Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, Hashimoto's disease and autoimmune thyroiditis, is an
autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
in which the
thyroid gland
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
is gradually destroyed.
Early on, symptoms may not be noticed.
Over time, the thyroid may enlarge, forming a painless
goiter.
[ Most people eventually develop hypothyroidism with accompanying weight gain, ]fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
, constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
, hair loss
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
, and general pains. After many years the thyroid typically shrinks in size. Potential complications include thyroid lymphoma. Further complications of hypothyroidism can include high cholesterol
Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...
, heart disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...
, heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF ...
, high blood pressure
Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...
, myxedema, and potential problems in pregnancy.
Hashimoto's thyroiditis is thought to be due to a combination of genetic and environmental factors. Risk factors include a family history of the condition and having another autoimmune disease.[ Diagnosis is confirmed with blood tests for TSH, ]thyroxine
Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...
( T4), antithyroid autoantibodies, and ultrasound
Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...
.[ Other conditions that can produce similar symptoms include ]Graves' disease
Graves' disease, also known as toxic diffuse goiter or Basedow's disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...
and nontoxic nodular goiter.
Hashimoto's is typically not treated unless there is hypothyroidism, or the presence of a goiter, when it may be treated with levothyroxine.[ Those affected should avoid eating large amounts of ]iodine
Iodine is a chemical element; it has symbol I and atomic number 53. The heaviest of the stable halogens, it exists at standard conditions as a semi-lustrous, non-metallic solid that melts to form a deep violet liquid at , and boils to a vi ...
; however, sufficient iodine is required especially during pregnancy.[ Surgery is rarely required to treat the goiter.][
Hashimoto's thyroiditis has a global prevalence of 7.5%, and varies greatly by region.] The highest rate is in Africa, and the lowest in Asia. In the US white people are affected more often than black. It is more common in low to middle income groups. Females are more susceptible with a 17.5% rate of prevalence compared to 6% in males. It is the most common cause of hypothyroidism in developed countries
A developed country, or advanced country, is a sovereign state that has a high quality of life, developed economy, and advanced technological infrastructure relative to other less industrialized nations. Most commonly, the criteria for eval ...
. It typically begins between the ages of 30 and 50. Rates of the disease have increased. It was first described by the Japan
Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
ese physician Hakaru Hashimoto in 1912. Studies in 1956 discovered that it was an autoimmune disorder.
Signs and symptoms
Signs
In the early stages of autoimmune thyroiditis, patients may have normal thyroid hormone levels and no goiter or a small one. Enlargement of the thyroid is due to lymphocytic infiltration and fibrosis. Early on, thyroid autoantibodies in the blood may be the only indication of Hashimoto’s disease. They are thought to be the secondary products of the T cell
T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
-mediated destruction of the gland.
As lymphocytic infiltration progresses, patients may exhibit signs of hypothyroidism in multiple bodily systems, including, but not limited to, a larger goiter, weight gain, cold intolerance, fatigue, myxedema, constipation, menstrual disturbances, pale or dry skin, and dry, brittle hair, depression, and ataxia
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
. Extended thyroid hormone deficiency may lead to muscle fibre changes, resulting in muscle weakness, muscle pain, stiffness, and rarely, pseudohypertrophy. Patients with goiters who have had autoimmune thyroiditis for many years might see their goiter shrink in the later stages of the disease due to destruction of the thyroid. Graves disease may occur before or after the development of autoimmune thyroiditis.
While rare, more serious complications of the hypothyroidism resulting from autoimmune thyroiditis are pericardial effusion
A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous Connective tissue, connective membrane and an inner two-layered serous membrane ...
, pleural effusion, both of which require further medical attention, and myxedema coma, which is an endocrine
The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
emergency.
Symptoms
Many symptoms are attributed to the development of Hashimoto's thyroiditis. Symptoms can include: fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
, weight gain, pale or puffy face, feeling cold, joint
A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
and muscle pain, constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
, dry and thinning hair, heavy menstrual flow or irregular periods, depression, a slowed heart rate, problems getting pregnant, miscarriages, and myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
. Some patients in the early stage of the disease may experience symptoms of hyperthyroidism
Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...
due to the release of thyroid hormones from intermittent thyroid destruction (also called "destructive thyrotoxicosis"). In non-medical settings, the term "flare" is used to refer to a sudden exacerbation of symptoms, whether hyper or hypo.
While most symptoms are attributed to hypothyroidism, similar symptoms are observed in Hashimoto's patients with normal thyroid hormone levels. According to one study, these symptoms may include lower quality of life, and issues of the "digestive system (abdominal distension
Abdominal distension occurs when substances, such as air (gas) or fluid, accumulate in the abdomen causing its expansion. It is typically a symptom of an underlying disease or dysfunction in the body, rather than an illness in its own right. Peo ...
, constipation and diarrhea), endocrine system (chilliness, gain weight and facial edema
Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
), neuropsychiatric system (forgetfulness, anxiety, depressed, fatigue, insomnia, irritability, and indifferent 'sic'' and mucocutaneous system (dry skin, pruritus, and hair loss)."
Causes
The causes of Hashimoto's thyroiditis are complex. Around 80% of the risk of developing an autoimmune thyroid disorder is due to genetic factors, while the remaining 20% is related to environmental factor
An environmental factor, ecological factor or eco factor is any factor, abiotic or biotic, that influences living organisms. Abiotic factors include ambient temperature, amount of sunlight, air, soil, water and pH of the water soil in which an ...
s (such as iodine, drugs, infection, stress, radiation).
