HISTORICAL BACKGROUND: In 1912, Hakaru Hashimoto published a description of the disorder named in his honor, Hashimoto’s thyroiditis (HT), in the German literature hoping that it would make his findings more available around the world. Four women, all over age 40, showed a preponderance of lymphoid follicles, with parenchymal and interstitial changes, one of whom was hypothyroid. He recognized the similarities of the histology of HT to that of Grave’s disease that was ruled out clinically and Riedel’s (fibrous) thyroiditis (that had a different pathology. He speculated there was a factor that caused the lymphocytic expansion of the thyroid size, naming it after its histologic characteristics, lymphomatous goiter, in the absence of a known cause. Goitrous lymphocytic thyroiditis was ignored until the 1930s when Hashimoto’s name became attached to the disease in American and British surgical texts.  McClintock and Wright reviewed the world’s literature in 1937 and found only 50 cases of HT. Between 1956 and 1958, two teams of investigators, each employing different techniques, ushered in fundamental concepts of thyroid autoimmunity, describing circulating thyroglobulin antibodies (Tg-Ab) in autoimmunized animals. With recognition of the pathologic entity and immune pathogenesis, there was a marked increase in the incidence of newly reported cases, and the entity became well entrenched in the endocrinology literature and synonymous with the commonest form of autoimmune thyroid disease (AITD).  
 

Antibodies to thyroid microsomal (cytoplasmic) antigens, more commonly termed thyroid peroxidase (TPO) and distinct from Tg were demonstrated using complement-fixation of human thyrotoxic extracts of postmortem or biopsy tissue, and later by a more sensitive indirect immunofluorescence technique using fresh thyrotoxic thyroid as substrate.  Although thyroid antibodies related to both goiter and thyroid atrophy, it was uncertain then as it is now, why some patients with HT failed to develop a goiter.
 

EPIDEMIOLOGY: Hashimoto's thyroiditis affects up to 2% of the general population and afflicts women ten-fold more than in men. The National Health and Nutrition Examination Survey III estimated the prevalence of subclinical and clinical hypothyroidism to be 4.6% and 0.3%, and the prevalence of spontaneous hypothyroidism at 1.5% in women and <0.1% in men. Subclinical hypothyroidism, characterized by an increase in serum thyrotropin (TSH) while serum levels of thyroxine (T4) and triiodothyronine (T3) remain normal, was reported in 8% of women and 3% of men in a twenty-year follow-up study of the Whickham Survey. Furszyfer and colleagues estimated that the incidence of clinical evident HT at 69 per 100 000 in Rochester, Minnesota. However, this figure greatly underestimated the actual incidence, since histologic evidence of the disease, which variably included infiltration of the thyroid by lymphocytes and gradual destruction of the gland, could be seen in 2% of unselected Caucasian females at autopsy.  
 

Hashimoto’s thyroiditis is the third most prevalent autoimmune disease in the U.S., and the commonest form of AITD. It leads to a dramatic loss of thyroid follicular cells, with concomitant hypothyroidism, goiter formation, and circulating autoantibodies, notably to the primary thyroid-specific antigens, Tg and TPO. Thyroglobulin is the main protein synthesized in the thyroid gland and serves both in the synthesis and in the storage of thyroid hormone. Its synthesis and iodine content play an important role in epitope recognition and autogenicity. Thyroid peroxidase, the other significant autoantigen in HT, catalyzes the oxidation of iodine to an iodinating species. Antibodies to TPO are heterogeneous with almost 180 forms cloned and sequenced. Both antibodies are found in patients with AITD, and noted with an overall estimated prevalence rate of 18.8% in a population survey of randomly selected subjects age 18 to 65 years in two areas of Denmark. The antibodies are more frequent in women than men, with prevalence rates at least in women that increase with age. In one-third of population sera, both antibodies are present in concentrations that are generally higher than in sera of those with only one antibody type.

Abundant epidemiologic and genome-wide association study (GWAS) data and animal models of AITD suggest a strong genetic basis for HT, with contributions from polymorphisms in major histocompatibility complex (MHC) and class I-III human leukocyte antigen (HLA) genes, immune modulatory genes, and epigenetic influences.  Hashimoto’s thyroiditis occurs with other autoimmune diseases such as type-1 diabetes (T1D), Celiac disease, rheumatoid arthritis, multiple sclerosis, and vitiligo. It can be part of the autoimmune polyendocrine syndrome type-2. Autoantibodies to TPO and Tg are inherited as a dominant Mendelian trait in women with reduced penetrance in men.  Thyroid abnormalities with clinical outcomes occur in one-third of offspring of patients with HT with a sibling risk ratio that supports a strong case for genetic influence on disease development. 

