Hashimoto’s Disease

Introduction

Hashimoto’s disease or Hashimoto’s thyroiditis or chronic lymphocytic thyroiditis is an autoimmune disease where the body’s own antibodies attack the cells of the thyroid. Hashimoto’s thyroiditis was first described by Hashimoto Hakaru in 1912. He named it struma lymphomatosa which was renamed as Hashimoto’s thyroiditis in 1931.

Hashimoto’s thyroiditis can be classified as primary or secondary types. Rarely, Hashimoto’s thyroiditis can be categorized under the polyglandular syndromes. Hashimoto’s thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid gland and production of antibodies that recognize thyroid-specific antigens. The pathogenesis is not yet completely understood. Thyroid cells undergo atrophy or transform into a type of follicular cell rich in mitochondria called Hurthle cell. It is currently thought that the disease is caused by abnormalities in cellular and humoral immunity which results in a localized cell-mediated immune response directed toward the thyroid parenchymal cells. This results in the decreased production of thyroid hormones.

Hashimoto’s thyroiditis is particularly common in middle aged women, Asians, and Whites. Hashimoto’s thyroiditis usually begins slowly and may progress to hypothyroidism. Complications include heart failure, lymphoma, myxedema, and cervical compression. A positive history of autoimmune diseases and certain drug use are suggestive of Hashimoto’s thyroiditis. The most common symptoms of Hashimoto’s thyroiditis include fatigue, constipation, and cold intolerance.

Laboratory findings consistent with the diagnosis of Hashimoto’s thyroiditis usually include increased thyroid stimulating hormone, decreased free T3 and free T4, and anti-thyroid peroxidase antibodies. Ultrasound findings associated with Hashimoto’s thyroiditis are reduced echogenicity, glandular irregularities, and nodules. 24-hour iodine-123 uptake is decreased in Hashimoto’s thyroiditis.

The mainstay of therapy for Hashimoto’s thyroiditis is synthetic levothyroxine. Corticosteroids and selenium can also be used in certain cases. Thyroidectomy is usually performed when the enlarged thyroid produces cervical compression symptoms and there is a high suspicion for malignancy.

Associated Anatomy

The thyroid gland, or simply the thyroid, is an endocrine gland in the neck, consisting of two lobes connected by an isthmus. It is found at the front of the neck, below the Adam’s apple. The thyroid gland secretes three hormones, namely the two thyroid hormones (thyroxine/T4 and triiodothyronine/T3), and calcitonin. The thyroid hormones primarily influence the metabolic rate and protein synthesis, but they also have many other effects, including effects on development. Calcitonin plays a role in calcium homeostasis.

 

Hormonal output from the thyroid is regulated by thyroid-stimulating hormone (TSH) secreted from the anterior pituitary gland, which itself is regulated by thyrotropin-releasing hormone (TRH) produced by the hypothalamus.

The thyroid may be affected by several diseases. Hyperthyroidism occurs when the gland produces excessive amounts of thyroid hormones, the most common cause being Graves’ disease, an autoimmune disorder. In contrast, hypothyroidism is a state of insufficient thyroid hormone production. Worldwide, the most common cause is iodine deficiency. Thyroid hormones are important for development, and hypothyroidism secondary to iodine deficiency remains the leading cause of preventable intellectual disability. In iodine-sufficient regions, the most common cause of hypothyroidism is Hashimoto’s thyroiditis, also an autoimmune disorder. In addition, the thyroid gland may also develop several types of nodules and thyroid cancer.

Causes

Hashimoto’s thyroiditis is usually caused by:

Common Causes

  • Autoantibodies against thyroid peroxidase and thyroglobulin
  • Abnormalities in the suppressor T cells and regulatory T cells
  • HLA-B, HLA-A and HLA-DRB4 involvement

Less common cause

  • Immunomodulatory drugs (e.g, interferon-alpha)
  • Monoclonal antibodies that block CTLA-4
  • Cancer vaccines
  • Micro RNA involvement
  • Polyglandular Syndrome

Differential Diagnosis

Hashimoto’s thyroiditis must be differentiated from other causes of thyroiditis, such as De Quervain’s thyroiditis, Riedel’s thyroiditis, and suppurative thyroiditis. Hashimoto’s thyroiditis must also be differentiated from other diseases which cause hypothyroidism. As Hashimoto’s thyroiditis may cause transient thyrotoxic symptoms, the diseases causing thyrotoxicosis must also be considered in the differential diagnosis.

