NORD gratefully acknowledges Dolores Shoback, MD, Professor of Medicine, UCSF Endocrine Research Unit - 111N, SF - VA Medical Center, for assistance in the preparation of this report.
Hypoparathyroidism is a rare condition in which the parathyroid glands fail to produce sufficient amounts of parathyroid hormone or the parathyroid hormone produced lacks biologic activity. The parathyroid glands are part of the endocrine system, the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. Parathyroid hormone (along with vitamin D and the hormone calcitonin, which is produced by the thyroid gland) plays a role in regulating the levels of calcium and phosphorus in the blood and in determining bone growth and bone cell activity. Due to a deficiency of parathyroid hormone, individuals may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus (hyperphosphatemia). Hypocalcemia can cause a variety of symptoms including weakness, muscle cramps, excessive nervousness, headaches, and/or uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms, legs, and/or face (tetany). Numbness and tingling around the mouth and in the fingers and toes can also occur. The most common cause of hypoparathyroidism is damage to or removal of the parathyroid glands due to surgery for another condition. Hypoparathyroidism can also be caused by an autoimmune process or can occur for unknown reasons (idiopathic) or in association with a number of different underlying disorders. In rare cases, hypoparathyroidism may occur as a genetic disorder. Such cases can include familial hypoparathyroidism, which may be inherited as an autosomal recessive, autosomal dominant or X-linked recessive trait. NORD has a separate report on familial isolated hypoparathyroidism.
The symptoms of hypoparathyroidism occur due to low levels of calcium in the blood. The severity of the condition can range from mild symptoms such as a tingling or numbness in the fingers, toes or around the lips (paresthesias) to severe muscle cramps and muscle spasms. The muscle symptoms are often called tetany, a condition characterized by uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, legs, and arms. In rare cases, seizures or fits can occur, or the level of consciousness can be depressed.
Additional symptoms that may be associated with hypoparathyroidism include fatigue, generalized weakness, muscle aches, anxiety or nervousness, and headaches. Affected individuals may also have dry, coarse skin, brittle nails, and patchy hair loss such as the thinning of the eyebrows. Some individuals with hypoparathyroidism, especially those with chronic hypoparathyroidism since childhood, may have abnormalities affecting the teeth including the underdevelopment of the hard outer layer of the teeth (enamel hypoplasia), malformation of the roots and an increased risk of cavities (dental caries).
Hoarseness or voice changes, wheezing and difficulty breathing (dyspnea) can also be associated with chronic hypoparathyroidism. Sudden, muscular spasms affecting the larynx (laryngospasm) and the bronchial tubes (bronchospasm) may also occur. Laryngospasm causes closure of the upper end of the trachea and prevents air from reaching the lungs. Bronchospasm can restrict the flow of air into and out of the lungs. These are serious issues and are rare.
Depression, irritability, confusion, disorientation, mood swings and loss of memory have also been reported in individuals with hypoparathyroidism. In children, chronic hypoparathyroidism can result in stunted growth and slow mental development if it is not treated.
Less often, more serious complications can occur in individuals with hypoparathyroidism especially when hypoparathyroidism goes untreated or persists. Such symptoms include clouding of the lens of the eyes (cataracts), seizures or convulsions, fainting, abnormal heartbeats (cardiac arrhythmias) and, potentially, signs of congestive heart failure. Some individuals may develop calcium deposits (calcifications) in the brain or the kidneys. If enough calcifications occur in the kidneys, kidney function can become impaired. Individuals with hypoparathyroidism may be prone to developing kidney stones. Increased pressure of cerebrospinal fluid in the skull (intracranial hypertension) can also occur and may cause severe headaches and vision changes.
Hypoparathyroidism may result from removal of or damage to the parathyroid glands or their blood supply, the absence of or failure to function properly of the parathyroid glands at birth (congenital hypoparathyroidism) or due to or in association with a number of different underlying disorders.
