Trial Report Possible Markers For Myalgic Encephalomyelitis / CFS Developed In Long Covid: Utility Of Serum Ferritin And Insulin-like Growth Factor-I,2023,Yamamoto

Based on the reference list citing their own work, up until now the authors seem to have largely focused on high ferritin in acute inflammatory conditions. I'm in skimming-only mode so I can't follow how they get from ferritin in acute to ferritin in chronic illness.

Further based on the reference list they also seem to have missed a couple of ME studies which found hints of suggestions of iron involvement in ME (Lipkins & Birch ring a bell?). I can't remember clearly now but I think it was about possible issues with getting iron into the cell and/or utilising it inside the cell. There doesn't appear to have been any follow up. Typical

As someone with an oddball form of haemochromatosis I've always wondered about the possibility of a link between iron and ME so will be looking out for the currently in-press ref #8 paper "Utility of serum ferritin for predicting myalgic encephalomyelitis / chronic fatigue syndrome in patients with long COVID"

Having said that, I'd be surprised if simple ferritin levels are in any way useful. PwME report anything from deficiency to very high levels. And in my own experience with high, normal and borderline deficient ferritin levels I've never noticed any correlation with my ME symptoms whatsoever.

@Wonko, are you being followed up? As @Arnie Pye said, clinical guidelines are changing all the time but where I live a ferritin reading of >1000 would still raise a big red flag and at the very least prompt a repeat test to see if it's a one-off or something more chronic in which case the doctor would be expected to investigate further.
 
Ravn said:
Based on the reference list citing their own work, up until now the authors seem to have largely focused on high ferritin in acute inflammatory conditions. I'm in skimming-only mode so I can't follow how they get from ferritin in acute to ferritin in chronic illness.

Further based on the reference list they also seem to have missed a couple of ME studies which found hints of suggestions of iron involvement in ME (Lipkins & Birch ring a bell?). I can't remember clearly now but I think it was about possible issues with getting iron into the cell and/or utilising it inside the cell. There doesn't appear to have been any follow up. Typical

As someone with an oddball form of haemochromatosis I've always wondered about the possibility of a link between iron and ME so will be looking out for the currently in-press ref #8 paper "Utility of serum ferritin for predicting myalgic encephalomyelitis / chronic fatigue syndrome in patients with long COVID"

Having said that, I'd be surprised if simple ferritin levels are in any way useful. PwME report anything from deficiency to very high levels. And in my own experience with high, normal and borderline deficient ferritin levels I've never noticed any correlation with my ME symptoms whatsoever.

@Wonko, are you being followed up? As @Arnie Pye said, clinical guidelines are changing all the time but where I live a ferritin reading of >1000 would still raise a big red flag and at the very least prompt a repeat test to see if it's a one-off or something more chronic in which case the doctor would be expected to investigate further.
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the research you mention is interesting but I realise I’m digressing from the original study in why because my issue is low ferritin and indeed I’ve more recently realised/confirmed it’s in ‘getting it absorbed’ or whatever as I’ve been tested even on iron tablets (previous gp of many years tended to refuse to test it or not provide the result and was keen to not give me iron tablets and when I’d been out on them as someone else tested me to get me off them - with threats of telling me my haemoglobin was ‘goin up’ which could have been untrue or inconsequential).

I feel hideous when my ferritin is low (despite GPs telling me I’m not anaemia we are talking a level of 5, and asking to be tested as I know it’s dropped - so there is something going on with gp guidelines there I think). I don’t know if or how it’s connected to ME as my ME isn’t ‘just that’ it’s there all the time but how much my ME has been ‘pushed’ does affect my ferritin levels even when I’m in iron tablets
 
Kitty said:
If the ferritin levels were higher than normal but not high enough to suggest iron overload, and patients had none of the symptoms classically associated with iron metabolism or storage issues, it wouldn't even raise an eyebrow in most primary care physicians
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This is my experience. My ferritin was sky high for a while, even higher than most with iron overload, but my iron wasn't. I was nearly anaemic. One point lower and I would have been in the anaemia range. The flip side happens too. My ferritin was high and I carry one gene that predisposes to iron overload, and several doctors decided I need to lose some blood (venesection). This despite I was borderline anaemic. Most doctors do not seem to look at ferritin much when they are concerned with iron overload. Its only there to confirm or rule out iron overload.
 
