Fact-checked by Grok 2 weeks ago

Hashimoto's thyroiditis

Hashimoto's thyroiditis, also known as Hashimoto's disease or autoimmune thyroiditis, is an autoimmune disorder in which the mistakenly attacks the gland, causing and progressive damage to thyroid cells, which often leads to (underactive thyroid). It is the most common cause of hypothyroidism in areas with sufficient iodine intake and affects approximately 5-10% of the global population, with women being 5-10 times more likely to develop it than men, typically between the ages of 30 and 50. First described by Japanese physician in 1912, the condition involves the production of autoantibodies, primarily against (TPO) and (Tg), which destroy thyroid follicular cells through cell- and antibody-mediated immune processes. The exact cause of Hashimoto's thyroiditis remains unclear, but it results from a complex interplay of genetic susceptibility—such as variations in HLA genes and TSH receptor genes—and environmental triggers, including excessive iodine intake, deficiency, viral infections, , or exposure to . Risk factors include a family history of autoimmune diseases, personal history of other autoimmune conditions (e.g., , celiac disease, or ), pregnancy, and certain medications or toxins. Pathophysiologically, the becomes infiltrated by lymphocytes (T-cells and B-cells), leading to and gradual loss of thyroid function, though early stages may present with transient known as Hashitoxicosis due to release from damaged cells. Symptoms of Hashimoto's thyroiditis often develop slowly and may be subtle initially, including , , sensitivity to cold, , dry skin and hair, , joint pain, , and irregular menstrual periods in women; a visible goiter (enlarged ) may also occur. In advanced , more severe effects like slowed , elevated , and can arise if untreated. typically involves blood tests measuring (TSH), free thyroxine (T4), and antibodies (anti-TPO present in over 90% of cases, anti-Tg in 50-80%), along with and sometimes to assess gland structure. biopsy is rarely needed but can rule out , as there is a slightly increased risk of (primary thyroid lymphoma accounts for 0.5-5% of all thyroid malignancies). Treatment primarily focuses on managing with lifelong oral (synthetic thyroid hormone) to normalize hormone levels, with dosage adjusted based on regular TSH monitoring. In cases of significant goiter causing , surgery may be considered, though most patients respond well to medication alone. Emerging research suggests potential benefits from supplementation (50-100 µg/day) in antibody-positive patients or if deficient, but dietary changes like gluten-free diets lack strong evidence and should not replace standard therapy. With proper management, prognosis is excellent, though about 5% of subclinical cases progress to overt annually, and lifelong follow-up is essential to prevent complications such as heart disease, , or in rare untreated instances.

Overview

Definition

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis or autoimmune thyroiditis, is a chronic autoimmune disorder characterized by the immune system's attack on the . In this condition, the body produces antibodies that target thyroid tissue, leading to and progressive damage to the . It is the most common cause of in iodine-sufficient regions, where adequate dietary iodine prevents other forms of thyroid dysfunction from predominating. The disease involves the gradual destruction of thyroid follicles through lymphocytic infiltration, resulting in fibrosis of the gland and eventual reduction in thyroid hormone production. This autoimmune process primarily affects the follicular cells responsible for synthesizing , leading to primary as the gland's function declines over time. Hashimoto's thyroiditis is recognized as the leading etiology of primary in adults, particularly in developed countries with sufficient iodine intake. The onset of Hashimoto's thyroiditis is typically insidious, with many individuals remaining for years before clinical manifests. Early detection often occurs incidentally through routine screening, as the condition progresses slowly without acute symptoms.

Classification

Hashimoto's thyroiditis is classified as a chronic autoimmune thyroid disease, characterized by lymphocytic infiltration of the thyroid gland leading to progressive destruction and , distinguishing it from hyperthyroid conditions like , which involves stimulating autoantibodies, and from non-autoimmune inflammatory disorders such as . It encompasses several clinical subtypes based on presentation and progression. The classic form predominantly manifests as due to gradual damage and . Hashitoxicosis represents an initial hyperthyroid phase in some patients, resulting from the release of preformed during early glandular destruction, which typically transitions to . The fibrous variant features extensive replacing normal tissue within the gland, leading to a firm consistency but typically without invasion of surrounding structures; it is distinct from the rarer Riedel's thyroiditis, which involves extrathyroidal extension and potential compression. Histologically, Hashimoto's thyroiditis is identified by dense lymphocytic infiltration with formation of germinal centers, accompanied by Hürthle cell (oxyphil) metaplasia, where thyroid epithelial cells enlarge and become granular due to mitochondrial accumulation; these features confirm the diagnosis on biopsy and differentiate it from other thyroiditides. It must be differentiated from IgG4-related thyroiditis, which shares fibroinflammatory elements and elevated IgG4 levels but exhibits a distinct systemic autoimmune profile involving multiple organs and responding better to steroids, unlike the thyroid-specific autoimmunity in Hashimoto's.

Epidemiology

Prevalence and demographics

Hashimoto's thyroiditis affects approximately 1-2% of the general worldwide, with estimates rising to 5-10% when considering subclinical cases or antithyroid positivity, particularly in iodine-sufficient regions. In women over 50 years of age, the can reach up to 10%, reflecting the condition's strong with aging and sex. The annual incidence of Hashimoto's thyroiditis is estimated at 0.3-1.5 cases per 1,000 individuals, based on recent epidemiological data. This rate shows significant sex disparity, with the condition occurring 5-10 times more frequently in females than in males, and peaking during reproductive years (ages 30-50). The incidence in women is reported as high as 3.5 per 1,000 per year, compared to 0.8 per 1,000 in men. Age distribution reveals that while the highest incidence occurs between 30 and 50 years, prevalence increases in the elderly due to cumulative exposure and secular trends in autoimmune diseases. Racial and ethnic variations show higher rates among Caucasians compared to populations of descent, where prevalence is notably lower; the condition is also rare among Pacific Islanders.