Genetics
Thyroid autoimmunity can be familial. Many patients report a family history of autoimmune thyroiditis or Graves' disease
Graves' disease, also known as toxic diffuse goiter or Basedow's disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...
. The strong genetic component is borne out in studies on monozygotic twins, with a concordance of 38–55%, with an even higher concordance of circulating thyroid antibodies not in relation to clinical presentation (up to 80% in monozygotic twins). Neither result was seen to a similar degree in dizygotic twins, offering strong favour for high genetic etiology.
The genes implicated vary in different ethnic groups and the impact of these genes on the disease differs significantly among people from different ethnic groups. A gene that has a large effect in one ethnic group's risk of developing Hashimoto's thyroiditis might have a much smaller effect in another ethnic group.
The incidence of autoimmune thyroid disorders is increased in people with chromosomal disorders, including Turner
Turner may refer to:
People and fictional characters
* Turner (surname), a common surname, including a list of people and fictional characters with the name
* Turner (given name), a list of people with the given name
*One who uses a lathe for tur ...
, Down, and Klinefelter syndrome
Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often n ...
s.
HLA genes
The first gene locus associated with autoimmune thyroid disease was the major histocompatibility complex
The major histocompatibility complex (MHC) is a large Locus (genetics), locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for Cell (biology), cell surface proteins essential for the adaptive immune system. The ...
(MHC) region on chromosome
A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
6p21. It encodes human leukocyte antigen
The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histo ...
s (HLAs). Specific HLA alleles have a higher affinity to auto-antigenic thyroidal peptides
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...
and can contribute to autoimmune thyroid disease development. Specifically, in Hashimoto's disease, aberrant expression of HLA II on thyrocytes has been demonstrated. They can present thyroid autoantigens and initiate autoimmune thyroid disease. Susceptibility alleles are not consistent in Hashimoto's disease. In Caucasians, various alleles are reported to be associated with the disease, including DR3, DR5, and DQ7.
CTLA-4 genes
CTLA-4 is the second major immune- regulatory gene related to autoimmune thyroid disease. CTLA-4 gene polymorphisms may contribute to the reduced inhibition of T-cell proliferation and increase susceptibility to autoimmune response. CTLA-4 is a major thyroid autoantibody susceptibility gene. A linkage of the CTLA-4 region to the presence of thyroid autoantibodies was demonstrated by a whole-genome linkage analysis. CTLA-4 was confirmed as the main locus for thyroid autoantibodies.
PTPN22 gene
'' PTPN22'' is the most recently identified immune-regulatory gene associated with autoimmune thyroid disease. It is located on chromosome 1p13 and expressed in lymphocytes. It acts as a negative regulator of T-cell activation. Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
in this gene is a risk factor for many autoimmune diseases. Weaker T-cell signaling may lead to impaired thymic deletion of autoreactive T cells, and increased PTPN22 function may result in inhibition of regulatory T cells, which protect against autoimmunity.
Immune-related genes
IFN-γ promotes cell-mediated cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of d ...
against thyroid mutations causing increased production of IFN-γ were associated with the severity of hypothyroidism. Severe hypothyroidism is associated with mutations leading to lower production of IL-4 (Th2 cytokine suppressing cell-mediated autoimmunity), lower secretion of TGF-β (inhibitor of cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
production), and mutations of FOXP3, an essential regulatory factor for the regulatory T cells
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg  ...
(Tregs) development. Development of Hashimoto's disease was associated with mutation of the gene for TNF-α (stimulator of the IFN-γ production), causing its higher concentration.
Existential (endogenous environmental)
Sex
Study of healthy Danish twins divided to three groups (monozygotic and dizygotic same sex, and opposite sex twin pairs) estimated that genetic contribution to thyroid peroxidase antibodies susceptibility was 61% in males and 72% in females, and contribution to thyroglobulin antibodies susceptibility was 39% in males and 75% in females.
The high female predominance in thyroid autoimmunity may be associated with the X chromosome. It contains sex and immune-related genes responsible for immune tolerance.
A higher incidence of thyroid autoimmunity was reported in patients with a higher rate of X-chromosome monosomy
Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing.
Human monosomy
Human conditions due to monosomy:
* Turner syndrome – Females ...
in peripheral white blood cells. Another potential mechanism might be skewed X-chromosome inactivation.
Pregnancy
In one population study, two or more births were a risk factor for developing autoimmune hypothyroidism in pre-menopausal women.
Environmental
Medications
Certain medications or drugs have been associated with altering and interfering with thyroid function. There are two main mechanisms of interference:
* Altering thyroid hormone serum transfer proteins. Estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
, tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...
, heroin
Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...
, methadone, clofibrate, 5-fluorouracil, mitotane, and perphenazine all increase thyroid binding globulin (TBG) concentration. Androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s, anabolic steroid
Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...
s such as danazol, glucocorticoids, and slow release nicotinic acid
Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan.
Nicotinic acid is also a prescription medication. Amounts f ...
all decrease TBG concentrations. Furosemide, fenoflenac, mefenamic acid
Mefenamic acid is a member of the Nonsteroidal anti-inflammatory drug#Anthranilic acid derivatives .28fenamates.29, anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to m ...
, salicylates, phenytoin, diazepam
Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
, sulphonylureas, free fatty acids, and heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
all interfere with thyroid hormone binding to TBG and/or transthyretin.
* Altering extra-thryoidal metabolism of thyroid hormone. Propylthiouracil, glucocorticoids, propranolol
Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...
, iondinated contrast agents, amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxys ...
, and clomipramine all inhibit conversion of T4 and T3. Phenobarbital
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ...
