Chronic autoimmune thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto’s thyroiditis, was first described by Hashimoto in 1912 (Table 1). He described four patients with goitre, the thyroid histology of which were all characterized by diffuse lymphocytic infiltration, atrophy of parenchymal cells, fibrosis, and eosinophilic change in some of the parenchymal cells. While this condition is common, there are several variants that differ somewhat from the one initially described by Hashimoto. Classically, the disorder occurs as a painless diffuse goitre (goitrous form) in a young or middle- aged woman, with or without concomitant hypothyroidism. The atrophic form of Hashimoto’s thyroiditis is less common and is usually diagnosed by serology in the hypo thyroid patient with a normal- sized or atrophic thyroid. The hall marks of this disorder are high circulating titres of antibodies to thyroid peroxidase (primarily) and thyroglobulin (less often).

Table1. Comparison between the syndromes of thyroiditis

In iodine- sufficient countries, the most common cause of goitre, hypothyroidism, and elevated thyroid antibody levels is Hashimoto’s thyroiditis. The incidence of autoimmune thyroiditis has increased over the past three generations, perhaps due to the increase in iodine intake that has occurred in many regions globally. Elevated serum thy roid antibody concentrations are found in approximately 10% of the US population and in up to 25% of US women over the age of 60. About 45% of older women will have lymphocytic infiltration within the thyroid gland. Autoimmune thyroiditis has a female predominance, with reported female to male ratios ranging between 5:1 and 9:1.

Aetiology and Pathogenesis

Hashimoto’s thyroiditis is an autoimmune disease. Thyroid auto immunity tends to aggregate in families, suggesting a genetic com ponent. This likely results from the interplay of genes which confer susceptibility and environmental triggers. Genes regulating the immune system as well as thyroid- specific genes have been implicated. Smoking decreases risk for hypothyroidism and thyroid auto immunity. Environmental factors which increase the risk for Hashimoto’s thyroiditis include excessive iodine intake, selenium deficiency, and exposure to ionizing radiation. It has been speculated that viral infection with human parvovirus B19 or hepatitis C virus may serve as a trigger for Hashimoto’s thyroiditis.

In Hashimoto’s thyroiditis T cells attack the thyroid gland, leading to exposure of thyroid antigens such as thyroid peroxidase (TPO) and thyroglobulin, against which antibodies are produced. TPO antibodies are detectable in about 90% of patients with Hashimoto’s thyroiditis. Thyroglobulin antibodies are in about 35– 60% of patients with Hashimoto’s thyroiditis. Thyroid- stimulating hormone (TSH) receptor antibodies that block TSH binding but do not stimulate thyroid cell function may play a role in the clinical presentation of Hashimoto’s thyroiditis, producing or exacerbating hypothyroidism in the absence of significant thyroid gland destruction. Such antibodies have been reported to bind to epitopes near the carboxyl end of the TSH receptor extracellular domain, in contrast to thyroid- stimulating antibodies, which bind to epitopes near the N- terminus. The prevalence of TSH receptor blocking anti bodies in adult hypothyroid patients has been reported to be as high as 10% and a decrease in the titre of these antibodies is likely to be responsible for ‘remission’ of hypothyroidism in occasional patients with Hashimoto’s thyroiditis. Antibodies to colloid antigen, other thyroid autoantigens, thyroxine (T4), and triiodo thyronine (T3), as well as other growth- promoting and inhibiting antibodies may also be present.

Pathologically, there is lymphocytic infiltration of equal pro portions of T and B cells and the formation of germinal centres (Figure 1a). The follicular cells undergo metaplasia into larger, eosinophilic cells known as Hürthle or Askanazy cells which are packed with mitochondria. These cells exhibit high metabolic activity but ineffective hormonogenesis. There is ongoing cellular destruction and progressive fibrosis, which may be extensive. The quantity of parenchymal tissue left in the thyroid is variable, as the pathological involvement ranges from focal regions to an entire lobe to the entire gland.

Fig1. Typical pathological changes of Hashimoto’s thyroiditis and subacute thyroiditis. (a) Hashimoto’s thyroiditis. A, lymphoid follicle with germinal centres; B, small lymphocytes and plasma cells; C, thyroid follicles with Hürthle cell metaplasia; D, minimal colloid material. (b) Subacute thyroiditis. A, multinucleate giant cell; B, mixed inflammatory infiltrate; C, fibrous band; D, residual follicles. Haematoxylin and eosin, ×200. Reproduced with permission from Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med, 2003; 348: 2646– 55. The Massachusetts Medical Society © 2003. All rights reserved.

Clinical Features

 Hashimoto’s thyroiditis occurs most frequently in middle- aged women but can occur at any age. The usual presentation is with symptoms of, or biochemical evidence for, hypothyroidism, although patients occasionally present with simple goitre. The usual course is for slow enlargement of the thyroid over years; however, the thyroid occasionally may enlarge rapidly and can produce compressive symptoms of dyspnoea and/ or dysphagia. Rarely, Hashimoto’s thyroiditis may be painful and must be distinguished from subacute thyroiditis (see next). Systemic symptoms of hypothyroidism will be present in up to 20% of patients at the time of diagnosis, although this incidence is a little higher with the atrophic form of the disorder.

Physical examination typically reveals a firm bumpy non- tender goitre, which is generally symmetrical and often has a palpable pyramidal lobe. Regional lymph node enlargement may be observed. While nodular thyroid disease can, and frequently does, occur in Hashimoto’s thyroiditis, suspicious nodules should be evaluated with a fine- needle aspiration biopsy to rule out a coexistent malignancy. Ophthalmopathy is present in a small subset of patients with Hashimoto’s thyroiditis and may be severe.