Geographic and temporal trends

Hashimoto's thyroiditis exhibits notable geographic variations in prevalence, with higher rates observed in iodine-sufficient regions such as and compared to iodine-deficient areas. A estimated the global prevalence at 7.5% (95% CI: 5.7–9.6%), but regional differences are pronounced: and around 8%, at 11%, and at 14.2% (95% CI: 2.5–32.9%), influenced by varying iodine levels. In iodine-replete populations, the spectrum of thyroid abnormalities, including autoimmune thyroiditis, predominates, whereas iodine deficiency correlates with lower autoimmune but higher goiter prevalence. Post-iodization programs in previously deficient regions have been associated with increased incidence of Hashimoto's thyroiditis. For instance, in , mandatory iodine fortification of salt led to a 50% rise in incidence among those with moderate initial iodine intake, linked to heightened autoimmune responses. Similarly, in , , following iodized bread introduction, incidence tripled, with over half of cases showing antithyroid antibodies consistent with autoimmune . A geographic hotspot exists in the of the , where historical iodine deficiency correction through iodization contributed to elevated autoimmune rates, as documented in mid-20th-century studies. Secular trends indicate a rising diagnosis rate since the , attributed to improved screening, diagnostic tools, and environmental shifts including iodization. In , female incidence rates escalated from 6.5 per 100,000 in 1935–1944 to 67.0 per 100,000 in 1955–1964, a pattern continuing into recent decades. A 2025 scoping review confirms global prevalence stabilization at 5–10%, with some areas exceeding 20%, reflecting ongoing temporal increases in awareness and iodine exposure. Migration to iodine-rich environments also elevates risk; South Asian immigrants to show higher odds, likely due to adaptation from lower-iodine native diets.90041-8/fulltext)

Etiology

Genetic factors

Hashimoto's thyroiditis (HT) exhibits a polygenic mode of , where multiple genetic variants contribute to disease susceptibility rather than a single Mendelian . Familial clustering is observed in approximately 20-30% of cases, with first-degree relatives of affected individuals facing a significantly elevated , estimated at 4.5 to 32 times higher than the general population. Twin studies further underscore the genetic component, estimating at 65-70%, indicating that genetic factors explain a substantial portion of the variance in disease occurrence. Among the key genetic associations, genes within the (HLA) complex on 6p21 play a prominent role in immune recognition and . Specific alleles such as HLA-DR3, , and HLA-DR5 have been consistently linked to increased HT risk, with relative risks ranging from 2- to 7-fold depending on ethnicity and disease subtype (e.g., goitrous versus atrophic HT). These associations highlight how variations in HLA molecules may enhance the presentation of thyroid autoantigens to T cells, promoting autoimmune responses. Polymorphisms in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, located on 2q33, also contribute to HT susceptibility by impairing T-cell regulation. The CT60 variant in the 3' (3'UTR) of CTLA-4 reduces expression levels of the inhibitory protein, leading to diminished negative feedback on T-cell activation and heightened . This polymorphism has been associated with both HT and , underscoring CTLA-4's role in broader autoimmune predisposition. The non-receptor type 22 (PTPN22) on 1p13 harbors the R620W (rs2476601), which disrupts negative regulation of T-cell signaling and is implicated in multiple autoimmune conditions, including HT. This variant increases susceptibility by enhancing autoreactive T-cell survival and activity, with studies confirming its association in diverse populations. Additional immune-related genes, such as the receptor (TSHR), forkhead box P3 (), and interleukin-2 receptor alpha (), have been identified through candidate gene studies as modulators of HT risk. Genome-wide association studies (GWAS) have further expanded this landscape, identifying over 10 susceptibility loci as of 2025, including novel variants near immune regulatory genes that collectively account for a portion of the polygenic risk. These findings emphasize the interplay of multiple low-penetrance alleles in HT etiology.

Environmental factors

Excessive iodine intake has been implicated as a trigger for Hashimoto's thyroiditis in genetically susceptible individuals by promoting and enhancing thyroid autoimmunity. High iodine levels can lead to the generation of within cells, exacerbating immune-mediated damage. Studies indicate that populations with iodized programs or high consumption show increased prevalence of autoantibodies when intake surpasses recommended levels. Certain medications can induce or worsen Hashimoto's thyroiditis through direct effects on thyroid function or immune activation. Interferon-alpha therapy, used in viral hepatitis treatment, is associated with the development of thyroid autoantibodies and overt thyroiditis in up to 15% of patients. Lithium, commonly prescribed for bipolar disorder, increases the risk of hypothyroidism and autoimmunity by interfering with iodine uptake and hormone release. Amiodarone, an antiarrhythmic drug, induces thyroiditis due to its high iodine content and propensity to cause destructive thyroid inflammation. Infections may trigger Hashimoto's thyroiditis via molecular mimicry, where microbial antigens resemble thyroid proteins, leading to cross-reactive immune responses. Epstein-Barr virus (EBV) infection has been linked to higher seropositivity for thyroid autoantibodies, potentially initiating through latent viral persistence in B cells. Similarly, , a bacterial , shares epitopes with , promoting production against self-antigens. Sex hormones, particularly , contribute to the female predominance in Hashimoto's thyroiditis, with women affected 7-10 times more often than men. enhances B-cell activity and antibody production, amplifying autoimmune responses in the thyroid. This hormonal influence is evident in the lower female-to-male ratio in prepubertal cases, suggesting puberty-related surges as a key modulator. Pregnancy and the postpartum period represent a high-risk window for the onset of Hashimoto's thyroiditis due to immune system shifts that reverse the relative immunosuppression of gestation. Postpartum immune rebound can precipitate thyroid autoantibody production, leading to thyroiditis in 30-50% of women with preexisting antibodies. Hormonal changes, including elevated human chorionic gonadotropin and estrogen fluctuations, further disrupt thyroid homeostasis during this time. Recent 2025 research highlights dysregulated signaling as an emerging environmental factor in Hashimoto's thyroiditis, with lower serum levels and altered expression in affected patients reducing . A in a Korean cohort demonstrated that correlates with upregulated inflammatory pathways in tissue, potentially exacerbating . Concurrently, gut and (SIBO) have been associated with increased risk, as alters gut motility and microbiota composition, fostering proinflammatory states. Data from the Endocrine Society's ENDO 2025 meeting showed that individuals with history have a higher SIBO , which may perpetuate through leaky gut mechanisms. Chronic stress and smoking exhibit moderate associations with Hashimoto's thyroiditis via immune modulation. Psychological stress activates the hypothalamic-pituitary-adrenal axis, promoting Th2-skewed responses that favor autoantibody production. Smoking, conversely, is linked to higher thyroid autoantibody levels and increased hypothyroidism risk, possibly through nicotine-induced oxidative stress and immune dysregulation.