, rifampin, phenytoin and carbamazepine all increase hepatic metabolism. Finally, cholestryamine, colestipol, aluminium hydroxide, ferrous sulphate, and sucralfate are all drugs that decrease T4 absorption or enhance excretion.
Iodine
Both excessive and insufficient iodine intake has been implicated in developing antithyroid antibodies. Thyroid autoantibodies are found to be more prevalent in geographical areas after increasing iodine levels. Several mechanisms by which excessive iodine may promote thyroid autoimmunity have been proposed:
* Via thyroglobulin iodination: Iodine exposure leads to higher iodination of thyroglobulin, increasing its immunogenicity by creating new iodine-containing epitopes or exposing cryptic epitopes.
* Via thyrocyte damage: Iodine exposure has been shown to increase the level of reactive oxygen species
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
. They enhance the expression of the intracellular adhesion molecule-1 on the thyrocytes, which could attract the immuno-competent cells into the thyroid gland. Iodine also promotes thyrocyte apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
.
* Via immune cell behaviour: Iodine has an influence on immune cells.
Comorbidities
Comorbid autoimmune diseases are a risk factor for developing Hashimoto's thyroiditis, and the opposite is also true.[ Another thyroid disease closely associated with Hashimoto's thyroiditis is Graves' disease.] Autoimmune diseases affecting other organs most commonly associated with Hashimoto's thyroiditis include celiac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spel ...
, type 1 diabetes, vitiligo
Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...
, alopecia
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
, Addison disease, Sjogren's syndrome, and rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
Autoimmune thyroiditis has also been seen in patients with autoimmune polyendocrine syndromes type 1 and 2.
Other
Other environmental factors include selenium deficiency, infectious diseases such as hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...
, rubella
Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...
, and possibly Covid-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic.
The symptoms of COVID‑19 can vary but often include fever ...
, toxins, dietary factors, radiation exposure, and gut dysbiosis.
Mechanism
The pathophysiology of autoimmune thyroiditis is not well understood. However, once the disease is established, its core processes have been observed:
Hashimoto's thyroiditis is a T-lymphocyte mediated attack on the thyroid gland. T helper 1 cells trigger macrophages
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
and cytotoxic lymphocytes to destroy thyroid follicular cells, while T helper 2 cells stimulate the excessive production of B cells
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
and plasma cells which generate antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
against the thyroid antigens
In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.
An ...
, leading to thyroiditis. The three major antibodies are: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies (TRAb), with TPOAb and TgAb being most commonly implicated in Hashimotos. They are hypothesized to develop as a result of thyroid damage, where T-lymphocytes are sensitized to residual thyroid peroxidase and thyroglobulin, rather than as the initial cause of thyroid damage. However, they may exacerbate further thyroid destruction by binding the complement system
The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...
and triggering apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
of thyroid cells. TPO antibody levels may correlate with the degree of lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
infiltration of the thyroid.
Gross morphological changes within the thyroid are seen in the general enlargement, which is far more locally nodular and irregular than more diffuse patterns (such as that of hyperthyroidism
Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...
). While the capsule is intact and the gland itself is still distinct from surrounding tissue, microscopic examination can provide a more revealing indication of the level of damage. Hypothyroidism is caused by replacement of follicular cells with parenchymatous tissue.
Partial regeneration of the thyroid tissue can occur, but this has not been observed to normalise hormonal levels.
Pathology
Gross pathology of a thyroid with autoimmune thyroiditis may show an symmetrically enlarged thyroid. It is often paler in color, in comparison to normal thyroid tissue which is reddish-brown.
Microscopic examination (histology
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
) will show lymphocytes (including plasma B-cells) diffusely infiltrating the parenchyma
upright=1.6, Lung parenchyma showing damage due to large subpleural bullae.
Parenchyma () is the bulk of functional substance in an animal organ such as the brain or lungs, or a structure such as a tumour. In zoology, it is the tissue that ...
. The lymphocytes are predominately T-lymphocytes with a representation of both CD4+ and CD8+ cells. The plasma cells are polyclonal, with present germinal centers resembling the structure of a lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
(also called secondary lymphoid follicles, not to be confused with the normally present colloid
A colloid is a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance. Some definitions specify that the particles must be dispersed in a liquid, while others exte ...
-filled follicles that constitute the thyroid).
In late stages of the disease, the thyroid may be atrophic. Colloid-filled follicles shrink and the cuboidal cells that usually line the follicles become Hürthle cells. Fibrous tissue may be found throughout the affected thyroid as well. Severe thyroid atrophy presents often with denser fibrotic bands of collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
that remains within the confines of the thyroid capsule.
Generally, pathological findings of the thyroid are related to the amount of existing thyroid function — the more infiltration and fibrosis, the less likely a patient will have normal thyroid function. A rare but serious complication is thyroid lymphoma, generally the B-cell type, non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
.
Diagnosis
Tests
Physical exam
Physicians will often start by assessing reported symptoms and performing a thorough physical exam, including a neck exam. Patients may have a "firm, bumpy, symmetric, painless goiter", however, up to 10% of patients may have an atrophied thyroid.
Antithyroid antibodies tests
Tests for antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
against thyroid peroxidase, thyroglobulin, and thyrotropin receptors can detect autoimmune processes against the thyroid. 90% of hashimoto's patients have elevated levels of thyroid peroxidase antibodies. However, seronegative (without circulating autoantibodies) thyroiditis is also possible. There may be circulating antibodies before the onset of any symptoms.
