathyroidism, hypoparathyroidism associated with genetic defects, and functional hypoparathyroidism.

Hypoparathyroidism is an 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.

Hypothyroidism most commonly occurs as a complication of neck surgery including thyroidectomy, parathyroidectomy, and radical neck dissection. Second most common cause for hypoparathyroidism is autoimmune including polyglandular autoimmune syndrome type 1 and isolated autoimmune hypoparathyroidism. Less common causes of hypoparathyroidism includes infiltration and/or destruction of parathyroid glands and genetic causes. Most common genetic cause of hypoparathyroidism is calcium-sensing receptor gene activating mutation.

Hypoparathyroidism should be differentiated from other causes of hypocalcemia. Causes of hypocalcemia other than hypoparathyroidism include pseudohypoparathyroidism, hypomagnesemia, hypovitaminosis D, chronic kidney disease, and relative hypocalcemia due to hypoalbuminemia.

In Denmark, the incidence of postsurgical hypoparathyroidism is approximately 0.8 per 100,000 person-years. In United States, the prevalence of hypoparathyroidism is approximately 37 per 100,000 person-years. Majority of patients with hypoparathyroidism are 45 years or older. The women to men ratio is approximately 3 to 1.

The most potent risk factor in the development of hypoparathyroidism is anterior neck surgery. Other common risk factors include autoimmune diseases. Less common risk factors include destruction and/or infiltration of parathyroid glands and congenital multisystem syndromes. Maternal hyperparathyroidism also increase the risk of neonatal hypoparathyroidism.

There is insufficient evidence to recommend routine screening for hypoparathyroidism. However, a significant number of patients of isolated idiopathic hypoparathyroidism with hypercalciuria may have a de novo calcium-sensing receptor (CASR) gene mutation. Molecular screening of CASR gene in patients with isolated idiopathic hypoparathyroidism with hypercalciuria is recommended during initial work-up as it has potentially important clinical relevance to the patient’s prognosis.

The symptoms and complications of hypoparathyroidism usually develop due to hypocalcemia. There is an increased risk of renal complications due to hypercalciuria in patients treated with calcium and vitamin D analogs. Majority of post-surgical patients have transient hypoparathyroidism. The prognosis of post-surgical hypoparathyroidism is usually good as it is transient and serum calcium levels becomes normal within 6 months of surgery. Hypocalcemia due to hypoparathyroidism leads to complications irrespective of treatment. These complications include renal complications and hypocalcemic seizures. Other complications include symptomatic hypocalcemia, symptomatic hypercalcemia, basal ganglia calcifications, complications of iv calcium extravasation, dilated cardiomyopathy, pathologic fractures. Patients on treatment of hypoparathyroidism should be actively monitored for hypercalciuria and renal complications by renal imaging and creatinine clearance.

The diagnosis of hypoparathyroidism is made when the following diagnostic criteria are met: Hypocalcemia (albumin-adjusted) confirmed on at least two occasions separated by at least 2 weeks, parathyroid hormone (PTH) concentration, by second- or third-generation immunoassay, that is undetectable or inappropriately low (ie, <20 pg/mL) in the presence of hypocalcemia on at least two occasions, phosphate levels in the upper normal or frankly elevated range (helpful but not mandatory), and chronic hypoparathyroidism is established only after 6 months after neck surgery.

The hallmark of acute hypocalcemia due to hypoparathyroidism is tetany. A positive history of neck surgery and symptoms of hypocalcemia is suggestive of hypoparathyroidism. The most common symptoms of hypoparathyroidism include tetany, paresthesia, carpopedal spasms, and circumoral numbness. Common symptoms of hypoparathyroidism include abdominal pain, biliary colic, fatigue, muscle cramps, myoclonic jerks, new onset seizure due to hypocalcemia or worsening of seizures, and painful menstruation. Less common symptoms of hypoparathyroidism include cognitive impairment, decreased concentration, hoarseness, palpitations, personality disturbances and/or mood changes, symptoms of acute cardiomyopathy, wheezing, and dyspnea.