Pathophysiology

Autoimmune mechanisms

Hashimoto's thyroiditis is characterized by a loss of immune self-tolerance, involving breakdowns in both central and peripheral mechanisms that normally prevent the activation of autoreactive T-cells against thyroid antigens such as and . This failure allows the escape and expansion of these self-reactive lymphocytes, initiating a chronic autoimmune response targeted at the gland. Genetic variations in immune-related genes, including those in the HLA complex, contribute to this susceptibility by altering and T-cell recognition. The autoimmune process is predominantly T-cell mediated, with CD4+ helper T-cells—particularly the Th1 and Th17 subsets—infiltrating the and orchestrating through the release of key cytokines like interferon-gamma (IFN-γ) from Th1 cells and interleukin-17 (IL-17) from Th17 cells. These cytokines amplify the by activating macrophages and promoting further T-cell recruitment, while + cytotoxic T-cells directly contribute to thyrocyte . Complementing this cellular immunity, B-cells differentiate into antibody-secreting plasma cells, producing anti-thyroid peroxidase (anti-TPO) antibodies in over 90% of patients and anti-thyroglobulin (anti-Tg) antibodies in 50-80% of cases, which can enhance tissue damage via antibody-dependent mechanisms. Cytokine dysregulation further sustains the inflammatory milieu, with elevated interleukin-6 (IL-6) and tumor factor-alpha (TNF-α) levels driving chronic activation of immune cells and endothelial changes that facilitate leukocyte infiltration. This pro-inflammatory cascade induces in thyroid follicular cells primarily through the Fas-Fas (Fas-FasL) pathway, where FasL expressed on activated T-cells binds to Fas receptors on thyrocytes, triggering caspase-mediated . Regulatory T-cell (Treg) deficiency plays a critical role in perpetuating , as these FOXP3-expressing cells, which normally suppress autoreactive T- and B-cell responses, exhibit functional impairments that fail to restore in .

In , the exhibits characteristic histological alterations driven by chronic inflammation. The hallmark feature is a dense lymphocytic infiltration involving the perivascular and interstitial spaces of the , composed predominantly of small mature lymphocytes and plasma cells that form well-developed germinal centers, mimicking lymphoid tissue. This infiltration disrupts normal architecture and is accompanied by oncocytic of follicular epithelial cells, known as Hürthle cells, which display abundant granular cytoplasm and scalloped colloid borders. Follicular atrophy is a prominent structural change, marked by shrunken thyroid follicles with markedly reduced or absent colloid and disrupted follicular integrity due to the surrounding inflammatory infiltrate. As the disease advances, progressive interstitial fibrosis develops, characterized by collagen deposition and scarring that replaces functional thyroid tissue, leading to initial glandular enlargement (diffuse goiter) followed by progressive atrophy and nodularity. The pathological process unfolds in distinct stages: an early hyperplastic phase with follicular enlargement and increased , a destructive phase dominated by intense lymphocytic invasion and follicular disruption, and an end-stage of extensive with near-total loss of functional , culminating in . In longstanding cases, these chronic changes confer an elevated risk of , particularly to primary , with relative risks reported as high as 40- to 80-fold compared to the general population, though the absolute incidence remains low at approximately 0.5%.

Clinical presentation

Signs

Hashimoto's thyroiditis often manifests with observable physical signs related to thyroid enlargement and the effects of resultant hypothyroidism. A prominent feature is the presence of a goiter, an enlargement of the thyroid gland that feels firm and rubbery on palpation and is typically nontender. This goiter arises from chronic lymphocytic infiltration and fibrosis within the gland, distinguishing it from more acute inflammatory conditions. Hypothyroidism secondary to the disease contributes to several characteristic physical findings detectable on examination. , or a slowed , is common due to reduced metabolic demands and can be assessed via or measurement. Delayed relaxation phase of deep tendon reflexes, known as the Woltman sign, occurs in a substantial proportion of cases and is elicited during neurological testing of reflexes such as the ankle jerk. changes include dry, rough, and scaly texture, often appearing pale or cool to the touch, while may exhibit thinning or loss, particularly on the scalp and outer eyebrows. Periorbital and a puffy facial appearance, indicative of myxedematous changes, further contribute to the hypothyroid observed in advanced cases. In rare instances, particularly with autoimmune overlap, or proptosis may occur, resembling features of , affecting approximately 6% of patients. Unlike , Hashimoto's thyroiditis lacks signs of acute , such as fever or thyroid tenderness, which helps differentiate it clinically.

Symptoms

Hashimoto's thyroiditis often presents with symptoms stemming from progressive due to autoimmune destruction of the , though some patients may initially experience a transient hyperthyroid phase known as hashitoxicosis. In the hypothyroid phase, patients commonly report and , which affect 68% to 83% of individuals with , the end-stage condition resulting from this disease. This profound tiredness can significantly impair daily activities and . Metabolic slowdown contributes to other frequent complaints, including unexplained in 24% to 59% of patients, intolerance to cold temperatures, and . These symptoms arise from reduced levels affecting energy expenditure, , and gastrointestinal motility. Women, who comprise the majority of cases, may also experience menstrual irregularities such as heavy or prolonged periods, as well as or difficulties conceiving due to ovulatory dysfunction. Psychological and cognitive effects are prominent, with reported in many patients and cognitive slowing—often described as "brain fog"—leading to difficulties with , concentration, and mental clarity. Nonspecific musculoskeletal complaints, including myalgias (muscle aches) and arthralgias ( pains), further contribute to discomfort and reduced mobility. In a minority of cases, an initial destructive phase releases stored thyroid hormones, causing hashitoxicosis with transient symptoms such as , anxiety, and , typically lasting weeks to months before develops.

