1 China-Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jioatong University, Shanghai, China.
2 2Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
3 Institute of Pathophysiology and Nuclear Medicine, University Clinical Hospital, Skopje, Macedonia.
# Contributed equally
Abstract
Background:
Resistance to thyroid hormones is a very rare condition, which is often misdiagnosed and mistreated. The cases where there is a concomitant autoimmune thyroid disorder are ultra-rare and particularly challenging to treat. Diagnostic and research-based genomic testing can sometimes identify pathogenic variants unrelated to the primary reason for testing (incidental findings).
Case presentation:
We present a patient with thyroid resistance associated with hypothyroid Hashimoto thyroiditis. The long diagnostic odyssey spanning over 20-years included repeated misdiagnoses and mistreatments and was concluded by a research-based genomic testing, identifying a "de novo" THRB pathogenic variant. The varying sensitivity of various tissues to thyroid hormones accompanied by hypothyroid Hashimoto thyroiditis continues to pose a significant treatment challenge.
Conclusions:
Thyroid hormone resistance continues to be an un(der)- and misdiagnosed thyroid condition whose management is particularly challenging when associated with autoimmune thyroid disease. Whole exome sequencing has the potential to identify THRB pathogenic variants as incidental findings. Reporting such secondary findings from genomic testing may be particularly important in the context of the rarity of the condition and the potential clinical consequences of misdiagnosis and mistreatment.
This patient presented when knowledge of RTH was in its infancy. Even so there is little understanding of RTH amongst most endocrinologists. It is rare and presents with elevated fT3, fT4 and non-suppressed TSH. It's not surprising there is a patient with RTH and Hashimoto's, a few percent of RTH cases will have Hashimoto's. It's thought the strain on the thyroid (having to secrete large amounts of hormone) may increase the rate of Hashimoto's. About half of RTH patients have a goitre. The Beta-1 receptors are more prevalent in the liver whereas the heart has more Alpha-1 receptors. Thus, RTH caused by mutant TRB1 receptors leads to hypothyroidism in the liver (high cholesterol) and hyperthyroidism in the heart. This makes management very difficult. This is rare.
That specific type of thyroid resistance, since it's a genetic defect, is different, IMO, from central hypothyroidism or non-specific thyroid resistance where a person requires supraphysiologic doses of thyroid, though I'll concede that the latter might be due to some genetic mutation. There's a similar analogy in men who require high doses and serum levels of testosterone, though the case is being made that it's related to hypothalamic/pituitary malfunction; sub clinical hypopituitarism, which includes central hypothyroidism.
Why the pituitary/hypothalamus begin to malfunction is a mystery. Inflammation and auto-immune issues are always mentioned but there could be a genetic component. Genetic medicine, as well as research in the microbiome, are in their infancy.
This study describes RTH caused by a mutation to the TRB gene which creates TRB1 and TRB2 receptors. It presents with elevated thyroid hormones and a non-suppressed TSH. Many patients need no treatment, perhaps some beta blockers to protect the heart. There's a similar set of mutations to the TRA gene which produces TRA1 and TRA2 receptors. This is thankfully very rare as it can present with severe mental and physical retardation. There are other rare genetic problems such as mutations to the gene producing MCT8 transport proteins that carry thyroid hormone into the cells. The point about all these disorders is that they are genetic and so there from conception.
Unfortunately, only genetic causes of RTH are considered. There are clearly non-genetic forms which I call 'Acquired Resistance to Thyroid Hormone' (ARTH). A major cause of RTH is endocrine disrupting chemicals (EDCs). EDCs as molecules that mimic hormones and disrupt hormone action. There are EDCs which can disrupt peripheral thyroid hormone action with negligible effect on the pituitary or hypothalamus, these EDCs produce peripheral hypothyroidism with normal blood hormone levels. I'm specifically interested in PBDEs, a PubMed search 'PBDE thyroid' returns 340 studies. Unfortunately, endocrinologists are ignorant of the effects of endocrine disruption (with the exception of the US journal 'Endocrinology').
I wouldn't classify it as such as it will apply to everyone and such deterioration would be in the pituitary also leading to an elevated TSH. Elderly may be more susceptible to EDCs because their clearance rate is lower. The foetus is also more susceptible to EDCs due to the role hormones have on development.
