Category of pathology

Genetic defect

Parathyroid gland destruction
Radiation therapy
Autoimmune: isolated or APECED

AIRE, 21q22.3

Reduced parathyroid gland function
Autosomal dominant hypocalcemic hypercalciuria

CASR, 3q13.3-21

PTH gene mutation

PTH, 11p15

Autoantibodies to CASR
Disorders of parathyroid gland formation
DiGeorge sequence

TBX1, 22q11; 10p; intrauterine exposure to alcohol, diabetes, isotretinoin

Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR)


Hypoparathyroidism-retardation-dysmorphism (HRD), Kenny-Caffey/Sanjad-Sakati syndromes


Autosomal recessive/dominant hypoparathyroidism


X-linked hypoparathyroidism


Other causes of hypoparathyroidism
Mitochondrial disease

Mitochondrial tRNA

Resistance to parathyroid hormone


Transient pseudohypoparathyroidism of the newborn

APECED autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, AIRE autoimmune regulator gene, CASR calcium sensing receptor gene, PTH, parathyroid hormone gene, TBX1 T-BoX protein 1 gene, GATA3 GATA binding protein 3 gene, TBCE tubulin binding (folding) cofactor E gene, GCM2 glial cells missing 2 gene, tRNA transfer RNA, GNAS Gs-alpha gene

Most patients with postsurgical hypoparathyroidism have the transient form of this disorder. Experience of the surgeon performing surgery is predictive of the incidence of postsurgical hypoparathyroidism. Immediate postoperative serum calcium and PTH levels may be useful in predicting which patients will develop permanent hypocalcemia due to postsurgical hypoparathyroidism [8].

Nonsurgical hypoparathyroidism may be due deficiency or excess of serum magnesium [9, 10]. Hypomagnesemia usually causes hypoparathyroidism when serum magnesium is less than 1.0 mg/dL. Up to 11 % of hospitalized patients may have hypomagnesemia, while up to 9 % may have hypermagnesemia [11]. Hypomagnesemia may be due to gastrointestinal losses associated with vomiting related to excessive alcohol intake, chronic diarrhea, steatorrhea, malabsorption, or intestinal resection, or renal tubular losses due to medications such as furosemide, aminoglycosides, cisplatin, cyclosporin, amphotericin B, pentamidine, tacrolimus, or proton pump inhibitors [12]. Rare genetic disorders such as Gitelman syndrome may contribute to hypomagnesemia. Hypomagnesemia occurs frequently in critically ill patients, which contributes to the hypocalcemia frequently seen in intensive care unit patients. Hypermagnesemia may occur in late-stage chronic kidney disease in patients treated with magnesium antacids, enemas, or infusions, or acute renal failure associated with rhabdomyolysis or tumor lysis syndrome [13].

Primary intestinal hypomagnesemia results from a rare inherited disorder causing magnesium malabsorption leading to hypomagnesemia in early infancy. This condition is thought to primarily occur due to deficient intestinal magnesium absorption, but there may also be defects in renal magnesium reabsorption. Patients usually present with neurological symptoms, including tetany, muscle spasms, and seizures due to both hypomagnesemia and hypocalcemia associated with hypoparathyroidism. Lifelong high oral intake of magnesium supplements decreases symptoms and restores serum calcium levels to normal. Mutations in the TRMP6 gene on chromosome 9 have been identified to cause this disorder [14, 15]. The TRMP6 protein is a member of the transient receptor membrane potential channel family that complexes to TRPM7, a calcium- and magnesium-permeable cation channel.

Other acquired causes of hypoparathyroidism are much rarer. Hypoparathyroidism may result from metastases to the parathyroid glands in extremely rare circumstances [16]. Infiltration and destruction of the parathyroid glands by iron overload may occur in hemochromatosis, or thalassemia requiring multiple blood transfusions [17]. Copper overload occurring due to Wilson’s disease may also result in hypoparathyroidism [18].

