Postpartum thyroiditis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]
Overview
The exact pathogenesis of pppostpartum thyroiditis[[ "PPT" is not fully understood. However, studies have shown that it is an autoimmune disorder in which thyroid tissue antigens are recognized as non-self-antigens and our immune cells mediate inflammatory response to thyroid gland and destroy it, then lead to sudden release of stored thyroid hormone in blood and appearance of clinical and laboratory hyperthyroid picture transiently followed by recovery to euthyroid state or hypothyroid state depending on level of destruction of thyroid gland, persistence of inflammatory state, and recovery strength of gland. Studies have also shown that pregnancy is stage of reduced immunity to protect fetus from unwanted exposure of immunity which at the end of pregnancy escalate sudden immunity, leading to beginning of slowly evolving autoimmune response to thyroid auto-antigens, in rapid sequences and appearance of thyroiditis. Studies are going on in search of exact auto-antibody and auto-antigens triggering an autoimmune response, which correlates with a clinical and pathological picture of postpartum thyroiditis. TPO auto-antibody is significantly linked to occurrence of postpartum thyroiditis.
Pathophysiology
Pathophysiology:
- Thyroid is endocrine gland which synthase and secretes thyroid hormones in bloodstream directly.
- It is regulated by hypothalamus and pituitary gland.
- Thyroid hormones are of two biochemical structures. , triiodothyronine (T3), which is true and potent form and its pro-hormone, thyroxine (T4) majorly is secretory form later converted to T3 in peripheral tissues by deiodinase enzyme.
- Thyroid hormones has negative feedback on thyroid receptors located on hypothalamus and pituitary gland.
- Thyroid hormones majorly effects every part of body and maintains metabolic rate by acting on thyroid receptors which are nuclear receptors mediating gene expression.
- Functional unit of thyroid gland is thyroid follicles, which are aliened in continuous circular form forming hallow cavity between them called thyroid cavity. On basal side of thyroid follicle is connective tissue containing blood vessels for transport of thyroid hormone and blood cells and iodine. Apical side of thyroid follicle faces toward thyroid cavity where it has TPO enzymes located, which help in conversion of iodide to iodine. Iodine is organified to tyrosine residue of thyroglobin, which is synthesized and stored in thyroid follicle cavity. It forms mono-idodo or di-iodo thyroglobin and then they combine to form tri-iodo or trata-iodo thyroglobin. On demand of body thyroglobin goes in proteolysis and release T3,T4 in blood stream across thyroid follicle.
Pathogensis:
- Pregnancy is challenging for body immune system to accept alloantigen of paternal origin.
- It is overcome by dormant set of regulatory T cells[1] CD25 CD 4 positive, a subset of T helper cell, which withholds T cell sensitization to fetal antigens[2].
- However it does not suppress immunity but modulates towards fetal alloantigen.
- In fact, successful implantation of fetus in uterine cavity requires adequate NK cell, dendritic cell, macrophages, T cell, and B cells.[3]
- Subsequently after delivery on first day there is significant decline in T reg cells and this elevates CD4 T cells and so forth immune and autoimmune responses to foreign and self-antigens.[4]
- Role of anti-TPO abs and anti-thyroglobin abs:
- TPO is found inside functional unit of thyroid gland Thyroid follicle.
- Significant evidence has proven that Anti- TPO antibodies has been seen occurring with PPT.
- Rebound escalation of immunity in postpartum period leads to development and immune complex formation of Anti-TPO antibody-antigen, subsequent activation of inflammatory response leading to destruction of Thyroid tissue.
- In contrast to Hashimoto throiditis there is significant data suggesting that anti-thyroglobin presence is inconsistent with occurrence of PPT.
- Levels of Anti- TPO antibody are not consistent with thyroid destruction.
- Anti TPO antibody are IgG, which has 4 subgroups.
- IgG 1 been seen with activation of complements and destructive lysis of thyroid follicular cells.[5]
- Subsets 2 and 3 are under studies with conflicting outcomes.
- IgG subset 4 has been not found with occurrence of PPT.[6]
- There are studies suggesting that level of hypothyroidism is related to activation of complement cascade by IgG Anti-TPO antibody-antigen either by complement fixation or direct activation of C3 esterase.[7]
- It has also been observed that with subsequent pregnancies the levels of anti-TPO antibody are increasing.[8]
- Role of T-cell :
- In pregnancy, cortisol, progesterone and estrogen levels are high and they modifies the levels of Lymphocytes as TH1 TH2 T reg NK-cells and around 36 weeks of pregnancy cortisol levels declines leading to increase in lymphocytes.[9]
- While studies have shown that in PPT there is increased ratio of CD4+/CD8+, increased activation of T-cells and increased.[10]
- However T cell secrets IL4 IL10 and interferon Gamma which carries out destruction in thyroid gland.
- Interestingly T reg secreting TGF-beta is found in high levels in Thyrotoxicosis stage of PPT, suppressing CD4 T cells and CD8 T cells from further destruction.[11]
Genetics
- Genes involved in the pathenogenesis of PPT include[12]
- CT- 60 Cytotoxic T- cell Lymphocyte Antigen-4 CTLA-4 gene polymorphisum showing evidences of developing more hypothyroid cases.[13]
- HLA DR 4
- HLA DR 3
- HLA DR5.