Drugs

Levothyroxine sodium (Levoxyl, Synthroid, Levothroid)

This is a synthetic thyroid hormone (T4). It is available in 12 strengths for easy dose adjustment. Absorption of levothyroxine sodium is 48-79% when it is administered orally; absorption is higher in persons in a fasting state. Normal T4 levels are achieved within 24 hours and normal T3 levels are reached within a few days. Thyroid hormone is involved in normal metabolism, growth, and development.

Epidemiology

Worldwide, the most common cause of hypothyroidism is iodine deficiency. However, Hashimoto thyroiditis remains the most common cause of spontaneous hypothyroidism in areas of adequate iodine intake. The annual incidence of Hashimoto thyroiditis worldwide is estimated to be 0.3-1.5 cases per 1000 persons.

The incidence of Hashimoto thyroiditis is estimated to be 10-15 times higher in females. The most commonly affected age range in Hashimoto thyroiditis is 30-50 years, with the peak incidence in men occurring 10-15 years later. The overall incidence of hypothyroidism increases with age in men and women.

Natural Progression

The disease begins slowly. The patient usually has the neck swelling and presents with symptoms of hypothyroidism such as fatigue, weight gain, constipation, and dry skin. Some patients may also present with hyperthyroidism. It may take months or even years for the condition to be detected. If left untreated, Hashimoto’s thyroiditis may lead to muscle failure including heart failure, other features associated with hypothyroidism and complications such as myxedema Coma and Hashimoto’s encephalopathy.

Pathophysiology

Hashimoto’s thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid gland and production of antibodies that recognize thyroid-specific antigens. The pathogenesis is not yet completely understood. Thyroid cells undergo atrophy or transform into a type of follicular cell rich in mitochondria called Hurthle cell. It is currently thought that the disease is caused by abnormalities in cellular and humoral immunity which results in a localized cell-mediated immune response directed toward the thyroid parenchymal cells. This results in the decreased production of thyroid hormones.

Possible Complications

Complications that can develop as a result of Hashimoto’s thyroiditis are:

  • Hypothyroidism
  • Hyperthyroidism
  • Heart failure
  • Myxedema Coma
  • Tracheal and/or esophageal compression
  • Hashimoto’s encephalopathy
  • Papillary thyroid carcinoma (PTC)
  • Thyroid lymphoma

Myxedema coma

Myxedema coma is a state of extreme hypothyroidism with a very high mortality rate (approaching 60%). Patients with this condition usually present with an acute precipitating condition, most often in the following settings:

  • Long-standing, undiagnosed hypothyroidism
  • Discontinuation of T4 replacement therapy
  • Failure to institute T4 replacement after radioactive iodine ablation of the thyroid in Graves disease or after total thyroidectomy

Myxedema coma typically manifests in winter (or during extremely cold weather) in an elderly woman who has long-standing hypothyroidism. Hospitalized patients may have a history of sedating medication use. Typical clinical findings include hypothermia, obtundation or coma, hypoventilation, bradycardia, hyponatremia, hypoglycemia, and hypotension. Besides having an elevated TSH level, these patients may have undetectable free T4 levels.

Possible Treatment

The treatment of choice for Hashimoto thyroiditis (or hypothyroidism from any cause) is thyroid hormone replacement. The drug of choice is orally administered levothyroxine sodium, usually for life.

Tailor and titrate the dose of levothyroxine sodium to meet the individual patient’s requirements. The goal of therapy is to restore a clinically and biochemically euthyroid state. The standard dose is 1.6-1.8 mcg/kg lean body weight per day, but the dose is patient dependent. The free T4 and TSH levels are within reference ranges in the biochemically euthyroid state, with the TSH level in the lower half of the reference range.

Patients younger than 50 years who have no history or evidence of cardiac disease can usually be started on full replacement doses.

Start patients older than age 50 years and younger patients with cardiac disease on a low dose of 25 mcg (0.025 mg) per day, with clinical and biochemical reevaluation in 6-8 weeks. Carefully titrate the dose upward to achieve a clinical and biochemical euthyroid state. Rarely, it may not be possible to achieve a euthyroid state in a patient with baseline cardiac dysrhythmic disease without worsening his or her cardiac status. In such cases, the astute clinician is content to achieve the clinically euthyroid state and to accept a slightly elevated TSH level.

