Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study (2018) Ruiz-Núñez et al.

[Cheshire]

Begoña Ruiz-Núñez, Rabab Tarasse, Emar Vogelaar, Janneke Dijck-Brouwer and Frits Muskiet

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation. We studied 98 CFS patients (21-69 years, 21 males) and 99 age- and sex-matched controls (19-65 years, 23 males).

We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation. Most remarkably, CFS patients exhibited similar TSH, but lower FT3 (difference of medians 0.1%), TT4 (11.9%), TT3 (12.5%), %TT3 (4.7%), SPINA-GD (14.4%), SPINA-GT (14.9%), 24-hour urinary iodine (27.6%) and higher %rT3 (13.3%). FT3 below the reference range, consistent with the 'low T3 syndrome', was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% CI=1.00 - 6.54). Most observations persisted in two sensitivity analyses with more stringent cut-off values for BMI, hsCRP and WBC.

We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4 and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels.

The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of 'non thyroidal illness syndrome' and 'low T3 syndrome' experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with e.g. T3 and iodide supplements might be indicated.

https://www.frontiersin.org/articles/10.3389/fendo.2018.00097/abstract

 

[Hoopoe]

More evidence that this is a hypometabolic syndrome? Is this reliable work?

 

[Arnie Pye]

They resemble a mild form of 'non thyroidal illness syndrome' and 'low T3 syndrome' experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with e.g. T3 and iodide supplements might be indicated.

Very interesting, but I'm dubious about the iodide suggestion. Low iodine is a cause of hypothyroidism in parts of the world where iodine is low in the soil that crops are grown in. But elsewhere in the world giving iodine to iodine-replete patients is likely to suppress thyroid activity, not give it a boost.

 

[MErmaid]

More evidence that this is a hypometabolic syndrome? Is this reliable work?

My subtype is hypo for many different types of hormones. I doubt what I have resembles what Whitney has. I think what the evidence tells us it is that there are many subtypes, and thats why the current style of academic scientific research, one that collects massive amounts of data, is failing us.

 

[Marky]

My subtype is hypo for many different types of hormones. I doubt what I have resembles what Whitney has. I think what the evidence tells us it is that there are many subtypes, and thats why the current style of academic scientific research, one that collects massive amounts of data, is failing us.

What else can u do though? There`s not any obvious place to narrow down the research

 

[MErmaid]

What else can u do though? There`s not any obvious place to narrow down the research

I don’t have answers ATM, but I feel this topic of discussion needs to be addressed, possibly after the MillionsMissing May 12 protests. I think that advocacy for May needs to be our top priority now.

 

[adambeyoncelowe]

You could start with the narrowest definition of ME, find out what rules seem to apply to that group, and then see if other groups are different. Hyde or Ramsay ME are the strictest definitions (Ramsay seems looser than Hyde). With MS, they use very narrow criteria to start with, for example, and in FMS studies they often use only women without co-morbid illnesses. Perhaps that's how we start, instead of the kitchen sink approach, and see what defines the 'classic' post-viral, acute onset ME patients with demonstrable CNS injury. Then look at, say, gradual onset, or autoimmune ME, or ME possibly caused by chemicals. See how they compare or not.

Younger seems to think there are at least three broad subgroups (viral, autoimmune, metabolic), but until we see his study it's hard to see how he's reached this conclusion.

 

[Eagles]

MEA Website: Frontiers Press Release: Chronic fatigue syndrome possibly explained by lower levels of key thyroid hormones

http://www.meassociation.org.uk/201...levels-of-key-thyroid-hormones-20-march-2018/

 

[Barry]

What might be the implications for someone whose ME began when they contracted a flu bug whilst recovering from a thyroid operation, but never then recovered their energy levels again. Been on thyroid treatment ever since.

 

[adambeyoncelowe]

Byron Hyde noted more thyroid issues in his patients. I know MEA says they've not seen evidence of a link before (from their survey, I think?), but I wonder if many patients at the higher end of the 'normal' range (bear in mind some US docs treat when TSH > 3, whereas here we wait until it's >4.5) might unknowingly have issues with T3 production?

My thinking, however, is that any thyroid issues will be like the HPA issues--i.e., secondary to mitochondrial or some other dysfunction. It's quite clear that few systems are entirely untouched in ME, since it seems to cause a cascade of problems.

 

[Andy]

Opening section from the MEA's article.

Discovery of a crucial link between chronic fatigue syndrome and lower levels of key thyroid hormones raises hopes for treating this common yet debilitating disease

Frontiers in Endocrinology

New research demonstrates a link between chronic fatigue syndrome (CFS) symptoms and lower thyroid hormone levels. Published in Frontiers in Endocrinology, the study indicates that CFS, a condition with unknown causes, can be explained by lower thyroid hormones — but may be distinct from thyroidal disease. This finding can be seen as a first step to finding treatment for a debilitating illness for which there is no recognized treatment.

