Hashimoto’s Thyroiditis

Hashimoto’s thyroiditis, or chronic lymphocytic thyroiditis, is the most common cause of hypothyroidism in iodine-sufficient regions. The condition is an autoimmune disorder leading to destruction of the thyroid cells and thyroid failure. The gradual clinical course of Hashimoto’s thyroiditis starts with a transient hyperthyroid state (“hashitoxicosis”) followed by subclinical hypothyroidism. Eventually, progression to overt hypothyroidism occurs, which is permanent. Patients may have a painless goiter, but in later stages, the gland is atrophic. Diagnosis is by laboratory tests showing elevated thyroid-stimulating hormone (TSH), low free thyroxine (T4), and positive antibodies against thyroglobulin and thyroid peroxidase. In uncertain cases, imaging is required. Radioactive iodine uptake will show low iodine uptake and ultrasound demonstrates diffuse symmetric enlargement. Biopsy shows lymphocytic infiltration with Hurthle cells. Treatment is lifelong thyroid hormone replacement.

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Overview

Definition

Hashimoto’s thyroiditis is an autoimmune thyroid disease resulting in the destruction and failure of the thyroid gland.

Epidemiology

  • Age of onset is usually between 30 and 50 years.
  • More common in women than men: 10–20:1 ratio
  • Most common cause of hypothyroidism in iodine-sufficient regions
  • 2nd-most common cause of hypothyroidism worldwide, after iodine deficiency

Etiology

Exact cause unknown, although genetic and environmental factors play a role:

  • Genetic risk factors:
    • ↑ Risk with polymorphisms in immunoregulatory genes including CTLA4, PTPN22, IL2RA (all encoding T cell regulatory responses)
    • Associated with HLA-DR3, DR4, and DR5
    • Disease clusters found in families suggest genetic susceptibility.
    • ↑ Incidence in patients with Down’s syndrome and Turner’s syndrome
  • Non-genetic risk factors possibly precipitate the disease:
    • Pregnancy 
    • Iodine and amiodarone
    • Stress
    • Irradiation
    • Sex steroids

Pathophysiology

Immunology

When thyroid autoimmunity is induced, progressive depletion of thyroid epithelial cells ensues.

Thyroid cell destruction mediated by:

  • T cell–mediated cytotoxicity: CD8+ cytotoxic T cells destroy thyroid cells.
  • Local production of cytokines:
    • Tumor necrosis factor and interferon-ɣ impair cell function.
    • Recruitment of macrophages
  • Antibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO): secondary role in thyroid cell death but are markers of thyroid autoimmunity

Lymphocytic infiltration and fibrosis of thyroid cells → follicles are disrupted and release thyroid hormones:

  • Transient ↑ of thyroxine (T4) and triiodothyronine (T3): “hashitoxicosis”
  • Compensatory ↓ thyroid-stimulating hormone (TSH) follows → T3/T4 stores gradually decline
  • End result: ↑ TSH + hypothyroidism (often permanent)
Classic negative feedback loop hashimoto

Hypothalamus-pituitary-thyroid axis feedback loop:
When the thyroid hormones are low, the hypothalamus releases thyrotropin-releasing hormone (TRH), which triggers the pituitary gland to secrete TSH. The effect of this process is that the thyroid gland produces thyroxine (T4) and triiodothyronine (T3) (more T4 is produced, as it gets converted to T3). An increase in thyroid hormones (free or unbound T3/T4) creates a negative feedback, inhibiting the release of TRH and TSH.

Image: “Classic Negative Feedback Loop” by OpenStax College. License: CC BY 3.0, edited by Lecturio.

Pathology

Immunologic response seen histologically as:

  • Infiltrates of lymphocytes and plasma cells
  • Well-developed germinal centers

Thyroid cell destruction:

  • Atrophic thyroid follicles
  • Hurthle cells:
    • Oncocytic cells with abundant eosinophilic granular cytoplasm
    • Metaplastic change resulting from chronic injury
  • Increased connective tissue/fibrosis (limited within the capsule)
Lymphoid tissue hashimoto

Florid Hashimoto’s thyroiditis: reactive lymphoid tissue with germinal center (hematoxylin and eosin stain, 200x magnification)

Image: “Florid Hashimoto’s thyroiditis” by Division of Endocrinology and Metabolism, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. License: CC BY 2.0

Clinical Presentation

Clinical course

  • Thyroiditis typically presents with a triphasic clinical course.
  • Hashimoto’s thyroiditis presents similarly, without the final euthyroid phase.
  • Phases:
    • Hashitoxicosis: initial transient hyperthyroidism
    • Subclinical hypothyroidism: 
      • Gradual loss of thyroid function
      • Asymptomatic
    • Overt hypothyroidism

Manifestations

Hypothyroidism common symptoms:

  • Fatigue, cold intolerance, weight gain
  • Dry skin, hair loss
  • Difficulty concentrating and poor memory
  • Hoarse voice, impaired hearing
  • Constipation
  • Menstrual irregularities (menorrhagia, then oligomenorrhea or amenorrhea)
  • Paresthesia

Hypothyroidism common signs:

  • +/- Goiter (some glands are atrophic in later stages)
  • Dry, coarse skin; alopecia; cool extremities
  • Puffy face, hands, and feet (nonpitting edema/myxedema)
  • Bradycardia
  • Delayed relaxation of tendon reflexes
  • Carpal tunnel syndrome

Diagnosis

Initial evaluation

  • Thyroid hormone levels will differ in each phase:
    • Hashitoxicosis: ↓ TSH + ↑ free T3/T4
    • Subclinical hypothyroidism: ↑ TSH + normal free T3/T4 
    • Overt hypothyroidism: ↑ TSH + ↓  free T3/T4 
  • Positive anti-thyroid peroxidase (TPO) and anti-thyroglobulin antibodies (Tg): 
    • Noted in > 95% of cases of Hashimoto’s thyroiditis
    • Antibodies may predict the progression to overt hypothyroidism.