Diagnosis

Laboratory tests

of Hashimoto's thyroiditis primarily relies on laboratory evaluation of thyroid function and autoimmunity markers. (TSH) levels are typically elevated, with subclinical defined by TSH between 4.5 and 10 mIU/L alongside normal free thyroxine (T4), while overt features TSH greater than 10 mIU/L with low free T4. Free T4 and (T3) levels are decreased in overt disease, reflecting impaired thyroid production. Antithyroid antibody testing confirms the autoimmune etiology, with anti-thyroid peroxidase (anti-TPO) antibodies present in over 90% of cases and anti-thyroglobulin (anti-TG) antibodies detected in 50-80% of patients. These antibodies are highly specific for Hashimoto's thyroiditis when combined with abnormal . Additional laboratory findings associated with include on , observed in 30-40% of cases due to reduced production, and characterized by elevated total cholesterol, (LDL), and triglycerides. These abnormalities often improve with thyroid hormone replacement. Recent advancements include the identification of metabolic biomarkers for early detection using , as demonstrated in a 2025 case-control analyzing profiles in euthyroid patients with Hashimoto's thyroiditis. This approach highlights potential shifts in amino acid and lipid metabolism as predictive indicators before overt dysfunction emerges. To exclude secondary causes of , such as pituitary disorders, prolactin levels should be assessed, as they may be elevated in primary due to thyrotropin-releasing hormone effects; (MRI) of the pituitary is warranted if atypical features like low TSH or marked hyperprolactinemia suggest central .

Imaging and other procedures

Ultrasound is the primary imaging modality for evaluating the in suspected Hashimoto's thyroiditis, providing detailed assessment of glandular structure and . The typical appearance includes a diffusely hypoechoic and heterogeneous echotexture, reflecting lymphocytic infiltration and , which can be observed even in early stages before significant develops. Increased intrathyroidal , detected via color Doppler, is often present due to inflammatory hyperemia, though less intense than in . Pseudonodules, which are areas of relative hyperechogenicity amid the hypoechoic , may mimic true nodules but represent uneven rather than discrete lesions; these are common in advanced and do not typically require intervention unless suspicious features suggest . Nuclear medicine scintigraphy, using technetium-99m pertechnetate or iodine-123, assesses thyroid function and can reveal characteristic patterns in Hashimoto's thyroiditis, though it is less commonly used than ultrasound due to radiation exposure. In early active phases, scans may show diffusely increased or uneven tracer uptake, mimicking hyperthyroid conditions like . As the disease progresses to , uptake becomes reduced and patchy, with areas of normal or low function creating an irregular, multinodular pattern often described as uneven or "Swiss cheese"-like due to interspersed hypo- and normofunctioning regions. This modality helps differentiate Hashimoto's from other causes of goiter but is typically reserved for cases where functional assessment is needed beyond ultrasound findings. Fine-needle aspiration (FNA) is rarely indicated in uncomplicated Hashimoto's thyroiditis, as the is primarily clinical and serological, but it may be performed under guidance for suspicious nodules to rule out coexisting , given the slightly increased risk of and in patients with longstanding Hashimoto's thyroiditis. Cytological examination typically reveals a lymphocytic infiltrate involving epithelial cell clusters, with mixed follicular and Hürthle cells and scant , consistent with autoimmune thyroiditis. These findings often classify as Bethesda III (atypia of undetermined significance) or benign, but suspicious or malignant results warrant further evaluation, particularly given the increased risk in longstanding disease. Magnetic resonance imaging (MRI) and are not routine for Hashimoto's thyroiditis but are employed when compressive symptoms from a large goiter are present or to assess for complications like . On , the thyroid exhibits high and inhomogeneous signal intensity on T2-weighted images due to and , with homogeneous enhancement relative to adjacent muscle; diffusion-weighted imaging may aid in distinguishing it from other thyroiditides. demonstrates low-attenuation, inhomogeneous with possible glandular enlargement and lobulated margins, useful for evaluating extrinsic on trachea or in massive goiters. In cases of suspected , a known with Hashimoto's, these modalities delineate mass extent, nodal involvement, and invasion, showing hypodense lesions with variable enhancement.

Management

Thyroid hormone replacement

The primary treatment for hypothyroidism resulting from Hashimoto's thyroiditis is lifelong replacement therapy with (L-T4), a synthetic form of thyroxine (T4), which is available under brand names such as Synthroid, Levoxyl, and Unithroid. The standard starting dose is approximately 1.6 mcg/kg of ideal body weight or lean body mass per day for most adults, with adjustments made every 4-6 weeks based on (TSH) levels until euthyroidism is achieved, typically targeting a TSH within the . This approach restores normal thyroid hormone levels, alleviating symptoms and preventing complications associated with untreated . For patients who experience persistent symptoms despite normalized TSH on monotherapy, combination therapy with and (L-T3, synthetic ) may be considered, particularly in cases of suboptimal symptom relief. A large 2025 observational study of over 1.26 million patients with found that L-T4 plus L-T3 therapy was associated with a reduced risk of and all-cause mortality compared to L-T4 alone, suggesting potential benefits in mitigating long-term neurological risks. However, this approach remains controversial due to limited evidence and the need for careful dosing to avoid cardiac strain from T3's shorter . Dosing adjustments are essential for specific populations to minimize risks. In elderly patients or those with cardiac conditions such as ischemic heart disease, a lower starting dose of 12.5-50 mcg/day is recommended to prevent exacerbation of arrhythmias or , with gradual . During , levothyroxine requirements often increase by 20-50% due to elevated demands, necessitating prompt dose escalation upon confirmation of and close monitoring. Over-replacement with can lead to iatrogenic , manifesting as symptoms including , arrhythmias, and accelerated bone loss, particularly in postmenopausal women where it may contribute to . Adherence to therapy is crucial for maintaining euthyroidism, but variability between and brand-name formulations can pose challenges. Switching between different products has been linked to fluctuations in serum TSH levels in up to 44% of patients, potentially leading to suboptimal control and reduced adherence due to perceived instability in symptom management. Some studies indicate that consistent use of a single brand, such as Synthroid, may improve TSH target achievement and long-term adherence compared to frequent switches. Patients are advised to discuss formulation preferences with their healthcare provider to optimize therapy consistency.

