Is Hashimoto’s Hypothyroidism Genetic?
Chronic Autoimmune Thyroiditis or Hashimoto’s Thyroiditis(HT) is an inflammatory disease characterized by diffuse lymphocytic infiltration, fibrosis, and parenchymal atrophy. Hashimoto’s Thyroiditis is the most common cause of primary hypothyroidism which continues to be a common problem, especially in women.
Circulating autoantibodies against thyroglobulin and thyroid peroxidase (TPO) were present in almost all patients with autoimmune hypothyroidism. Thyroid Stimulating Hormone Receptor Antibody (TSH-R Ab) blocks the receptor instead of stimulating it as in graves’ diseases. In some cases of Hashimoto’s Thyroiditis, the exact mechanisms underlying autoimmune thyroiditis are not fully understood. The hypothesis relies on both genetic and environmental involvement.
Clinically, the disease can present as gradual thyroid failure, with or without goitre formation due to autoimmune-mediated apoptosis of the thyroid epithelial cells.
The typical markers of the disease, found in almost all cases are the antibodies against one or more thyroid antigens, diffuse lymphocytic infiltration of the thyroid (predominantly thyroid-specific Band T cells), and follicular destruction, which is the characteristic sign of thyroiditis.
The epidemiology of Hashimoto’s Thyroiditis is related to other autoimmune diseases affecting other endocrine organs. However, Hashimoto’s Thyroiditis is by far the most common endocrine autoimmune disease.
Hashimoto’s Thyroiditis also primarily affects middle-aged women, can occur in men and women of all ages as well as children, and has recently been recognized as the most common cause of pediatric thyroid disease. Autoimmunity review by Cooper et al. in 2003 83% of cases were estimated to be female.
Autoimmune thyroid diseases (AITD) result from the complex interplay of exogenous and endogenous factors. The cause of Hashimoto’s thyroiditis is thought to be a mix between genetic susceptibility and environmental factors.
The familial association with Graves’ disease (GD) and the undeniable fact that Graves’ Disease and Hashimoto’s Thyroiditis may sometimes evolve into one another proves that the two disorders are closely related. It is observed that many patients are prone to familial aggregation of Hashimoto’s thyroiditis.
Genetic factors have been related to susceptibility in 70% to 80% while environmental factors have been demonstrated only in 20% to 30% of cases of Autoimmune Thyroid Disease. Relatives of Autoimmune Thyroid Disease patients carry a high risk of contracting the disease themselves.
Advances in genetic techniques have led to significant advances in the diagnosis of complex diseases using new genetic techniques. In the diagnosis of complex autoimmune diseases, such as Autoimmune Thyroid Disease, four phases are described: Phase 1- candidate gene analyses; Phase 2 is a genome-wide linkage study; Phase 3- genome-wide association studies (GWAS); Phase 4 is whole genome sequencing. In Autoimmune Thyroid Disease, major thyroid antigens are implicated in thyroid autoimmunity.
TSH-R mRNA has also been detected in other tissues, and although the role of TSH in most tissues is unclear, data suggest that TSH may regulate bone cell and adipocyte function. Post-ocular expression of TSH-R is associated with thyroid eye disease (graves orbitopathy) and anterior tibialmyxoma (thyroid dermatopathy).
Other genes such as HLA-DR3 and, in some cases, HLA-DR4 are susceptible to Graves’ Disease and Hashimoto’s Thyroiditis. The cytotoxic T lymphocyte-associated protein 4 (CTLA-4) genes, a member of the immunoglobulin family, are also associated with Hashimoto’s Thyroiditis. The mechanism is to encode a protein that sends an inhibitory signal to the T cell. Mutations in this gene have been associated with T1D, Graves’ Disease, Hashimoto’s Thyroiditis, celiac disease, systemic lupus erythematosus(SLE), and other autoimmune diseases. It is reported that high production of IFN-gamma and low production of IL-4 are more common in patients with severe Hashimoto’s Thyroiditis than in patients with mild H.
New analytical approaches will reveal many other genes that may represent small etiological contributions to clinical symptom variability. For example, combinations of novel genetic markers have been investigated, and the results show an association of TPO-Ab positivity with an increased risk of hypothyroidism. The MAGI3 gene has been studied as a marker that can predict whether TPO-Ab- positive patients are particularly at risk of developing clinical thyroid dysfunction. The importance of genetic factors causing autoimmune hypothyroidism is indicated by the frequent presence of thyroid antibodies and other autoimmune diseases in relatives. Scientific data has been demonstrated in twin studies showing a high concordance rate (0.55) in identical twins.