Ultrasound
An ultrasound
Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...
may be useful in detecting Hashimoto thyroiditis, especially in those with seronegative thyroiditis, or when patients have normal laboratory values but symptoms of autoimmune thyroiditis. Key features detected in the ultrasound of a person with Hashimoto's thyroiditis include " echogenicity, heterogeneity, hypervascularity, and presence of small cysts." Images obtained with ultrasound can evaluate the size of the thyroid, reveal the presence of nodules, or provide clues to the diagnosis of other thyroid conditions.
Nuclear medicine
Nuclear imaging showing thyroid uptake can also be helpful in diagnosing thyroid function, particularly differential diagnosis.
TSH levels test
Elevated Thyroid-stimulating hormone (TSH) levels may indicate hypothyroidism (underpeforming thyroid). Hypothyroidism is a common symptom and potential indication of Hashimoto's disease. As blood levels of thyroid hormones fall due to hypothyroidism, the anterior pituitary gland increases production of TSH, which stimulates increased production of thyroid hormones in the thyroid. The elevation is usually a marked increase over the normal range. TSH is the preferred initial test of thyroid function as it has a higher sensitivity to changes in thyroid status than free T4.
Biotin can cause this test to read "falsely low". Time of day can affect the results of this test; TSH peaks early in the morning and slumps in the late afternoon to early evening, with "a variation in TSH by a mean of between 0.95 m IU/mL to 2.0 mIU/mL". Hypothyroidism is diagnosed more often in samples taken soon after waking.
T3 or T4 levels test
These tests detect levels of two thyroid hormones: Thyroxine
Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...
( T4) and Tri-iodothyronine ( T3). Low levels of these hormones (hypothyroidism) may indicate autoimmune damage to the thyroid due to Hashimoto's, while elevated levels may indicate an attack of destructive thyrotoxicosis. Hashimotos with normal levels is possible however.
Free or total levels can be measured. Typically, Free T4 is the preferred test for hypothyroidism, as Free T3 immunoassay tests are less reliable at detecting low levels of thyroid hormone, and they are more susceptible to interference. Both immunoassay tests of Free T4 and Free T3 may overestimate concentrations, particularly at low thyroid hormone levels, which is why results are typically read in conjunction with TSH, a more sensitive measure. LC-MSMS assays are rarer, but they are "highly specific, sensitive, precise, and can detect hormones found in low concentrations."
Muscle Biopsy
Muscle biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
is not necessary for diagnosis of myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
due to hypothyroid muscle fibre changes, however it may reveal confirmatory features.
Treatment
There is no cure for Hashimoto's Thyroiditis. There is currently no known way to stop auto-immune lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
infiltrating the thyroid or to stimulate regeneration of thyroid tissue. However, the condition can be managed.
Managing hormone levels
Hypothyroidism caused by Hashimoto's thyroiditis is treated with thyroid hormone replacement agents such as levothyroxine (LT4), liothyronine (LT3), or desiccated thyroid extract (T4+T3). In most cases, the treatment needs to be taken for the rest of the person's life.
The standard of care is levothyroxine (LT4) therapy, which is an oral medication identical in molecular structure to endogenous
Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell.
For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
thyroxine (T4). Levothyroxine sodium has a sodium
Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
salt added to increase the gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...
absorption of levothyroxine. Levothyroxine has the benefits of a long half-life Half-life is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''Half Life: ...
leading to stable thyroid hormone levels, ease of monitoring, excellent safety and efficacy record, and usefulness in pregnancy as it can cross the fetal blood-brain barrier.
Levothyroxine dosing to normalise TSH is based on the amount of residual endogenous
Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell.
For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
thyroid function and the patient’s weight, particularly lean body mass. The dose can be adjusted based upon each patient, for example, the dose may be lowered for elderly patients or patients with certain cardiac conditions, but is increased in pregnant patients. It is administered on a consistent schedule. Levothyroxine may be dosed daily or weekly, however weekly dosing may be associated with higher TSH levels, elevated thyroid hormone levels, and transient " echocardiographic changes in some patients following 2-4 h of thyroxine intake".
Some patients elect combination therapy with both levothyroxine and liothyronine (which is identical in molecular structure to tri-iodothyronine) however studies of combination therapy are limited, and five meta-analyses
Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
/reviews "suggested no clear advantage of the combination therapy." However, subgroup analysis found that patients who remain the most symptomatic while taking levothyroxine may benefit from therapy containing liothyronine.
There is a lack of evidence around the benefits, side effects and long-term risks of desiccated thyroid extract. It is no longer recommended for the treatment of hypothyroidism.
Side Effects
Side effects of thyroid replacement therapy are associated with "inadequate or excessive doses." Symptoms to watch for include, but are not limited to, anxiety
Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, tremor
A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
, weight loss, heat sensitivity, diarrhea, and shortness of breath. More worrisome symptoms include atrial fibrillation
Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
and bone density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although medicine#Clinical practice, clinically it is measured by ...
loss. Long term over-treatment is associated with increased mortality and dementia
Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
.
Monitoring
Thyroid Stimulating Hormone (TSH) is the laboratory value of choice for monitoring response to treatment with levothyroxine. When treatment is first initiated, TSH levels may be monitored as often as a frequency of every 6–8 weeks. Each time the dose is adjusted, TSH levels may be measured at that frequency until the correct dose is determined. Once titrated to a proper dose, TSH levels will be monitored yearly. The target level for TSH is the subject of debate, with factors like age, sex, individual needs and special circumstances such as pregnancy being considered. Recent studies suggest that adjusting therapy based on thyroid hormone levels (T4 and/or T3) may be important.
Monitoring liothyronine treatment or combination treatment can be challenging. Liothyronine can suppress TSH to a greater extent than levothyroxine. Short-acting Liothyronine's short half-life can result in large fluctuations of free T3 over the course of 24 hours.
