Hypoparathyroidism overview

# Overview
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.

# Historical Perspective
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).

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

# Pathophysiology
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.

# Causes
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.

# Differentiating ((Page name)) from Other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

# Screening
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 patients prognosis.

# Natural History, Complications, and 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.

# Diagnosis

## Diagnostic Criteria
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.

## History and Symptoms
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
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.

## Laboratory Findings
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.

## Electrocardiogram
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.

## X-ray
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.

## CT scan
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.

## MRI
There are no MRI findings associated with hypoparathyroidism.

## Ultrasound
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.

## Other Imaging Findings
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).

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

# Treatment

## Medical Therapy
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.

## Surgery
Surgical intervention is not recommended for the management of hypoparathyroidism.

## Primary Prevention
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".

## Secondary Prevention
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.

## Future or Investigational Therapies=
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 134 (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.