Monitoring and adjunctive therapies

Once thyroid hormone replacement therapy has been initiated, regular of (TSH) levels is essential to ensure euthyroidism and adjust dosing as needed. Guidelines recommend checking TSH every 6-8 weeks during the initial stabilization phase until levels are within the target range, typically 0.5-2.5 mIU/L for most patients on replacement, after which annual suffices unless symptoms or life changes warrant more frequent assessment. Some patients with Hashimoto's thyroiditis experience persistent symptoms such as , , or cognitive fog despite normalized TSH and free thyroxine levels, prompting evaluation for alternative explanations. The low tissue (T3) hypothesis posits that inadequate conversion of thyroxine (T4) to T3 in peripheral tissues may contribute to these complaints, though evidence remains limited and routine T3 measurement is not standard. Comprehensive assessment for comorbidities, including , , or sleep disorders, is crucial to identify and address contributing factors beyond thyroid dysfunction. Adjunctive therapies may support management in select cases. Selenium supplementation at 200 mcg daily has been shown to mildly reduce antibody levels in patients with Hashimoto's thyroiditis, potentially slowing autoimmune progression, though it does not replace . For individuals with concomitant celiac disease, which overlaps with Hashimoto's in up to 5-10% of cases, a can improve gastrointestinal symptoms and may indirectly benefit thyroid autoimmunity by reducing inflammation. Surgical intervention, such as total , is reserved for complications like a large goiter causing compressive symptoms (e.g., or dyspnea) or suspicion of , as Hashimoto's increases risk. Postoperatively, lifelong replacement is required, with close monitoring to prevent recurrence. Psychosocial support plays a key role in addressing associated challenges, including and cognitive impairments, which affect up to 40% of patients. Interventions such as cognitive-behavioral therapy or support groups can alleviate emotional distress and improve , particularly when symptoms persist despite biochemical control.

Emerging treatments

Recent research into emerging treatments for Hashimoto's thyroiditis emphasizes immunomodulatory approaches to halt autoimmune destruction of the thyroid gland, moving beyond symptomatic hormone replacement. These investigational therapies aim to reduce autoantibody production, modulate immune responses, and potentially restore thyroid function, with several showing promise in preclinical models, small clinical trials, and early-phase studies as of 2025. Immunomodulators such as rituximab, which targets on B cells to deplete antibody-producing cells, have demonstrated temporary reductions in anti-thyroid (TPO) antibodies and improved thyroid function in limited case series and pilot studies involving patients with autoimmune . For instance, in a small of patients with refractory Hashimoto's, rituximab administration led to a 20-40% decrease in TPO antibody levels within 6-12 months, though antibody titers often rebounded after cessation, highlighting the need for larger randomized trials to assess long-term efficacy and safety. Other B-cell depleting agents are under exploration, but rituximab remains the most studied in this context. Stem cell therapies, particularly those using mesenchymal stem cells (MSCs) derived from or , are gaining attention for their immunomodulatory properties, which may suppress autoreactive T cells and promote regulatory T-cell expansion in Hashimoto's models. A 2025 review highlights that MSCs can reduce thyroid inflammation and antibody levels in animal studies of autoimmune thyroiditis, with preliminary human trials reporting stabilized hormone levels and decreased autoantibody titers in 10-20 patients after intravenous , though larger phase II trials are required to confirm these effects. These cells also show potential in regenerating tissue, addressing both immune dysregulation and glandular damage. Vitamin D supplementation addresses common deficiencies in Hashimoto's patients that impair by disrupting regulatory T-cell function and enhancing Th17-mediated . A 2025 systematic review indicates that daily doses of 2000-4000 in vitamin D-deficient individuals (<20 ng/mL) can lower TPO levels by 15-30% and reduce TSH concentrations, particularly in euthyroid patients with subclinical , thereby potentially slowing progression to overt . However, benefits are less pronounced in advanced cases or those with normal baseline levels, underscoring the importance of personalized dosing based on serum 25(OH)D measurements. Microbiome interventions, including , target gut and (SIBO), which exacerbate in Hashimoto's by promoting and . Data from the 2025 meeting reveal that increases SIBO prevalence to 33% compared to 15% in controls, with therapy reducing this risk by improving gut motility; adjunctive (e.g., multi-strain formulations with and ) further stabilize levels and alleviate in hypothyroid patients by modulating the gut-thyroid axis. These approaches may prevent fluctuations, though optimal strains and durations require further validation. Anti-cytokine drugs focus on blocking pro-inflammatory pathways implicated in thyroid autoimmunity, such as IL-17/IL-23 and TNF-α signaling, which drive Th17 cell activation and tissue damage. A 2025 therapeutic landscape analysis notes that inhibitors like (TNF-α blocker) and emerging oral agents such as isomyosamine (MYMD-1, a selective TNF-α inhibitor) have entered phase II planning after promising phase I data, showing reduced inflammatory markers and antibody levels in autoimmune models, with potential to induce remission in early Hashimoto's. , targeting IL-6, has similarly demonstrated preliminary benefits in lowering autoantibodies in small cohorts. While IL-17/IL-23 antagonists (e.g., ) are established in other autoimmunities, their application in Hashimoto's remains investigational, supported by genetic and profiling studies linking these pathways to severity. Gene therapy holds early-stage potential by editing susceptibility loci like PTPN22 and CTLA-4, which impair T-cell regulation and increase risk in Hashimoto's. Preclinical research as of explores CRISPR-based corrections of these polymorphisms to enhance function and reduce autoreactive responses, though no human trials have been reported, positioning this as a long-term frontier contingent on advances in delivery and safety. Overall, these emerging strategies underscore a shift toward disease-modifying therapies, with ongoing trials expected to clarify their roles in clinical practice by the late 2020s.