One such example is the famous Danish study, which found that the concordance of identical twins was between 30% and 60%. Siblings have been shown to have a higher risk of recidivism than 20.
The role of T cells in the pathophysiology of Hashimoto’s thyroiditis
One of the key steps in pathogenesis is the activation of autoreactive CD4+ T cells.T helper (Th) cells specific for thyroid autoantigens. Th type 1 (Th1) cells activate cytotoxic T lymphocytes (CD8+ lymphocytes) and macrophages that directly destroy thyroid follicle cells. Th1 and Th2 T helper cell subsets influence damage patterns and outcomes in Autoimmune Thyroid Disease. Immune responses that increase Th1 or Th2 reflect different inflammatory pathways and disease outcomes.
Many studies confirm an increase in Th1 cells in patients with severe Hashimoto’s Thyroiditis(p<0.05) and an increase in Th2 cells in patients with mild Hashimoto’s Thyroiditis (p<0.001). Thus, the Th1/Th2 ratio is considered an important prognostic factor.
Another subset of Th cells that play a role in the development and progression of chronic inflammation and tissue damage in Hashimoto’s Thyroiditis are Th17 cells. A higher proportion of Th17 cells and higher cytokine levels were detected in Hashimoto’s Thyroiditis patients than in healthy controls in peripheral blood and thyroid tissue.
T- Regulatory cells (Treg) have also been observed to accumulate in the thyroid tissue of Hashimoto’s Thyroiditis patients. They have shown an immunosuppressive role in the pathogenesis of Hashimoto’s Thyroiditis, contributing to the autoimmune destruction of thyroid tissue.
Several environmental factors are also associated with a high incidence of Hashimoto’s Thyroiditis. The thyroid gland is rich in selenium and contains more per gram of tissue than any other organ in our body. Low levels of selenium are associated with decreased immune function and a higher prevalence of viral infections.
Selenium intake was therefore thougHashimoto’s Thyroiditis to help the immune system by reducing TPO antibody levels. This has been tested in several studies, but the results were not significantly different from the placebo group.
One of the most recent studies of this type was conducted by De Farias et al in 2015 (25). Further studies are needed to establish a link between low selenium intake and Hashimoto’s Thyroiditis. Low levels of vitamin D have been identified as risk factors for several autoimmune diseases (T1D, rheumatoid arthritis, and multiple sclerosis).
There have been many cross-sectional studies evaluating the relationship between blood vitamin D levels and Autoimmune Thyroid Disease, but the results have been inconsistent. The only prospective study in this area failed to confirm these data showing that vitamin D deficiency is not associated with the early stages of thyroid autoimmunity.
Mild iodine deficiency is associated with a lower prevalence of Hashimoto’s thyroiditis and hypothyroidism, whereas excessive iodine intake is associated with a higher prevalence. For example, in China, Autoimmune Thyroid Disease was found in 0.3% of iodine-deficient and 1.3% of the iodine-excess individual. Similarly, iodine-rich drugs such as amiodarone often cause autoimmune thyroiditis.
In some cases, excessive maternal iodine intake has been shown to cause hypothyroidism in infants. A balance of oxidants and antioxidants is essential for optimal thyroid function. High oxidative stress is also implicated in the pathogenesis of thyroid cancer. This explains the evolution of Hashimoto’s Thyroiditis in thyroid cancer as described in the literature. Environmental and lifestyle factors are known to affect the balance between oxidants and antioxidants.
Exposure to exogenous sources of oxidants such as cigarette smoke, ozone, ionizing radiation, heavy metal ions, poor diet, and reduced physical activity induce oxidative stress.
However, further investigations are needed to confirm that environmental factors influence the pathogenesis of Hashimoto’s Thyroiditis and do not trigger in the genetically predisposed host.
Hence, it is concluded that Genetic factors play an important role in the development of Hashimoto’s Thyroiditis. This leads to a familial set of diseases. One of the critical steps in pathogenesis is the activation of autoreactive CD4+ T cells.
Environmental factors can cause disease in genetically predisposed patients. Further studies are needed to conclude whether they have independent effects on disease. Although there are reports of an increased incidence of Hashimoto’s Thyroiditis today, it is important to note that the disease has only been diagnosed relatively recently and awareness is growing.
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