Aetiology
The biochemical profile (low serum calcium, high serum phosphate) may be seen in hypoparathyroidism, as well as in pseudohypoparathyroidism, a defect in the activation of the parathyroid hormone (PTH) receptor or PTH resistance. Intact plasma PTH levels are often markedly elevated in pseudohypoparathyroidism, and distinguish the two disorders clinically.
Postsurgical hypoparathyroidism
The major aetiology, accounting for approximately 75% of cases in adults.[1]
During thyroid surgery, one or more parathyroid gland(s) may be inadvertently removed or devascularised.
Depending on the extent of surgery to treat primary or uraemic secondary hyperparathyroidism, the blood supply to the remaining gland(s) may be compromised so that secretory function never fully recovers postoperatively. This is of particular concern if there have been prior neck explorations resulting in scarring and distortion of anatomical landmarks.
Subtotal parathyroidectomies to treat hyperplasia place any remaining tissue at risk for viability postoperatively.
Transient postoperative hypocalcaemia may be seen when remaining parathyroid tissues have been chronically suppressed by the high serum calcium levels of primary hyperparathyroidism or of tertiary hyperparathyroidism in patients with end-stage renal disease. Days to weeks may be required for those glands to regain their secretory capacity.
Transient postoperative hypocalcaemia, usually accompanied by hypophosphataemia, should raise the spectre of 'hungry bone syndrome'. This can occur after thyroid surgery, when thyrotoxicosis is present, or after parathyroidectomy for moderate to severe primary or secondary hyperparathyroidism.
DiGeorge syndrome, estimated to occur in 1/4000 to 1/6000 live births, is caused by the heterozygous deletion of genes on chromosome 22 (22q11.2), which causes developmental defects of the heart, thymus, parathyroid glands, and other tissues.[8][9] TBX1 gene defects are one of the most prominent aetiologies for this syndrome. The syndrome has a varied spectrum of severity. Cardiac defects can include truncus arteriosus, atrial or ventricular septal defects, tetralogy of Fallot, vascular rings, and others. Immunodeficiency may be mild or severe. Hypocalcaemia may present at birth with the biochemical profile reflecting parathyroid gland hypoplasia, or the hypocalcaemia may be mild with PTH levels that are only modestly lowered and present later in life. The syndrome may even be diagnosed in adulthood.
Mutations in two critical genes in the pathway of extracellular calcium-sensing by parathyroid cells underlie autosomal dominant hypoparathyroidism types 1 and 2. Types 1 and 2 are caused by gain of function mutations in the extracellular calcium-sensing receptor (CASR) and the G-protein subunit (G-alpha 11) genes, respectively.[10][11] CASR mutations are likely to be the most common cause for isolated (non-surgical) hypoparathyroidism.[11] These disorders typically cause mild hypocalcaemia with inappropriately low PTH levels. CASR mutations can cause a presentation in infancy or early childhood with severe hypocalcaemia, seizures, and a picture of salt-wasting and Bartter syndrome type V.[11]
Mutations in key transcription factors required for the development of the parathyroid glands, such as GATA3 or GCM2, are other genetic aetiologies. With loss of function mutations in GATA3, renal anomalies and deafness often accompany hypoparathyroidism in an autosomal dominant inheritance pattern.[7] Hypoparathyroidism due to GCM2 mutations is isolated; both autosomal recessive and dominant inheritance have been noted.
Autoimmune polyendocrine syndrome type 1 (APS1) is caused by loss of function mutations in the autoimmune regulator (AIRE) gene and is generally of autosomal recessive inheritance. Initial presentation of the disorder involves mucocutaneous candidiasis in the first few years of life, followed by hypoparathyroidism and/or adrenal insufficiency, typically with onset in childhood.[12]
Hypoparathyroidism occurs in the syndrome of osteocraniostenosis (small dense bones, short stature, high perinatal mortality) and in Kenny-Caffey syndrome, both of which are allelic disorders due to heterozygous mutations in FAMIIIA.[13]
Mitochondrial disorders associated with hypoparathyroidism include Kearns-Sayre syndrome and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).[7]
Sanjad-Sakati syndrome includes hypoparathyroidism, short stature, and mental disability due to autosomal recessive mutations in tubulin-folding cofactor E.[7]
Mutations in the gene encoding PTH are very rare but well described, occurring with autosomal recessive or dominant inheritance.
Other aetiologies
Hypomagnesaemia and hypermagnesaemia are both functional states of hypoparathyroidism.[14][15][16] In patients with hypomagnesaemia, the low plasma PTH levels are readily reversed by magnesium repletion. Several risk factors, such as proton-pump inhibitor therapy, can contribute to chronic hypomagnesaemia, and a large number of genetic disorders of magnesium metabolism can cause it.[14][15][16] Chronic alcoholism, malnutrition, diarrhoea, and malabsorption can produce hypomagnesaemia.[16][17]
Cases of isolated autoimmune hypoparathyroidism (without other endocrinopathy or immune dysfunction) may occur at any age.[12]
Patients with Riedel thyroiditis can develop hypoparathyroidism; this is thought to be due to the marked fibrosis and inflammatory responses of the IgG4-mediated disease that can lead to thyroid destruction.[18][19]
Infiltrative diseases such as haemochromatosis (including secondary iron overload from blood transfusions in thalassaemia), Wilson's disease, and metastasis can cause hypoparathyroidism.[20]
Radiation-induced damage (including radioactive iodine treatment) can occur, but is very rare.[20]
Pathophysiology
Hypocalcaemia results from the deficient actions of parathyroid hormone (PTH) to reabsorb calcium from the urine, to generate sufficient 1,25-dihydroxyvitamin D in the kidney to absorb calcium from the gut, and to reabsorb calcium from bone. Hypocalcaemia, both acutely and chronically, produces irritability within the nerves leading to muscle cramping and stiffness, tetany, paraesthesias, altered mentation, and even seizures. Chronic hypocalcaemia impairs left ventricular contractility.
Hyperphosphataemia results from the lack of PTH action on renal phosphate transport to clear phosphate via the kidney. Chronically high phosphate levels along with near normal serum calcium levels elevate the calcium x phosphate product, which can contribute to soft tissue calcifications and cataracts.
Hypocalcaemia, in states of magnesium depletion and hypomagnesaemia, results from insufficient PTH levels as well as a failure of PTH to activate its receptors in the target tissues of kidney and bone, a form of reversible PTH resistance.
Constitutively active or gain of function mutations in two genes in the parathyroid calcium-sensing signal transduction pathway (CASR and G-alpha 11) mediate suppression of PTH secretion, even though serum calcium concentrations are low, producing a state of functional hypoparathyroidism.
Hypermagnesaemia, a relatively infrequent cause of hypocalcaemic hypoparathyroidism (e.g., with tocolytic therapy), results from magnesium-induced suppression of PTH secretion through activation of the calcium-sensing receptor.
Chronic alcoholism causes magnesium wasting through renal mechanisms.
Classification
Classification by mechanism
Iatrogenic: post-surgical
Congenital: many syndromes and isolated gene defects
Functional: reversible suppression of parathyroid hormone secretion by magnesium depletion, maternal hypercalcaemia, post-parathyroidectomy for parathyroid adenoma or uraemic secondary hyperparathyroidism, and hypermagnesaemia
Destruction of parathyroid tissue: autoimmune, heavy metal deposition, radiation damage, and fibrosis
Idiopathic: many cases, even with genetic testing, do not have a mutation identified.
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