Causes and Risk Factors of Hypoparathyroidism

Hypoparathyroidism is a rare condition that results when the parathyroid glands in the neck don’t produce enough parathyroid hormone. Having too little parathyroid hormone leads to low levels of calcium (hypocalcemia) and high levels of phosphorous in the body. 

There are different types of hypoparathyroidism­, including acquired, autoimmune, congenital, and familial types:

• Acquired: This is the most common type. It occurs after removal of or damage to the parathyroid glands, either through surgery or an injury.
• Autoimmune: This is the second most common type of hypoparathyroidism and occurs because the immune system mistakenly attacks the parathyroid gland or the parathyroid hormone.
• Congenital: This is a much rarer type of hypoparathyroidism that appears at birth. It is the result of gene mutations in the parathyroid hormone process, or someone being born without parathyroid glands.
• Familial: If you have a family history of hypoparathyroidism, you have a higher risk of developing familial hypoparathyroidism.

The type of hypoparathyroidism a person has will be based on the cause.

Causes of hypoparathyroidism are:

• Neck surgery or injury to one or more of the parathyroid glands
• Autoimmune diseases and other endocrine (hormone-related) disorders
• DiGeorge syndrome
• Hypomagnesemia (low magnesium levels)
• Extensive cancer treatment of the face or neck
• Cancer from another body area
• Heavy metal overload (iron and copper)
• Genetics

In this article, we will discuss the causes of hypoparathyroidism, the role of genetics, and risk factors for the condition.

Common Causes

Hypoparathyroidism occurs when one or more of the four small parathyroid glands in your neck do not secrete enough parathyroid hormone. 

Factors that can lead to hypoparathyroidism are:

Neck Surgery or Neck Injury

The most common cause of hypoparathyroidism is accidental damage to or removal of one or more parathyroid glands during neck surgery. Neck surgery might be done to treat a thyroid condition or neck or throat cancer. Acquired hypoparathyroidism from the anterior (front) neck surgery is responsible for about 75% of hypoparathyroidism cases.

Autoimmune Diseases and Other Endocrine Disorders

Additional common causes of hypoparathyroidism are autoimmune diseases that affect either the parathyroid glands alone or multiple endocrine glands. Autoimmune hypoparathyroidism can appear on its own, or it can be associated with autoimmune polyglandular syndrome type I (APS1).

APS1 is a rare inherited disorder of immune cell dysfunction that presents as a group of symptoms, including life-threatening endocrine gland and gastrointestinal disorders. This is frequently seen with familial type hypoparathyroidism.

Autoimmune hypoparathyroidism is also linked to other autoimmune diseases, including chronic mucocutaneous candidiasis (recurrent or persistent infections affecting the nails, skin, and oral and genital membranes caused by Candida yeast) and pernicious anemia (autoimmune anemia where vitamin B12 cannot be absorbed).

DiGeorge Syndrome

DiGeorge syndrome is a childhood disease in which a child is born without parathyroid glands. It is caused by the loss of a small part of chromosome 22.

One of the many signs of the condition is hypocalcemia, which is the result of the lack of parathyroid glands. While rare, DiGeorge syndrome is the most common cause of congenital hypoparathyroidism.

Hypomagnesemia

Abnormally low magnesium levels (hypomagnesemia) can lead to hypoparathyroidism. This type of hypoparathyroidism is called functional hypoparathyroidism because it often resolves when magnesium gets back to normal levels.

Magnesium plays a vital role in helping the parathyroid glands to function. Low levels of magnesium often coexist with low calcium levels.

Causes of hypomagnesemia include chronic alcohol use, malnutrition, malabsorption disorders, chronic diarrhea, kidney disorders, and the use of certain medicines, including diuretics, proton pump inhibitors, and aminoglycoside antibiotics.

Although rare, hypermagnesemia, an excess amount of magnesium in the bloodstream, can also lead to hypoparathyroidism. It is a rare condition and usually the result of renal failure or poor kidney function.

Hypermagnesemia can lead to hypoparathyroidism when magnesium activates certain proteins on parathyroid cells and affects the way the parathyroid hormone works throughout the body.