Physical examination of patients with hypoparathyroidism is usually due to hypocalcemia. The presence of tetany on physical examination is diagnostic of hypocalcemia which is commonly caused by hypoparathyroidism. The presence of Chvostek’s sign and Trousseau’s sign on physical examination is highly suggestive of hypocalcemia which is commonly caused by hypoparathyroidism.

Diagnosis of hypoparathyroidism is made by measurement of serum calcium (total and ionized), serum albumin (for correction), phosphate, intact parathyroid hormone (PTH), and 25-hydroxy vitamin D levels. Normal or inappropriately low serum intact parathyroid hormone (PTH) concentration in patients with subnormal serum albumin corrected total or ionized calcium concentration diagnostic of hypoparathyroidism.

An ECG may be helpful in the diagnosis of cardiac dysfunction due to hypoparathyroidism. Findings on an ECG suggestive of cardiac dysfunction due to hypoparathyroidism include prolongation of QT interval.

An X-ray may be helpful in the diagnosis of hypoparathyroidism. Findings on an X-ray suggestive of hypoparathyroidism include generalised osteosclerosis, calvarial thickening, hypoplastic dentition, and soft tissue calcifications.

Peripheral quantitative computed tomography (pQCT) and microcomputed tomography (microCT) may be helpful in the diagnosis of hypoparathyroidism. Findings on pQCT scan suggestive of hypoparathyroidism include increase in volumetric bone mineral density (vBMD) as well as bone mineral density (BMD) of both cortical and trabecular bones. Findings on microcomputed tomography include greater trabecular bone volume (BV/TV), markedly increased trabecular number (Tb.N) and trabecular thickness (Tb.Th); lower trabecular separation (Tb.Sp), and markedly elevated connectivity density (Conn D). A non-enhanced computed tomography of head may be helpful in the diagnosis of complications of hypoparathyroidism, which include bilateral and symmetrical intracranial calcifications in basal ganglia (mainly globus pallidus), cerebellum (dentate nuclei) and at the grey-white matter junction.

There are no MRI findings associated with hypoparathyroidism.

There are no ultrasound findings associated with hypoparathyroidism. However, a renal ultrasound may be helpful in the diagnosis of complications of hypoparathyroidism, which include nephrolithiasis and nephrocalcinosis.

Dual-energy X-ray absorptiometry (DXA) may be helpful in the diagnosis of hypoparathyroidism. Findings on an DXA suggestive of hypoparathyroidism include increased bone mineral density (BMD).

Genetic testing and/or family screening should be considered in patients with hypoparathyroidism of unknown etiology.

Pharmacologic medical therapies for hypoparathyroidism include calcium and Vitamin D3 supplementation. Severe hypocalcemia, a potentially life-threatening condition, is treated as soon as possible with intravenous calcium (e.g. as calcium gluconate). Generally, a central venous catheter is recommended, as the calcium can irritate peripheral veins and cause phlebitis. Natpara (rhPTH) is a synthetic recombinant human parathyroid hormone approved by U.S. FDA in 2015 for treatment of hypoparathyroidism.

Surgical intervention is not recommended for the management of hypoparathyroidism.

Effective measures for the primary prevention of chronic hypoparathyroidism include avoidance of injuries to parathyroid glands during anterior neck surgery by meticulous surgical dissection and intensive medical treatment of hypocalcaemia: “Parathyroid splinting”.

Effective measures for the secondary prevention of hypoparathyroidism is monitoring of patients on conventional therapy. Monitoring guidelines on conventional therapy include measurement of serum calcium (corrected for albumin), phosphorus, and creatinine concentrations; 24 hour urinary calcium excretion and creatinine, and other imaging studies and examinations.

