Autoimmune thyroid disease (AITD) is a disease in which the body interprets the thyroid glands and its hormone products triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) as threats, therefore producing special antibodies that target the thyroid’s cells, thereby destroying it. It presents with hypothyroidism (low production of thyroid hormone) or hyperthyroidism (excessive production of thyroid hormone) and the presence or absence of goiters (Pic. 1). AITD is the most common autoimmune condition, affecting approximately 2% of the female population and 0.2% of the male population and the prevalence of AITD increases also with age.

AITD can be initiated in individuals genetically predisposed to AITD by non-genetic (environmental) triggers (Pic. 2). This interaction leads to different clinical phenotypes of thyroid autoimmunity such as Graves' disease, Hashimoto's thyroiditis or production of thyroid antibodies. Hashimoto's thyroiditis and Graves' disease are two distinct but related clinical outcomes of AITD. It seems that both thyroid diseases have common pathogenic mechanisms as their initial steps including breakdown of the immune tolerance and accumulation of T lymphocytes in the thyroid gland.

Classification

  • Autoimmune thyroiditis

The inflammatory disease, of which the most typical example is Hashimoto's thyroiditis, arises from the immune dysregulation with the production of antibodies which attack the thyroid gland and gradually destroy it. First signs are increased thyroid hormone secretion and subsequently hypothyroidism develops. 

Hashimoto's thyroiditis (Pic. 3) is the most common cause of hypothyroidism in areas of the world where dietary iodine is sufficient and is defined by the presence of goiter and serum thyroid autoantibodies. It affects about 5% of the population and it typically begins between the ages of 30 and 50. Morphologically, the disease consists in a gradual atrophy of thyroid tissue following gland invasion with lymphocytic cells, follicular atrophy, and hyperemia (increased blood flow) accompanied by oncocytic metaplasia (benign non-cancerous change) of follicular cells. This leads to the development of hypothyroidism, though the disease may occur with a normal thyroid activity.

Transient thyroiditis seems to be a variant presentation of autoimmune thyroiditis. It is characterized by an autoimmune-mediated lymphocytic inflammation of the thyroid gland resulting in a destructive thyroiditis with release of thyroid hormone and transient hyperthyroidism, frequently followed by a hypothyroid phase and full recovery. The condition is particularly common in the postpartum period, but it has been observed also in children. 

If the symptoms of thyroiditis appear in women after giving birth, it is attributed to such and therefore called postpartum thyroiditis. The effects of this disease may be permanent but can sometimes be transient. Symptoms may come and go depending on whether the patient receives treatment, and whether the treatment takes effect. Although treatment could be started immediately and may still not have the effect desired.

This type of thyroid dysfunction occurs within the first 12 months of delivery as a consequence of the postpartum immunological rebound that follows the immune tolerant state of pregnancy. Postpartum thyroiditis is a destructive thyroiditis with similar pathogenetic features to Hashimoto's thyroiditis. 

Typically there is a transient hyperthyroid phase that is followed by a phase of hypothyroidism. Permanent hypothyroidism occurs in as much as 30% of cases after 3 years, and in 50% at 7–10 years. The hyperthyroid phase will not usually require treatment but, rarely, propanolol may be used for symptom control in severe cases. The hypothyroid phase should be treated with thyroxine if patients are symptomatic, planning to get pregnant, or if TSH levels are above 10 mU/L. Long-term follow up is necessary due to the risk of permanent hypothyroidism.

  • Graves' disease

Graves' disease (GD) is an autoimmune disorder, in which the body produces antibodies to the receptor for TSH. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)

These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.

Mechanism

Thyroid autoantibodies appear mostly with the presence of lymphocytes in the targeted organ. Lymphocytes produce antibodies targeting three different thyroid proteins: thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and thyroid stimulating hormone receptor antibodies (TRAb). Some patients who are healthy may be positive for more than one of these antibodies. Doctors who attend to such patients will most likely do routine follow-ups on the patient’s health since, even though it is highly unlikely that they will present any thyroid problems, there is still a chance that they will develop some type of dysfunction with time.

Diagnosis

The diagnosis of AITD is based on finding of antibodies in blood sample. 