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Arnie Pye said:
Although labs aren't moving quickly on this in the UK, NICE has brought out guidelines for iron deficiency anaemia (last revised Nov 2021) that mention ferritin and it raised the lowest part of the range from 13 to 30 mcg/L. The standard range for women for many years was 13 - 150 mcg/L, and in many labs it still is.

I don't know if people who aren't in the UK can read NICE guidelines.

https://cks.nice.org.uk/topics/anaemia-iron-deficiency/diagnosis/investigations/

In the above link, in the section on "Interpreting ferritin levels" :



The problem is that people can have very low ferritin and yet still have haemoglobin which is high enough not to be classified as anaemia.

I don't know what guidelines doctors actually use, but in my case it seems if my haemoglobin is in range then I don't need to be treated, even if my ferritin is very low in range. And of course, serum iron is almost never tested in primary care, as far as I'm aware. I found one reference in my records to serum iron being under range and it was never mentioned to me at the time, nor was it tested again.

On the same link as above :



I bought a copy of my medical records a few years ago and discovered that a normal course of events was :

1) Get a Full Blood Count (FBC) done.

2) If haemoglobin is within "normal" range nothing else needs to be done. So ferritin was rarely measured.

It seems, at least in my case, that doctors use the FBC (haemoglobin and MCV) and ferritin measurements in whichever way they can to reduce the chance of having to spend money on a prescription for iron supplements. So I could have low in range ferritin and bottom of range haemoglobin and/or MCV and I would not be given a prescription for iron.

One thing that improved my life enormously was when I found out that I could buy prescription-strength iron supplements without a prescription. I could also pay for an iron panel to be done privately without requiring a doctor to get involved.

...

Regarding the top of the range for ferritin and having high ferritin...

I'm aware that one lab in the UK has fairly recently changed its upper level of the range for men and post-menopausal women to 650 mcg/L. That is an eye-watering jump from a top of range of 150 mcg/L which that lab still uses for the top of range in women before the menopause.
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Non ME aunts ferritin is currently 660mcg/L. She had bloods done last week and they have been repeated so will see if it's confirmed next week. She asked for blood tests as she is constantly feeling tired and is light headed on and off.
Practice nurse is taking an interest and discovered kidney function slightly under par .
We'll see what next week brings ..
 
Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID


Abstract:
Objective: The most common symptom of post-acute coronavirus disease 2019 (COVID-19) is fatigue, and it potentially leads to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, a specific prognosticator is lacking. We aimed to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19.

Methods: In this retrospective observational study, patients who visited Okayama University Hospital for long COVID between February 2021 and March 2022 were investigated.

Results: Of the 234 patients, 139 (59.4%) had fatigue symptoms. Fifty patients with fatigue symptoms (21.4%) met the criteria for ME/CFS (ME/CFS group), while the other 89 patients did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group). Although the patients’ backgrounds were not significantly different between the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and the Self-Rating Depression Scale (SDS). Furthermore, serum ferritin levels, which were correlated with FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/mL, interquartile range (IQR): 58.8–353.8) than in the non-ME/CFS group (98.2 μg/mL, 40.4–251.5) and no-fatigue group (86.7 μg/mL, 37.5–209.0), and a high serum ferritin level was prominent in female patients. Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in serum and that insulin-like growth factor-I levels were inversely correlated with ferritin levels (R = −0.328, p < 0.05).

Conclusions: Serum ferritin level is a possible predictor of the development of ME/CFS related to long COVID, especially in female patients.

https://www.mdpi.com/2077-0383/12/14/4737
 
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InitialConditions said:
This is probably next to useless, seeing as they think ME/CFS is just fatigue and low ferritin is associated with fatigue anyway.
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They seem to have made a good effort to diagnose ME/CFS:
The patients were categorized into the following three groups: (1) an “ME/CFS group”, which included patients with a clinical diagnosis of ME/CFS based on all of the three internationally standardized criteria, including the Fukuda criteria [18], the Canadian Consensus Criteria (CCC) [19], and the Institute of Medicine criteria (IOM) [20]; (2) a “non-ME/CFS group”, which included patients who had a complaint of fatigue but did not meet the ME/CFS criteria; and (3) a “no-fatigue group”, which included patients without any fatigue.
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Of the patients with fatigue symptoms, 50 patients (40.0%) met all of the three sets of diagnostic criteria for ME/CFS (Fukuda criteria, CCC, and IOM criteria), and these patients were included in the ME/CFS group, whereas the remaining 89 patients with fatigue were included in the non-ME/CFS group.
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Sly Saint said:
the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and the Self-Rating Depression Scale (SDS).
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It seems reasonable to me that people who are chronically ill, with no hope of recovery any time soon, will answer self-rating questionnaires differently from other groups of people.