In 1996, Winer and collegues demonstrated a reduction in calcium excretion in patients of hypoparathyroidism when treated with PTH 1-34 (teriparatide) when compared with treatment with calcitriol and calcium. PTH 1–34 (teriparatide) twice daily administered subcutaneoulsy provides a safe and effective alternative to calcitriol therapy and is capable of maintaining normocalcemia without hypercalciuria for at least 3 yr in patients with hypoparathyroidism. PTH 1-34 (teriparatide) has shown to improve the mental and physical health in hypoparathyroid patients.

Template:WikiDoc Sources

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]

In 1909, William George MacCallum and Carl Voegtlin, demonstrated association between parathyroid gland, calcium, and tetany. In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone. In 1925, James Bertram Collip along with Douglous B Leitch treated tetany with the help of parathyroid extract. In 2015, use of recombinant human parathyroid hormone 1-84 (rhPTH 1-84) for the management of hypoparathyroidism was approved by the U.S. Food and Drug Administration (FDA).

• In 1852, Sir Richard Owen, Hunterian Professor and Conservator of the Museum in the Royal College of Surgeons of England, described parathyroids in rhinoceros.^[1]
• In 1880, Ivar Sandström, a Swedish anatomist, described parathyroids in human following 50 autopsies. He found two parathyroid glands bilaterally in 43 out of 50 autopsies.^[2]
• In 1909, William George MacCallum and Carl Voegtlin, demonstrated association between parathyroid gland, calcium, and tetany.^[3]
• In 1942, Albright et. al. first described the term pseudohypoparathyroidism. It is an example of Seabright-Bantam syndrome. In pseudohypoparathyroidism hypocalcemia and hyperphosphatemia is resistant to parathyroid hormone administration.^[4]
• In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone.^[5] They also isolated the active polypeptide (parathormone B) from bovine parathyroid gland and gave its tentative formula in 1961.^[6]

• In 1925, James Bertram Collip along with Douglous B Leitch treated tetany with the help of parathyroid extract. They names the extract as parathyrin.^[7]
• In 1996, Winer and collegues demonstrated a reduction in urinary calcium excretion in patients of hypoparathyroidism when treated with PTH 1-34 (teriparatide) when compared with treatment with calcitriol and calcium.^[8]
• In 2015, use of recombinant human parathyroid hormone 1-84 (rhPTH 1-84) for the management of hypoparathyroidism was approved by the U.S. Food and Drug Administration (FDA).^[9]

Template:WH Template:WS

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]

Hypoparathyroidism may be classified according to etiology into following groups including post-surgical hypoparathyroidism, autoimmune hypoparathyroidism, hypoparathyroidism associated with genetic defects, and functional hypoparathyroidism.

• Hypoparathyroidism may be classified according to etiology into following groups:^[1]
  • Post-surgical hypoparathyroidism
  • Autoimmune hypoparathyroidism
  • Hypoparathyroidism associated with genetic defects
  • Functional hypoparathyroidism including:
    • Reversible suppression of parathyroid hormone secretion by magnesium depletion
    • Neonatal hypoparathyroidism due to maternal hyperparathyroidism and/or hypercalcaemia

Template:WH Template:WS

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]

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.

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

• 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.

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 are present on parathyroid glands. They are a type of 7-transmembrane receptors in G-protein coupled receptors superfamily of receptors.^[3]
• Calcium-sensing receptors sense change in extracellular concentration of ionized calcium.^[4]

• 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

• 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 of Hypoparathyroidism
Hypoparathyroidism				Inheritance	Gene mutation	Clinical features
Autoimmune		Autoimmune polyglandular hypoparathyroidism	Autoimmune polyendocrine syndrome type 1[9]	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[10]	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[11]	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[12]	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[11][13]	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[14]	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia) Paresthesia in fingertips, toes, and perioral area Carpopedal spasms Circumoral numbness
		Autosomal dominant hypercalcemia[15]	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.[16][17]
			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[18]		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[19]		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[20]		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[21]		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[22]		Autosomal recessive	Mutation in TBCE gene	Exclusively found in arabian descent population Presents with: Hypoparathyroidism Intellectual disability Dysmorphism
		Barakat syndrome[23][24]		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[25]	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)[26][27]		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)[28]		Autosomal recessive	G1528C gene mutation	Clinical features of LCHAD deficiency include: Hypoglycemia Hepatopathy Hypotonia Cardiomyopathy Retinopathy
	Heavy metal storage disorders	Hemochromatosis[29][30]		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[31][32]		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

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

• 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

• There is no gross pathology findings for hypoparathyroidism.