Though 'tis curious how it is said so often that, as we age, our bodies become less able to function properly. Yet somehow our pituitaries are pointed out as over-functioning and producing too much TSH.
To me, it seems quite likely that our pituitaries would not produce enough TSH, resulting in age-related central hypothyroidism.
mine went rock bottom when I seemed to be getting near to the optimal dose of Levo, so of course it was reduced. Rewind and then fast forward 6 months or so and I'm back where I was in January, on 100mcg and a possibility of a further increase if necessary. Wonderful!!!
In another health-related issue there is a similar problem. The vast majority of people who are prescribed acid-blockers like PPIs are elderly. I once queried this with a doctor who claimed that people produced more stomach acid as they aged. I was stunned that they had the gall to say what they did - but perhaps they really did believe it, who knows?
I wouldn't have known either. But there, I'm not a doctor. Trouble is, even the good doctors are probably fed lots of wrong ideas and don't have time to keep up with the latest research even if they want to. Good ones would want to.
I think the reason that older people are so often prescribed PPIs is to protect their stomachs from the harm caused by the other medications, such as asprin.
So what are the rs or snp numbers to these thyroid resistance hormones as I Have loads of double genetic faults in THRB and others but searching the RS numbers would be much easier for me ,Im wondering if they took my thyroid out for THR and made a big error thats why I have never felt good after sub thyroidectomy....as I didnt have the getting hot with Hyperthyroid ?? any clues ?? going round in circles here on it all then just think I understand it and I get all confused again.. I have recently found I can not tolerate T4 it has been causing me other problems one being severe asthma since staring it, aches and pains and CFC well loads of things stopped when I stopped T4 I was taking that around 16-17 yrs and didnt think the T4 was causing everything,, but being more clear headed and GP medical records i have worked out what I started as soon as put on T4 and what I stopped finishing it..... and they say T4 works for all,, not for me it didnt not without a huge price on health .. a bit better on NDT but they left me no meds so GP gave me T3 mono and seem much better on it than anything else I have tried... So GP said stay on t3 mono My GP thinks they will discover my genetics in 20 years,, I can not tolerate any prodrugs at all , So now on medical records I can not tolerate Prodrugs ! well its mad expecting someone with many genetic faults to even convert them into the active drug,, mad they made Prodrugs so complicated...
I'm not that deep into genetics, there are thousands of gene mutations and I'm not familiar with them other than the rs225014 (Thr92Ala) DIO2 polymorphism. I doubt that you have a TRB gene mutation, this is only tested at one centre in the UK and they would treat you appropriately if you were posistive for the mutation.
Home genetic testing is a complete waste of time, the companies do not explain the consequences (they usually just subcontract and don't understand the results). Most polymorphisms have little known effects.
Are you sure you have mutations of the THRB gene? Where was it diagnosed?
I had 23 and me done ages ago and I have loads of THRB gene faults put on Livewello to see what came up from all of them, some they have probably not looked into as only a few of them came up ............................................................ THRBrs11129141GTT-/-
THRBrs1466119TTT+/+
THRBrs1667746CCT+/-
THRBrs1700936TCT+/-
THRBrs17014251CCT+/-
THRBrs1705734AAG+/-
THRBrs2167115GAG+/-
THRBrs2596620CTT-/-
THRBrs2596623TCT+/-
THRBrs2683529GAG+/-
THRBrs4404389GAA-/-
THRBrs5014281GAA-/-
THRBrs6550857AGG-/-
THRBrs6550858GAA-/-
THRBrs7609823AGG-/-
THRBrs7617186TCC-/-
THRBrs7619754AAA+/+
THRBrs7652347TCC-/-
THRBrs826216GAG+/-
THRBrs844103TGT+/-
THRBrs9830674TCT+/-
THRBrs9850879AAA+/+
THRBrs9852824CCC+/+
these ones below are on 23 and me so I think i have a few of them ... What do you think? I alos have dio1 and dio2 faults
Genes Marker (SNP) Genomic Position Variants Your Genotype
I did an introductory course on genetics last year. Genetics is very complex. The tutor said that the 23andme tests are useless and we shouldn't waste money on them. I would ask 23andme to explain what each of these means and how they affect you. I don't think they are 'faults', just normal variances that makes us individual.