Prognosis

Long-term outcomes

In patients diagnosed with overt due to Hashimoto's thyroiditis, thyroid hormone replacement therapy is typically required on a lifelong basis, as the autoimmune destruction of tissue is progressive and irreversible in the majority of cases. Studies indicate that approximately 90% of such patients will need ongoing supplementation to maintain euthyroidism, with only a small fraction achieving sustained remission without . Antithyroid (anti-TPO) antibodies, a hallmark of the disease, persist in 70-80% of treated patients over the long term, though their levels often decline significantly with therapy. In one retrospective analysis of 38 patients followed for a mean of 50 months, anti-TPO levels decreased by 70% after five years of treatment, from a mean initial value of 4779 /mL to 1456 /mL, reflecting reduced antigenic stimulation of the . However, to below detectable levels occurred in only about 16% of cases, underscoring the chronic autoimmune nature of the condition. Spontaneous remission is rare in Hashimoto's thyroiditis, occurring in less than 5% of patients with overt hypothyroidism, as the underlying autoimmunity rarely resolves without intervention. Remission rates are somewhat higher in early subclinical stages, where up to 30% of cases may normalize over three years and 60% over five years, particularly if antibody titers are low and thyroid function is only mildly impaired. With appropriate thyroid hormone replacement, quality of life generally improves substantially, alleviating symptoms such as fatigue, weight gain, and cognitive fog in most patients. Nonetheless, approximately 20% report residual symptoms, including chronic fatigue and mood disturbances, even when achieving biochemical euthyroidism, potentially linked to persistent autoimmunity or other factors. A 2025 study from the (UTMB) highlighted the potential benefits of (levothyroxine plus liothyronine) in , including cases due to Hashimoto's thyroiditis, showing it was associated with reduced risks of (approximately 1.4-fold lower) and mortality (over 2-fold lower) compared to monotherapy, even in patients with normal TSH levels.

Complications and comorbidities

Untreated or longstanding Hashimoto's thyroiditis, which often leads to , is associated with increased cardiovascular risks, primarily through accelerated driven by and . In overt , approximately 90% of patients exhibit , characterized by elevated total and low-density lipoprotein (LDL-C), contributing to plaque formation in arteries. Subclinical similarly elevates LDL-C levels, further promoting , while reduced production impairs vascular relaxation. Additionally, induces diastolic due to heightened systemic , with prevalence rates up to 41.3% in subclinical cases compared to 25.6% in euthyroid individuals. These factors collectively heighten the overall burden in affected patients. Hashimoto's thyroiditis frequently overlaps with other autoimmune conditions in autoimmune polyglandular syndrome type 2 (APS-2), also known as Schmidt syndrome, which involves combinations of , mellitus, and . The triad of these conditions occurs in about 11.6% of APS-2 cases. Hashimoto's thyroiditis commonly coexists with , with present in up to 30% of patients due to shared genetic and immunological etiologies. Hashimoto's thyroiditis is a component of autoimmune polyglandular syndrome type 2 (APS-2), which also includes and/or , with occurring in conjunction with in a subset of cases. This polyglandular involvement underscores the need for screening for concurrent endocrinopathies. Patients with longstanding Hashimoto's thyroiditis face an elevated risk of malignancy, particularly primary , with an incidence of approximately 0.5-0.6% among those with the condition, representing a 60-fold increase compared to the general . This risk arises from chronic lymphocytic infiltration in the , potentially progressing to over 20-30 years. Furthermore, the frequent association with autoimmune (with antibodies present in 10-40% of cases) heightens the risk of gastric cancer, with an annual incidence of 0.5% in affected individuals, often linked to and . Endoscopic surveillance is recommended every 3-5 years for those with . Recent 2025 research highlights emerging links between Hashimoto's thyroiditis and gut , particularly (SIBO), which elevates infection risk through bacterial translocation and impaired gut barrier function. According to findings presented at ENDO 2025, individuals with autoimmune like Hashimoto's have a 2.4-fold higher SIBO (33% vs. 15% in controls), attributable to reduced gut motility from . Thyroid hormone replacement may mitigate this risk. A concurrent Nature study on metabolomic profiles in Hashimoto's patients revealed antibody-specific alterations: thyroid peroxidase antibody (TPOAb) positivity correlates with elevated bile acids and glycerophospholipids, associating with , higher LDL-C, and fatty liver severity, while thyroglobulin antibody (TgAb) positivity shows suppressed potentially protective against . These changes link Hashimoto's to broader metabolic disruptions, including increased and susceptibility. Hypothyroidism from Hashimoto's thyroiditis induces low bone turnover by suppressing both osteoblast-mediated formation and osteoclast-mediated resorption, potentially delaying bone remodeling and mineralization, though direct evidence for heightened osteoporosis risk remains limited. This imbalance can contribute to reduced bone quality over time, particularly in untreated cases, warranting bone density monitoring per general osteoporosis guidelines. Hashimoto's thyroiditis impairs female fertility and increases miscarriage risk primarily through ovulatory dysfunction, as regulate the hypothalamic-pituitary-ovarian axis essential for secretion and follicle maturation. Untreated disrupts in up to 25% of cases, leading to or irregular cycles. Antithyroid antibodies, such as TPOAb, further compromise quality by crossing the blood-follicle barrier, elevating early loss rates by 2-4 fold in subclinical cases. Thyroid optimization can improve outcomes, though detailed management is addressed elsewhere.

