Written by Dr. Sanjana V.B Bhms,dbrm,cdn

Founder & medical director of siahmsr wellness.in

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Reviewed by SIAHMSR medical team.

 Thyroid is an important gland vulnerable to autoimmune attack by immune cells. Autoimmune thyroid diseases [ AITDs] affect 2 - 5% of the population with great variability between genders (i.e., women 5–15% and men 1–5%). Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are important autoimmune diseases affecting thyroid. They are the leading causes of hypothyroidism and hyperthyroidism, respectively [1, 2].

Autoimmune thyroid diseases (AITDs) are the most common autoimmune diseases, affecting approximately 5% of the general population, with a female gender predominance.

Causes of autoimmune thyroid diseases

  The etiology of AITDs is complex and multifactorial, as environmental and genetic factors contribute to thyroid autoimmunity. Genetic factors pose 80% risk for developing AITDs, while the remaining 20% is due to environmental factors such as iodine, drugs, infection, stress, radiation.

  The major genes related to AITDs include thyroid-specific genes and immune-regulatory genes. The thyroid-stimulating hormone receptor (TSHR) gene, located on chromosome 14q31, seems to be responsible for causing Graves’ disease. Other genes associated with Graves’ s disease include CD25 and CD40 genes, located on chromosome 10p15 and 22q11.

 Hashimoto’s thyroiditis[HT]  is caused by  an abnormal humoral (autoantibodies) and cellular immune response against thyroid autoantigens, with the contribution of genetic and environmental factors.

Thyroid cancers and thyroid autoimmunity

  A few research studies have suggested that thyroid cancer coexists with autoimmune thyroid diseases like Hashimoto Thyroiditis (HT) and Graves’ disease (GD).

 Thyroid cancer and thyroid autoimmunity seem to be situated at opposite extremes of the immune response spectrum. That means, in thyroid cancer the immune response seems tolerant, allowing for tumor growth. In thyroid autoimmunity the immune response is apparently destructive, ending in thyroid failure. However, several studies show that autoimmune thyroid diseases are linked to thyroid cancers.

  The interplay between autoimmunity and cancer recently became a hot topic of study & discussion after the introduction of “immune check-point inhibitors” for cancer treatment. These cancer immunotherapeutic drugs are now clearly associated with endocrine immune-related adverse effects like autoimmune thyroid diseases and type 1 diabetes [3].

   Cytological studies show that thyroid cancer is usually surrounded by a significant number of immune “reactive” cells. Tumor associated leucocytes and macrophages (TAL and TAM) are frequently described in pathology reports of patients operated for thyroid cancer. Macrophages play a crucial role in the progression/regression of cancer.

 Macrophage phenotype which stimulates tumor growth is M2/repair type whereas macrophages which inhibit/slow the tumor growth are M1/kill-type.

Silent and overt autoimmune thyroid disorders & development of thyroid cancer

   The risk of developing thyroid cancer is higher in patients with a silent form of autoimmune thyroid disease – For example, euthyroid Hashimoto Thyroiditis. The risk is enhanced in patients with functional thyroid and undetectable/low titers of thyroid peroxidase antibodies (TPO), while the risk for cancer is diminished in patients with total thyroid failure and high TPO antibody titers[4].

Hashimoto’s thyroiditis[HT] and Euthyroid Hashimoto’s thyroiditis

  HT & EHT are phenotypically different thyroid autoimmune diseases. In HT, thyroid glands have lymphocytic infiltrates functionally different than those accompanying thyroid cancers in EHT. Lymphocytes present in HT are mainly effector cells while lymphocytes accompanying thyroid cancer in EHT appear to be inactive and under immune regulation.

Graves’ disease &thyroid cancers

 Some studies point out that thyroid cancer coexisting with another form of autoimmune thyroid disease - Graves’ disease are more frequent and aggressive as compared to that found in patients without Graves [5].  However, considerable controversy also exists regarding the cancer cell behavior in Graves’ s disease.

The close relationship of TSH to the stimulating TSH-R antibodies (TSH-R AB) seen in Graves' disease has been led to the assumption that thyroid cancer occurring with Graves' disease may become more aggressive as a result of stimulation by these autoantibodies.

  In Graves’ disease, the presence of functionally active NK cells and higher M1/M2 macrophage ratio may provide Graves’ patients with a more effective form of tumor immunity.

However, in the absence/low count of active NK cells, macrophage plasticity allows M0 to differentiate to the M2 phenotype. This may explain the higher risk of thyroid cancer in Euthyroid Hashimoto’s thyroiditis EHT.

   According to biomed central The presence of a strong humoral autoimmune response in the form of high antibodies such as TPO-Ab, Tg-Ab and TR-Ab titers appears to be protective from Differentiated thyroid cancers DTC such as papillary carcinoma in patients with Graves’s disease [3].

Hashimoto’s thyroiditis& occurrence of thyroid cancers

  The complex relations between Hashimoto’s thyroiditis and papillary thyroid carcinoma PTC are still debated. The studies provide evidence that multiple factors related to thyroid autoimmunity (serumanti thyroid antibodies ATA, inflammatory molecules, and free radicals with secondary RET/PTC rearrangements, genetic/environmental conditions, and increased TSH represent independent risk factors for papillary thyroid carcinoma [PTC], supporting the notion that overt HT rather than nonspecific serologic reactivity, may be linked to thyroid malignancy.

  Thus, thyroid autoimmunity could exert a promoting effect on thyroid tumor growth either directly or through secondary increase of TSH values as a consequence of initial autoimmune thyroid failure. so far, no causal genetic linkage has been confirmed.

   Evidences are consistent with the hypothesis that autoimmune thyroid inflammation is per se tumorigenic and Hashimoto’s Thyroiditis -related hypothyroidism may also cause tumor growth through TSH receptor stimulation.

As per FNAC studies, the association between Hashimoto’s thyroiditis [HT] and Papillary Thyroid carcinoma [PTC] is based on the comparison of anti-thyroid autoantibodies (ATA) (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb]), thyroid function (TSH), and cytology with histology of thyroid nodules and lymphocytic thyroid infiltration (LTI) of operated thyroid glands.

  Several studies provided a positive relationship between ATA and PTC, particularly with TgAb.

Two recent FNAC studies have clearly demonstrated an independent risk for thyroid malignancy conferred by both TPOAb and TgAb, confirming the role of increased TSH levels, and found a significant association between Papillary Thyroid Carcinoma and Anti Thyroid Antibodies and diffuse lymphocytic infiltration at histology.

Most of the pathological studies found a high prevalence rate of Papillary Thyroid Cancers in Hashimoto’s Thyroiditis.

References

1.       https://pubmed.ncbi.nlm.nih.gov/15030506/

https://www.hindawi.com/journals/crie/2020/5647273/

2.       Hashimoto’s Thyroiditis and Graves’ Disease in Genetic Syndromes in Pediatric Age  https://www.mdpi.com/2073-4425/12/2/222

3.       https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0483-y

4.       Romero P, Dunbar PR, Valmori D, Pittet M, Ogg GS, Rimoldi D, et al. Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med. 1998;188:1641–50[googlescholar].

5.       https://pubmed.ncbi.nlm.nih.gov/14605602/

6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567004/

7. Iliadou PK, Effraimidis G, Konstantinos M, Grigorios P, Mitsakis P, Patakiouta F, Pazaitou-Panayiotou K. Chronic lymphocytic thyroiditis is associated with invasive characteristics of differentiated thyroid carcinoma in children and adolescents. Eur J Endocrinol. 2015;173:827–833. https://pubmed.ncbi.nlm.nih.gov/26369577/