Patients may have to adjust their dosage several times over the course of the disease. Endogenous thyroid hormone levels may fluctuate, particularly early in the disease. Patients may sometimes develop hyperthyroidism, even after long-term treatment. This can be due to a number of factors including acute attacks of destructive thyrotoxicosis (autoimmune attacks on the thyroid resulting in rises in thyroid hormone levels as thyroid hormones leak out of the damaged tissues). This is usually followed by hypothyroidism.
Reverse T3
Measuring reverse tri-iodothyronine (rT3) is often mentioned in the lay (non-medical) press as a possible marker to inform T4 or T3 therapy, "however, there is currently no evidence to support this application" as of 2023. Although cited in the lay press as a possible competitor to T3, it is unlikely that rT3 causes hypothyroid symptoms by out-competing T3 for thyroid hormone receptors, as it has a binding affinity 200 times weaker. It is also unlikely that rT3 causes poor T4 to T3 conversion; despite being demonstrated ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' to have the potential to inhibit DIO-mediated T4 to T3 conversion, this is considered improbable at normal body hormone concentrations.
Persistent Symptoms
Multiple studies have demonstrated persistent symptoms in Hashimoto's patients with normal thyroid hormone levels (euthyroid) and an estimated 10%-15% of patients treated with levothyroxine monotherapy are dissatisfied due to persistent symptoms of hypothyroidism. Several different hypothesised causes are discussed in the medical literature:
Low tissue tri-iodothyronine (T3) hypothesis
Peripheral tissue T4 to T3 conversion may be inadequate: Some patients on LT4 monotherapy may have blood T3 levels low or below the normal range, and/or may have local T3 deficiency in some tissues. Although both molecules
A molecule is a group of two or more atoms that are held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemistry ...
can have biological effects, thyroxine (T4) is considered the "storage form" of thyroid hormone with much less effect, while tri-iodothyronine (T3) is considered the active form used by body tissues. Thus the body must convert thyroxine into tri-iodothyronine. Tri-iodothyronine is produced primarily by conversion in the liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
, skeletal muscle
Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
and pituitary gland
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
.
Adequate conversion requires sufficient levels of the micronutrients zinc
Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
, selenium
Selenium is a chemical element; it has symbol (chemistry), symbol Se and atomic number 34. It has various physical appearances, including a brick-red powder, a vitreous black solid, and a grey metallic-looking form. It seldom occurs in this elem ...
, iron
Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
, and possibly vitamin A
Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...
. Conversion rates may decline with age. Since deiodinase type 2 is necessary for T4 to T3 conversion in some peripheral tissues, "patients with ''DIO2'' gene polymorphisms may have variable peripheral T3 availability", leading to localised hypothyroidism in some tissues. The Thr92Ala ''DIO2'' polymorphism is present in 12–36% of the population.
For the latter patients, levothyroxine monotherapy may not be sufficient and patients may have improvement on combination therapy of T4 and T3. As standard immunoassay tests can overestimate blood T4 and T3 levels, Ultrafiltration LC-MSMS T4 and T3 tests may help to identify patients who would benefit from additional T3.
Inadequate markers hypothesis
There is ongoing debate about how to define euthyroidism and whether TSH is its best indicator. TSH may be useful to detect poor thyroid output and may reflect the state of thyroid hormones in the hypothalamic-pituitary-thyroid axis, but not the presence of hormones in other body tissues. As a result, LT4 monotherapy may not result in a "truly biochemically euthyroid state." Patients may express a preference for "low normal or below normal TSH values" and/or T4 and T3 monitoring. The monitoring of other biomarkers that reflect the action of thyroid hormone on tissues has also been proposed.
As immunoassay
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...
Free T3 and Free T4 tests can overestimate levels, particularly at low thyroid hormone levels, hypothyroidism may be undertreated. LC-MSMS tests may provide more reliable measures.
Extra-thyroidal effects of autoimmunity hypothesis
It is hypothesised that autoimmunity may play some role in euthyroid symptoms. Hypothesised mechanisms include the proposal that TPO-antibody-producing lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
may travel out of the thyroid to other tissue, creating symptoms and inflammation due to cross-reaction, or "the inflammatory nature of ..persistently increased circulating cytokine levels." Multiple studies find that antibodies coincide with symptoms even in euthyroid patients, and higher levels are associated with increased symptoms, however "the found association does not prove a causality". No treatment currently exists for Hashimoto's autoimmunity, although observed wellbeing improvements after surgical thyroid removal are hypothesised to be due to removing the autoimmune stimulus.
Physical and psychosocial co-morbidities hypothesis
It is hypothesised that euthyroid symptoms may not be due to Hashimoto's or hypothyroidism, but some other "physical and psychosocial co-morbidities".
Improving wellbeing
Some patients may perceive improved wellbeing while in thyrotoxicosis, however overtreatment has risks (known risks for levothyroxine and unknown risks for liothyronine). One study demonstrated surgical thyroid removal may substantially improve fatigue and wellbeing, see Surgery considerations, below.
Reducing antibodies
It is not established that reducing antithyroid antibodies in Hashimoto's has benefits. A systematic review and meta-analysis of selenium trials found that while selenium reduces TPO antibodies, there was a lack of evidence of effects on "disease remission, progression, lowered levothyroxine dose or improved quality of life
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
".
Selenium, vitamin D
Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
, and metformin can reduce thyroid peroxidase antibodies. There is preliminary evidence that levothyroxine, aloe vera
''Aloe vera'' () is a succulent plant species of the genus ''Aloe''. It is widely distributed, and is considered an invasive species in many world regions.