External beam radiation therapy to the neck for treatment of malignant disease, or radioactive iodine therapy for Graves’ disease , may also rarely result in destruction of the parathyroid glands [19].

Inherited causes of hypoparathyroidism include autosomal dominant hypocalcemia with hypercalciuria (ADHH) , a condition in which there is a gain-of-function mutation in the CaSR gene [20]. This type of mutation changes the threshold of PTH secretion by parathyroid cells in response to circulating ionized calcium, leading to low or inappropriately low-normal PTH secretion despite hypocalcemia. Most of the mutations reported to date affect the extracellular N-terminal or transmembrane domains of the receptor. The mutant receptors may show both increased receptor sensitivity to calcium and increased maximal signal transduction capacity. Since this activating mutation is also expressed in the CaSR protein on proximal renal tubular cells in the thick ascending limb of Henle, absolute or relatively increased 24-h urinary calcium excretion is a hallmark of the disorder. Most patients with ADHH are asymptomatic and have mild hypocalcemia with significant hypercalciuria, but occasional patients may present with moderate or severe hypocalcemia. This form of CaSR-mediated hypoparathyroidism may cause increased risk of nephrocalcinosis compared to other forms of hypoparathyroidism. In one series, almost half of the patients evaluated had nephrocalcinosis associated with hypercalciuria [21]. Calcium and calcitriol supplementation must therefore be carefully monitored in this condition.

Occasional reports have described patients with CaSR gene gain-of-function mutations associated with a Bartter-like syndrome, suggesting that the CaSR protein may also play a role in sodium chloride regulation [22]. These patients present with hypocalcemia, hypercalciuria, and nephrocalcinosis, associated with hypokalemic alkalosis, renal salt wasting that may cause hypotension, hyperreninemic hyperaldosteronism, and increased urinary prostaglandin excretion. Extensive burns may also lead to upregulation of the CaSR, with lower than normal serum calcium suppressing PTH secretion, resulting in hypocalcemia and hypoparathyroidism.

Autoimmune hypoparathyroidism is thought to be the second most common form of adult acquired hypoparathyroidism. Isolated autoimmune destruction of the parathyroid glands may occur, resulting in idiopathic hypoparathyroidism, or autoimmune destruction may occur in association with other autoimmune conditions as part of autosomal recessive autoimmune polyglandular endocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) [23]. This syndrome is caused by mutations in the autoimmune regulator AIRE gene, which results in abnormal thymic expression of tissue antigens, generation of autoreactive T-cells, ultimate loss of central tolerance to specific self-antigens, and the development of multiple autoimmune disorders [24]. Antibodies against the CaSR have been identified in some individuals with both idiopathic hypoparathyroidism and APECED syndrome [25, 26], but it is not yet clear if these antibodies are causative or simply markers of disease [27]. Idiopathic autoimmune hypoparathyroidism most often occurs in the teenage years or young adulthood, but may occur at any age. APECED usually presents in childhood, and is characterized by chronic mucocutaneous candidiasis in addition to variable expression of endocrine and other autoimmune diseases. Variation in the clinical phenotype of individuals with identical mutations in AIRE is incompletely understood, but this suggests that other genetic loci or environmental factors are important in development of the phenotype.

