Hypoparathyroidism

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.

Subdivisions of Hypoparathyroidism
 acquired ypoparathyroidism
 autoimmune hypoparathyroidism
 congenital hypoparathyroidism
 idiopathic hypoparathyroidism

General Discussion
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.

Signs & Symptoms

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.

Causes
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.)

Affected Populations
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.

Related Disorders
Symptoms of the following disorders can be similar to those of hypoparathyroidism.
Comparisons may be useful for a differential diagnosis.
Pseudohypoparathyroidism is a rare disorder characterized by the resistance of the
body to parathyroid hormone. Unlike hypoparathyroidism, in which there are abnormally
low levels of functional parathyroid hormone, individuals with
pseudohypoparathyroidism produce enough parathyroid hormone, but are unable to use
it properly. There are three main subtypes – pseudohypoparathyroidism 1a and 1b and
pseudohypoparathyroidism II. All forms of pseudohypoparathyroidism are extremely
rare. Common symptoms include abnormalities of the bone and teeth, behavioral
problems, cognitive deficits and short stature. Additional symptoms that may develop
include cataracts, seizures, and osteoporosis. Affected individuals may have a round
face with full cheeks and be prone to obesity. Albright’s hereditary osteodystrophy, a
unique constellation of developmental and skeletal defects, occurs mostly in type 1a,
which is due to a mutation of a specific gene encoding for a G-protein.
Pseudohypoparathyroidism is inherited as an autosomal dominant trait. (For more
information on this disorder, choose “pseudohypoparathyroidism” as your search term in
the Rare Disease Database.)

Diagnosis
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.

Standard Therapies
Treatment
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.
Available from: https://rarediseases.org/rare-diseases/hypoparathyroidism/