• There is no microscopic pathology findings for hypoparathyroidism.

Template:WH Template:WS

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]

Hypothyroidism most commonly occurs as a complication of neck surgery including thyroidectomy, parathyroidectomy, and radical neck dissection. Second most common cause for hypoparathyroidism is autoimmune including polyglandular autoimmune syndrome type 1 and isolated autoimmune hypoparathyroidism. Less common causes of hypoparathyroidism includes infiltration and/or destruction of parathyroid glands and genetic causes. Most common genetic cause of hypoparathyroidism is calcium-sensing receptor gene activating mutation.

Life threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Life threatening cause for hypoparathyroidism incude:

• Metastatic cancer to parathyroid glands

• Post-surgical (most common cause)^[1]
  • Thyroidectomy
  • Parathyroidectomy
  • Radical neck dissection
• Autoimmune (2nd most common cause)^[2]
  • Polyglandular autoimmune syndrome type 1
    • Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or acquired hypoparathyroidism associated with autoimmune hypothyroidism
  • Isolated autoimmune hypoparathyroidism

• Infiltration and/or destruction of parathyroid glands
  • Metal overload
    • Iron overload^[3]
      • Hemochromatosis
      • Thalassemia (due to repeated blood transfusion) ^[4]
    • Copper overload^[5]
      • Wilson’s disease
    • Aluminium deposition^[6]
      • Usually seen in patients with end-stage renal disease on hemodialysis
    • Hypermagnesemia^[7]
  • Radiation-induced destruction parathyroid glands^[8]
  • Hypomagnesemia^[9]
  • Metastatic cancer to parathyroid glands including:^[10][11]
    • Metastatic prostate cancer
    • Metastatic breast cancer
  • Granulomas infiltrating parathyroid glands^[12]
  • Amyloid deposition in all four parathyroid gland^[13]
  • Infections
    • Syphilis^[14]
    • HIV infection^[15]
• Maternal hyperparathyroidism leading to neonatal hypoparathyroidism^[16]
• Genetic causes

• Autoimmune
  • Autoimmune polyglandular hypoparathyroidism
    • Autoimmune polyglandular endocrinopathy type 1: Mutation in AIRE gene^[17]
• Isolated hypoparathyroidism
  • Autosomal dominant inheritence
    • Autosomal dominant familial isolated hypoparathyroidism caused by PTH gene mutation^[18]
    • Autosomal dominant familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation^[19]
    • Autosomal dominant hypocalcemia^[20]
      • Autosomal dominant hypocalcemia type 1 (Most common genetic form): Calcium-sensing receptor gene activating mutation.
      • Autosomal dominant hypocalcemia type 2 : G protein G11 (GNA11) mutation.
  • Autosomal recessive inheritence
    • Autosomal recessive familial isolated hypoparathyroidism caused by PTH gene mutation^[21]
    • Autosomal recessive familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation^[22][19]
  • X-linked inheritence
    • X-linked recessive familial isolated hypoparathyroidism : Mutation in gene variant FHL1 (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27.^[23]
• Congenital multisystem syndromes
  • DiGeorge syndrome: 22q11.2 deletion^[24]
  • CHARGE syndrome: CHD7 G744S missense mutation^[25]
  • Kenny-Caffey syndrome type 1: Deletion of the TBCE gene^[26]
  • Kenny-Caffey syndrome type 2: Mutation of FAM111A gene^[27]
  • Sanjad-Sakati syndrome: Mutation in TBCE gene^[28]
  • Barakat syndrome: Mutations in the GATA3 gene^[29][30]
• Metabolic diseases
  • Mitochondrial polyneuropathies^[31]
    • Kearns–Sayre syndrome
    • Maternally inherited diabetes and deafness (MIDD)
  • Mitochondrial enzyme deficiencies
    • Mitochondrial trifunctional protein deficiency (MTP deficiency)^[32]
    • Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)^[33]
  • Heavy metal storage disorders
    • Hemochromatosis^[3]
    • Wilson’s disease^[5]