There are various tests that can be made depending on the symptoms the patient presents. Doctors may search for TPOAb when the patient has symptoms that suggest hypothyroidism, or when said patient will be started on a drug therapy associated with risks of developing hypothyroidism. This antibody is related to Hashimoto's thyroiditis and Grave’s disease.

They may look for TgAb whenever a thyroglobulin test is performed to see if the antibody is present and likely to interfere. It can also be ordered in regular intervals after the patient has been diagnosed with thyroid cancer, and just like TPOAb, it can be associated with Hashimoto’s thyroiditis.

In the case that the patient presents symptoms for hyperthyroidism, the doctors are more likely to test for TRAb, as well as monitoring the effects of anti- thyroid therapy, also associated with Grave’s disease.

Associated diseases

  • alopecia areata – an autoimmune disease causing hair loss
  • thyroid disorders
  • type 1 diabetes
  • celiac disease
  • rhematoid arthritis
  • multiple sclerosis
  • vitiligo
  • Addison´s disease - the adrenal glands don´t produce enough steroid hormones
  • thyroid cancers
  • endometriosis
  • erectile dysfunction

Complications

  • heart defects
  • miscarriage
  • anemia in pregnancy
  • pre-eclampsia – a pregnancy complication characterized by high blood pressure
  • placental abruption
  • premature birth
  • low birth weight
  • birth defects
  • menstrual disorders
  • infertility

Risk factors

  • being female
  • genetic predisposition
  • advanced age
  • cigarette smoking
  • high iodine intake
  • bacterial and viral infection
  • cytokine therapy
  • probably pregnancy
  • stress
  • pregnancy
  • radiation exposure
  • fetal microchimerism – a persistence of low numbers of fetal cells in the mother after a pregnancy
  • family history of the condition and having another autoimmune diseases


From the perspective of pregnancy outcomes in AITD patients, there is 3-5 times more abortus regardless of thyroid dysfunction. Certainly, genetics, infection, hormones and environmental factors may have a role in etiology of abortus. 

Thyroid autoimmunity is the main cause of hypothyroidism, which itself may lead to failure of sex steroids by disrupting the functioning of hypothalamo-pituitary-ovarian axis (hypothalamus, pituitary gland, ovary). Thus, a clinical picture in close relationship with menstrual irregularity, infertility, miscarriage and complications of unwanted pregnancy may occur. During pregnancy, there is higher risk of overt and subclinical hypothyroidism in women who are positive for thyroid antibodies before conception.

As it’s known, cells such as oocytes, cumulus cells and granulose cells contain thyroid hormone receptors. In hypothyroidism, both the local effect of thyroid hormones on these receptors and prevention of release of pulsatile gonadotropin-releasing hormone (GnRH) from hypothalamus lead to failure of healthy ovulation and prevent formation of high quality oocytes. Concurrently, corpus luteum insufficiency due to disruption of luteinizing hormone (LH) release and hyperpolactineamia due to increased thyrotropin-releasing hormone (TRH) release may also increase negative influences over normal menstrual cycle.

Antithyroid antibodies are well studied part of immunological mechanisms having negative impact over fertility and also ART. In early stage of pregnancy thyroid hormones are actively involved in the stage of placentation. The presence of antithyroid antibodies may react against the structures of the placenta or fertilized egg and cause problems in embryo implantation. Other mechanism by which antithyroid antibodies negatively affect fertility is through zona pellucida (a glycoprotein layer surrounding oocytes) it has antigen groups similar to thyroid.

In regards to the prevention of autoimmune thyroiditis, there is no real access to adopt to avoid. However, it can be good for certain people with different risk factors to monitoring, as well as people with personal or family history of autoimmune disease. 

Iodine intake should be increased during pregnancy to prevent post partum thyroiditis.

The symptoms for autoimmune thyroiditis may vary depending on the stage of the disease. Classically, at the initial stage, the thyroid cells are destructed which leads to release of thyroid hormones and the symptoms of hyperthyroidism. Then the thyroid gland shrinks and symptoms of hypothyroidism appear.

