Hashimoto's thyroiditis

• 1. Introduction

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  In 1912, a Japanese physician named Hakaru Hashimoto, working at the medical school of Kyushu University, published a paper of 30 pages with 5 illustrations. His evidence came from only four women. In each of them, the thyroid gland was crowded with immune cells, a pattern he named struma lymphomatosa. Today the condition carries his name. Hashimoto's thyroiditis, also called chronic lymphocytic thyroiditis or autoimmune thyroiditis, destroys the thyroid gland bit by bit, with the body's own immune defenses doing the damage. It is the most common cause of hypothyroidism, an underactive thyroid, in developed countries. Its early signs can pass unnoticed. So how does the disease announce itself, and how do doctors catch it? Why did it take decades for anyone to accept it as a separate illness? What sets it off in some people and not in others? And why do some patients still feel unwell once treatment is under way?

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• 2. Slow Recognition

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  For years after the paper appeared, European doctors had a ready-made label for what Hashimoto described: Riedel's thyroiditis, a common disease at the time. Hashimoto himself noted that the tissue resembled that of Mikulic's disease. He also stressed two features that no one had reported before, a heavy infiltration of lymphocytes and lymphoid follicles with germinal centers. His paper ran in the German journal Archiv für Klinische Chirurgie. Other researchers published cases of their own, yet his struma lymphomatosa was still read as an early phase of Riedel's thyroiditis through the early 1900s.

  Not until 1931 did that change. Allen Graham and colleagues in Cleveland reported the symptoms and presentation in the same careful detail Hashimoto had used, and the disease was finally treated as its own condition.

  The deeper insight arrived in 1956. Doctors Rose and Witebsky immunized rodents with extracts of other rodents' thyroid tissue and produced a condition resembling the human disease. They also found anti-thyroglobulin antibodies in blood serum from the animals. Later that same year, researchers at Middlesex Hospital in London tested human patients with similar symptoms. They purified anti-thyroglobulin antibody from the patients' serum and concluded that these people were reacting immunologically to their own thyroglobulin. From this, they proposed that Hashimoto's struma was an autoimmune disease of the thyroid. The result helped establish the very idea of an organ-specific autoimmune disease.

  In 1962, the same Middlesex researchers published an article in The Lancet that included a portrait of Hakaru Hashimoto. After that, the disease appeared more and more often in textbooks. Hashimoto had lived from 1881 to 1934, more than two decades before his disease was shown to be autoimmune.

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• 3. Inherited Risk

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  Roughly 80% of a person's risk of developing an autoimmune thyroid disorder comes from genes, and the remaining 20% from the environment. Twin studies show how strong the inherited part is. Among identical twins, concordance for the disease runs from 38% to 55%. For circulating thyroid antibodies alone, with no clinical illness, it climbs as high as 80%. Fraternal twins showed nothing close to either figure. Many patients also report a relative with autoimmune thyroiditis or Graves' disease.

  The genes that matter differ between ethnic groups. A gene with a large effect in one population may count for much less in another. The incidence of autoimmune thyroid disorders is also higher in people with chromosomal conditions, namely Turner, Down and Klinefelter syndromes.

  The first gene region tied to autoimmune thyroid disease sits on chromosome 6p21 and encodes the human leukocyte antigens, or HLAs. Some versions bind thyroid proteins more tightly and can help start an autoimmune attack. In Hashimoto's disease, thyroid cells show abnormal HLA II expression, which lets them present thyroid proteins to the immune system. In Caucasians, the alleles DR3, DR5 and DQ7 have been linked to the disease, though susceptibility alleles are not consistent.

  CTLA-4 is the second major immune-regulatory gene. Its variants may weaken the brake on T-cell proliferation, and a whole-genome linkage analysis confirmed it as the main locus for thyroid autoantibodies. PTPN22, on chromosome 1p13, is the most recently identified of the three. It acts as a negative regulator of T-cell activation, and a mutation in it raises the risk of many autoimmune diseases. Other variants affect immune signals such as IFN-γ, IL-4, TGF-β, FOXP3 and TNF-α. Some are tied to how severe the hypothyroidism becomes, and one to whether the disease develops at all.

