What causes Hashimoto's disease?

Causes of Hashimoto's Thyroiditis

Hashimoto's thyroiditis is primarily caused by a complex interplay of genetic susceptibility, environmental triggers, and autoimmune mechanisms that lead to T-cell and B-cell mediated destruction of the thyroid gland. 1

Genetic Factors

• Genetic predisposition plays a crucial role in the development of Hashimoto's thyroiditis:
  • Strong HLA associations, particularly with HLA-DR/DQ genes that can be either predisposing or protective 2
  • Family history is significant, with up to 42% of patients reporting family history of the condition 1
  • X-chromosome inactivation patterns contribute to the female predominance (7-10 times more common in women than men) 3
  • Genetic polymorphisms of vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1α-hydroxylase (CYP1α) may predispose to Hashimoto's development 4

Autoimmune Mechanisms

• Autoimmune destruction of thyroid cells occurs through:
  • Cellular immunity: T-cell inflammatory infiltration of the thyroid gland 5
  • Humoral immunity: Production of thyroid-specific autoantibodies 1
    • Anti-thyroid peroxidase antibodies (TPO-Ab)
    • Anti-thyroglobulin antibodies (TG-Ab)
  • Abnormal expression of MHC class II surface HLA-DR antigens on thyrocytes 4
  • Production of inflammatory cytokines (especially IFN-γ) by T helper (Th1) lymphocytes 4

Environmental Triggers

Several environmental factors have been implicated in triggering Hashimoto's thyroiditis:

• Iodine intake: Excessive iodine consumption may trigger autoimmune thyroiditis in genetically susceptible individuals 2, 6
• Infections: Various bacterial and viral infections may serve as triggers 6
• Vitamin D deficiency: Significantly associated with Hashimoto's thyroiditis development due to vitamin D's immunomodulatory role 4
• Stress: Psychological stress may contribute to immune dysregulation 6
• Microbiome composition: Alterations in gut microbiota may influence autoimmune processes 3

Associated Conditions

Hashimoto's thyroiditis frequently coexists with other autoimmune disorders:

• Other autoimmune thyroid diseases (10-23% of patients) 1
• Systemic lupus erythematosus (2.8-3% of patients) 1
• Sjögren syndrome (2.8-7% of patients) 1
• Rheumatoid arthritis (2-4% of patients) 1
• Inflammatory bowel disease (2-11.4% of patients) 1
• Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia 2

Pathophysiological Process

The pathogenesis involves a sequential process:

1. Initial genetic susceptibility and environmental trigger exposure
2. Loss of self-tolerance to thyroid antigens
3. Infiltration of thyroid by lymphocytes and formation of lymphoid follicles with germinal centers 5
4. Production of thyroid-specific autoantibodies
5. Progressive destruction of thyrocytes leading to parenchymal atrophy 5
6. Development of hypothyroidism as the gland's ability to produce hormones diminishes

Clinical Implications

The understanding of these causal factors has important clinical implications:

• Screening for vitamin D deficiency and supplementation may be beneficial for patients with Hashimoto's thyroiditis 4
• Monitoring for other autoimmune conditions is warranted in patients with Hashimoto's thyroiditis
• TPO antibody status may influence treatment outcomes and should be tested alongside TSH and Free T4 1
• 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 3

Understanding these multifactorial causes helps guide appropriate monitoring and management of patients with Hashimoto's thyroiditis to improve morbidity, mortality, and quality of life outcomes.