Chronic fatigue syndrome is a common disease marked by lengthy spells of weakness, fatigue and depression. Its diagnosis is predominantly based on symptoms and on ruling out any underlying medical condition, rather than on laboratory tests and physical examination.

Interestingly, several symptoms resemble those of hypothyroidism — a condition where the thyroid gland does not produce enough thyroid hormone. In hypothyroidism, the body tries to encourage thyroid hormone activity by releasing more thyroid-stimulating hormone — however, this does not happen in patients with chronic fatigue syndrome.

This contrast in thyroid-stimulating activity led the study’s authors to hypothesize that chronic fatigue syndrome is caused by low activity of thyroid hormones in the absence of thyroidal disease.

 

[Trish]

I don't know who wrote their press release, but I find this concerning:

Chronic fatigue syndrome is a common disease marked by lengthy spells of weakness, fatigue and depression.

The full paper is available here:
https://www.frontiersin.org/articles/10.3389/fendo.2018.00097/full

Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study
Begoña Ruiz-Núñez et al.

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation.

We studied 98 CFS patients (21–69 years, 21 males) and 99 age- and sex-matched controls (19–65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation.

Most remarkably, CFS patients exhibited similar thyrotropin, but lower free triiodothyronine (FT3) (difference of medians 0.1%), total thyroxine (TT4) (11.9%), total triiodothyronine (TT3) (12.5%), %TT3 (4.7%), sum activity of deiodinases (14.4%), secretory capacity of the thyroid gland (14.9%), 24-h urinary iodine (27.6%), and higher % reverse T3 (rT3) (13.3%).

FT3 below the reference range, consistent with the “low T3 syndrome,” was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% confidence interval = 1.00–6.54). Most observations persisted in two sensitivity analyses with more stringent cutoff values for body mass index, high-sensitive C-reactive protein (hsCRP), and WBC.

We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4, and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls.

Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels.

The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy.

Our study needs confirmation and extension by others. If confirmed, trials with, e.g., T3 and iodide supplements might be indicated.

 

[adambeyoncelowe]

I don't know who wrote their press release, but I find this concerning:



The full paper is available here:
https://www.frontiersin.org/articles/10.3389/fendo.2018.00097/full

I gather the Dutch are, like the UK, usually quite obsessed with the BPS model of ME. Although that seems to be (slowly) changing. I'm not sure why it's included in the MEA write-up, however.

 

[Amw66]

this could link to hypometabollic state?
see also potential for ROS activation-

https://www.ncbi.nlm.nih.gov/pubmed/9633610-
3,5,3'-triiodothyronine induces mitochondrial permeability transition mediated by reactive oxygen species and membrane protein thiol oxidation.

http://www.tiredthyroid.com/rt3-4.html

 

[Russell Fleming]

I don't know who wrote their press release, but I find this concerning:



The full paper is available here:
https://www.frontiersin.org/articles/10.3389/fendo.2018.00097/full

The Press Release was written by Frontiers:

For more details, and the full journal report, contact Frontiers:
Emma Duncan
press@frontiersin.org
Science Communications Manager
T +41 21 510 17 04

It had an embargo until 10.00am this morning. The BBC were going to write about it and we had given them comment from Dr Shepherd, but then they changed their mind, so we went ahead with the Frontier's release in its entirety.

 

[Trish]

From the introduction:

Chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis, is a complex heterogeneous disease, most commonly characterized by disabling fatigue, cognitive impairment, disrupted sleep and concomitant skeletal and muscular pain, lasting for more than 6 months and not improving with rest (1, 2) [for a broader definition, see Ref. (3)]. Impaired physical and social functioning, vitality, emotional well-being and role limitations due to emotional problems (4) contribute to an impaired quality of life (5).

my bold.

They used Fukuda criteria which has PEM as an optional symptom.

This makes me uneasy about the conclusions - were they actually studying people with ME/CFS, or with idiopathic chronic fatigue, possibly caused by the sort of thyroid problems they found, or by depression.

Can someone with more knowledge help here?

 

[Londinium]

From the introduction:

my bold.

They used Fukuda criteria which has PEM as an optional symptom.

This makes me uneasy about the conclusions - were they actually studying people with ME/CFS, or with idiopathic chronic fatigue, possibly caused by the sort of thyroid problems they found, or by depression.

Can someone with more knowledge help here?

Worth noting they used the 'CBO criteria' which is based on Fukuda 'with the exclusion criteria of Reeves' which does at least seem to rule out some kinds of psychiatric disorder. But (from my read at least) I think you're right in that PEM might not be mandatory. My impression is that the authors do not try and come down on a specific side on whether it it has an immunological/metabolic/neurological/psychiatric pathology.

Still, it's an interesting study and I'm pleased the MEA is looking to fund any applicants who want to try and replicate it.