  Women are affected between 8 and 15 times more often than men. The X chromosome may play a part, since it holds sex-related and immune-related genes responsible for immune tolerance. Thyroid autoimmunity was reported more often in patients with higher rates of X-chromosome monosomy in their white blood cells. Skewed X-chromosome inactivation is another possible mechanism. A study of healthy Danish twins put the genetic contribution to thyroid peroxidase antibody susceptibility at 61% in males and 72% in females. Other researchers look instead to the placenta or to sex hormones as the source of the gap.

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• 4. Outside Triggers

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  Iodine is one of the best-studied outside influences, and both too much and too little have been implicated. Thyroid autoantibodies become more common in regions after iodine levels rise. Societies with high dietary iodine, such as the United States and Japan, show a higher prevalence among genetically susceptible people. In areas with sufficient iodine, Hashimoto's is the leading cause of hypothyroidism.

  Several mechanisms have been proposed for how excess iodine pushes the thyroid toward autoimmunity. Extra iodine makes thyroglobulin more heavily iodinated, which can create new targets for the immune system or expose hidden ones. It also raises reactive oxygen species, which increase the expression of intracellular adhesion molecule-1 on thyroid cells and may draw immune cells into the gland. Iodine also promotes thyrocyte apoptosis, a form of programmed cell death. Treating iodine deficiency with large amounts of salt should be done with caution, because a sudden dietary change can raise the risk of Hashimoto's.

  Geography shapes the picture further. The highest rate of the disease is in Africa and the lowest is in Asia, though regions define and report the disease differently, which can skew comparisons.

  Viral infections have also been implicated, including hepatitis C, Epstein-Barr, herpes simplex and human parvovirus B19. Two proposed routes are immune upregulation and molecular mimicry, in which a virus resembles a body protein closely enough to confuse the immune system.

  Psychological stress offers a different route. Stress activates the hypothalamic-pituitary-adrenal axis, which releases glucocorticoids and catecholamines. These push immune cells toward the Th2 type rather than Th1, raising antibodies against thyroid peroxidase and thyroglobulin. Chronic stress continues this pattern and has been linked to a higher incidence of Hashimoto's and other autoimmune conditions.

  The list goes on. Lower temperature and less sunlight, chemical pollutants, heavy metals, radiation, selenium deficiency, gut dysbiosis and possibly COVID-19 have all been named. Certain drugs interfere with thyroid hormone, either by altering the proteins that carry it in the blood or by changing how the body processes it.

  Having another autoimmune disease is itself a risk factor, and the link runs both ways. Celiac disease, type 1 diabetes, vitiligo, alopecia areata, Addison disease, Sjogren's disease and rheumatoid arthritis are the most common companions. Autoimmune thyroiditis has also appeared in patients with autoimmune polyendocrine syndromes types 1 and 2.

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• 5. Inside the Gland

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  Under the microscope, Hashimoto's thyroiditis is an assault carried out by T lymphocytes. T helper 1 cells call in macrophages and cytotoxic lymphocytes, which destroy the follicular cells of the thyroid. T helper 2 cells drive a surge of B cells and plasma cells that make antibodies against thyroid proteins. The main antibodies are directed at thyroid peroxidase, at thyroglobulin, and at the thyroid stimulating hormone receptor, with the first two most often involved. Researchers hypothesize that these antibodies follow the damage rather than start it, though they may make the destruction worse by engaging the complement system and triggering cell death. A meta-analysis of 26 studies found more inflammatory helper T cell 17 and fewer regulatory T cells in patients.

  A healthy thyroid is reddish-brown. A thyroid with autoimmune thyroiditis is often paler and symmetrically enlarged. Histology shows lymphocytes spread through the tissue, mostly T cells carrying both CD4 and CD8 markers. Polyclonal plasma cells form germinal centers that resemble the structure of a lymph node. In late disease, the colloid-filled follicles shrink, and the cuboidal cells that normally line them turn into Hürthle cells. Fibrous bands of collagen may run through the gland, which can become atrophic. Partial regeneration of tissue can occur, but it has not been seen to restore normal hormone levels.

