Hashimoto Thyroiditis; Pathogenesis, Mechanisms & Treatments
Hashimoto thyroiditis (HT) is a chronic disease, characterised by destruction of the thyroid gland by abnormal lymphocytic activation which targets self-tissues and leads to thyroid failure if left untreated (Cogni and Chiovato, 2013, p19).
There is a comprehensive presence of a lymphocytic infiltrate within the thyroid gland. There is an existence of circulating thyroid auto-antibodies, explicitly Thyroid Peroxidase autoantibodies (TPOAb) (Cogni and Chiovato, 2013). The lymphocytic infiltrate then becomes responsible for B and T cell lymphocyte autoreactivity leading to chronic disease of inflammatory origin (Cogni and Chiovato, 2013).
Dendritic cells (DC) are a type of antigen presenting cell (APC) which present immunogenic epitopes of thyroglobulin to T cells in a class two major histocompatibility complex (MHC-II) molecular environment (Cogni and Chiovato, 2013). The upregulation of T Cells and the types of T Cells secreted by DCs lead to the transmission of a whole host of cytokines; this in turn initiates the immune response in AITD. A Th1, Th2 and Th17 response is instigated leading to the secretion of pro-inflammatory cytokines namely IFN-γ, IL-4, IL-10, IL-12, IL-17 and TNF-α. It’s clear that in the pathophysiological processes of AITD, Th1 and Th17 infiltration of thyrocytes lead to perpetual inflammation (Cogni and Chiovato, 2013; Batelli, E. et al, 2007). CD4+ T cells are the main lymphocytic cells present in thyrocytes, characterised by a rich T effector and T regulatory cell population of a heterogeneous composition (Cogni and Chiovato, 2013, pp19-20). The induction of T-cell autoreactivity and an inflammatory response; eventually leads to thyrocyte injury and apoptosis (Swain et al., 2005). The MHC-II molecule expressed in the thyroid follicles can be stimulated by viral infections. Viruses behave as non-professional APCs (express only MHC-I molecular environment) and present themselves as well as foreign antigens triggering the autoimmune response (Ranganathan and Thiagarajan, 2015; Desailloud, R. and Hober, D. 2009).
T helper (Th) cells are responsible for stimulating B cells and plasma cells in the production of antithyroid antibodies. The most common antithyroid auto-antibodies found are TPOAb and Thyroglobulin antibodies (TgAb). Due to the expansive response of thyroid specific CD4+ T cells which appear to upregulate IFN-γ. IFN-γ results in the enhanced expression of MHC-II molecules on thyrocytes leading to the recruitment of autoreactive B lymphocytes which are receptive to the circulating thyroid autoantibodies for which new epitopes are born in to existence (TPOAb). Whereas, TgAb is usually involved in ADCC (antibody mediated cytotoxicity) (Swain et al., 2005, p12).
The T cell response by way of CD4+, CD8+ and an increase in T cell activation markers such as HLA (Human Leukocyte Antigen) leads to a wide array of cytokines being released namely IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-15, IFN-γ and TNF-α which are all pro-inflammatory cytokines produced by lymphocytes; this explanation has been repeated to place a detailed emphasis on the T cell response in AITD and HT (Swain et al., 2005, p12).
MHC-II behaves as an APC further enhancing the immune response. IL-1, TNF-α and IFN-γ play an important role and enhance the expression of MHC-I, ICAM-1 (intercellular adhesion molecule 1) and LFA-3 (lymphocyte function associated antigen 3), released from thyrocytes enabling and augmenting the ability of cytotoxic T cells to facilitate cell lysis and thyrocyte injury (Swain et al., 2005; Figueroa-Vega, N. et al, 2010).
Thyroid cell destruction is mediated by perforin containing cells which are found in increasing concentrations within thyroid follicular cells and Fas dependent mechanisms (Swain et al., 2005). In addition, pro-inflammatory cytokines, nitric oxide species (NOS), and reactive oxygen species (ROS) are also instrumental in thyroid cell injury.