Associated Conditions
Postpartum thyroid dysfunction
Gross Pathology[14]
- On gross pathology mild enlargement, no nodules, and painless are characteristic findings of Postpartum thyroiditis.
Microscopic Pathology[15]
- On microscopic picture focal or diffuse lymphocytic infiltration, follicular destruction, and hyperplasia of follicles are characteristic findings of PPT.
- Degree of destruction and hyperplasia of follicles varies with stages of Postpartum thyroitis.
- Fibrosis and Hurthle cells are not seen
- Hyperplasia is responce to TRH secerated in responce to hypothyroid stage.
- Lymphocytes are found inside follicles are not destructive
- T-cell activation levels and T reg cell levels found in histology specimen are determinant of thyroid functional status.
References
- ↑ La Rocca C, Carbone F, Longobardi S, Matarese G (2014). "The [[immunology]] of [[pregnancy]]: regulatory [[T cells]] control maternal immune tolerance toward the [[fetus]]". Immunol Lett. 162 (1 Pt A): 41–8. doi:10.1016/j.imlet.2014.06.013. PMID 24996040. URL–wikilink conflict (help)
- ↑ Lima J, Martins C, Nunes G, Sousa MJ, Branco JC, Borrego LM (2017). "Regulatory T Cells Show Dynamic Behavior During Late Pregnancy, Delivery, and the Postpartum Period". Reprod Sci. 24 (7): 1025–1032. doi:10.1177/1933719116676395. PMID 28618983.
- ↑ Mor G, Cardenas I (2010). "The immune system in pregnancy: a unique complexity". Am J Reprod Immunol. 63 (6): 425–33. doi:10.1111/j.1600-0897.2010.00836.x. PMC 3025805. PMID 20367629.
- ↑ Lima J, Martins C, Nunes G, Sousa MJ, Branco JC, Borrego LM (2017). "Regulatory T Cells Show Dynamic Behavior During Late Pregnancy, Delivery, and the Postpartum Period". Reprod Sci. 24 (7): 1025–1032. doi:10.1177/1933719116676395. PMID 28618983.
- ↑ Briones-Urbina R, Parkes AB, Bogner U, Mariotti S, Walfish PG (1990). "Increase in antimicrosomal antibody-related IgG1 and IgG4, and titers of antithyroid peroxidase antibodies, but not antibody dependent cell-mediated cytotoxicity in post-partum thyroiditis with transient hyperthyroidism". J Endocrinol Invest. 13 (11): 879–86. PMID 2090668.
- ↑ Jansson R, Thompson PM, Clark F, McLachlan SM (1986). "Association between thyroid microsomal antibodies of subclass IgG-1 and hypothyroidism in autoimmune postpartum thyroiditis". Clin Exp Immunol. 63 (1): 80–6. PMC 1577331. PMID 3754185.
- ↑ Parkes AB, Othman S, Hall R, John R, Richards CJ, Lazarus JH (1994). "The role of complement in the pathogenesis of postpartum thyroiditis". J Clin Endocrinol Metab. 79 (2): 395–400. doi:10.1210/jcem.79.2.8045954. PMID 8045954.
- ↑ Chan WF, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, Nelson JL (2012). "Male microchimerism in the human female brain". PLoS One. 7 (9): e45592. doi:10.1371/journal.pone.0045592. PMC 3458919. PMID 23049819.
- ↑ Argatska AB, Nonchev BI (2014). "Postpartum thyroiditis". Folia Med (Plovdiv). 56 (3): 145–51. PMID 25434070.
- ↑ Stallmach A, Schäfer F, Hoffmann S, Weber S, Müller-Molaian I, Schneider T; et al. (1998). "Increased state of activation of CD4 positive T cells and elevated interferon gamma production in pouchitis". Gut. 43 (4): 499–505. PMC 1727291. PMID 9824577.
- ↑ Olivieri A, De Angelis S, Vaccari V, Valensise H, Magnani F, Stazi MA; et al. (2003). "Postpartum thyroiditis is associated with fluctuations in transforming growth factor-beta1 serum levels". J Clin Endocrinol Metab. 88 (3): 1280–4. doi:10.1210/jc.2002-020990. PMID 12629119.
- ↑ Lazarus JH, Ammari F, Oretti R, Parkes AB, Richards CJ, Harris B (1997). "Clinical aspects of recurrent postpartum thyroiditis". Br J Gen Pract. 47 (418): 305–8. PMC 1313006. PMID 9219408.
- ↑ Zaletel K, Krhin B, Gaberscek S, Bicek A, Pajic T, Hojker S (2010). "Association of CT60 cytotoxic T lymphocyte antigen-4 gene polymorphism with thyroid autoantibody production in patients with Hashimoto's and postpartum thyroiditis". Clin Exp Immunol. 161 (1): 41–7. doi:10.1111/j.1365-2249.2010.04113.x. PMC 2940147. PMID 20408864.
- ↑ Premawardhana LD, Parkes AB, Ammari F, John R, Darke C, Adams H; et al. (2000). "Postpartum thyroiditis and long-term thyroid status: prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity". J Clin Endocrinol Metab. 85 (1): 71–5. doi:10.1210/jcem.85.1.6227. PMID 10634366.
- ↑ Muller AF, Drexhage HA, Berghout A (2001). "Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care". Endocr Rev. 22 (5): 605–30. doi:10.1210/edrv.22.5.0441. PMID 11588143.