Does chronic thyroid inflammation explain persistent symptoms in Hashimoto thyroiditis?

Lead Research Organisation: Newcastle University
Department Name: Translational and Clinical Res Institute

Abstract

Around 10% of the female population have Hashimoto thyroiditis as judged by positive thyroid peroxidase antibodies in their blood, and approximately 50% of these people progress to thyroid failure, manifest as thyroid underactivity (hypothyroidism) over several decades. When seen under a microscope, there is progressive destruction of the thyroid cells by inflammatory lymphocyte white blood cells, which are targeted to destroy the thyroid hormone producing cells. Once thyroid underactivity is recognised, the standard treatment is thyroid hormone replacement using levothyroxine tablets. However, about 10% of patients remain dissatisfied with standard levothyroxine treatment, typically leaving fatigue, muscle aches and cognitive symptoms often referred to as 'brain fog'. Multiple randomised clinical trials have shown that improvement in the blood thyroid hormone levels or adding tri-ioidothyronine (T3, the active thyroid hormone) does not help these people. This raises the possibility that the thyroid inflammation itself rather than the consequent hormonal deficiency is responsible for the residual symptoms in hypothyroid patients.

We will perform a double blind, randomised controlled trial of an immunosuppressant/ anti-inflammatory drug called mycophenolate, which will kill off the lymphocytes in the thyroid and reduce the thyroid inflammation. Forty-eight women with Hashimoto thyroiditis will be in the trial for 16 weeks, with thirty taking the active mycophenolate and eighteen taking placebo. The primary outcome measurement will be the change in the number of inflammatory lymphocytes in thyroid samples taken before and after the experimental treatment by fine-needle aspiration. We will also perform a multimodal investigation including fatigue, other symptom and quality of life questionnaires, cognitive tests, blood 'acute-phase' inflammation markers, cytokine assays and functional imaging of the activity of inflammatory cells in the thyroid by FDG-PET. This will demonstrate whether thyroid inflammation can be reduced by mycophenolate and whether this will improve the persistent symptoms and poor QoL for these patients. Mycophenolate is now an inexpensive drug and if successful, this treatment could improve the health of around 100,000 working-age women in the UK who have Hashimoto thyroiditis and who have persistent symptoms during conventional levothyroxine treatment.

Publications

10 25 50
 
Description Academic collaboration on antigen-specific B cells with Prof S Todryk 
Organisation Northumbria University
Department School of Life Sciences Northumbria
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been working with Prof Todryk to identify TRAb-secreting plasma cells using PBMC from Graves' disease patients and ELISpot technique
Collaborator Contribution Providing PBMC and thyroid samples. Interpreting data
Impact Developing methodology to identify antigen-specific B cells in human samples relevant to autoimmune disease
Start Year 2024
 
Description British Thyroid Foundation 'Healthcare Consumer input' 
Organisation British Thyroid Foundation (BTF)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I designed a research questionnaire, analysed the results and wrote up the paper. 2024: Further work with BTF involved designing a questionnaire concerning fatigue and other symptoms of hypothyroidism. >1300 responses received thyroid social media links and paper has been submitted for publication (Eur Thyroid J).
Collaborator Contribution My work on the TRISH study cemented an excellent working relationship with this consumer group who subsequently approached me to help with some research into National thyroxine prescribing policies. Together we conducted a national consumer survey which was then published: Mitchell AL, Hickey B, Hickey JL, Pearce SH. Trends in thyroid hormone prescribing and consumption in the UK. BMC Public Health 2009;9:132. PMID: 19432950
Impact Mitchell AL, Hickey B, Hickey JL, Pearce SH. Trends in thyroid hormone prescribing and consumption in the UK. BMC Public Health 2009;9:132. PMID: 19432950
Start Year 2007
 
Description Collaboration with RSR ltd. 
Organisation RSR Ltd
Country United Kingdom 
Sector Private 
PI Contribution We are developing ELISpot and flow cytometry assays for identifying TSHRAb-secreting plasma cells
Collaborator Contribution RSR have shared their TSHR260STABL reagent to allow us to validate assays for TSHR-specific B/ plasma cells
Impact Work in progress
Start Year 2021
 
Description Prevalence and severity of fatigue in treated hypothyroidism: Results of a UK survey 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Abstract

Background: A substantial proportion of patients taking thyroid hormone replacement for hypothyroidism show persistent symptoms. We sought to explore the prevalence and degree of fatigue in this patient group.
Methods: An online survey including the FACIT-F fatigue scale was distributed by two UK patient support organisations, the British Thyroid Foundation (BTF) and The Thyroid Trust (TTT). Overall, 1,334 responses were received, of which 1250 were complete, unique and from patients with primary hypothyroidism/ Hashimoto thyroiditis who reported taking thyroid hormone replacements.
Results: Ninety eight percent of respondents were women and the median duration of treatment was 7 yrs. The median fatigue score on the FACIT-F scale was 19 [IQR 13-27], with 89% of respondents fulfilling criteria for abnormal fatigue. Fatigue scores were not significantly different between respondents of different ages or taking different thyroid hormone replacements. FACIT-F scores were positively correlated with self-declared overall health state (Spearman r=0.572 p<0.00001). (Pearson r=0.576, p=<0.001)
Conclusions: Fatigue in treated hypothyroidism is very common, and the FACIT-F scores reported are comparable or worse than those recorded for many other chronic conditions. This study suggests that addressing fatigue in this patient group will be key to improving wellbeing and quality of life.
Year(s) Of Engagement Activity 2024