More recent interest has been focused on the candidate role of HLA polymorphisms and cytotoxic T-cell -associated 4 (CTLA4) as primary determinants of the risk of developing HT. Genome-wide association studies showed associations with HLA-DR4 in 56 multiplex families of 354 individuals with AITD, as well as with HLA DR5 in goitrous HT, and DR3 in atrophic HT. The mechanism of CTLA4 susceptibility to autoimmune disease including HT, results from a failure to establish and maintain immunologic non-responsiveness or tolerance to self-antigens. In humans, disease susceptibility in HT maps to a noncoding 6.1-kb 3-prime region of the CTLA4 gene, the common allelic variation of which correlates with lower mRNA levels of the soluble alternative splice form of CTLA4. The role of CTLA4 has been investigated in several case-control studies of HT.  

The influence of environmental factors that interact with susceptibility genes to produce a synergistic effect in triggering autoimmune thyroid disease though epigenetic modulation and regulating gene expression and phenotypes without altering the genetic code in deoxyribonucleic acid (DNA), occurs through methylation, histone modifications, and non-coding ribonucleic acids (RNA).  DNA methylation mainly results in transcriptional repression especially when it occurs in the region of 5’ promoter regions with high density, as occurs in the CTLA4 gene in AITD. Polymorphisms in histone modifier genes, which have key roles in the compaction of DNA to form tightly compacted chromatin, can lead to susceptibility to AITD and higher levels of thyroid autoantibodies.  MicroRNA (miRNA) are small non-coding RNA molecules that contain about 22 nucleotides and function as silencers and regulators of mRNA that conveys genetic information from DNA, to specify the amino acid sequence of the protein products of gene expression through the process known as post-transcription gene regulation. Recent studies reveal that some miRNA are also involved in the development of AITD in modulating the differentiation or activation of immune cells and immune responsiveness. 
 

CLINICAL PRESENTATION: Patients with HT may present with hypothyroidism, goiter, or both. According to the Whickman survey, affected patients are typically <45 years of age, with the risk of a goiter increasing with age and one-half of those with goiter between age 45 and 64 years. Autoimmune thyroid disease accounts for up to 40% of goiters in adolescents. Common presenting symptoms of HT include fatigue, weight gain, pale or puffy face, feeling cold, joint and muscle pain, constipation, dry and thinning hair, heavy menstrual flow or irregular periods, depression, panic disorder, bradycardia, and difficulty becoming pregnant or maintaining pregnancy.  Joint stiffness, aching pain, arthralgia, myalgia, fatigue, fibrositis, shoulder and pelvic girdle pain and disturbed sleep were reported in 23.5%) of cases seen at the Mayo Clinic in a seminal study that noted inordinately increased prevalence of rheumatoid arthritis, spondylitis, scleroderma, lupus erythematosus, and other connective tissue disorder. 
 

LABORATORY INVESTIGATIONS: Patients with multinodular goiter and thyroid cancer harbor low serum titers of Tg and TPO antibodies, but titers of >1:6400 or >200 IU/ml respectively, strongly suggests AITD including HT. In areas with sufficient iodine, an increased serum thyrotropin level should be viewed as evidence of AITD.  Histologically, a goitrous thyroid gland is diffusely enlarged with a firm consistency, and irregular surface. There can be extensive fibrosis results in a hard mass that may be confused with malignant disease. Affected patients rarely complain of laryngeal or esophageal pain, tightness in the neck, focal glandular pain or palpable tenderness.  Goiters may be asymmetric and mistaken for a solitary nodule or multinodular goiter in a euthyroid patient, however patients with atrophic autoimmune thyroiditis will not have a goiter. Thyroid-associated ophthalmopathy is far more common in Graves' disease than HT. Subclinical hypothyroidism develops into overt hypothyroidism at a rate of 4% cases per year.