Elderly patients usually require a smaller replacement dose of levothyroxine, sometimes less than 1 mcg/kg lean body weight per day.

Elderly patients and patients on androgens for various reasons usually require decreased levothyroxine replacement dosing.

Patients who have undergone bowel resection and have short-bowel syndrome (or malabsorption for any reason) often require increased doses of levothyroxine to maintain the euthyroid state.

In their previously described study of 830 patients with Hashimoto thyroiditis, Tagami et al found that, following treatment with small doses of levothyroxine in 32 of the study’s patients with subclinical hypothyroidism, significant decreases occurred in the patients’ total cholesterol, LDL, and non-HDL levels, as well as in their LDL/HDL ratios.

Combination therapy

One popular treatment, more so among patients than physicians, is the combined use of liothyronine (T3) and levothyroxine in an effort to mimic more closely thyroid hormone physiology. However, a literature review found that out of 9 controlled clinical trials, only 1 indicated that combined therapy seemed to improve the mood, quality of life, and psychometric performance of patients more than did levothyroxine alone.

Until investigators can demonstrate a definite advantage to the administration of levothyroxine plus liothyronine, the use of levothyroxine alone should remain the treatment of choice for replacement therapy in hypothyroidism.

Prognosis

With early diagnosis, timely institution of levothyroxine replacement therapy, informed patient follow-up care, and attention to other attendant complications, the prognosis in Hashimoto thyroiditis is excellent, with patients leading a normal life. Untreated myxedema coma has a poor prognosis and a high mortality rate.

Morbidity related to Hashimoto thyroiditis typically results from failure to make the diagnosis of hypothyroidism or to institute L-thyroxine replacement therapy in adequate doses, or from failure on the part of the patient to take the replacement medication.

The increased prevalence of lipid disorders in association with untreated hypothyroidism has the potential to increase morbidity from coronary artery disease.

The risk for papillary thyroid carcinoma is increased in patients with Hashimoto thyroiditis. These cancers are not clearly more aggressive than other papillary thyroid carcinomas. In fact, a study by Liang et al suggested that in patients with papillary thyroid carcinoma, those with concurrent Hashimoto thyroiditis have a better prognosis than do patients without it. Subjects with both papillary thyroid carcinoma and Hashimoto thyroiditis tended to have a smaller tumor size, a less advanced TNM stage, and a decreased lymph node metastasis rate.

Primary Prevention

Unfortunately, there is no known way to prevent Hashimoto’s thyroiditis.

Risk factors

The risk factors for Hashimoto’s thyroiditis are:

Common Risk factors

  • Female gender
  • Family history
  • Other autoimmune diseases like vitiligo, rheumatoid arthritis, Addison’s disease, type 1 diabetes and pernicious anemia.

Less common risk factors

  • Hygienic environment
  • Selenium deficiency
  • Irradiation
  • Drugs (cytokines, especially interferon-α, tyrosine kinase inhibitors, alemtuzumab)
  • HHV-6 and Yersinia infection (low level of evidence)

Signs or Symptoms

Hypothyroidism typically has an insidious onset with subtle signs and symptoms that may progress to more advanced or even florid signs and symptoms over months to years. The presentation of patients with hypothyroidism may also be subclinical, diagnosed based on routine screening of thyroid function. Such patients may have nonspecific symptoms that are difficult to attribute to thyroid dysfunction. They frequently do not improve with thyroid hormone supplementation..

Early nonspecific symptoms may include the following:

  • Fatigue
  • Constipation
  • Dry skin
  • Weight gain

More advanced/florid symptoms may include the following:

  • Cold intolerance
  • Voice hoarseness and pressure symptoms in the neck from thyroid enlargement
  • Slowed movement and loss of energy
  • Decreased sweating
  • Mild nerve deafness
  • Peripheral neuropathy
  • Galactorrhea
  • Depression, dementia, and other psychiatric disturbances
  • Memory loss
  • Joint pains and muscle cramps
  • Hair loss
  • Menstrual irregularities
  • Sleep apnea and daytime somnolence

Studies

Active Not Recruiting

Number of studies: 1

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Completed

Number of studies: 21

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Enrolling by Invitation

Number of studies: 0

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Not Yet Recruiting

Number of studies: 4

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Recruiting

Number of studies: 9

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Results Available

Number of studies: 0

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Results Not available

Number of studies: 40

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Suspended

Number of studies: 0

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Terminated

Number of studies: 0

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Withdrawn

Number of studies: 0

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Types

Hashimoto’s thyroiditis (HT) can be classified on the basis of the etiology to the primary and secondary types as follows:

Primary

Primary HT is the most common form of thyroiditis and comprises the cases that do not currently have identifiable causes. Primary HT encompasses a spectrum of the following main types:

  • Classic form
  • Fibrous variant
  • IgG4-related variant
  • Juvenile form
  • Hashitoxicosis

Two forms of painless thyroiditis, sporadic and postpartum thyroiditis were considered the form of Hashimoto’s thyroiditis. These are now regarded as different from Hashimoto’s thyroiditis.