Hypoparathyroidism most often occurs because of the surgical removal of some or all of the parathyroid glands. Surgical damage or removal of parathyroid tissue usually occurs following treatment for another condition, especially hyperparathyroidism (in which there is too much production of parathyroid hormone). Hyperparathyroidism may be treated by the surgical removal of parathyroid tissue. In some cases, such surgery may result in too much parathyroid tissue being removed and, consequently, cause hypoparathyroidism.
Surgery to treat cancer of the thyroid (nearby the parathyroid glands) or goiter (enlargement) of the thyroid gland may also cause hypoparathyroidism, usually through damage to the blood supply for the parathyroid glands or inadvertent removal of the glands during surgery. In such cases, hypoparathyroidism may be temporary (transient in 75% of cases) depending upon the extent of the damage. Transient post-surgical hypoparathyroidism can become permanent (25% of cases). Post-surgical hypoparathyroidism may occur shortly after surgery or appear months to years later. When hypoparathyroidism occurs due to external factors such as surgery, these cases are sometimes referred to as acquired hypoparathyroidism.
Although very rare, cancer from another tissue can spread to the parathyroid glands and alter their function. In extremely rare cases, hypoparathyroidism is caused by extensive radiation therapy to the neck region as may be done as part of a cancer treatment regimen.
In rare cases, hypoparathyroidism occurs as an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue for unknown reasons. These cases may be called autoimmune hypoparathyroidism and develop when the body’s own immune system mistakenly attacks parathyroid tissue and leads to the loss of the secretion of parathyroid hormone. Autoimmune hypoparathyroidism can occur as part of a larger autoimmune syndrome (complex of diseases occurring together in the same person) that damages many organs of the body or as isolated damage to the parathyroid glands. This may be called the autoimmune polyendocrine syndrome type 1 or APS1.
Congenital hypoparathyroidism refers to infants who are born without parathyroid tissue, the ability to make parathyroid hormone, or with parathyroid glands that do not function properly. Congenital hypoparathyroidism that occurs during the first few months of life may be temporary (transient) or permanent. In some patients, the cause of hypoparathyroidism is unknown (idiopathic). In some of these cases, hypoparathyroidism may resolve (spontaneously), but most do not resolve and usually need treatment.
Congenital hypoparathyroidism may also occur in infants whose mothers have hyperparathyroidism. As opposed to “hypo”-parathyroidism, “hyper”-parathyroidism results in excessive calcium levels in the bloodstream. In a pregnant woman, the excess calcium may cross the placenta reaching the developing fetus and suppress fetal parathyroid hormone production by the growing infant’s parathyroid glands. In a newborn infant, this may result in abnormally low levels of blood calcium after birth. However, this is only a temporary condition and is not associated with permanent changes in the infant’s parathyroid glands. They will recover later in the newborn period and do their job of making parathyroid hormone. It will just take some time. Transient hypoparathyroidism can also occur in preterm infants of women who have diabetes mellitus. This may resolve but should be carefully watched until it does.
Congenital hypoparathyroidism can also refer to cases that occur as an isolated genetic disorder. (For more information these disorders, choose “familial isolated hypoparathyroidism” as your search term in the NORD Rare Disease Database.)
One of the more common causes (after post-surgery) of hypoparathyroidism is an activating mutation of the extracellular calcium-sensing receptor (CASR) gene. This has been called autosomal dominant hypocalcemia type 1. The CASR gene encodes for a protein that is found in the chief cells of the parathyroid gland. Activating mutations of this gene ultimately lead to suppression of parathyroid hormone secretion and hypoparathyroidism. In many affected individuals, this condition is mild and often detected incidentally. Treatment may not be needed unless symptoms develop. This mutation may be inherited as an autosomal dominant trait, but sporadic cases occur as well. In most cases in addition to the low blood calcium levels, there are high urinary calcium levels. This is because the same gene — the CASR — is also important in controlling calcium excretion by the kidneys. Recently, another gene encoding for the production of a G protein (G-alpha 11) that works with the CASR in the parathyroid gland to control the synthesis of parathyroid hormone was also shown to be involved in calcium-sensing by the parathyroid cell. Mutations in that gene also cause autosomal dominant hypoparathyroidism and this is the form called type 2.