Cellular immunity exacerbates cell mediated damage as a secondary process by direct complement attachments to TPOAb and by ADCC (Swain et al., 2005). Complement attack dysregulates the metabolism of thyroid cells and results in the secretion of IL-1, IL-6, ROS and prostaglandins from thyroid cells which all augment the T cell immune response in totality.
The continued inflammatory insult of the thyroid gland, by way of T and B cell autoreactivity leads to AITD and a chronic disease of the thyroid gland ensues. However, a number of different mechanisms exist for HT (Swain et al., 2005).
Twin studies specifically in monozygotes have shown a genetic link with HT (Swain et al., 2005). The studies have enabled the identification of several genetic areas that are linked with AITD. In some of the genetic areas AITD susceptibility genes have been acknowledged, some of the genes are unique to HT and GD (Grave’s disease), on the other hand other genes have been recognised that have a common link between HT and GD and this demonstrates a shared genetic relationship and susceptibility in both conditions. The susceptibility genes both consist of immune modifying (HLA, cytotoxic T-lymphocyte antigen-4 (CTLA-4)) and thyroid specific genes (TSHR, Tg). It’s believed that these genes may influence the disease phenotype and severity (Swain et al., 2005).
One of the most important susceptibility factors noted in research literature is the association of AITD with MHC-I genes such as HLA-DR alleles. HLA-DR plays a major role in triggering the adaptive immune system and initiating the immune response. There is variation in HLA alleles dependent upon race; in Caucasian populations HT is associated with HLA-DR3. In non-Caucasian populations other HLA alleles are associated with HT such as in Japanese populations the major alleles are HLA B35, B46, A2 and DPB1*0501. In Indian populations the HLA alleles are A10, B8 and DQw2. Within the afro-Caribbean population the HLA alleles susceptible to HT and AITD are DR1 and DR3 respectively (Swain et al., 2005, p10).
Regarding the CTLA-4 gene, it has been reported that a negative encoding for the regulating gene of the T-lymphocyte response has been implicated in AITD and HT; normally this would not transpire and the T-lymphocyte response would be downregulated. AITD susceptibility has been mapped to the specific coding segment of 6.1-KB3’UTR of the CTLA-4 gene where three single nucleotide polymorphisms of CT60, JO31 and JO30 showed a strong association with AITD in Caucasians. However, in Japanese populations the JO31 single nucleotide polymorphism was more susceptible and exhibited a strong association with AITD (Swain et al., 2005; Tapia, G. et al, 2003). This association is not well understood and epigenetics may play a role. With the genetic susceptibilities borne in mind coupled with the right environmental conditions can trigger autoimmunity and autoreactivity leading to the development of HT.
Recent research has demonstrated an association between the gastrointestinal system, dysbiosis, and auto-immune diseases such as HT via inappropriate post-translational modification of host proteins (PTMP). The microbiome of the gastrointestinal tract (GIT) consists of 1000 bacterial species of which firmicutes and becteroidetes phyla dominate. Dysbiotic conditions, PTMP and enzyme production of dysbiotic commensal bacteria within the GIT can result in autoimmune pathologies such as HT (Lerner et al., 2016). It is hypothesised that enzyme synthesis of dysbiotic populations and abnormal PTMP produces neo-epitopes that are autoimmunogenic and thus induce systemic autoimmune responses resulting in autoimmune disease such as HT. It has been elucidated that germ-free animals have an impaired immune system and when commensal bacteria are restored, immune system function is restored (Lerner et al., 2016). This evidence demonstrates the relationship between immune system function and microbiome composition in the GIT. In GIT dysbiosis several sub-mechanisms have been stipulated which promote autoimmunity. Firstly, it could be molecular mimicry where microbial peptides resemble close similarity to self-peptides. It has been agreed that bystander activation during active infection is a cause leading to cytokine production by APCs which may present self-antigens as well. Thirdly, the intensification of the autoimmune response by cytokine proliferation, stimulated by microbial activation of professional APCs and T cells to produce pro-inflammatory cytokines. The final proposed mechanism is the involvement of the whole GIT, dysbiotic microbiome and exogenous enzymes produced by the dysbiotic microbiome coupled with the corresponding PTMP activity which leads to the genesis of neo-epitopes. These neo-epitopes could induce the autoimmune response and perpetuate autoreactivity. An example is tTg and mTg (microbial transglutaminases) inducing neo-epitopes on Tg peptide docked complexes or citrullination by peptidylarginine deiminase leading to autoantibody formation in celiac disease and rheumatoid arthritis. Bacteria such as Porphyromonas gingivalis possess the ability to citrullinate human proteins via peptidylarginine deiminase. Therefore, it has been suggested that citrullination by such bacteria can cause neo-epitope generation and trigger an autoimmune response (Lerner et al., 2016, p2).