  For the patient, the early years may be quiet. Hormone levels can be normal, and the only clue may be thyroid autoantibodies in the blood. As the lymphocytes advance, a painless goiter may appear. Symptoms can include fatigue, weight gain, a pale or puffy face, feeling cold, joint and muscle pain, constipation, dry and thinning hair, depression and a slowed heart rate. Heavy or irregular periods, trouble getting pregnant and miscarriages are also reported. Some people feel better and some worse at different times. Early on, damaged tissue can leak stored hormone, causing a temporary burst of overactive-thyroid symptoms called destructive thyrotoxicosis. Outside medicine, people often call a sudden worsening a flare.

  In one study, patients with normal hormone levels still reported a lower quality of life and complaints across the digestive, endocrine, neuropsychiatric and skin systems. After many years, the goiter often shrinks as the gland is destroyed.

  Rare complications are serious. Pericardial and pleural effusions need further medical attention, and myxedema coma is an endocrine emergency. Primary thyroid B-cell lymphoma affects fewer than one in 1000 people. Yet patients with long-standing Hashimoto's face a 67- to 80-fold higher risk of it.

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• 6. Reading the Signs

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  A physician may begin with nothing more than a neck exam. The classic finding is described as a "firm, bumpy, symmetric, painless goiter," though up to 10% of patients instead have an atrophied thyroid. Doctors also weigh other conditions that can look similar, such as Graves' disease and nontoxic nodular goiter.

  Blood tests carry most of the load. About 90% of Hashimoto's patients have raised levels of thyroid peroxidase antibodies, and these can circulate before any symptoms appear. Yet seronegative thyroiditis, without circulating autoantibodies, also exists. In those cases, and when labs look normal but symptoms persist, ultrasound can help. Its key features are described as "echogenicity, heterogeneity, hypervascularity, and presence of small cysts." Ultrasound can also size the gland and reveal nodules.

  The preferred first test of thyroid function is thyroid-stimulating hormone, or TSH. When thyroid hormone falls, the anterior pituitary gland raises TSH to drive the thyroid harder, so the rise is usually a marked jump above the normal range. TSH reacts more sensitively than free T4 to changes in thyroid status. It has quirks, though. Biotin can make the result read falsely low. TSH peaks early in the morning and slumps from late afternoon into early evening, and hypothyroidism is diagnosed more often in samples taken soon after waking.

  Tests for the hormones T4 and T3 add detail. Low levels point to autoimmune damage, while high levels can signal an attack of destructive thyrotoxicosis, and normal levels remain possible. Free T4 is preferred for hypothyroidism because free T3 immunoassays are less reliable at low concentrations. Both immunoassays may overestimate levels, which is why results are read alongside TSH. A rarer method, LC-MSMS, is described as "highly specific, sensitive, precise, and can detect hormones found in low concentrations."

  Diagnosis usually comes between the ages of 30 and 50. Antibody tests tell a different story in older people, with positive results as frequent as 33 percent in women aged 70 or older.

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• 7. Lifelong Treatment

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  There is no cure for Hashimoto's thyroiditis, and no known way to halt the lymphocytes entering the thyroid or to regrow the tissue. Treatment aims at the hormone deficit instead. Options are levothyroxine, liothyronine, or desiccated thyroid extract, which is no longer recommended because evidence for its benefits and risks is lacking. In most cases, treatment continues for life.

  Levothyroxine, a pill identical in molecular structure to the body's own thyroxine, is the standard of care. A sodium salt is added to improve absorption. Its long half-life keeps hormone levels steady, and it has an excellent record for safety and effectiveness. Doses depend on how much thyroid function remains and on lean body mass. They may be lowered for elderly patients or those with certain heart conditions, and raised in pregnancy.

  Monitoring starts frequently. TSH may be checked every 6-8 weeks at first and after each dose change, then yearly once the dose is right. Too much medication brings anxiety, tremor, weight loss, heat sensitivity and diarrhea. More worrying are atrial fibrillation and bone density loss, and long-term over-treatment is linked to higher mortality and dementia. Patients may need several adjustments over the years. Some develop hyperthyroidism even after long treatment, often from an acute attack of destructive thyrotoxicosis, usually followed by hypothyroidism. About 5% of people with subclinical hypothyroidism and chronic autoimmune thyroiditis progress to thyroid failure each year.