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	Polyglandular autoimmune syndrome type 1, Isolated autoimmune hypoparathyroidism
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	Wilson’s disease, autosomal dominant familial isolated hypoparathyroidism caused by PTH gene mutation, autosomal dominant familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation, autosomal dominant hypocalcemia type 1, autosomal dominant hypocalcemia type 2, Autosomal recessive familial isolated hypoparathyroidism caused by PTH gene mutation, Autosomal recessive familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation, X-linked recessive familial isolated hypoparathyroidism hypoparathyroidism,22q11.2 deletion syndrome, DiGeorge syndrome, 22q11.2DS, CATCH 22 syndrome, Cayler cardiofacial syndrome, conotruncal anomaly face syndrome (CTAF), deletion 22q11.2 syndrome, Sedlackova syndrome, Shprintzen syndrome, VCFS, velocardiofacial syndrome, velo-cardio-facial syndrome, CHARGE syndrome, Kenny-Caffey syndrome type 1, Kenny-Caffey syndrome type 2, Sanjad-Sakati syndrome, Barakat syndrome, [[chromosome 10, monosomy 10p], and chromosome 10p deletion 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),
Hematologic	Hemochromatosis, Thalassemia
Iatrogenic	Parathyroidectomy, radiation-induced parathyroid destruction, radical neck dissection, thyroidectomy
Infectious Disease	HIV infection, syphilis
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	Maternal hyperparathyroidism leading to neonatal hypoparathyroidism
Oncologic	Metastatic prostate cancer, metastatic breast cancer
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	Aluminium deposition due to end-stage renal disease on hemodialysis, Hypermagnesemia, Hypomagnesemia
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	Granulomas infiltrating parathyroid glands, amyloid deposition in all four parathyroid gland

Template:WS Template:WH

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]

Hypoparathyroidism should be differentiated from other causes of hypocalcemia. Causes of hypocalcemia other than hypoparathyroidism include pseudohypoparathyroidism, hypomagnesemia, hypovitaminosis D, chronic kidney disease, and relative hypocalcemia due to hypoalbuminemia.

Hypoparathyroidism should be differentiated from other causes of hypocalcemia. Causes of hypocalcemia other than hypoparathyroidism include:

• Pseudohypoparathyroidism
  • Pseudohypoparathyroidism type 1
    • Pseudohypoparathyroidism type 1a
    • Pseudohypoparathyroidism type 1b
    • Pseudohypoparathyroidism type 1c
    • Pseudopseudohypoparathyroidism
  • Pseudohypoparathyroidism type 2
• Hypomagnesemia
• Hypovitaminosis D
• Chronic kidney disease
• Hypoalbuminemia (relative hypocalcemia)