Thyroiditis (hypothyroidism)

  • fatigue
  • weight gain
  • overweight
  • pale or puffy face
  • depression
  • dry skin
  • hair loss
  • intolerance to cold
  • constipation
  • slowing in the heart rate
  • a drop in body temperature
  • joint and muscle pain
  • heavy menstrual flow (menorrhagia) or irregular periods
  • panic disorder
  • problems getting pregnant and maintaining pregnancy
  • rarer symptoms: swelling of the legs, vague aches and pains, decreased concentration, ...

Graves´ disease (hyperthyroidism)

  • goiter
  • irritability
  • insomnia
  • anxiety
  • fatigue
  • muscle weakness
  • sleeping problems
  • fast heartbeat
  • poor tolerance of heat
  • diarrhea
  • weight loss
  • sweating
  • hand tremors
  • difficulty sleeping
  • thickening of the skin in the shins (pretibial myxedema)
  • bulging eyes (also known as Graves´ophthalmopathy - the lids do not close completely at night) (Pic. 4)

Diet

People with autoimmune thyroid disease should not eat foods high in iodine, such as edible seaweed and kelps.

Pharmacotherapy

  • Autoimmune thyroiditis:

Synthetic T4 hormone

In hypothyroidism, it is needed to manage normal thyroid hormone levels. Synthetic T4 hormone (thyroxine), also called levothyroxine, is usually used. It is degraded much slower than biosynthetic alternatives. Brand names for these drugs include Synthroid, Levothroid and Levoxyl. Natural thyroid hormone from pigs is also used, especially for people who cannot tolerate the synthetic version. A tablet is taken once a day generally keeps the thyroid hormone levels normal. Additionally, various problems including fertility performance improves after using levothyroxine for treatment. 

  • Graves´ disease:

Anti-thyroid drugs

Anti-thyroid medication blocks the production of thyroid hormones by thyroid gland and has the additional action of inhibiting the extrathyroidal conversion of T4 to T3. The medication is used in hyperthyroidism treatment and includes Propylthiouracil, Carbimazole or Methimazole, or rarely Lugol's solution. Methimazole and Propylthiouracil are the most commonly used anti-thyroid drugs. 

Beta blockers

These drugs don´t block the production of thyroid hormones, but they block their effect on the body and thus control the symptoms. These drugs aren´t recommended for those patients with asthma or diabetes due to side effects of the medication. Beta blockers include Propranolol (Inderal), Atenolol (Tenormin), Metoprolol (Lopressor, Toprol-XL) and Nadolol (Corgard).

Iodine and iodine-containing drugs 

Iodine and iodine-containing drugs such as Amiodarone may precipitate Graves’ disease, or a recurrence of Graves’ disease, in a susceptible individual. Iodine is most likely to precipitate thyrotoxicosis in an iodine deficient population simply by allowing the TSHR-Ab to be effective in stimulating the production of thyroid hormone. Whether there is any other precipitating event is unclear. Iodine and Amiodarone may also damage thyroid cells directly and release thyroid antigens to the immune system.

Surgical therapy

Thyroidectomy

Total thyroidectomy is the most common surgical procedure in autoimmune thyroid disease wherein the thyroid gland is removed. It is followed by low complication rate in specialized centers. 

Thyroidectomy is rarely used electively for the definitive therapy of GD, except with massive thyromegaly (over eight times normal size or thyroid weight 80 g) or for patients in whom coexisting nodules are suspicious for carcinoma by fine needle aspiration. 

After the surgery, it is needed to supply body with normal amounts of thyroid hormones by pharmacotherapy.

Other therapies

Radioiodine

Hyperthyroidism as well as thyroid tumors may be treated with radioactive iodine I-131. Radioiodine therapy involves taking iodine-131 by mouth which is then concentrated in and destroys the thyroid over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormone.

Mean radioactive iodine (370 MBq) dose used in treating hyperthyroidism is curative and it doesn’t affect gonadal performance. Still, because of teratogenic safety not to become pregnant for 6 months is recommended. Also, before planning a pregnancy to be sure that hypothyroidism is not present is essential.