Special considerations

Pregnancy

Women with Hashimoto's thyroiditis planning should optimize function preconceptionally by targeting a TSH level below 2.5 mIU/L to enhance and reduce risks of early gestational . Recent indicates that achieving even lower preconception TSH thresholds—approximately 30-50% below 2.5 mIU/L, such as 1.25-1.75 mIU/L—may better maintain euthyroidism in early for those on . During pregnancy, women who are thyroid peroxidase antibody (anti-TPO)-positive have an increased risk of developing , with progression rates reported in 10-20% of cases in some studies, necessitating close monitoring of thyroid function. For those with preexisting , levothyroxine requirements typically rise by 25-50% due to increased maternal and fetal demands, and an immediate dose adjustment upon pregnancy confirmation is recommended to prevent complications. Anti-TPO antibodies are associated with adverse fetal outcomes, including a roughly two-fold increased risk of compared to antibody-negative women, as well as higher rates of . In the , women with Hashimoto's thyroiditis are at risk for disease exacerbation and , with studies showing dysfunction in up to 40% of cases, often requiring increased dosing. As of 2025, emerging insights highlight how pregnancy-induced immune shifts and fetal —where fetal cells persist in maternal tissues—may contribute to the persistence or worsening of maternal in Hashimoto's thyroiditis. is safe during , with minimal transfer to and no adverse effects on infants; however, of the infant's TSH levels is advised if maternal doses are high.

Pediatrics and other populations

Hashimoto's thyroiditis is less common in pediatric populations, with a prevalence of approximately 1-2% in children and adolescents, compared to higher rates in adults. In children, the condition often presents more aggressively than in adults, with symptoms including goiter, fatigue, weight gain, and notably, growth retardation due to impaired linear growth from hypothyroidism. Severe, untreated cases may rarely lead to precocious puberty as part of van Wyk-Grumbach syndrome, characterized by ovarian cysts and menstrual bleeding in girls, alongside delayed bone age. Children with the disease also face a higher risk of comorbid autoimmune conditions, such as type 1 diabetes mellitus and celiac disease, necessitating vigilant monitoring for autoimmune clustering. Prevalence and risks may vary by ethnicity, with higher rates reported in Caucasian populations. Prognostically, pediatric cases show a higher potential for remission compared to adults, with rates ranging from 16% to 53% during long-term follow-up, often influenced by early levothyroxine therapy and antibody titer reductions. In elderly populations, Hashimoto's thyroiditis often manifests as subclinical , which has a of about 10-15% in those over 65 years, with autoimmune causes like Hashimoto's being common. This form is associated with elevated cardiovascular risks, including increased incidence of coronary heart disease and , particularly when (TSH) levels exceed 10 mIU/L. in older adults requires cautious thyroid hormone replacement, starting at lower doses of 25-50 μg daily to avoid cardiac complications like arrhythmias, with gradual titration based on TSH monitoring. Among other human subpopulations, transplant recipients exhibit unique dynamics due to ; Hashimoto's thyroiditis can emerge or recur post-transplantation, potentially increasing risks of graft rejection, as seen in renal transplant patients where thyroid correlates with higher failure rates.

History

Discovery and early research

Hashimoto's thyroiditis was first identified in 1912 by Japanese surgeon , who described the condition as "struma lymphomatosa" based on pathological examinations of glands from four women undergoing for goiter. He noted distinctive features including lymphoid infiltration, , and the absence of , distinguishing it from other disorders, though his findings received limited attention outside at the time. The condition gained broader recognition in Western medicine during , when pathologists began to differentiate it more clearly from other forms of . In 1931, American physicians Alvis Graham and E. Perry McCullagh published a seminal paper using "Hashimoto" in the title for the first time, emphasizing the chronic and as a unique entity rather than a variant of Riedel's thyroiditis or simple goiter. This work helped establish struma lymphomatosa as a distinct pathological process, prompting further histopathological studies that highlighted its progressive nature. A pivotal advancement came in 1956, when researchers Noel R. Rose and Ernst Witebsky demonstrated the autoimmune basis of the disease through experiments in rabbits. They induced thyroid-specific antibodies and histological changes resembling human Hashimoto's thyroiditis by immunizing animals with autologous thyroid extracts, providing the first experimental evidence of organ-specific autoimmunity. Concurrently, in 1956-1957, Ivan Roitt, Deborah Doniach, and Roby Hudson detected circulating anti-thyroid antibodies (initially against ) in the sera of patients with Hashimoto's thyroiditis, confirming the role of immune-mediated destruction in the disease's pathogenesis. Prior to the widespread availability of synthetic hormones, initial management of associated with Hashimoto's thyroiditis relied on desiccated thyroid extracts derived from animal glands, a practice dating back to the late but commonly used through the early . These extracts provided thyroid replacement but varied in potency and purity; the introduction of synthetic in the mid-1950s offered a more standardized alternative, marking a shift toward precise dosing for affected patients.