Secondary

Secondary HT is of more recent description. It includes the forms where an etiologic agent can be clearly identified. It is more commonly iatrogenic and induced by the administration of:

  • Immunomodulatory drugs (e.g, interferon-alpha)
  • Monoclonal antibodies that block CTLA-4
  • Cancer vaccines
  • Polyglandular autoimmune syndromes

In rare cases, Hashimoto’s thyroiditis may be associated with other endocrine disorders caused by the immune system. Based on the involvement of other endocrine disease involvements, Hashimoto’s thyroiditis may be classified under the polyglandular autoimmune syndromes.

Typical Test

Physical examination

Physical findings are variable and depend on the extent of the hypothyroidism and other factors, such as age. Examination findings may include the following:

  • Puffy face and periorbital edema typical of hypothyroid facies
  • Cold, dry skin, which may be rough and scaly
  • Peripheral edema of hands and feet, typically nonpitting
  • Thickened and brittle nails (may appear ridged)
  • Bradycardia
  • Elevated blood pressure (typically diastolic hypertension)
  • Diminished deep tendon reflexes and the classic prolonged relaxation phase
  • Macroglossia
  • Slow speech
  • Ataxia

Laboratory Workup

  • Laboratory studies and potential results for patients with suspected Hashimoto thyroiditis include the following:
  • Serum thyroid-stimulating hormone (TSH) levels: Sensitive test of thyroid function; levels are invariably raised in hypothyroidism due to Hashimoto thyroiditis and in primary hypothyroidism from any cause
  • Free T4 levels: Needed to correctly interpret the TSH in some clinical settings; low total T4 or free T4 level in the presence of an elevated TSH level further confirms diagnosis of primary hypothyroidism
  • T3 levels: Low T3 level and high reverse T3 level may aid in the diagnosis of nonthyroidal illness
  • Thyroid autoantibodies: Presence of typically anti-TPO (anti-thyroid peroxidase) and anti-Tg (anti-thyroglobulin) antibodies delineates the cause of hypothyroidism as Hashimoto thyroiditis or its variant; however, 10-15% of patients with Hashimoto thyroiditis may be antibody negative
  • The following tests are not necessary for the diagnosis of primary hypothyroidism but may be used to evaluate complications of hypothyroidism in some patients, as indicated:
  • Complete blood count: Anemia in 30-40% of patients with hypothyroidism
  • Total and fractionated lipid profile: Possibly elevated total cholesterol, LDL, and triglyceride levels in hypothyroidism
  • Basic metabolic panel: Decreased glomerular filtration rate, renal plasma flow, and renal free water clearance in hypothyroidism; may result in hyponatremia
  • Creatine kinase levels: Frequently elevated in severe hypothyroidism
  • Prolactin levels: May be elevated in primary hypothyroidism

Imaging tests

Features of Hashimoto thyroiditis are usually identifiable on an ultrasonogram; however, a thyroid ultrasonogram is usually not necessary for diagnosing the condition. This imaging modality is useful for assessing thyroid size, echotexture, and, most importantly, whether thyroid nodules are present.

Chest radiography and echocardiography are not usually performed and are not necessary in routine diagnosis or evaluation of hypothyroid patients.

Procedures

Hashimoto thyroiditis is a histologic diagnosis. Therefore, perform fine-needle aspiration of any dominant or suspicious thyroid nodules to exclude malignancy or the presence of a thyroid lymphoma in fast-growing goiters.

References:

https://www.wikidoc.org/index.php/Hashimoto%27s_thyroiditis
https://www.ncbi.nlm.nih.gov/books/NBK459262/
https://emedicine.medscape.com/article/120937-overview
https://www.webmd.com/women/hashimotos-thyroiditis-symptoms-causes-treatments#1

 

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