An evergreen perennial plant, perennial, it originates from the Arabian Peninsula, but ...
juice and black cumin seed may reduce thyroid peroxidase antibodies. Metformin can reduce thyroglobulin antibodies. It is not established that a gluten-free diet can reduce antibodies when there is no comorbid coeliac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spelt ...
. Gluten-free diets have been shown in several studies to reduce antibodies, and in other studies to have no effect, however there were significant confounding issues in these studies, including not ruling out comorbid coeliac disease.
One study found surgical thyroid removal can substantially reduce anti-thyroid antibody levels, see Surgery considerations, below.
Surgery considerations
Surgery is not the initial treatment of choice for autoimmune disease, and uncomplicated Hashimoto's thyroiditis is not an indication for thyroidectomy. Patients generally may discuss surgery with their doctor if they are experiencing significant pressure symptoms, or cosmetic concerns, or have nodules present on ultrasound. One well-conducted study of patients with troublesome general symptoms and with anti-thyroperoxidase (anti-TPO) levels greater than 1000 IU/ml (normal <100 IU/ml) showed that total thyroidectomy caused the symptoms to resolve and median anti-thyroid peroxidase levels to reduce from 2232 to 152 IU/mL, but post-operative complications were higher than expected: infection
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
(4.1%), permanent hypoparathyroidism (4.1%) and recurrent laryngeal nerve
The recurrent laryngeal nerve (RLN), also known as nervus recurrens, is a branch of the vagus nerve ( cranial nerve X) that supplies all the intrinsic muscles of the larynx, with the exception of the cricothyroid muscles. There are two recur ...
injury (5.5%).
Other
Zinc
Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
may increase free T3 levels. A small pilot study found Ashwagandha Root may increase T3 and T4 levels, however, there's a lack of strong evidence of this benefit and Ashwagandha has a potential to cause adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...
.
As of 2022, there has been only one study of low-dose naltrexone in Hashimoto's, which did not demonstrate efficacy, therefore nothing supports its use; Removing dairy products in those without lactose intolerance
Lactose intolerance is caused by a lessened ability or a complete inability to digest lactose, a sugar found in dairy products. Humans vary in the amount of lactose they can tolerate before symptoms develop. Symptoms may include abdominal pain ...
has not been found to be supported. While soy isoflavones have the potential to theoretically affect T3 and T4 production, studies in those with sufficient iodine
Iodine is a chemical element; it has symbol I and atomic number 53. The heaviest of the stable halogens, it exists at standard conditions as a semi-lustrous, non-metallic solid that melts to form a deep violet liquid at , and boils to a vi ...
find no effect.
Prognosis
Overt, symptomatic thyroid dysfunction is the most common complication, with about 5% of people with subclinical hypothyroidism and chronic autoimmune thyroiditis progressing to thyroid failure every year. Transient periods of thyrotoxicosis (over-activity of the thyroid) sometimes occur, and rarely the illness may progress to full hyperthyroid Graves' disease
Graves' disease, also known as toxic diffuse goiter or Basedow's disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...
with active orbitopathy (bulging, inflamed eyes).
Rare cases of fibrous autoimmune thyroiditis present with severe shortness of breath
Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...
and difficulty swallowing, resembling aggressive thyroid tumors, but such symptoms always improve with surgery or corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
therapy. Although primary thyroid B-cell lymphoma affects fewer than one in 1000 persons, it is more likely to affect those with long-standing autoimmune thyroiditis, as there is a 67- to 80-fold increased risk of developing primary thyroid lymphoma in patients with Hashimoto's thyroiditis.
Myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
as a result of muscle fibre changes due to thyroid hormone deficiency may take months or years of thyroid hormone treatment to resolve.
Anti-thyroid antibodies
Thyroid peroxidase antibodies typically (but not always) decline in patients treated with levothyroxine, with decreases varying between 10% and 90% after a follow-up of 6 to 24 months. One study of patients treated with levothyroxine observed that 35 out of 38 patients (92%) had declines in thyroid peroxidase antibody levels over five years, lowering by 70% on average. 6 of the 38 patients (16%) had thyroid peroxidase antibody levels return to normal.
Children
Many children diagnosed with Hashimoto's disease will experience the same progressive course of the disease that adults do. However, of children who develop anti-thyroid antibodies and hypothyroidism, up to 50% are later observed to have normal antibodies and thyroid hormone levels. One case of true remission has been observed in a 12-year-old girl. Her thyroid was observed via ultrasound
Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...
to progress from early inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
to severe end-stage Hashimoto's thyroiditis with hypothyroidism, and then return to "almost normal with only minimal features of inflammation" and euthyroidism.
Epidemiology
Hashimoto's Disease is estimated to affect 2% of the world's population. About 1.0 to 1.5 in 1000 people have this disease at any time.
Sex
Anyone may develop this disease, but it occurs between 8 and 15 times more often in women than in men. Some research suggests a connection to the role of the placenta
The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...
as an explanation for the sex difference. Other research suggests the difference in prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
amongst genders is due to the effects of sex hormones.
High iodine consumption
Autoimmune thyroiditis has a higher prevalence in societies that have a higher intake of iodine
Iodine is a chemical element; it has symbol I and atomic number 53. The heaviest of the stable halogens, it exists at standard conditions as a semi-lustrous, non-metallic solid that melts to form a deep violet liquid at , and boils to a vi ...
in their diet, such as the United States and Japan, and among people who are genetically susceptible. It is the most common cause of hypothyroidism in areas of sufficient iodine. Also, the rate of lymphocytic infiltration increased in areas where the iodine intake was once low, but increased due to iodine supplementation.