Key historical developments

In the , significant advancements in understanding the genetic basis of Hashimoto's thyroiditis emerged through the identification of associations with (HLA) alleles, establishing a clear link to . Pioneering work by Grumet et al. in 1973 reported an between HLA-B8 and autoimmune thyroid diseases, including Hashimoto's thyroiditis, marking one of the earliest demonstrations of genetic susceptibility in this condition. Subsequent studies throughout the decade, such as those by Farid et al. in 1976, confirmed HLA-DR associations, particularly 3 and 5, which increased by 2- to 7-fold in affected populations, laying the foundation for recognizing the disease's polygenic inheritance. The 1980s brought breakthroughs in identifying key autoantigens, with the cloning of (TPO) as the primary target in Hashimoto's thyroiditis. In 1987, Libert et al. successfully cloned and sequenced the complete human TPO cDNA, revealing its role in thyroid hormone synthesis and as the dominant antigen for autoantibodies in over 90% of patients. This discovery enabled the development of more accurate and standardized assays, such as enzyme-linked immunosorbent assays (ELISAs) for anti-TPO antibodies, which improved diagnostic precision and monitoring of disease progression compared to earlier thyroglobulin-focused tests. During the 1990s, linkage studies implicated additional immune-regulatory genes, notably CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), in Hashimoto's thyroiditis susceptibility. In 1997, Donner et al. first reported an association between a CTLA-4 codon 17 polymorphism and the disease in a cohort, showing increased prevalence of the GG (odds ratio approximately 1.5). CTLA-4 encodes a protein that inhibits T-cell activation and thus modulates . These findings underscored the involvement of T-cell checkpoint pathways in disease pathogenesis. The 2000s saw genome-wide association studies (GWAS) solidify the polygenic nature of Hashimoto's thyroiditis, identifying multiple susceptibility loci beyond HLA. A landmark 2009 GWAS by Tomer et al. confirmed associations at HLA-DRβ1, CTLA-4, and FOXP3, while revealing novel loci like FCRL3 and TSHR, collectively accounting for about 20-30% of heritability and emphasizing shared genetics with other autoimmune disorders. Concurrently, clinical trials explored adjunctive therapies, including selenium supplementation; a 2002 randomized controlled trial by Gärtner et al. demonstrated that 200 μg daily selenomethionine reduced anti-TPO antibody levels by up to 40% over 3 months in selenium-deficient patients, suggesting an antioxidant role in mitigating oxidative stress in thyroid tissue. From the 2010s to 2025, research expanded into environmental and immunomodulatory factors, with studies implicating the gut microbiome and in disease modulation. Investigations in the mid-2010s, such as a 2018 review by Virili et al., linked —characterized by reduced Firmicutes/Bacteroidetes ratios—to increased and systemic in Hashimoto's patients, potentially exacerbating inflammation through molecular mimicry. Similarly, meta-analyses from 2014 onward, including Kivity et al., established (levels <20 ng/mL) as a risk factor, with odds ratios of 2.1 for autoantibody positivity, prompting trials showing that 4,000 daily supplementation lowered anti-TPO titers by 20-30% in deficient individuals. In parallel, experimental and biologics trials advanced; preclinical studies from 2017 demonstrated regeneration and reduced infiltration in murine models.

In other animals

Occurrence in veterinary medicine

Hashimoto's thyroiditis, known in as autoimmune or lymphocytic , primarily affects and leads to primary in the majority of cases. The condition has an annual prevalence of approximately 0.2-0.3% in the population, with an annual incidence of about 0.04% (one case per 2,500 ). Over 90-95% of canine cases are attributed to this immune-mediated destruction of the gland. It is rare in other species, such as cats and horses, where true is infrequently documented and autoimmune is not commonly recognized. In dogs, clinical presentation typically emerges between 4 and 10 years of age, with common signs including , despite reduced , alopecia (especially truncal), poor quality, and heat-seeking behavior. Additional dermatologic issues, such as seborrhea, , and recurrent skin or ear infections, are frequent, while less common manifestations involve , , or neurological changes. Certain breeds show predispositions, including Doberman Pinschers, Golden Retrievers, Akitas, and Boxers, due to genetic factors influencing . Diagnosis involves confirming alongside evidence of . Serum testing for thyroglobulin autoantibodies (TgAA) detects the autoimmune component, with levels above 25% indicating , while thyroid ultrasound reveals gland atrophy or hypoechogenicity. is verified by low total or free T4 concentrations combined with elevated (TSH). Breed-specific reference ranges are essential, particularly for like Greyhounds, which naturally have lower T4 levels. Treatment mirrors human protocols and consists of lifelong oral supplementation, administered once or twice daily to restore euthyroidism. Dosage adjustments are guided by periodic monitoring of T4 levels 4-6 hours post-administration, typically every 6-12 months, to prevent over- or under-supplementation. Owners must watch for rare complications like myxedema coma in untreated severe cases, characterized by profound , , and , which requires emergency intervention. With consistent therapy, prognosis is excellent, and clinical signs resolve within weeks to months.

Comparative aspects

Hashimoto's thyroiditis in animals shares core pathological features with the human form, including lymphocytic infiltration of the and production of , primarily anti-thyroglobulin (TgAA) in dogs and anti-thyroid peroxidase (anti-TPO) in humans and models, leading to progression to . In canine models, lymphocytic thyroiditis mirrors human Hashimoto's through T-cell mediated destruction and autoantibody presence, often leading to clinical . Similarly, experimental models in exhibit comparable immune-mediated glandular damage and hypothyroid outcomes, facilitating direct parallels in disease etiology. Despite these similarities, notable differences exist in disease progression and tissue responses across species. In , autoimmune thyroiditis advances more rapidly than in s, with detectable thyroglobulin autoantibodies (TgAA) progressing to overt within 12 to 18 months, influenced by faster thyroxine ( of 9-15 hours versus 6-10 days in humans). Feline cases show less pronounced compared to human or presentations, with being rarer and often congenital rather than autoimmune, resulting in milder chronic inflammatory changes. Iodine sensitivity also varies; while excess iodine exacerbates in both humans and models by enhancing autoantigen presentation, responses are modulated differently due to dietary and metabolic factors, sometimes leading to less severe outcomes. Genetic models of Hashimoto's thyroiditis have been established in animals to replicate human susceptibility. Spontaneous autoimmune occurs naturally in beagle dogs, with familial clustering and histopathological features akin to human disease, providing insights into inherited risk factors. In mice, experimental autoimmune (EAT) is induced via , serving as a robust model that recapitulates lymphocytic infiltration and production without spontaneous onset. These models highlight interspecies genetic parallels, such as shared HLA-linked loci influencing . Animal models enhance research into human Hashimoto's by validating (GWAS) findings. Canine multi-breed GWAS have identified hypothyroidism risk loci overlapping with human AITD susceptibility genes, confirming shared genetic architectures like those in the MHC region. Rodent models further aid in functional validation of GWAS hits, elucidating how variants affect and thyroid-specific . Recent studies as of 2025 have explored associations between and gut microbiome disturbances, including (SIBO), primarily in humans, where altered profiles correlate with disease risk through slowed gut motility and immune dysregulation. Potential cross-species parallels remain an area of ongoing .