A proposed theory as the final element in autoimmune pathogenesis relative to the GIT is “Leaky Gut”. This theory examines the integrity of the GIT mucosal barrier, GIT tight junctions (TJ) and passage of macromolecules (antigens) in to the submucosal zone of the GIT triggering an immune response via gut associated lymphoid tissue (GALT). The interplay between environment (gluten), gliadin, zonulin pathway and HLA have been postulated in autoimmune diseases, specifically celiac disease, rheumatoid arthritis and HT. The disease only occurs when TJs become compromised. When gluten is avoided, GIT physiology and autoimmune biomarkers return to normal; a clear proof for this new theory, one that is not limited to celiac disease but a range of autoimmune diseases (Fasano, 2011; Drago et al., 2006; Luorio, et al, 2007). Ch’ng et al (2007) suggested the link between HT, GD and Gut disease in 2007 which links in with Allesio Fesano’s (2011) view of autoimmune responses secondary to passage of macromolecules and TJ compromise of the mucosal barrier and Lerner et al’s (2016) recent research on intestinal dysbiosis. Is it then fair to call this a theory when adequate evidence exists to prove otherwise?
Accumulating evidence shows that many environmental chemicals are xenobiotics in that they resemble T4 and T3 closely and specifically affect thyroid hormone function. These chemicals are known more generally as endocrine disrupting chemicals (EDC). Specifically, they are polychlorinated biphenyls (PBC), bisphenol A (BPA), brominated flame retardants (BFRs), heavy metals and phthalates (Boas et al., 2006; Kashiwagi et al., 2009). They mimic T4 and T3 and act as agonists or antagonists on thyroid hormone receptors. In the majority of cases these EDCs do not trigger inflammation or autoimmunity however heavy metals such as cadmium a common environmental pollutant especially in the water supply is known to stimulate the immune system and autoimmunity (Leffel et al., 2003; Boas et al., 2006; Kashiwagi et al., 2009; Yorkshire Water, 2014). Pthalates, BPA and its derivatives are widely used in the plastics industries (epoxy resins, polycarbonate plastics). As a human race we are exposed heavily by these EDCs because they’re used in food contact materials as one example. An important note is that BPA and its derivatives have been restricted in Canada for my very explanation of its endocrine disrupting properties (Health Canada, 2014)
Recent evidence has shown a link between vitamin D and HT. Particularly the immunomodulatory and anti-inflammatory actions of this important steroid prohormone. The majority of its biological effects are mediated through the vitamin D receptor (VDR) which is regulated by the vitamin D binding protein (BDP) and the CYP1α isozyme. Genetic studies have demonstrated that polymorphisms of VDR, BDP and CYP1α isozymes reduce the biological activity of vitamin D confirming the link between genetic susceptibility and AITD (Mazokopakis and Kotsiris, 2014, p38; Proal et al., 2009).
Dietary deficiencies in iodine, tyrosine, zinc, selenium, vitamin A and E can cause HT. Deficiency leads to lower production of active thyroid hormones. (Prasad, 1983; Nishiyama, 1994). Although selenium deficiencies do not prevent T4 to T3 conversion in the pituitary or thyroid gland however, it does result in a large decrease in other cells of the body (Toro, 1991; Meinhold et al., 1992; Berry and Larsen, 1992; Gartner et al., 2001).
In summary, the causes of AITD specifically HT are multimodal and a number of pathological processes need to take place to trigger autoimmunity. In particular, and in my professional opinion; a genetic predisposition needs to exist and being exposed to environmental toxins, vitamin D deficiency, intestinal dysbiosis, poor diet (lacking in essential vitamins and minerals) and compromised or hypofunctioning liver detoxification mechanisms lead to AITD. Simply put, the influence of the environment on our epigenetics brings out a phenotypic trait variation which leads to chronic inflammatory disease.