In community surveys, 50% to 75% of individuals with circulating anti-thyroid antibodies may be euthyroid, however up to one-half may have subclinical hypothyroidism, and up to 10% may be overtly hypothyroid. In addition to a full panel of thyroid function tests and available thyroid autoantibodies, patients with HT should undergo screening chemistries, erythrocyte sedimentation rate (ESR), hemoglobin A1c, serum protein electrophoresis (SPEP) or immunofixation (IFE), and screening antinuclear antibodies (ANA) for the recognized association of HT with autoimmune disorders, multiple endocrine neoplasia type II, and POEMS syndrome of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. 

Patients with suspected HT should undergo ultrasonography for an enlarged thyroid gland that typically shows diffuse hypoechogenicity in up to three-quarters of cases, but the finding is nonspecific. Radionuclear scanning is generally unnecessary and can be misleading.  The uptake of radionuclide is characteristically normal or elevated in patients with goitrous HT, even in the presence of hypothyroidism, whereas in those with subacute or silent thyroiditis, the uptake is low. Fine-needle aspiration should be reserved for clinically suspicious areas in patients with enlarged goitrous nodular glands. 
 

IMMUNOPATHOGENESIS: In individuals genetically predisposed to AITD, non-genetic or environmental triggers set in motion the initial steps that break down immune tolerance leading to glandular inflammation, goiter formation, and thyroid hypofunction.  In the initial stages, MHC class II-positive antigen presenting dendritic and macrophages cells (APC) infiltrate the gland leading to thyrocyte insult and release of host-specific antigens. These peptides, presented on the surface of APC cells to naïve T-cells, cause activation and clonal expansion of autoreactive CD4+ T-cells, CD8+ cytotoxic T-cells and immunoglobulin (IgG) autoantibodies in draining lymph nodes. Lymphoid tissue later develops directly in the gland itself with distinct cords of antibody producing plasma cells, and occasional multinuclear giant cells with enlarged epithelial cells and a distinctive eosinophilic cytoplasm, owing to increased number of mitochondria.  The process itself is mediated by T helper type 1 (TH1) cells which secrete interleukins,   interferon, and tumor necrosis factor. In the final stages of HT, autoreactive T-cells, B-cells, and antibody cause a massive depletion of thyrocytes via antibody-, cellular-, cytokine-mediated, and apoptotic mechanisms of cytotoxicity that leads to hypothyroidism and progressive glandular atrophy. 

The immunopathologic potential for HT resides in the cellular elements of the thyroid gland. Thyrocytes from HT glands, but not from non-autoimmune thyroids, express TNF receptor superfamily, member 6 (Fas), and its ligand FasL, which regulates cellular apoptosis. Interleukins, abundantly produced in HT glands, induces Fas expression in normal thyrocytes. Cross-linking of Fas results in massive thyrocyte apoptosis. Exposure to ILs, induced thyrocyte apoptosis, and prevented by antibodies that block Fas, suggest that IL-induced Fas expression may be an important limiting factor for thyrocyte destruction.  

Notwithstanding, a tendency for systemic autoimmunity in HT was recognized by Becker and coworkers a half century ago in an analysis of 506 cases seen at the Mayo Clinic in which 23.5% were found to have systemic concomitant connective tissue diseases with varying degrees of vascular involvement and autoimmune hypersensitivity reactions.  Later reports of two children with nephrotic syndrome, both with glomerular staining for TPO and Tg antigens and either hyperthyroid or hypothyroid AITD, and others with vasculitic neuropathy or giant-cell arteritis, showed that patients with HT might have widespread extrathyroid abnormal autoimmune activity including systemic vasculitis. 
 

TREATMENT: Patients with overt hypothyroidism are treated with L-thyroxine, and the dose adjusted to normalize the TSH level. The role of thyroxine in patients with subclinical hypothyroidism is more controversial. In placebo-controlled trial of 33 cases randomly assigned to receive placebo or L-thyroxine therapy and followed for 1 year with thyroid function tests and other metabolic determinants, symptoms were significantly improved in the treatment group (P<0.05). Treatment is generally recommended in patients with any symptoms potentially attributable to hypothyroidism especially if the TSH level is >10 mU per liter, and the patient is at high risk for progressing to overt hypothyroidism because of strongly positive TPO antibodies, age>45 years, and male sex. Up to a quarter of patients with hypothyroidism due to AITD, and treated with L-thyroxine for >1 year, experience a spontaneous recovery with disappearance of autoantibodies. Concomitant with a gradual increase in serum free T4 and T3 levels, and a fall in TSH levels, there can be a gradual decrease in thyroid gland size by up to one-third.