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 postpartum thyroiditis (PPT) is not completely understood. However, studies have shown that PPT is an autoimmune disorder in which thyroid tissue antigens are recognized as non-self-antigens. The immune cells mediate inflammatory response to thyroid gland leading to its destruction. This destruction is followed by sudden release of stored thyroid hormone in blood and the appearance of clinical as well as laboratory picture of hyperthyroidism transiently. This is followed by recovery to euthyroid or hypothyroid state depending on the extent of destruction of thyroid gland, persistence of inflammatory state, and recovery strength of gland. Pregnancy is understood to be associated with reduced immunity to protect fetus from unwanted exposure to maternal immune system. At the end of pregnancy the suppressed immunity is suddenly escalated, leading to the slow evolution of autoimmune response to thyroid auto-antigens, resulting in thyroiditis. The search of exact auto-antibody and auto-antigens triggering an autoimmune response, which correlates with a clinical and pathological picture of postpartum thyroiditis, is still ongoing. Thyroid peroxidase (TPO) auto-antibody is significantly associated with the pathogenesis of postpartum thyroiditis.
Pathophysiology
Pathophysiology:
The normal physiology of thyroid gland and thyroid hormones can be understood as under:
- Thyroid is an endocrine gland which synthesizes and secretes thyroid hormones directly in the bloodstream.
- Thyroid hormones regulated by hypothalamus and pituitary gland.
- Thyroid hormones are of two biochemical structures. Triiodothyronine (T3), which is true as well as potent form of thyroid hormone. Thyroxine (T4), which is a pro-hormone, primarily found in secretory form later converted to T3 in peripheral tissues by deiodinase enzyme.
- Thyroid hormones have a negative feedback on thyroid hormone receptors located on the hypothalamus and pituitary gland.
- Thyroid hormones may effect any part of body and maintain metabolic rate by acting on thyroid receptors which are nuclear receptors mediating gene expression.
- Functional unit of thyroid gland are thyroid follicles, which are aliened in continuous circular pattern forming a hollow cavity (thyroid cavity) between them. Connective tissue containing blood vessels is seen on the basal side of thyroid follicle and is responsible for the transport of thyroid hormone, blood cells, and iodine. Apical side of thyroid follicle faces towards thyroid cavity where TPO enzymes are located, which help in the conversion of iodide to iodine.
- Iodine is organified to tyrosine residue of thyroglobulin, which is synthesized and stored in thyroid follicle cavity.
- This leads to the formation of mono-idodo or di-iodo thyroglobulin which combine to form tri-iodo or tetra-iodo thyroglobulin.
- On demand, thyroglobin is proteolysed to release T3 and T4 in blood stream across the thyroid follicle.
Pathogenesis:
- Pregnancy is associated with a modification of immune system making it possible to accept alloantigens of paternal origin.
- This challenge is overcome by dormant set of regulatory T cells, CD25 CD4 positive, a subset of T helper cells, which withholds T cell sensitization to fetal antigens.[1][2]
- This does not suppress immunity but modulates immune response to fetal alloantigen.
- Successful implantation of fetus in uterine cavity requires adequate NK cell, dendritic cell, macrophages, T cell, and B cells.[3]
- Subsequently on first postpartum day there is a significant decline in T regulatiory cells leading to the elevation of CD4 T cells. CD4 T cells potentiate immune as well as autoimmune responses to foreign and self-antigens.[4]
- Role of anti-TPO antibodies and anti-thyroglobulin antibodies:
- TPO is found inside the thyroid follicles. Anti-TPO antibodies have therefore been associated with PPT.
- Rebound escalation of immunity in postpartum period leads to the development of anti TPO antibodies and immune complex formation of anti-TPO antibody-antigen. Subsequent activation of inflammatory response targeted against these antibodies leads to destruction of thyroid tissue.
- In contrast to Hashimoto throiditis, the presence of anti-thyroglobulin antibody is inconsistent with occurrence of PPT.
- The level of anti-TPO antibodies is not proportional to thyroid destruction.
- Anti-TPO antibodies are IgG antibodies containng 4 subgroups:
- The level of hypothyroidism is related to the activation of complement cascade by IgG anti-TPO antibody-antigen complexes, either by complement fixation or direct activation of C3 esterase.[7]
- An increase in the levels of anti-TPO antibodies has also been observed with subsequent pregnancies.[8]
- Role of T-cell:
- In pregnancy, cortisol, progesterone, and estrogen levels are high.
- These hormones modify the levels of lymphocytes such as TH1, TH2, T reg, and NK-cells. Around 36th week of pregnancy, cortisol levels decline leading to increase in lymphocytes.[9]
- In PPT an increased ratio of CD4+ to CD8+ and increased activation of T-cells is found.[10]
- However, T cell secretes IL4, IL10, and interferon gamma which carry out destruction of thyroid gland.
- Interestingly, T reg secreting TGF-beta is found in high levels in thyrotoxicosis stage of PPT, preventing CD4 T cells and CD8 T cells from further destruction.[11]
Genetics
Genes involved in the pathogenesis of PPT include:[12]
- CT- 60 cytotoxic T- cell lymphocyte antigen-4 CTLA-4 gene polymorphisum (hypothyroid)[13]
- HLA-DR4
- HLA-DR3
- HLA-DR5
Associated Conditions
- DM type -1
- Grave's disease
- Autoimmune thyroiditis
- Postpartum thyroid dysfunction
- Postpartum depression
- Postpartum psychosis
Gross Pathology
On gross pathology, mild enlargement and absence of nodules are characteristic of postpartum thyroiditis.[14]
Microscopic Pathology
On microscopy, focal or diffuse lymphocytic infiltration, follicular destruction, and hyperplasia of follicles are characteristic findings of PPT.[15]
- Degree of destruction and hyperplasia of follicles varies with stages of postpartum thyroiditis
- Absence of fibrosis ( seen in Ridel's tyroiditis) and Hurthle cells (seen in Hashimoto's thyroiditis)
- Hyperplasia (hypothyroid stage)
- Lymphocytes found inside the follicles are not destructed
- T-cell activation levels and T reg cell levels are found on histopatholog of the specimen (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.