Iodine deficiency disorder is combated using an increase in iodine in a person's diet. When a dramatic change occurs in a person's diet, they become more at-risk of developing hypothyroidism and other thyroid disorders. Treating iodine deficiency disorder with high salt intakes should be done carefully and cautiously as risk for Hashimoto's may increase.
Geographic influence of dietary trends
Geography plays a large role in which regions have access to diets with low or high iodine. Iodine levels in both water and salt should be heavily monitored in order to protect at-risk populations from developing hypothyroidism. Geographic trends of hypothyroidism vary across the world as different places have different ways of defining disease and reporting cases. Populations that are spread out or defined poorly may skew data in unexpected ways.
North America
Hashimoto's thyroiditis may affect up to 5% of the United States' population. Hashimoto's thyroiditis disorder is thought to be the most common cause of primary hypothyroidism in North America.
Age
Hashimoto's thyroiditis can occur at any age, including children, but more commonly appears in middle age
Middle age (or middle adulthood) is the age range of the years halfway between childhood and old age. The exact range is subject to public debate, but the term is commonly used to denote the age range from 45 to 65 years.
Overall
This time span ...
, particularly for men. Incidence peaks in the fifth decade of life, but patients are usually diagnosed between age 30–50. The highest prevalence from one study was found in the elderly members of the community. It has been shown that the prevalence of positive tests for thyroid antibodies increases with age, "with a frequency as high as 33 percent in women 70 years old or older."
Race
The prevalence of Hashimoto's varies geographically. The highest rate is in Africa, and the lowest in Asia. In the US, the African-American population experiences it less commonly but has greater associated mortality.
Autoimmune diseases
Those that already have an autoimmune disease are at greater risk of developing Hashimoto's as the diseases generally coexist with each other. See Causes > Comorbidities, above.
Secular trends
The secular trends of hypothyroidism reveal how the disease has changed over the course of time given changes in technology and treatment options. Even though ultrasound technology and treatment options have improved, the incidence of hypothyroidism has increased according to data focused on the US and Europe. Between 1993 and 2001, per 1000 women, the disease was found varying between 3.9 and 4.89. Between 1994 and 2001, per 1000 men, the disease increased from 0.65 to 1.01.
History
Also known as Hashimoto's disease, Hashimoto's thyroiditis is named after Japanese physician Hakaru Hashimoto (1881−1934) of the medical school at Kyushu University, who first described the symptoms of persons with ''struma lymphomatosa'', an intense infiltration of lymphocytes within the thyroid, in 1912 in the German journal called . This paper
Paper is a thin sheet material produced by mechanically or chemically processing cellulose fibres derived from wood, Textile, rags, poaceae, grasses, Feces#Other uses, herbivore dung, or other vegetable sources in water. Once the water is dra ...
was made up of 30 pages and 5 illustrations all describing the histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
changes in the thyroid tissue. Furthermore, all results in his first study were collected from four women. These results explained the pathological characteristics observed in these women especially the infiltration of lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
and plasma cells as well as the formation of lymphoid follicles with germinal centers, fibrosis, degenerated thyroid epithelial cells and leukocytes in the lumen. He described these traits to be histologically similar to those of Mikulic's disease. As mentioned above, once he discovered these traits in this new disease, he named the disease ''struma lymphomatosa.'' This disease emphasized the lymphocyte infiltration and formation of the lymphoid follicles with germinal centers, neither of which had ever been previously reported.
Despite Hashimoto's discovery and publication, the disease was not recognized as distinct from Riedel's thyroiditis, which was a common disease at that time in Europe. Although many other articles were reported and published by other researchers, Hashimoto's struma lymphomatosa was only recognized as an early phase of Riedel's thyroiditis in the early 1900s. It was not until 1931 that the disease was recognized as a disease in its own right, when researchers Allen Graham et al. from Cleveland reported its symptoms and presentation in the same detailed manner as Hashimoto.
In 1956, Drs. Rose and Witebsky were able to demonstrate how immunization
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent (known as the antigen, immunogen). When this system is exposed to molecules that are foreign to the body, called ' ...
of certain rodents with extracts of other rodents' thyroid resembled the disease Hakaru and other researchers were trying to describe. These doctors were also able to describe anti-thyroglobulin antibodies in blood serum samples from these same animals.
Later on in the same year, researchers from the Middlesex Hospital in London were able to perform human experiments on patients who presented with similar symptoms. They purified anti-thyroglobulin antibody from their serum and were able to conclude that these sick patients had an immunological reaction to human thyroglobulin. From this data, it was proposed that Hashimoto's struma could be an autoimmune disease of the thyroid gland: "Following these discoveries, the concept of organ-specific autoimmune disease was established and HT recognized as one such disease."
Following this recognition, the same researchers from Middlesex Hospital published an article in 1962 in ''The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal, founded in England in 1823. It is one of the world's highest-impact academic journals and also one of the oldest medical journals still in publication.
The journal publishes ...
'' that included a portrait of Hakaru Hashimoto. The disease became more well known from that moment, and Hashimoto's disease started to appear more frequently in textbooks.
Pregnancy
Conception
It is recommended that hypothyroidism be treated with levothyoxine before conception, to prevent adverse effects on the course of the pregnancy and on the development of the child. In IVF, embryo transfer
Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique - which is often used in connection with in vitro fertili ...
is improved when hypothyroidism is treated.