When treating infertility caused by thyroid disease, fertility treatment may be an effective option. If conservative medical treatments fail to achieve a full term pregnancy, the physician may suggest the patient undergo in vitro fertilization (IVF). IVF and ART generally start with stimulating the ovaries to increase egg production. Most fertility medications are agents that stimulate the development of follicles in the ovary. Examples are gonadotropins and gonadotropin releasing hormone. After stimulation, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. Fertilization takes place outside the body, and the fertilized egg is reinserted into the woman's reproductive tract, in a procedure called embryo transfer.

Intracytoplasmic sperm injection (ICSI) is beneficial in the case of male factor infertility where sperm counts are very low or failed fertilization occurred with previous IVF attempt(s). The ICSI procedure involves a single sperm carefully injected into the center of an egg using a microneedle. With ICSI, only one sperm per egg is needed. Without ICSI, you need between 50,000 and 100,000. 

Two techniques that enable to some extent the selection of physiologically normal spermatozoa have recently been developed. One of these is termed intracytoplasmic morphology-selected sperm injection (IMSI). Here, spermatozoa are selected for ICSI and analysed digitally prior to the microinjection procedure in order to deselect morphologically abnormal spermatozoa. With this technique, abnormalities not visible in standard ICSI procedures have been observed. IMSI increases the pregnancy rate during ICSI cycles, and some data suggests that the level of pregnancy termination is also decreased. A second technique recently introduced to assisted reproduction is that of sperm selection with hyaluronic acid (HA), e.g. PICSI. In this technique, mature sperm with HA receptors are distinguished from immature and abnormal sperm since these do not express such receptors.

Infertile couples may also resort to egg donation or embryo donation when the female partner cannot have genetic children because her own eggs cannot generate a viable pregnancy. Surrogacy via a gestational carrier is also an option when a patient's medical condition prevents a safe pregnancy, when a patient has ovaries but no uterus due to congenital absence or previous surgical removal, and where a patient has no ovaries and is also unable to carry a pregnancy to full term.

Among women with older reproductive age, with history of repetitive abortions or genetic disorders, genetic analysis is highly recommended. The PGS/PGD allows studying the DNA of eggs or embryos to select those that carry certain damaging characteristics. It is useful when there are previous chromosomal or genetic disorders in the family, within the context of in vitro fertilization programs. 

The rate of success for IVF is correlated with a woman’s age. More than 40 percent of women under 35 succeed in giving birth following IVF, but the rate drops to a little over 10 percent in women over 40.

Find more about related issues

Sources

Autoimmune Thyroid Disorders ―by Iddah and Macharia licensed under CC BY 3.0
Thyroid disease in pregnancy ―sourced from Wikipedia licensed under CC BY-SA 3.0
Goitre ―sourced from Wikipedia licensed under CC BY-SA 3.0
Thyroid disorders and fertility ―by Karaca and Akpak licensed under CC BY-NC 4.0
Hashimoto's thyroiditis ―sourced from Wikipedia licensed under CC BY-SA 3.0
Autoimmune thyroiditis ―sourced from Wikipedia licensed under CC BY-SA 3.0
Immunogenetics of Hashimoto's thyroiditis ―by Chistiakov licensed under CC BY 2.0
Autoimmune Thyroid Diseases in Children ―by Cappa et al. licensed under CC BY 3.0
Clonal anergy ―sourced from Wikipedia licensed under CC BY-SA 3.0
Graves' disease ―sourced from Wikipedia licensed under CC BY-SA 3.0
Graves' ophthalmopathy ―sourced from Wikipedia licensed under CC BY-SA 3.0
Hyperthyroidism ―sourced from Fertilitypedia licensed under CC BY-SA 4.0
Preimplantation genetic diagnosis ―sourced from Wikipedia licensed under CC BY-SA 3.0
Infertility ―sourced from Wikipedia licensed under CC BY-SA 3.0
Egg donation ―sourced from Wikipedia licensed under CC BY-SA 3.0
Assisted reproductive technology ―sourced from Wikipedia licensed under CC BY-SA 3.0
Struma 001 ―by Drahreg01 licensed under CC BY-SA 3.0
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