Differential diagnosis of hyperparathyroidism on the basis of hypocalcemia
Disorders		Mechanism of hypocalcemia	Laboratory findings
			Serum PTH	Serum Calcium	Serum Phosphate	Other findings
Hypoparathyroidism		There is deficiency of parathyroid hormone in hypoparathyroidism. Deficiency of parathyroid hormone causes body to decrease: Reabsorption of calcium from bone Excretion of phosphate Reabsorption of calcium from distal tubules Vitamin D mediated absorption of calcium from intestine	↓	↓	↑	↓ 1,25 Dihydroxy vitamin D Normal urinary cAMP Normal urinary phosphate
Pseudohypoparathyroidism[1][2][3]	Type 1a	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs.	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 1b	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Familial– heterozygous deletions in STX16, NESP55, and/or AS exons or loss of methylation at GNAS.	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 1c	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs.	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 2	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH).	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D Normal urinary cAMP ↓ Urinary phosphate
	Pseudopseudohypoparathyroidism	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Combination of inactivating mutations of GNAS1 and Albright’s osteodystrophy.	Normal	Normal	Normal	—
Hypomagnesemia[4][5]		Decreased parathyroid hormone (PTH) secretion. Skeletal resistance to parathyroid hormone.	Inappropriately ↓	Normal/↓	—	↓ Serum magnesium ↓/Normal serum potassium
Hypoalbuminemia		Majority of calcium in blood is bound to albumin. So, when there is a decrease in concentration of albumin due to any condition, there is a relative hypocalcemia as well.	—	↓	—	↓ Serum albumin Normal albumin-corrected serum total calcium Normal ionized calcium
Hypovitaminosis D		Decrease in vitamin D mediated calcium absorption from intestine.	↑	↓	↓/Low-normal	↓ 25 Hydroxy vitamin D
Chronic kidney disease		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/calcitriol).	↑	↓/Normal	↑	↓ Glomerular filtration rate

Template:WH Template:WS

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]

In Denmark, the incidence of postsurgical hypoparathyroidism is approximately 0.8 per 100,000 person-years. In United States, the prevalence of hypoparathyroidism is approximately 37 per 100,000 person-years. Majority of patients with hypoparathyroidism are 45 years or older. The women to men ratio is approximately 3 to 1.

• In Denmark, the incidence of postsurgical hypoparathyroidism is approximately 0.8 per 100,000 person-years.^[1]

• In United States, the prevalence of hypoparathyroidism is approximately 37 per 100,000 person-years.^[2]
• In Denmark, the prevalence of postsurgical hypoparathyroidism is approximately 22 per 100,000 person-years.^[2]
• In Denmark, the prevalence of nonsurgical hypoparathyroidism is approximately 2.3 per 100,000 person-years.^[3]
• In Japan, the prevalence of idiopathic hypoparathyroidism ranges from a low of 55 per 100,000 persons to a high of 88 per 100,000 persons with an average prevalence of 72 per 100,000 persons.^[4]
• In Japan, the prevalence of pseudohypoparathyroidism ranges from a low of 0.26 per 100,000 persons to a high of 0.42 per 100,000 persons with an average prevalence of 0.34 per 100,000 persons.^[4]

• Majority of patients with hypoparathyroidism are 45 years or older.^[5]

• Women are more commonly affected by hypoparathyroidism than men. The women to men ratio is approximately 3 to 1.^[5]

Template:WH Template:WS

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]

The most potent risk factor in the development of hypoparathyroidism is anterior neck surgery. Other common risk factors include autoimmune diseases. Less common risk factors include destruction and/or infiltration of parathyroid glands and congenital multisystem syndromes. Maternal hyperparathyroidism also increase the risk of neonatal hypoparathyroidism.

The most potent risk factor in the development of hypoparathyroidism is anterior neck surgery. Other common risk factors include autoimmune diseases. Less common risk factors include destruction and/or infiltration of parathyroid glands and congenital multisystem syndromes. Maternal hyperparathyroidism also increase the risk of neonatal hypoparathyroidism.^[1][2]

• Common risk factors in the development of hypoparathyroidism include:^[1]
  • Anterior neck surgery : Predisposing factors for post-surgical hypoparathyroidism include:^[3][4]
    • Young age
    • Female gender
    • Graves’ disease
    • Lymphadenectomy
    • Accidental parathyroidectomy (including biopsies during surgery for hyperparathyroidism)
    • Parathyroid auto-transplantation
    • The number of functioning parathyroid glands remaining in-situ (most important factor)
  • Autoimmune diseases

• Less common risk factors in the development of hypoparathyroidism include:^[1]
  • Destruction and/or infiltration of parathyroid glands
  • Congenital multisystem syndromes
  • Maternal hyperparathyroidism and/or maternal hypercalcemia^[2]

Template:WH Template:WS

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]

There is insufficient evidence to recommend routine screening for hypoparathyroidism. However, a significant number of patients of isolated idiopathic hypoparathyroidism with hypercalciuria may have a de novo calcium-sensing receptor (CASR) gene mutation. Molecular screening of CASR gene in patients with isolated idiopathic hypoparathyroidism with hypercalciuria is recommended during initial work-up as it has potentially important clinical relevance to the patient’s prognosis.