Hypoparathyroidism may be diagnosed at birth or during childhood due to a variety of genetic mutations causing congenital syndromes, the most widely known being the DiGeorge (velocardiofacial) sequence [28]. This disorder is caused by abnormal development of neural crest cells in the third and fourth branchial pouches. In 90 % of cases, the syndrome is caused by heterozygous chromosomal deletion of the TBX1 gene in the region of chromosome 22q11. Thirty-five genes have been identified in this region, so deletion of other genes, alone or in combination, could also cause this syndrome, but the TBX1 gene is a major determinant of cardiac, thymus, and parathyroid cell phenotypes. A region on chromosome 10p (DiGeorge critical region II) has also been linked to the sequence. DiGeorge syndrome is associated with distinctive facial abnormalities, cleft lip and/or palate, conotruncal cardiac anomalies, and mild to moderate immune deficiency. Hypocalcemia due to hypoparathyroidism has been reported in 17–60 % of affected children [29]. DiGeorge syndrome is estimated to occur in as many as 1:2000–1:3000 births, with the incidence rate of new mutations estimated at 1:4000–1:6000. Because the clinical phenotype varies, findings may be subtle and therefore overlooked, and mild hypocalcemia may be easily missed. In one study of adults with chromosome 22q11.2 deletion, about half were hypocalcemic, with a median age of presentation of 25 years, and a maximum age of diagnosis of up to 48 years [30]. This disorder may rarely be diagnosed for the first time as late as the mid-60s, with late onset of mild hypocalcemia, and is not infrequently diagnosed in affected parents in their 20s or 30s after the birth of an affected child.

Finally, a variety of other rare genetic or inherited disorders may cause hypocalcemia that is usually recognized in infancy or childhood. Familial isolated hypoparathyroidism due to autosomal recessive or dominant mutations in the pre-proPTH gene on chromosome 11p15 [31, 32], or parathyroid gland dysgenesis due to mutations in various transcription factors regulating parathyroid gland development such as GCMB (glial cells missing B) [33] or GCM2 (glial cells missing 2) [34], GATA3 [35, 36], or Sry-box 3 (SOX3) [37], are thought to be very rare. Autosomal dominant hypoparathyroidism associated with deafness and renal anomalies has been linked to mutations in the GATA3 gene on chromosome 10p14-10-pter [35, 36]. Hypoparathyroidism has been very rarely associated with X-linked recessive mutations on Xq26-27, leading to disruption of SOX3 transcription [37]. The syndrome of autosomal recessive hypoparathyroidism, growth and mental retardation, and dysmorphism due to mutations in the TBCE gene on chromosome 1q42-q43 is another very rare cause of hypoparathyroidism [38]. Hypoparathyroidism with metabolic disturbances and congenital anomalies has been associated with rare maternal mitochondrial gene defects [39, 40].

Symptoms of Hypoparathyroidism

Regardless of the cause of their hypoparathyroidism, patients most often present with tingling paresthesias about their finger and toe tips, lips, or tongue, and diffuse muscle cramps [41, 42]. Occasionally patients develop more severe cramps or carpopedal spasm (tetany). More severely affected patients may develop seizures, bronchospasm, laryngospasm, or cardiac rhythm disturbances due to prolongation of their QT interval related to hypocalcemia. Occasional patients with mild hypoparathyroidism may be asymptomatic much or most of the time. Rare severely affected patients may die due to untreated hypocalcemia. The severity of symptoms reported generally correlates with the severity of hypocalcemia. Table 11.2 describes recognized symptoms and signs of hypocalcemia that may be seen in patients with hypoparathyroidism.

Table 11.2
Symptoms and signs of hypocalcemia associated with hypoparathyroidism


Circumoral and finger and toe tip tingling paresthesias

Increased neuromuscular irritability


Muscle cramps and twitching

Muscle weakness

Abdominal cramps



Altered CNS function

Altered mental functioning

Seizures of all types

Papilledema or pseudotumor cerebri

Choreoathetoid movements



Congestive heart failure

Generalized fatigue


Chvostek’s sign

Trousseau’s sign

Prolongation of QTc interval


Basal ganglia and other intracerebral calcifications

Complications of Hypoparathyroidism

Complications of hypoparathyroidism are thought to depend in part on treatment for the disorder, because most patients are unable to function well or survive without treatment for very long. Most patients require treatment with high-dose calcium and vitamin D supplementation to correct their hypocalcemia. Recent studies have shown that a variety of comorbidities is associated with hypoparathyroidism. Commonly recognized complications include hypocalcemia, hypercalcemia, hypercalciuria, calcium-containing kidney stones, cataracts, and basal ganglia and other intracerebral calcifications [41].