Extensive Cancer Treatment of the Face or Neck

Radiation cancer treatment of the neck or face can lead to the destruction of the parathyroid glands. According to a 2020 report in the Journal of Evolution of Medical and Dental Sciences, radiation-induced damage is a rare cause of hypoparathyroidism.

Radioactive iodine treatment used to treat hyperthyroidism (when the thyroid produces too much thyroid hormone) can also lead to hypoparathyroidism.

Immune checkpoint inhibitors, a type of immune therapy for cancer, have also been linked to the development of immune-related hypoparathyroidism, according to a 2020 case study. While this finding is extremely rare, the study's authors highlighted the need for awareness of this complication.

Cancer

Cancer from another body area can spread to the parathyroid glands and affect how they function. This is extremely rare.

Heavy Metal Overload

Heavy metal overload is a less common cause of hypoparathyroidism, but different types of metals are known for causing primary hypoparathyroidism. This includes hemochromatosis and thalassemia, which are both linked to iron overload.

Wilson disease with copper overload is also linked to primary hypoparathyroidism, but it is one of the rarest types. In this condition, copper deposits are to blame for the destruction of the parathyroid glands.

Genetics

There are different types of genetic defects that might lead to hypoparathyroidism.

For example, congenital hypoparathyroidism can occur with no known causes, or it can occur in combination with autoimmune and genetic defects. It can occur as a sporadic mutation (change in the genes) or a familial disorder that is inherited by autosomal dominant, recessive, or X-linked patterns.

DiGeorge syndrome results from a genetic defect in chromosome 22, and it is linked to hypoparathyroidism and hypocalcemia. There have also been instances of hypoparathyroidism described with facial dysmorphisms (a classical facial feature of many syndromes), growth problems, and intellectual disability.

Additional gene defects that might lead to hypoparathyroidism include single mutations of the prepro-PTH allele and mutations of chromosome arm 3q13.

Familial isolated hypoparathyroidism refers to a mix of disorders that are characterized by abnormal calcium metabolism and low parathyroid hormones. It is the most common genetic cause of hypoparathyroidism and is transmitted in an autosomal dominant pattern.

Mutation of chromosome arm 3q13, which encodes a protein called calcium-sensing receptor (CaSR), can lead to autosomal dominant or sporadic hypoparathyroidism. The CaSR gene directs the formation of the protein responsible for the production of the parathyroid hormone.

People with mutations of this gene have low parathyroid hormone linked to an abnormal calcium-sensing receptor (calciostat), which leads to faulty sensing of elevated blood calcium even when calcium levels are low. The faulty sensing causes excessive calcium.

Another rare form of familial isolated hypoparathyroidism is caused by variants of the GNA11 gene responsible for the Gα11 protein. This protein is directly connected to the intracellular activity of the CaSR gene receptor signaling.

Risk Factors 

Being aware of the factors that could increase your risk of hypoparathyroidism can help you to make informed decisions with your healthcare professionals and give you a better understanding of any symptoms of the condition you might experience.

Risk factors for hypoparathyroidism include:

• Low magnesium levels
• Prior neck surgery
• Prior treatment for cancer of the neck or face with radiation
• Having certain autoimmune or endocrine conditions
• Being born without parathyroid glands
• A family history of the condition
• Age: The research suggests the majority of people with hypoparathyroidism are over age 45. But the condition can affect anyone regardless of age, including babies and young children.
• Sex: Permanent hypoparathyroidism is more common in women than in men. Research on all parathyroid syndromes finds all types are more common in females ages 45 and up.

Summary

Hypoparathyroidism occurs when one or more of the parathyroid glands are underactive. The most common cause is injury to or accidental removal of one or more of the four parathyroid glands. Some people are born without these glands.

Other causes of hypoparathyroidism are autoimmune diseases and endocrine disorders, DiGeorge syndrome, low magnesium levels, cancer treatments, cancer, heavy metal overload, and genetics. Women and people ages 45 and up have a higher risk of the condition, but anyone can develop it.

A Word From Verywell

The most common symptoms of hypoparathyroidism are painful, uncontrollable spasms of the face, hands, arms, and feet, and pins and needles of the hands and feet and around the mouth. Severe or untreated hypoparathyroidism can lead to seizures and breathing problems.

If you or a child has signs or symptoms of the condition, reach out to your doctor for an evaluation. Seek out emergency care for seizures or difficulty breathing.