• There is insufficient evidence to recommend routine screening for hypoparathyroidism.
• However, a significant number of patients of isolated idiopathic hypoparathyroidism with hypercalciuria may have a de novo calcium-sensing receptor (CASR) gene mutation.^[1]
• All patients require treatment with vitamin D3 supplementation for correction of hypocalcemia.
• As vitamin D3 supplementation may precipitate prolonged episode of hypercalciuria, the treatment decision should be evaluated on an individual basis in asymptomatic or mildly symptomatic patients.
• Molecular screening of CASR gene in patients with isolated idiopathic hypoparathyroidism with hypercalciuria is recommended during initial work-up as it has potentially important clinical relevance to the patient’s prognosis.^[2]

Template:WH Template:WS

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]

The symptoms and complications of hypoparathyroidism usually develop due to hypocalcemia.There is an increased risk of renal complications due to hypercalciuria in patients treated with calcium and vitamin D analogs. Majority of post-surgical patients have transient hypoparathyroidism. The prognosis of post-surgical hypoparathyroidism is usually good as it is transient and serum calcium levels becomes normal within 6 months of surgery. Hypocalcemia due to hypoparathyroidism leads to complications irrespective of treatment. These complications include renal complications and hypocalcemic seizures. Other complications include symptomatic hypocalcemia, basal ganglia calcifications, complications of intravenous calcium extravasation, dilated cardiomyopathy, pathological fractures. Patients on treatment of hypoparathyroidism should be actively monitored for hypercalciuria and renal complications by renal imaging and creatinine clearance.

• The symptoms and complications of hypoparathyroidism usually develop due to hypocalcemia.^[1]
• There is an increased risk of renal complications due to hypercalciuria in patients treated with calcium and vitamin D analogs.
• Transient hypoparathyroidism:^[2][3][4]
  • Most common cause of hypoparathyroidism is anterior neck surgery.
  • Majority of post-surgical patients have transient hypoparathyroidism.
  • This hypoparathyroidism is due to post-surgical “stunning of parathyroid glands“.
• The features of hypoparathyroidism should persist for atleast 6 month after surgery to be diagnosed as chronic hypoparathyroidism.
• Hypocalcemia due to hypoparathyroidism leads to complications irrespective of treatment. The common complications include renal complications and hypocalcemic seizures.^[1]

• Common complications of hypoparathyroidism include:^[1][5][6][7]
  • Renal complications:
    • Nephrolithiasis
    • Nephrocalcinosis
    • Impaired renal function
  • Symptomatic hypocalcemia
  • Posterior subcapsular cataracts
  • Basal ganglia calcifications^[8]
  • Complications of iv calcium extravasation
  • Hypocalcemic seizure
  • Dilated cardiomyopathy
  • Pathological fractures
  • Depression and other types of neuropsychiatric diseases
  • Increased risk of infections

• The prognosis of post-surgical hypoparathyroidism is usually good as it is transient and serum calcium levels becomes normal within 6 months of surgery.^[3][4]
• However, chronic hypoparathyroidism has a negative impact on quality of life of patients.^[9][10]
• Hypocalcemia due to hypoparathyroidism leads to complications irrespective of treatment.^[1]
• Patients on treatment of hypoparathyroidism should be actively monitored for hypercalciuria and renal complications by renal imaging (X-ray, CT scan without contrast) and creatinine clearance.

Template:WH Template:WS