Another common cause of hypoparathyroidism is abnormally low levels of magnesium (hypomagnesemia) in the blood. This is often called functional hypoparathyroidism because it resolves when magnesium is restored. Magnesium is a mineral that is very important in the function of the parathyroid glands. When magnesium levels are low, it often leads to low levels of calcium in the blood as well. Without proper levels of magnesium, the parathyroid glands fail to function normally. One common cause of low levels of magnesium in the body is chronic alcoholism. Other causes of hypomagnesemia include malnutrition, malabsorption, diabetes, chronic diarrhea, certain kidney disorders, and the use of certain medications.
Less often, hypoparathyroidism can be caused by abnormally high levels of magnesium (hypermagnesemia) in the blood. Magnesium can activate the CASR protein on the parathyroid chief cells (hormone-secreting cells) and inhibit the secretion of parathyroid hormone. Hypermagnesemia can be occur when magnesium accumulates because of impaired kidney function or when magnesium is given as a therapy as in tocolytic therapy (which is given to women to suppress preterm labor).
Hypoparathyroidism can also develop as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome (sometimes called DiGeorge syndrome), Barakat syndrome (hypoparathyroidism – sensorineural deafness – renal disease also called the HDR syndrome), Kenney-Caffey disease, Sanjad-Sakati syndrome (hypoparathyroidism – intellectual disability – dysmorphism), autoimmune polyendocrine syndrome type 1 (APS1) or lymphedema-hypoparathyroidism syndrome. It can also occur as part of certain mitochondrial disorders such as Kearns-Sayre syndrome or MELAS syndrome. In some patients, hypoparathyroidism may occur in association with Wilson disease (due to copper accumulating in the parathyroid glands) or hemochromatosis (due to iron accumulating in the parathyroid glands). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Hypoparathyroidism affects males and females in equal numbers. The incidence and prevalence of hypoparathyroidism in the general population are unknown. There are approximately 70,000 people with hypoparathyroidism in the United States. Hypoparathyroidism can affect individuals of any age.
A diagnosis of hypoparathyroidism is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal abnormal levels of calcium, phosphorus, magnesium, creatinine and intact parathyroid hormone. Urine tests can reveal if the body is excreting too much calcium.
In addition, the Food and Drug Administration (FDA) has approved the use of the synthetic parathyroid hormone, teriparatide as a diagnostic agent to distinguish hypoparathyroidism from pseudohypoparathyroidism.
Additional tests may be performed to detect complications that may be associated with hypoparathyroidism. For example, an electrocardiogram, a test that records electrical activity of the heart, can reveal arrhythmias that are sometimes associated with low calcium levels and hypoparathyroidism. An ophthalmologic exam should also be done to check for cataracts.
Molecular genetic testing is available through commercial and academic research laboratories to detect specific gene mutations that cause genetic forms of hypoparathyroidism.
The treatment of hypoparathyroidism is directed toward the specific symptoms that are apparent in each individual and the lab tests. Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium in the blood (hypercalcemia) or in the urine (hypercalciuria). The specific therapies used may vary depending upon the disease severity, the specific symptoms present, an individual’s age and overall health, personal preference and additional factors. Individuals are recommended to see a physician who specializes in diagnosing and treating disorders affecting the endocrine system (endocrinologist) for optimal treatment of hypoparathyroidism and family screening and specialized testing.
The primary therapies for individuals with hypoparathyroidism are calcium supplements and activated vitamin D, except in individuals whose condition is caused by hypo- or hypermagnesemia. In these cases, hypoparathyroidism is treated by normalizing magnesium levels (e.g., taking magnesium supplements to treat hypomagnesemia).