Additional tests

  • Laboratory tests:
    • ↑ Cholesterol, triglycerides
    • CBC shows normocytic anemia.
  • Imaging:
    • Not necessary for diagnosis
    • Obtained in cases of asymmetric goiter and/or + suspicion of nodules
    • Tests:
      • Radioactive iodine uptake (RAIU): low uptake (cold thyroid)
      • Ultrasound: hypertrophic enlargement or atrophic reduction depending on the type and phase. 
  • Fine needle aspiration:
    • If there is a dominant nodule or suspicion of malignancy
    • Shows Hurthle cells and lymphocytic infiltration with germinal centers
Thyroid uptake scan

Thyroid uptake scans (thyroiditis versus other thyroid diseases):
A: normal
B: Graves’ disease: diffuse increased uptake in both thyroid lobes
C: toxic multinodular goiter: “hot” and “cold” areas of uneven uptake
D: toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid
E: thyroiditis: decreased or absent uptake

Image: “Technetium 99” by Endocrine Unit, Freeman Hospital, Newcastle upon Tyne, United Kingdom. License: CC BY 4.0

Management and Complications

Thyroid-replacement therapy

  • Levothyroxine: synthetic form of T4 that is peripherally converted to T3
  • Dosage: 
    • 1.6 mcg/kg body weight per day in young and healthy patients 
    • Starting dose of 25 mcg per day in the elderly
    • Different dose for pediatric population
  • Duration: lifetime
  • Absorption reduced by antacids, iron, calcium
  • Measure TSH after 6 weeks, and adjust the dose.
Management algorithm of hashimoto

Schematic diagram of the management of Hashimoto’s thyroiditis:
Note that the adjustments depend on TSH levels.

Image by Lecturio.

Complications

  • Myxedema coma: severe hypothyroidism characterized by slowing function of multiple organs
    • Considered a medical emergency 
    • Can lead to shock and death (mortality rate up to 50%)
  • Patients with Hashimoto’s thyroiditis have increased risk of:
    • Other autoimmune disease (e.g., type 1 diabetes mellitus, autoimmune adrenalitis)
    • B cell lymphoma of the thyroid gland

Differential Diagnosis

  • Granulomatous thyroiditis (De Quervain’s syndrome): thyroid inflammation usually associated with a previous viral infection and the most common cause of thyroid pain. Presentation includes neck tenderness with goiter. Work-up shows low TSH, elevated free T4, increased sedimentation rate, and a low or absent radioactive iodine uptake. Often a self-limited course that can go through a hyperthyroid state and then a euthyroid state followed by hypothyroidism. Recovery to normal thyroid function takes months.
  • Subacute lymphocytic thyroiditis (painless thyroiditis): an autoimmune disease with diffuse enlargement of the thyroid gland. The same process occurs in postpartum thyroiditis. Laboratory tests depend on the phase of the disease but the initial hyperthyroidism shows low TSH and elevated T4. The condition is associated with a low radioactive iodine uptake. The disease pattern is a transient hyperthyroid state and then hypothyroid followed by recovery. Some cases do not become euthyroid, however.
  • Riedel’s thyroiditis: rare form of thyroiditis characterized by extensive fibrosis of the thyroid gland and neck area. Riedel’s thyroiditis differs from Hashimoto’s thyroiditis, in which fibrosis does not extend beyond the capsule. Examination will show a hard, fixed thyroid gland, which is associated with other sites of fibrosis in the body.
  • Hypopituitarism: a disorder characterized by a deficiency in the pituitary hormone production, which results from disease of the hypothalamus or the pituitary gland itself. Hypofunction results in reduced secretion of growth hormone, TSH, gonadotropins, prolactin, and adrenocorticotropic hormone, which produces a complex syndrome depending on the hormones affected.

References

  1. Davies, T. (2020). Pathogenesis of Hashimoto’s thyroiditis (chronic autoimmune thyroiditis). UpToDate. Retrieved February 11, 2021, from https://www.uptodate.com/contents/pathogenesis-of-hashimotos-thyroiditis-chronic-autoimmune-thyroiditis
  2. Lee, S., Nagelberg, S. (2020). Hashimoto Thyroiditis. Medscape. Retrieved January 25, 2021, from  https://emedicine.medscape.com/article/120937-overview 
  3. Maitra, A. (2021). The Endocrine System. Kumar V., Abbas, A., Aster, J. , Robbins & Cotran Pathologic Basis of Disease, 10e. Elsevier.

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