Recent long-term studies using the Danish National Patient Registry of patients with hypoparathyroidism [3, 5] have shown a threefold increased risk of renal disease, with a threefold increased risk of renal insufficiency in postsurgical cases, and sixfold increase in nonsurgical cases. Patients in the registry had a fourfold increased risk of hospitalization for calcium-containing kidney stones. Cardiovascular risk in patients with postsurgical hypoparathyroidism was not increased compared to the general population, but was increased twofold in the nonsurgical cases, with borderline increased risk of stroke and cardiac dysrhythmia.

In another study using the same national registry [4], neuropsychiatric disease was increased 2.45-fold in both postsurgical and nonsurgical patients, with depression and bipolar disorder increased twofold in postsurgical cases. Risk of infections was increased 1.42-fold in postsurgical patients, and 1.94-fold in nonsurgical cases. The most common infection seen was urinary tract infection (UTI), with a borderline increase in UTI in postsurgical patients, and a 3.84-fold increased risk in nonsurgical patients. Risk of hospitalization for seizures was increased by 3.82-fold in postsurgical patients, and tenfold in nonsurgical cases. Risk of cataracts was seen only in nonsurgical cases, with a 4.2-fold increased risk. Fractures overall did not differ between patients with postsurgical or nonsurgical hypoparathyroidism and the general population, but there was a mildly increased risk of upper extremity fractures in nonsurgical patients, and a decreased risk of upper extremity fractures in postsurgical patients.

Treatment of Hypoparathyroidism

Guidelines for the clinical management of hypoparathyroidism have recently been published [40, 41]. Treatment of hypoparathyroidism is intended primarily to improve or eliminate symptoms, reverse increased skeletal mineralization to the degree it is present, heal osteomalacia if present, maintain minimum goal-range serum total and ionized calcium, reduce hyperphosphatemia, minimize hypercalciuria to 24-h urine calcium of <300 mg, and avoid renal dysfunction, kidney stones, nephrocalcinosis, cataracts, and basal ganglia and other intracerebral calcifications [42, 43].

Acute Hypoparathyroidism

Patients who require emergent or urgent treatment due to symptoms such as severe muscle cramps, tetany, seizures, laryngospasm, bronchospasm, cardiac rhythm disturbances, altered mental status, or severe hypocalcemia, require intravenous calcium, usually given as calcium gluconate. One standard approach is to add ten 10-mL ampules of calcium gluconate, with 93 mg elemental calcium per ampule, to 900 mL of 5 % dextrose, and to slowly infuse 10 mL over 10 min to improve symptoms, with repeat infusions given once or twice more as needed [42, 43]. Calcium chloride is usually not recommended for intravenous replacement due to the risk of venous and soft tissue irritation associated with extravasation, unless a central venous line is present [44]. Cardiac monitoring is recommended during intravenous calcium infusion [45].

Because hypocalcemia will usually recur rapidly after 2–3 bolus infusions if no further treatment is given, a maintenance infusion of calcium gluconate at the same concentration is then started at 10–100 mL/h to minimize symptoms and improve serum calcium to the lower end of the normal range at around 8.5 mg/dL (2.12 mmol/L), with an ionized calcium of around 4 mg/dL (1.0 mmol/L) [45, 46]. The infusion rate is usually titrated to give 0.3–1.0 mg elemental calcium/kg/h.

Once the patient is stabilized with an intravenous calcium infusion, oral calcium supplementation is then started, giving the patient at least 500 mg elemental calcium three to four times a day. The calcium gluconate infusion is gradually tapered as serum calcium approaches the target level at the lower end of the normal range, the patient’s symptoms improve, and oral calcium supplements are continued.

If the serum 25-hydroxyvitamin D level is greater than 20 ng/mL, vitamin D3 supplementation is frequently started at 1000 International Units each day to improve absorption of the calcium supplements. If serum 25-hydoxyvitamin D is less than 20 ng/mL, higher-dose vitamin D3 supplementation is typically started, often at 50,000 International Units once weekly for 2 months to restore vitamin D levels to the desired range of 30–100 ng/mL [47].

