What is the pathophysiology of Hashimoto's (Hashimoto's thyroiditis) thyroiditis?

Pathophysiology of Hashimoto's Thyroiditis

Hashimoto's thyroiditis is an autoimmune disorder characterized by chronic lymphocytic infiltration of the thyroid gland leading to progressive destruction of thyroid tissue and eventual hypothyroidism. The pathophysiology of Hashimoto's thyroiditis involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation resulting in a T-cell mediated autoimmune attack against thyroid tissue.

Genetic Factors

• Hashimoto's thyroiditis has a strong genetic component with specific HLA associations, particularly HLA-DR/DQ alleles that can be either predisposing or protective 1
• Family history of autoimmune disorders significantly increases risk, as Hashimoto's thyroiditis often clusters with other autoimmune conditions 1, 2
• Genome-wide association studies have identified specific genetic loci associated with autoimmune thyroid disorders, including genes involved in immune function and barrier integrity 1, 3
• Women are affected 7-10 times more frequently than men, suggesting X-chromosome inactivation patterns play a role in disease susceptibility 2

Immune Mechanisms

• The primary pathogenic mechanism involves loss of self-tolerance leading to an autoimmune response against thyroid antigens 3
• T-cell mediated immunity plays the central role, with excessive stimulation of CD4+ T cells and their differentiated cells 4
• The immune response is predominantly T-helper type 1 (Th1) and Th17 driven, with production of inflammatory cytokines 3
• B cells produce autoantibodies against thyroid peroxidase (TPOAbs) and thyroglobulin (TgAbs), which serve as diagnostic markers and contribute to thyroid destruction 2, 5
• Antigen-presenting cells present thyroid antigens to T cells, initiating the autoimmune cascade 3

Thyroid Destruction Process

• Lymphocytic infiltration of the thyroid gland is the hallmark histopathological feature 5
• Progressive destruction of thyrocytes occurs through multiple mechanisms:
  • Antibody-mediated cytotoxicity via TPOAbs 2
  • T-cell mediated cytotoxicity 3
  • Apoptotic processes triggered by inflammatory cytokines 3
• This gradual destruction leads to reduced thyroid hormone production and eventually clinical hypothyroidism 2

Environmental Triggers

• Environmental factors that may trigger Hashimoto's thyroiditis in genetically susceptible individuals include:
  • Infections that may initiate autoimmunity through molecular mimicry, where viral or bacterial peptides activate T cells specific for thyroid antigens 1
  • Medications, particularly immune checkpoint inhibitors used in cancer treatment 1
  • Iodine intake (both excessive and deficient) can influence disease development 4
  • Gut microbiome composition may contribute to disease development by affecting immune regulation 4

Clinical Progression

• The clinical course of Hashimoto's thyroiditis typically progresses through several phases:
  • Initial thyrotoxicosis (Hashitoxicosis) when stored thyroid hormones are released from destroyed follicles 2
  • Euthyroid phase when preserved thyroid tissue compensates for destroyed thyrocytes 2
  • Progressive hypothyroidism as thyroid destruction continues and hormone production becomes insufficient 2, 5

Associated Conditions

• Hashimoto's thyroiditis frequently coexists with other autoimmune disorders:
  • Type 1 diabetes mellitus, celiac disease, autoimmune hepatitis 1
  • Systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome 1
  • Vitiligo, alopecia 5
• Patients with Hashimoto's thyroiditis have a 1.6 times higher risk of papillary thyroid cancer and 60 times higher risk of thyroid lymphoma compared to the general population 2

Understanding the complex pathophysiology of Hashimoto's thyroiditis is essential for proper diagnosis, treatment, and management of this common autoimmune thyroid disorder.