These are several different types of calcium supplements available. Some brands may work better for certain people. High doses of calcium can cause gastrointestinal side effects such as constipation and should only be taken at the instruction of a physician.
The main supplemental form of vitamin D used for individuals with hypoparathyroidism is calcitriol. Another form of vitamin D that may be used is ergocalciferol or cholecalciferol. Outside the USA, doctors use alpha calcidol. Ergocalciferol and cholecalciferol have a longer duration of action than calcitriol or alpha calcidol because the former two forms of vitamin D are stored in the body for long times. Long-term therapy with vitamin D and its analogues and metabolites (like calcitriol) carries a risk of serious side effects including calcium deposits accumulating in the kidneys (nephrocalcinosis), the development of kidney stones and, ultimately, improper function of the kidneys if blood tests are not carefully monitored.
Some individuals, especially those with severe symptoms due to low blood calcium levels, may require immediate relief through intravenous calcium therapy, even if their calcium levels are only mildly reduced. Intravenous therapy means that a substance (e.g., calcium) is delivered into the bloodstream through an injection or infusion directly into a vein.
In 2015, the US Food and Drug Administration approved the use of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] as a treatment for adult patients with chronic hypoparathyroidism who are uncontrolled with conventional therapy (calcium and activated vitamin D). Their approval was based on open-label studies conducted at Columbia University which have now reported out on 6 years of treatment; studies from Denmark using rhPTH(1-84) as an add-on to conventional therapy; and a phase 3 randomized controlled multinational clinical trial of 24 weeks duration. Ongoing studies continue to look at long-term safety of that medication.
Some individuals with severe hypoparathyroidism that do have a high urinary calcium level may be treated with thiazide diuretics. These drugs enhance calcium absorption in the kidneys and can help control or prevent hypercalciuria in individuals taking vitamin D and calcium.
Some individuals with hypoparathyroidism may be encouraged to make dietary changes to help treat their condition. Affected individuals may be encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables. Affected individuals may also be encouraged to avoid foods high in phosphorus such as carbonated soft drinks, eggs and meat to keep the blood phosphorus levels as low as possible.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com.
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Researchers are studying treating individuals with hypoparathyroidism by replacing the missing hormone with man-made (synthetic) versions.
Researchers continue to study the use of teriparatide [PTH (1-34)] for the treatment of individuals with hypoparathyroidism. Teriparatide is a recombinant form of parathyroid hormone and has been used for years to treat osteoporosis. Some individuals with hypoparathyroidism have reported an improvement in their symptoms when treated with teriparatide, which is usually given as an injection under the skin (subcutaneously) once or twice a day. Teriparatide has been given to some affected individuals who did not respond to conventional therapies with positive results.
In studies with PTH (1-34) for the treatment of individuals with hypoparathyroidism, researchers have found decreased urinary calcium excretion. They may be able to reduce the need for calcium and vitamin D supplements in individuals with hypoparathyroidism. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for individuals with hypoparathyroidism.
A group of clinicians and investigators convened several meetings and reviewed the evidence from the literature to come up with Guidelines on how to best manage the disorder of chronic hypoparathyroidism in adults. The European Society of Endocrinology sponsored one set of guidelines which were published in 2015. That same year a group of international experts in the field of hypoparathyroidism held a meeting to discuss all aspects of hypoparathyroidism and to bring together guidance for clinicians managing patients with this disorder across the world. This led to another set of guidelines published in 2016. Although the number of trials is small and the number of patients enrolled in them is few, endocrinologists now have two documents to help guide the best evidence-based therapy for adults with hypoparathyroidism.
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Eunice Kennedy Shriver National Institute of Child Health and Development. Hypoparathyroidism: Overview. Available at: http://www.nichd.nih.gov/health/topics/hypopara/Pages/default.aspx Accessed December 14, 2016
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