I will forward hem to my GP as he knows quite a bit on genetics , if he doesnt know he will find out, I only found these yesterday,, Livewello all the top ones have expalanations on what they mean and all say Thyroid hormone resistance, I only discovered them by mistake,, but I read about this few years ago, and wondered then had the killed thyroid off for wrong reason as I didnt have typical hyperthyroid as was never hot I was a bit cold if anything and I felt dreadful after sub thyroidectomy then worse after starting T4 .never did well on T4 NDY my bloods said hyper but i knew i was hypo and gained weight on it,,my bloods look good but I never feel what my bloods say .. I have just last week started T3 mono and start to feel ok again .. so does make me wonder on it all
Thank you so far so much better I was applying NDT funding and they left me un medicated so had to get Emergency Endo to change treatment T3 mono Im so glad the CCG were being ignoraant taking time to decide or I may never have tried T3 mono and may never have known how it was to feel this good ,, GP Endo both support me on T3 mono so up the CCG for that one + Ha Ha but if these genetics do mean something it may bring a stronger case if they try to stop the profesionals precribing me T3 .. x
As far as I know RTH presents with just one mutation on the gene, at various loci. If you had elevated fT3, fT4 with non-suppressed TSH then it is possible you have RTH and was wrongly diagnosed as hyperthyroid. This used to happen a lot, before the word got out about RTH. I can't believe all these polymorphisms indicate RTH, it would be quite a surprise. Get hold of your TSH, fT3, fT4 at diagnosis and see if they are consistent with RTH. If so ask for a referral to an endocrinologist with a view to a referral to the Addenbrooke's RTH team (a GP can't refer to this team).
I Thank you Jimh dont know any of my hyper thyroid bloods as all my notes have been destroyed from that hospital so I will never know,, My ,Mpther dealt with it all at time and she is not here anymore to ask The Consultant retired so no way of finding much out,,I thought they were supposed to keep notes l100 years after you died but thats not the case and nothing i can do about it as gone,, half GP med records are missing all the blood tests apart form few after thyroidectomy I will ask GP to look at my genetics and if its not on there will get him to get that gene tested and go from there,,
RTH caused by a mutation of the TRB gene would be reflected in current blood tests, your TSH would be comparatively high for your fT3, fT4 levels. Are you on thyroid supplementation and do you have some blood test results?
23andme testing is fun! For the lay person mine was very well laid out and detailed everything that was tested. I found out that I have a slightly higher risk for celiacs disease and that I’m a carrier of the CF gene which is incredibly important because now I can get my kids tested so that they never have to go through the heartache of having a child with CF.
I think your tutor may have just been a bit snobby about 23andme and the like, even the trivial data that I got was fascinating. I always knew I and my family were mainly Irish and all white but it was interesting to see where else my roots might have come from. My husbands was a little more diverse but not really, the only exciting part of his was ‘Native American’ with blonde hair and blue eyes that was really funny!
So my view is if you want serous genetic testing you’ll have to pay big money for it but if it’s a bit of fun then these home test kits are interesting.
yes their is that bit as well which was quite interesting,, what worries me is I have siblings all over the world and my dad used to travel to all those countries lol
The thing with 23and me you do know all you are geting is the raw data, so they owe no explanation tbh,, it was cheap so cant expect them to explain it all as hundreds f genes given,, some probably haven't even had any research donjon them yet , 20 years we will know more maybe too late for me but hey ho .. but the ones i have checked out with the NHS genetics are what they say they are,, so they are not fake they are real ,, just a pain to have to keep researching them all on Pub med and other research places ,, but will get therein the end and GP is very interested in genetics so will give him these to sort out .
It is difficult to make generalisations about THR since the vast majority of people with the condition have not been diagnosed, but are living with diagnoses such as ME, CFS, Fibromyalgia or depression.
There are many genetic causes of ISTH and in order to identify a specific genetic defect it is necessary to find a group of people who may have that same defect. This can be difficult to do and this has meant that much of the research so far has made use of obvious signs such as specific physical and mental disabilities as the primary symptom in their research to identify cases for investigation. It therefore follows that the syndromes identified are almost all syndromes which cause extreme symptoms such as severe disability. For most people with ISTH the specific gene causing their problem has not yet been identified and there remains a massive task to discover these unknown genetic defects.