For the ferritin levels, the difference might be the confusion between fatigue and ME's "fatigue-like symptom", and how those actual differences affect diet, activity, etc. What results will you get if you rate apples and bananas on the same scale of "deliciousness"?
 
this paper said:
Furthermore, serum ferritin levels, which were correlated with FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/mL, interquartile range (IQR): 58.8–353.8) than in the non-ME/CFS group (98.2 μg/mL, 40.4–251.5) and no-fatigue group (86.7 μg/mL, 37.5–209.0), and a high serum ferritin level was prominent in female patients.
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Just looking at the inter-quartile ranges, there's a great deal of overlap:
ME/CFS: 59 - 354
Fatigue, not ME/CFS: 40 - 252
No fatigue: 38-209

My ferritin levels have been around the 75 ug/L (micrograms per litre). If I google, I get:
google said:
The normal range for ferritin in your blood serum is: 24 to 336 ng/mL for adult males. 24 to 307 ng/mL for adult females.
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One microgram/litre (ug/L) equals one nanogram/millilitre (ng/mL)
But this paper talks about micrograms/millilitre (ug/mL).
I've googled a bit more, and I'm pretty sure that their ferritin unit should have been ug/L or ng/mL.

I think this paper might have consistently got the unit wrong? That's hard to believe, but I've checked a couple of times.
 
The sex ratios are not consistent in the groups (lower percentage of men in ME/CFS group), and they seem to have found very different levels of ferritin in females in teh different groups. See Figure 3. I can't look at this carefully right now, I might come back to it, or someone else could look at it.
Screen Shot 2023-07-19 at 9.52.46 am.png

There's probably not anything revelatory about ME/CFS, but it looks a bit odd.
 
InitialConditions said:
This is probably next to useless, seeing as they think ME/CFS is just fatigue and low ferritin is associated with fatigue anyway.
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I was trying to think my head around the potential 'confounder' of the fact that whereas those without a condition will, as a group of females in particular, include quite a lot of people who have been allowed to be anaemic or at least really low in ferritin due to the way the health system and guidelines work (even the reference range being different for women and men notes there isn't an anatomical reason why 'lower would be just as good for women', just that the 'norm' will be lower because of periods in women).

Surely those who get that ill might be more likely to have at least had such tests done (I say more likely, not that all might have just that more than those who aren't tired at all or those who are tired but perhaps not as long as severely). Which effectively removes or thins the bottom part of the distribution and ergo from the average if taking the mean. The interquartile ranges seem to suggest this is the case, with 'less low' bottoms for ME/CFS vs fatigue vs healhy controls - as well as higher 'top ends'.

It sort of doesn't matter whether you exclude those 'receiving ferritin treatment' or not from being participants as I can't think of a recruitment strategy that could work around this issue?
 
Ferritin is not just a marker for iron levels , it's involved in lots of processes .
@SNT Gatchaman linked a paper on a previous thread ( sorry don't know how to link it )

My ME aunt does have high ferritin .
My non ME aunt also has high ferritin which seemed to be related to arthritis onset - inflammatory marker.
 
https://academic.oup.com/jes/article/7/Supplement_1/bvad114.1370/7290078

THU581 Possible Markers For Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Developed In Long Covid: Utility Of Serum Ferritin And Insulin-like Growth Factor-I

Yukichika Yamamoto et al.

Journal of the Endocrine Society, Volume 7, Issue Supplement_1, October-November 2023, bvad114.1370, https://doi.org/10.1210/jendso/bvad114.1370
Published:

05 October 2023

Abstract
Disclosure: Y. Yamamoto: None. Y. Otsuka: None. K. Tokumasu: None. N. Sunada: None. Y. Nakano: None. H. Honda: None. Y. Sakurada: None. T. Hasegawa: None. H. Hagiya: None. F. Otsuka: None.