Pregnancy
The Endocrine Society
The Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed t ...
recommends screening in pregnant women who are considered high-risk for thyroid autoimmune disease. Universal screening for thyroid diseases during pregnancy is controversial, however, one study "supports the potential benefit of universal screening". Pregnant women may have antithyroid antibodies (5%–14% of pregnancies), poor thyroid function resulting in hypothyroidism, or both. Each is associated with risks:
Anti-thyroid antibodies in pregnancy
The presence of Thyroid peroxidase antibodies at the outset of pregnancy are associated with a greater risk to the mother of hypothyroidism and thyroid impairment in the first year after delivery.
The presence of antibodies is also associated with "a 2 to 4-fold increase in the risk of recurrent miscarriages, and 2 to 3-fold increased risk of preterm birth
Preterm birth, also known as premature birth, is the Childbirth, birth of a baby at fewer than 37 weeks Gestational age (obstetrics), gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 ...
", however the reason why is unclear. Thyroid peroxidase antibodies are speculated to indicate other autoimmune processes against the placental-fetal unit.
Levothyroxine treatment in euthyroid women with thyroid autoimmunity does not significantly impact the relative risk of miscarriage and preterm delivery, or outcomes with live birth. "Therefore, no strong recommendations regarding the therapy in such scenarios could be made, but consideration on a case-by-case basis might be implemented."
Hypothyroidism in pregnancy
Women who have low thyroid function that has not been stabilized are at greater risk of complications for both parent and child. Risks to the mother include gestational hypertension
Gestational hypertension or pregnancy-induced hypertension (PIH) is the development of new hypertension in a pregnant woman after 20 weeks of gestation without the presence of protein in the urine or other signs of pre-eclampsia. Gestational hype ...
including preeclampsia and eclampsia
Eclampsia is the onset of seizures (convulsions) in a pregnant woman with pre-eclampsia. Pre-eclampsia is a hypertensive disorder of pregnancy that presents with three main features: new onset of high blood pressure, large amounts of proteinuria ...
, gestational diabetes, placental abruption, and postpartum hemorrhage
Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume fo ...
. Risks to the infant include miscarriage, preterm delivery, low birth weight, neonatal respiratory distress, hydrocephalus
Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...
, hypospadias
Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...
, fetal death, infant intensive care unit admission, and neurodevelopmental delays (lower child IQ, language delay or global developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in two or more areas of development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech delay, spe ...
).
Successful pregnancy outcomes are improved when hypothyroidism is treated. Levothyroxine treatment may be considered at lower TSH levels in pregnancy than in standard treatment. Liothyronine does not cross the fetal blood-brain barrier, so liothyronine (T3) only or liothyronine + levothyroxine (T3 + T4) therapy is not indicated in pregnancy.
Close cooperation between the endocrinologist and obstetrician
Obstetrics is the field of study concentrated on pregnancy, childbirth and the postpartum period. As a medical specialty, obstetrics is combined with gynecology under the discipline known as obstetrics and gynecology (OB/GYN), which is a surgi ...
benefits the woman and the infant.
Immune changes during pregnancy
Hormonal changes and trophoblast
The trophoblast (from Greek language, Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after Human fertilization, fertilization in humans. They provide nutrients to the embryo an ...
expression of key immunomodulatory molecules lead to immunosuppression and fetal tolerance. The main players in regulation of the immune response are Tregs. Both cell-mediated and humoral immune responses are attenuated, resulting in immune tolerance and suppression of autoimmunity. It has been reported that during pregnancy, levels of thyroid peroxidase and thyroglobulin antibodies decrease.
Postpartum
Thyroid peroxidase antibodies testing is recommended for women who have ever been pregnant regardless of pregnancy outcome. " evious pregnancy plays a major role in development of autoimmune overt hypothyroidism in premenopausal women, and the number of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women 'sic''"
Postpartum thyroiditis can occur in women with Hashimoto's. In healthy women, Postpartum thyroiditis can occur up to 1 year after delivery and should be differentiated from Hashimoto's thyroiditis as it is treated differently.
After giving birth, Tregs rapidly decrease and immune responses are re-established. It may lead to the occurrence or aggravation of autoimmune thyroid disease. In up to 50% of females with thyroid peroxidase antibodies in the early pregnancy, thyroid autoimmunity in the postpartum period exacerbates in the form of postpartum thyroiditis. Higher secretion of IFN-γ and IL-4, and lower plasma cortisol
Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone.
Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
concentration during pregnancy has been reported in females with postpartum thyroiditis than in healthy females. It indicates that weaker immunosuppression during pregnancy could contribute to the postpartum thyroid dysfunction.
Fetal microchimerism
Several years after the delivery, the chimeric male cells can be detected in the maternal peripheral blood, thyroid, lung, skin, or lymph nodes. The fetal immune cells in the maternal thyroid gland may become activated and act as a trigger that may initiate or exaggerate the autoimmune thyroid disease. In Hashimoto's disease patients, fetal microchimeric cells were detected in thyroid in significantly higher numbers than in healthy females.
Other animals
Hashimoto's disease is known to occur in chicken
The chicken (''Gallus gallus domesticus'') is a domesticated subspecies of the red junglefowl (''Gallus gallus''), originally native to Southeast Asia. It was first domesticated around 8,000 years ago and is now one of the most common and w ...
s, rat
Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include '' Neotoma'' (pack rats), '' Bandicota'' (bandicoo ...
s, mice
A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
, dogs, and marmosets, but Graves' disease does not.
See also
* Hashimoto's encephalopathy
* Myxedematous psychosis
* Hashitoxicosis
* Hoffmann Syndrome
References
{{DEFAULTSORT:Hashimoto's Thyroiditis
Aging-associated diseases
Autoimmune diseases
Endocrine diseases
Wikipedia medicine articles ready to translate
Wikipedia neurology articles ready to translate
Thyroid disease
Diseases named after discoverers