 

[Arnie Pye]

Byron Hyde noted more thyroid issues in his patients. I know MEA says they've not seen evidence of a link before (from their survey, I think?), but I wonder if many patients at the higher end of the 'normal' range (bear in mind some US docs treat when TSH > 3, whereas here we wait until it's >4.5) might unknowingly have issues with T3 production?

Many doctors in the UK won't treat hypothyroidism until TSH is > 10 and Free T4 is below the reference range. It is institutionalised torture for many people.

From this link (NICE Clinical Knowledge Summaries, which carry approximately zero weight): https://cks.nice.org.uk/hypothyroidism#!diagnosissub:1

• Arrange investigations including:
  • Blood tests for thyroid stimulating hormone (TSH) and free thyroxine (FT4):
    • Diagnose overt hypothyroidism (OH) if TSH is greater than 10 mU/L and FT4 is below the reference range.
    • Suspect subclinical hypothyroidism (SCH) if TSH is above the reference range and FT4 is within the reference range. In non-pregnant people repeat TSH and T4 (ideally at the same time of day) 3–6 months after the initial result to exclude transient causes of a raised TSH (such as intercurrent illness) and to confirm the diagnosis of SCH.
    • Suspect secondary hypothyroidism if the clinical features are suggestive and T4 is low without raised TSH. Be aware that in secondary hypothyroidism TSH may also be low, normal, or slightly elevated due to circulation of bio-inactive forms of TSH.

 

[Esther12]

Daily Mail coverage of this:

http://www.dailymail.co.uk/health/article-5522831/Could-cause-chronic-fatigue-syndrome.html

Some good:

SCIENTISTS ANGRY AT 'FLAWED' TRIAL
The study findings come after angry scientists threw cheap insults at each other regarding the 'flawed' results of a landmark £5 million British study on chronic fatigue syndrome.

One medical journal dedicated its entire August edition to ripping apart the 'unreliable' PACE trial, which was funded by taxpayers.

In response, three editors at the Journal of Health Psychology, who are all scientists, have resigned. One said the journal displayed 'unacceptable one-sidedness'.

An upset co-editor of the journal hit back and told him to 'f*** off' for his 'attempted bullying', leaked emails obtained by The Times show.

He also called him a 'disgusting old fart neoliberal hypocrite' - despite once considering him a 'hero' and referring to him as a 'Trotskyite' in his younger days.

Some mixed to bad:

A lack of evidence for a clear physical cause encouraged doctors to believe it was a psychological condition.

But for years infuriated campaigners have insisted it is to do with an infection or a failure of their immune system.

A landmark study in 2011 published in the prestigious medical journal The Lancet, which has since been disputed, formed the basis of treatment.

The results of the PACE trial sparked the ongoing debate that the controversial condition is merely psychological.

Treatment for CFS is delivered by psychologists and involves therapy, which has only angered sufferers more by suggesting it is all in their head.

The new study comes after Bristol University research in September, published in the Archives of Disease, revealed that a controversial treatment for children with debilitating CFS can actually help in some cases.

The Lightning Process - a course which claims to retrain the brain to improve physical health - worked when combined with specialist medical care.

The £620 course has been praised by celebrities such as Martine McCutcheon and the wife of England rugby union player Austin Healey.

But some experts and campaigners have condemned the £620 course – which is not available on the NHS - as pseudoscience' and 'quack medicine'.

 

[Hutan]

I don't know who wrote their press release, but I find this concerning:

Chronic fatigue syndrome is a common disease marked by lengthy spells of weakness, fatigue and depression.

Oddly, the paper itself doesn't mention depression as a symptom.
From the abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s).

And from the introduction:

Chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis, is a complex heterogeneous disease, most commonly characterized by disabling fatigue, cognitive impairment, disrupted sleep and concomitant skeletal and muscular pain, lasting for more than 6 months and not improving with rest

But there is some weird stuff in there, for example:

The mean age of onset is 29–35 years and the mean illness duration ranges from 3 to 9 years (6), which implies that the symptoms are reversible.

Psychological trauma, particularly during childhood, can also activate the CDR and produce chronic inflammation (91, 94). It has recently been shown that CFS patients are endowed with different psychological vulnerability factors, notably perfectionism and high moral standards (95). These may render them more susceptible to the psychological stress of current society, with possible effects on the immune system and thyroid axis

.
(I think psychology researchers could use a few more of the psychological vulnerability factors of perfectionism and high moral standards...)

It's not the first time we've seen European papers covering biomedical aspects of CFS that appear to have been written by two completely different people, at least one of whom is a BPS nutter.

Possible faulty patient selection criteria notwithstanding, I think there may be some useful stuff in the paper although it's going to take me some time to go through it and understand it fully.

My son and I both have low-normal T4 results with normal to low-normal TSH (and the T3 hasn't been measured) - so I think, at first pass, our results fit with what they found. But some of the differences in the medians for the results from patients and controls aren't super large.