Laboratory evaluation and Diagnosis

The hallmark of Hashimoto’s thyroiditis is elevated TPO antibody levels. The majority of individuals with elevated TPO antibody levels are biochemically euthyroid. Up to 10% of postmenopausal women with an elevated TPO antibody level will have an increased TSH but a minority of these (about 0.5%) will have overt hypothyroidism. Individuals with elevated TPO antibody levels have been reported to develop overt hypothyroidism at a rate of 2– 4% per year. Mild thyrotoxicosis (‘Hashitoxicosis’) has rarely been reported to be the initial manifestation in some patients with Hashimoto’s thyroiditis [18]. The clinical course in these patients follows a pattern similar to that observed in sporadic silent or postpartum thyroiditis, suggesting that differentiation between these disorders may be largely semantic. Finally, while the hallmark of the disease is a painless goitre, occasionally Hashimoto’s thyroiditis can be quite painful.

While the diagnosis of Hashimoto’s thyroiditis is confirmed by the presence of TPO antibodies, the titre of antibodies does not necessarily indicate the severity of the disease or even if hypothyroidism is present. Serum T4 and TSH concentrations depend solely on the level of thyroidal dysfunction that is present. Serum T3 concentrations are often preserved in all but the most severely hypothyroid patients and, thus, are of little clinical value. Similarly, the radioactive iodine uptake is usually not helpful, as it may be elevated, normal, or depressed. Thyroid isotope scanning usually reveals patchy uptake and, in general, provides little useful information unless a dominant thyroid nodule is present. Ultrasound examination of the thyroid frequently reveals marked hypoechogenicity with pseudonodules.

When imaged, an enlarged thymus gland is frequently found in Hashimoto’s thyroiditis and may be important in the pathogenesis of the condition. In both affected patients and their relatives, there is an association with other autoimmune diseases including type 1 diabetes mellitus, pernicious anaemia, Addison’s disease, and vitiligo. Thyroid lymphoma is rare; however, the risk is increased in those individuals with Hashimoto’s thyroiditis by a factor of 67. In patients in whom a fine- needle aspiration biopsy is performed, lymphocyte subsets should be determined on the biopsy specimen if the more typical pathological features of Hashimoto’s thyroiditis are not present.

Treatment

Treatment of Hashimoto’s thyroiditis consists of thyroid hormone replacement if hypothyroidism is present. L- thyroxine is the hormone of choice for thyroid hormone replacement therapy because of its consistent potency and prolonged duration of action. The average daily adult replacement dose of L- thyroxine sodium is 1.6 µg/ kg body weight. Institution of therapy in healthy younger individuals can begin at full replacement doses. Because of the prolonged half- life of thyroxine (7 days), new steady- state concentrations of the hormone will not be achieved until 4– 6 weeks after a change in dose. Thus, re- evaluation with determination of serum TSH concentration need not be performed at intervals of less than 4– 6 weeks. The goal of thyroxine replacement therapy is to achieve a TSH value in the normal range, as over- replacement of thyroxine suppressing TSH values to the subnormal range may induce osteo porosis and cause cardiac dysfunction. In non- compliant young patients, the cumulative weekly doses of L- thyroxine may be given as a single weekly dose which is safe, effective, and well tolerated. In older individuals or those with known cardiovascular disease, institution of therapy at a lower daily dose of L- thyroxine (25 μg/ day) is indicated to avoid exacerbation of underlying and undiagnosed cardiac disease. Daily doses of thyroxine may be interrupted periodically because of intercurrent medical or surgical illnesses that prohibit taking medications by mouth. A lapse of several days of hormone replacement is unlikely to have any significant metabolic consequences. However, if more prolonged interruption in oral therapy is necessary, L- thyroxine may be given intravenously at a dose 25– 50% less than the patient’s daily oral requirements. Euthyroid asymptomatic patients require monitoring, but no treatment. Recommendations for treatment of subclinical hypothyroidism (increased TSH without a corresponding low free T4 concentration) have varied, but the general consensus is that levothyroxine treatment should be initiated when the serum TSH is >10 mIU/ L and treatment considered for TSH values 5– 10 mIU/ L, particularly in the setting of hypothyroid symptoms or detectable TPO antibodies.

In addition to replacement therapy, thyroid hormone therapy may be considered in patients with a serum TSH in the normal range in an attempt to decrease the size of a goitre. While goitre suppression with L- thyroxine is frequently not fruitful, in the subset of patients with Hashimoto’s thyroiditis early in the course of the disease and before fibrosis develops such therapy may be useful. However, goitre suppression with L- thyroxine is unlikely to be successful if the initial TSH is less than 1 mIU/ L. The goal of L- thyroxine suppression therapy is to decrease the serum TSH into the subnormal range. Patients on L- thyroxine suppression therapy should be re- evaluated periodically and the suppressive hormone dose should be reduced or discontinued if significant goitre reduction is not achieved. Surgery is occasionally indicated for compressive goitres with local obstructive symptoms.

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مواضيع ذات صلة

Autoimmune Thyroid Disease : Mechanisms Altering Thyroid Function

B- cell Function in Autoimmune Thyroid Disease

T- cell Function in Autoimmune Thyroid Disease

Autoimmune Thyroid Disease: Autoantigens

Factors Determining Susceptibility of Autoimmune Thyroid Disease

Pathological Features of Autoimmune Thyroid Disease

The Spectrum of Thyroid Autoimmunity

Autoimmune lymphoproliferative syndrome

Severe Congenital Neutropenia

Autoimmune type 1 diabetes and immune checkpoint inhibitors

Autoimmune diabetes in adults

Genetic aetiology to initiate islet autoimmunity