Link Between Thyroid Disease and the MTHFR Gene

What the Presence of a Mutation Means and Doesn't Mean

A chromosome is a segment of DNA that holds many genes

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MTHFR mutation—changes to a gene linked to an increasing number of medical conditions, including thyroid disease—has become a controversial topic among scientists. While the National Institutes of Health lists five conditions directly linked to the genetic mutation, a growing body of evidence has linked it, either directly or indirectly, to a host of disorders affecting the heart, eyes, brain, thyroid gland, and other organ systems. The MTHFR mutation is also believed to predispose a person to certain cancers, birth defects, and autoimmune diseases.

The reason the subject remains so contentious is that much of the current evidence is either inconsistent, inconclusive, or contradictory. While a number of smaller studies have linked certain MTHFR variants (known as polymorphisms) to low thyroid function (hypothyroidism), there remains much that we do not know about how and how much the mutations contribute to the development and/or severity of a disease.

Understanding MTHFR

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme produced by the MTHFR gene. MTHFR interacts with folate (vitamin B9) to break down an amino acid called homocysteine so that it can be converted into another amino acid known as methionine. The body, in turn, uses methionine to build protein and other important compounds.

An MTHFR mutation is simply an error in the MTHFR gene that causes it to malfunction. If this happens, the gene may be less able to break down homocysteine, causing an accumulation of the enzyme in the blood. Depending on the genetic variant, a person may either have normal or elevated levels of homocysteine in the blood or urine.

Abnormally high levels of homocysteine, referred to as hyperhomocysteinemia, is associated with an array of medical conditions, in part because it depletes the amount of folate that the body needs to function normally. This is especially of heart, brain, and other bodily tissues that rely on folate to repair damaged DNA and ensure the healthy production of red blood cells

Conditions associated with hyperhomocysteinemia include, among other things:

  • Thrombosis (blood clots)
  • Microalbuminuria (increased albumin in urine associated with kidney and heart disease)
  • Atherosclerosis (hardening of the arteries)
  • Alzheimer's disease
  • Ectopia lentis (the displacement of the lens of the eye)
  • Bone fractures in elderly people

Despite their association with certain diseases, no one knows for sure how much the various MTHFR variants influence the risk of disease. As such, the mere presence of the mutation doesn't necessarily confer to illness.

Diseases Linked to MTHFR

According to findings published by the National Institutes of Health, five conditions have been strongly linked to MTHFR mutations:

  • Alopecia areata, an autoimmune disorder in which the immune system attacks hair follicle roots, causing patchy hair loss
  • Anencephaly, one of several neural tube defects associated with the MTHFR mutation, in which large parts of the brain is missing and/or have missing or incomplete skull bones
  • Homocystinuria, the inability to process homocysteine and methionine normally, contributing to the onset of hyperhomocysteinemia and the risk of associated disorders
  • Presbycusis (aging-related hearing loss), in which certain MTHFR polymorphisms affect folate levels needed to maintain the cellular integrity of the organs of the ear
  • Spina bifida, a birth defect in which the bones of the spinal column do not close completely around the nerves of the spinal cord

Other conditions tangentially associated with MTHFR mutations include heart disease, stroke, hypertension (high blood pressure), preeclampsia (high blood pressure during pregnancy), glaucoma, and cleft palate.

While current research remains highly inconsistent, certain MTHFR mutations are believed to increase the risk of breast cancer, endometrial cancer, esophageal cancer, stomach cancer, pancreatic cancer, and bladder cancer. By contrast, the same mutations are believed to decrease the risk of colorectal cancer, liver cancer, cervical cancer, and certain leukemias and lymphomas due to depletion of folate (the substance which can fuel certain cancers).

With all of this being said, having an MTHFR mutation does not mean that you will get heart disease, have a child with cleft palate, or develop cancer.

Even with MTHR-associated neural tube defects, the risk in parents with a known MTHFR mutation is roughly 0.14 percent, according to research from the Centers for Disease Control and Prevention.

MTHFR and Hypothyroidism

The association between the MTHFR mutation and hypothyroidism remain largely speculative. There have been a number of smaller studies that suggest a link, including one from the University of Tbilisi in which certain MTHFR polymorphisms were found in people with subclinical hypothyroidism (hypothyroidism with no observable symptoms) but not in others.

While the presence of hyperhomocysteinemia in people with hypothyroidism may suggest an association with the MTHFR mutation—a link popularly shared in many thyroid disease blogsites—it is important to note that hypothyroidism can trigger high homocysteine levels irrespective of whether the MTHFR mutation is there or. So can smoking, advanced age, and medications like methotrexate, Lipitor (atorvastatin), Tricor (fenofibrate), and niacin (vitamin B3).

Testing Recommendations

The value of MTHFR mutation remains uncertain given the high variability of what a positive result means. There are times, however, when testing is appropriate.

A test, called the MTHFR genotype, may be ordered if you have excessively high levels of homocysteine with no known cause. It may also be used if you or a family member has a history of blood clots or heart disease at an early age.

The aim of the test is not to screen for diseases but rather to identify if an MTHFR mutation affects how your body process folate. Doing so can aid in the selection of the right medications and supplements to treat cardiovascular disorders and other conditions.

An MTHFR genotype may be recommended if you are unable to control your homocysteine levels with levothyroxine or folic acid. This is especially true if you are at increased risk of cardiovascular disease and no other causes for the homocysteine elevation can be found.

The MTHFR genotype is not used for screening purposes. Neither the American Congress of Obstetricians and Gynecologists (ACOG), the American College of Medical Genetics, the American Heart Association, nor the College of American Pathologists recommends the test for the screening of disease or the identification of your carrier status.

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