Chronic Hypoparathyroidism

If hypoparathyroidism does not resolve after the acute episode, management of chronic hypocalcemia is required. Usually this involves long-term high-dose oral calcium and vitamin D supplementation, sometimes for life, with thiazide-type diuretics or magnesium supplementation as needed. Recent guidelines for management of hypoparathyroidism recommend reasonable goals for management include maintenance of (1) serum calcium in the low-normal range, (2) serum phosphorus in the high-normal range, (3) 24-h urine calcium less than 300 mg, and (4) serum calcium x phosphate product less than 55 mg2/dL2 [42, 43].

If serum magnesium level is decreased, the total body magnesium deficit is usually very large, but poorly reflected by the serum magnesium level, because magnesium is mostly an intracellular cation. Supplementation with magnesium usually takes months to fully replete body stores. As serum magnesium is gradually replaced, serum calcium and parathyroid levels will return toward normal.

Once serum calcium, phosphorus, vitamin D, and magnesium are stabilized, patients need to be monitored periodically. Table 11.3 summarizes the recommended frequency of follow-up of various biochemical and imaging studies for patients being followed for chronic hypoparathyroidism.

Table 11.3
Frequency of monitoring of biochemical and imaging tests in hypoparathyroidism during treatment

Serum Ca, P, and Cr

During initial treatment phase: weekly to monthly
After treatment stabilization: twice yearly to yearly

Follow-up evaluations

During initial treatment phase: every 1–2 weeks
After treatment stabilization: every 3–6 months

24-h urine Ca/Cr

Twice yearly

Kidney imaging

Yearly until stable, then as indicated

Ophthalmology evaluation


Brain imaging

As indicated


Oral calcium supplements of any type will restore serum calcium toward normal. In general, calcium carbonate or calcium citrate is used most commonly because they are widely available and relatively inexpensive [48, 49]. Calcium carbonate contains 40 % elemental calcium by weight, and calcium citrate 21 % calcium by weight. Calcium citrate absorbs well when stomach acid is reduced for any reason, including proton pump inhibitor therapy for gastroesophageal reflux, so is often preferred in patients with hypoparathyroidism [50].

Calcium supplements are given in divided doses each day, typically two and four times a day, with dosing often given at mealtimes to enhance absorption. Starting doses are usually 500–1000 mg elemental calcium two or three times each day, and titrated upward as needed based on tolerability, compliance, and the clinical target range. Many patients with hypoparathyroidism require 3000–5000 mg elemental calcium each day, but some need as little as 1000 mg, and some need as much as 9000 mg [44]. Rare patients may need frequent intravenous calcium and/or magnesium infusions several times a week to prevent significant hypocalcemia.

Vitamin D

Commonly, calcium supplementation alone is insufficient to achieve serum calcium in the range of 8.0–8.5 mg/dL (2.0–2.13 mmol/L). In this case, vitamin D supplementation is usually started. If renal function is normal, vitamin D2 (ergocalciferol) or D3 (cholecalciferol) is usually started at 1000–4000 International Units once each day, or alternatively, 50,000 International Units once each week to several times each week as needed, depending on intestinal absorption efficiency [47]. The serum 25-hydroxyvitamin D target level is usually 30–100 ng/mL, but may be lower than this in some patients. Patients with severe hypoparathyroidism typically require higher doses of vitamin D. Care must be used with vitamin D2 or D3, however, as their half-life is prolonged at 2–3 weeks due to storage in body fat, and toxic serum levels of 25-hydroxyvitamin D causing hypercalcemia may take up to 6–9 months to clear after supplementation is stopped. Commercial parenteral vitamin D is no longer available in the U.S., but some academic hospital pharmacies produce high-concentration intravenous vitamin D3 based on clinical need.

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Aug 28, 2017 | Posted by in OTOLARYNGOLOGY | Comments Off on Hypoparathyroidism
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