The management and treatment of HT is very simple in the majority of cases. It’s often due to this simplicity that we overlook the underlying cause(s) of the disease and instead of removing them, contemporary medicine simply treats the symptoms instead. This is not befitting of medicine in my view and opposes the Hippocratic oath and often overrides the view of holistic and individualised care, that we as professionals ought to provide.
The management and treatment is comprehensively medical, conservative and surgical intervention is rarely needed. Patients are often started on a low dose of levothyroxine (LT4) or 1.8mcg/kg/day and the dose is gradually increased according to response every 6-8 weeks, until normalisation of Thyroid Stimulating Hormone (TSH) and remission of symptoms are achieved (Anjanappa et al., 2015, p18; Khandelwal and Tandon, 2012, p25; Ranganathan and Thiagajaran, 2015, p8). The reason why blood tests are taken every 6-8 weeks is to allow adequate time for the pituitary-thyroid axis to reset after commencing levothyroxine supplementation (Khandelwal and Tandon, 2012, p25). Once a euthyroid state is established, monitoring is only required every 6-12 months with TSH with or without serum T4 levels (Khandelwal and Tandon, 2012, p25). However, monitoring can be instituted earlier if there is any evidence of deterioration in symptoms and health, the dose would then be adjusted accordingly after reviewing the patient and relevant blood tests as mentioned (Anjanappa et al., 2015, p18; Ranganathan and Thiagajaran, 2015, p8; Khandelwal and Tandon, 2012, p25). The problem with levothyroxine supplementation is that the underlying autoimmune dysfunction is not being corrected and in the majority of cases TPOAb remains raised despite thyroxine supplementation (Swain et al., 2005, p15).
Functional medicine (FM) focuses on treating the whole person, holistically with a view to removing the underlying root cause(s) of disease and thereby reinstating health and wellness at the molecular level. This medical model focuses on wellness and biological systems balance rather than solely disease control, which is the solitary focus of contemporary conventional medicine today. Conventional medicine in my experience does not give time to diet, lifestyle, stress and other situations which could lead to AITD, HT or any other chronic disease for that matter. It seems that diagnosing quickly, attaching an ICD-9 code to the patient and shutting down thyroid gland function with LT4 supplementation is the goal of conventional medicine, unfortunately. This is a converse view to FM which is a systems based approach seeking to root out the cause, treat appropriately and restore biological systems balance and wellness (Hyman, 2009).
The FM approach as stated by Hyman (2009) would typically investigate all the possible mechanisms of disease beyond what conventional medicine offers and what has been discussed here and then analyse and evaluate on a holistic level before beginning treatment. Nutritional status, GIT status, adrenal gland status, liver status, immune status, environmental toxin exposure, oxidative stress and pharmacological treatments would be investigated. Any hormonal imbalances, deficiencies, infections, and dysfunctional systems found would be corrected and restored, thereby returning patients to health and wellness (Hyman, 2009). This is true medicine and a direct critical appraisal of the conventional medicine method which only treats symptoms with pharmaceuticals, surgery, and radiotherapy when medical management fails and nothing else.
Concluding the above, a recent case study of a patient I treated with parts of the FM model was restored to health and wellness. The patient was diagnosed by her GP with AITD, thyroid hypofunction and a positively raised TPOAb of more than 1000. The patient’s diet, lifestyle, environmental toxin exposure and biological status was reviewed. Her interim plan was to stop LT4 supplementation, start essential vitamin and mineral replacement especially iodine, selenium, vitamin A, D and E and to stop tap water switching to pure spring water because the report by Yorkshire Water (2014) revealed levels of lead and cadmium; autoimmunogenic heavy metals (Leffel, et al., 2003). The result within 3 months was a normalisation in TPOAb, TSH, T3, T4 and omission of clinical symptoms, until today she remains well. Was she not to take up the challenge, my advice, and instead stick to conventional medicine; she would likely be on LT4 supplementation for the rest of her life, with no further exploration of her condition.
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