I'm sure milder cases are generally missed, not least because there has never been any concerted effort to find them. However, genetic conditions would in general be present from conception. Most of us were fine until we became hypothyroid and so genetics would not give an explanation, at least not once our hormone levels are restored back to where they were prior to developing hypothyroidism. Genetics would certainly influence susceptibility to developing hypothyroidism and the extent to which hormone levels would need to be normalised (e.g.. needing a little T3) but they do not explain why many patients do not get well when their thyroid hormones are put back to where they were prior to the onset of hypothyroidism. I fear we are barking up the wrong tree when looking for genetic explanations.
It is not just milder cases that are missed. Most GPs are not aware of the condition and if they have heard of it regard it as so rare that it is not worth considering. If someone has TSH in range they will give a diagnosis of CFS ME, fbro etc.
Some people even get diagnosed as hyperthyroid, even though their symptoms point to hypo.
The body's survival mechanisms try to compensate for thyroid hormone resistance, by for example increasing adrenaline. This can mean that a person can have good health for many years. Later however the adrenals can no longer cope, or a secondary condition such as an autoimmune condition develops and health deteriorates quickly.
Sorry, but I have to disagree on your statement " I fear we are barking up the wrong tree when looking for genetic explanations."
Assumption that the patient in front of the doctor has not got a rare disorder is a very serious issue.
All very well going on about zebras and horses, but that black and white striped animal in front of you, yes - you doctor, very definitely is a zebra, even if its hooves sound like a horse. Open your eyes, turn the light on, medically trained person.
The abject cruelty of denying that someone has a rare disorder can be worse than not accepthing they have anything wrong. We have seen all sorts of iatrogenic issues due to inappropriate treatment of both ISTH/RTH (including pituitary-specific) and central hypothyroidism.
It is vital to prove that the patient does not have one of these other disorders, not make an assumption.
(I think we all accept that assumptions sometimes have to be made in emergency situations but all too often we see people pleading to be believed for years.)
We will disagree on this. I feel environmental (in the widest sense) issues explain most cases. In particular, endocrine disruption is quite common and has the capability to disrupt peripheral hormone action with little effect on the pituitary leading to quite severe hypothyroidism with normal blood hormone levels. The rapid increase in endocrine disrupting chemicals from the 1970s onwards coincides with increases in cases of hypothyroidism, firbomyalgia and CFS/ME.
The environmental issues possibly explain some cases but I feel that there is a huge number with genetic issues. I frequently come across families with very definite genetic problems. There are examples from this forum:
1. My T3 and T4 were both good, but I still had all the hypothyroid symptoms. My mother also had thyroid problems. Also many relatives have severe depression (both grandparents and two uncles). I suspect I have thyroid resistance.
2. I am hypothyroid thanks to the genes I inherited from my dad! His mum, two sisters and a brother, most of my female cousins and their children are also hypo! I have been hypo eight years and now my younger sister has also been diagnosed. There is also Crohn's, pernicious anaemia, coeliac and gluten intolerance in the family.
3. Eight out of eleven in my immediate family have thyroid diseases. My brother has vitamin B12 deficiency and Type 1 diabetes and is hypothyroid. I am vitamin B12 deficient, hypothyroid and immunoglobulin A (IgA) deficient.
4. When I was diagnosed I thought I was the only one in my family but looking back on things, now I remember some of the things that my grandmother told me. Heavy periods, very thick hair but when bald on top, got a tummy when older. She also had trigeminal neuralgia (severe facial pain). She already had Pernicious Anaemia (vitamin B12 deficient). Her son, my dad was a keen climber and walker but walked very slowly. He often started things and took ages or never finished them. In later life he had many heart attacks but doctors were puzzled as to why. Sadly it was only after their deaths that I found her sister's son was on thyroxine.
5. In our family there is Pernicious Anemia, Hypothyroidism, genetic haemochromatosis, asthma, psoriasis, eczema, diabetes, Autism, dad had heart condition cardiomyopathy and ischaemic heart disease, parkinsons, dementia, cancer. Oh and my middle daughter took acute autoimmune haemolytic anaemia as a child. Several of us have had Helicobacter and other stomach issues.
Certainly genetics can predispose you to hypothyroidism and other disorders. This is quite different to genetic RTH which is a result of mutations to the TRB gene (and very rarely the TRA gene). Your genetics could predispose you to acquired RTH resulting from endocrine disrupting chemicals or other unknown causes or other forms of hypothryoidism such as Hashimoto's.
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