Almost three years have passed since coronavirus disease 2019 (COVID-19) pandemic broke out, and along with the number of acute COVID-19 patients, the number of patients suffering from chronic prolonged symptoms after COVID-19, long COVID, or post COVID-19 condition, has also increased.

We establised an outpatient clinic specialized for COVID-19 after care (CAC) in Okayama University Hospital in Japan in February 2021.

Our recent study has revealed that the most common symptom is “fatigue”, a part of which potentially may develop into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

However, the pathogenesis and specific prognosticator have yet to be elucidated. The aim of this study was to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19.

This retrospective observational study investigated the patients who visited our CAC outpatient clinic between February 2021 and March 2022.

Of the 234 patients, 139 (59.4%) had fatigue symptoms, of whom 50 (21.4%) met the criteria for ME/CFS (ME/CFS group), while other 89 did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group).

Although the patients’ backgrounds were not significantly different among the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and Self-Rating Depression Scale (SDS).

Of note, serum ferritin levels, which were correlated to FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/mL; interquartile range (IQR), 58.8-353.8) than those of non-ME/CFS (98.2 μg/mL; 40.4-251.5) and no-fatigue (86.7 μg/mL; 37.5-209.0) groups, and this trend was prominent in the female patients.

Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in the serum, and that insulin-like growth factor (IGF)-I levels were inversely correlated with ferritin levels (R = -0.328, p < 0.05).

Collectively, we revealed that serum ferritin levels could be a possible predictor for developing ME/CFS related to long COVID, especially in female patients.

Earlier studies have suggested that hyperferritinemia is a clinical feature in the patients of long COVID, in which hepcidin-like effects could also be involved.

Our present study also uncovered a relationship between hyperferrinemia and endocrine disorders among patients developing ME/CFS after COVID-19, although further investigations are necessary to understand the characteristics of ferritin metabolism.

Presentation: Thursday, June 15, 2023
https://twitter.com/user/status/1711790631842873643
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study excess iron Mice

“Excess iron comes from the body’s inability to process iron from the diet and is linked to inflammatory conditions, as well as cancer and aging,” said Chang.

To examine iron’s effects, the team used mice bred to lack the gene FLVCR1 in their T cells, resulting in an iron overload.

The study reveals for the first time that in the presence of too much iron, naïve T cells become defective.

Their mitochondria become hyperactive, resulting in spontaneous proliferation of the T cells.

“Excessive iron also leads to the premature death of T cells, called ferroptosis. In any disease condition, we don’t want to have T cells die before they are able to carry out their function,” said Kumar”

https://www.michiganmedicine.org/he...YaQqWKMB9KhuH3jbELySUP_8dPd6wAgvLGSwwoX3pygsB
https://www.michiganmedicine.org/he...YaQqWKMB9KhuH3jbELySUP_8dPd6wAgvLGSwwoX3pygsB
 
Arvijansen said:
study excess iron Mice
https://www.michiganmedicine.org/he...YaQqWKMB9KhuH3jbELySUP_8dPd6wAgvLGSwwoX3pygsB
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Based on this paper in PNAS. Paywalled - grrrr

Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism, 2024, Ajay Kumar et al
https://www.pnas.org/doi/abs/10.1073/pnas.2318420121

"Significance

Iron plays a crucial role in several physiological processes, including oxygen transport, DNA synthesis, mitochondrial function, and redox reactions. We have previously demonstrated that iron plays a critical role in the activation and proliferation of CD4 T cells. Iron overload leads to numerous immunological abnormalities, such as T cell dysfunction, but the mechanisms remain unclear. Here, our findings reveal that proper iron regulation is crucial for maintaining the quiescence and subsequent activation-induced proliferation of naive, but not effector, CD4 T cells. Using an iron-overloaded mouse model, we demonstrate that iron controls mitochondrial integrity and function in these cells. Moreover, the metabolic pathways are disrupted in iron-overloaded CD4 T cells, favoring the hexosamine biosynthetic pathway over glycolysis and glutaminolysis.

Abstract

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state."

A quick search for "hexosamine biosynthetic pathway" shows it's involved in metabolic signaling including metabolic circadian rhythms. Lots of research relating to cancer. No idea if it could be relevant to ME in any way
 
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