  Some patients stay unwell despite treatment. An estimated 10%-15% of those on levothyroxine alone are dissatisfied with persistent symptoms. One hypothesis concerns conversion. Thyroxine is a "storage form" with much less effect, and the body must convert it to the active form, tri-iodothyronine, mainly in the liver, kidney, skeletal muscle and pituitary gland. Conversion needs zinc, selenium, iron and possibly vitamin A. Patients with variants of the DIO2 gene may have variable T3 supply in tissues. The Thr92Ala variant is present in 12-36% of the population.

  Other hypotheses are that TSH is an imperfect marker of the state of the whole body, that autoimmunity itself causes symptoms, or that unrelated physical and psychosocial conditions are responsible. Five meta-analyses and reviews found no clear advantage from adding liothyronine, though the most symptomatic patients might benefit. Reverse T3, often discussed in the lay press, has no evidence to support its use as a guide, as of 2023.

  Selenium lowers thyroid peroxidase antibodies, but there is no evidence it changes remission, progression or quality of life. A gluten-free diet is not established as helpful without coexisting celiac disease.

  Surgery is not the first choice, and uncomplicated Hashimoto's is no reason for thyroidectomy. One well-conducted study followed patients with troublesome symptoms and anti-thyroid peroxidase levels above 1000 IU/ml. After total thyroidectomy, symptoms resolved and the median level fell from 2232 to 152 IU/mL. Complications were higher than expected, with infection at 4.1%, permanent hypoparathyroidism at 4.1% and recurrent laryngeal nerve injury at 5.5%.

  Children can follow a different path. Of those who develop antibodies and hypothyroidism, up to 50% later have normal antibodies and hormone levels. One reported case of true remission involved a 12-year-old girl, whose ultrasound showed the thyroid moving from early inflammation to severe end-stage disease and then back to "almost normal with only minimal features of inflammation."

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• 8. Pregnancy and Immunity

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  Doctors recommend treating hypothyroidism with levothyroxine before conception, to protect the course of pregnancy and the child's development. In IVF, embryo transfer also works better once hypothyroidism is treated. Between 5% and 14% of pregnancies involve antithyroid antibodies, poor thyroid function, or both.

  Antibodies alone carry risk. Thyroid peroxidase antibodies at the start of pregnancy raise the mother's risk of hypothyroidism in the year after delivery. They are also linked to "a 2 to 4-fold increase in the risk of recurrent miscarriages, and 2 to 3-fold increased risk of preterm birth," for reasons that are unclear. Treating women who have antibodies but normal thyroid function with levothyroxine did not significantly change miscarriage or preterm delivery, so decisions are made case by case.

  Untreated low thyroid function is a more clear-cut danger. For the mother, risks include preeclampsia, eclampsia, gestational diabetes, placental abruption and postpartum hemorrhage. For the infant, they include miscarriage, preterm delivery, low birth weight, neonatal respiratory distress, hydrocephalus, hypospadias, fetal death, intensive care admission and neurodevelopmental delays. Liothyronine does not cross the fetal blood-brain barrier, so treatment with T3 alone or with T4 and T3 together is not indicated during pregnancy. The Endocrine Society recommends screening for high-risk pregnant women, while universal screening remains controversial.

  Pregnancy also changes the immune system itself. Hormonal changes and the placenta's immune-modulating molecules produce tolerance of the fetus, with regulatory T cells leading the response. Autoimmunity is suppressed, and thyroid peroxidase and thyroglobulin antibody levels fall. After birth, regulatory T cells drop quickly and immune responses return. In up to 50% of women with thyroid peroxidase antibodies in early pregnancy, autoimmunity worsens as postpartum thyroiditis, which needs different treatment from Hashimoto's. In one population study, two or more births were a risk factor for autoimmune hypothyroidism in premenopausal women, so testing is recommended for any woman who has been pregnant.

  A stranger mechanism may operate as well. Several years after delivery, male cells from the fetus can be found in a mother's blood, thyroid, lung, skin or lymph nodes, a phenomenon called fetal microchimerism. These cells may be activated in the maternal thyroid and trigger or worsen autoimmune disease. In Hashimoto's patients, they were found in the thyroid in significantly higher numbers than in healthy women.

  The disease is not limited to people. It is known to occur in chickens, rats, mice, dogs and marmosets, while Graves' disease does not.

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