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

[Andy]

Merged thread, link and abstract added to post

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.



************
Editorial: Ferritin and myalgic encephalomyelitis/chronic fatigue syndrome in post COVID-19, an unexpected facet of the hyperferritinemic syndrome?

Coronavirus disease 2019 (COVID-19) has provoked a catastrophic medical emergency worldwide [1]. In the course of time from the beginning of this pandemic, subacute and long-term effects in patients suffering from COVID-19 have been increasingly recognised [1,2]. Thus, the term “long-COVID-19” has been proposed to describe this collection of signs and symptoms which may continue or sometimes develop following the SARS-CoV-2 infection. The latter is defined as post-COVID-19 syndrome [3]. In a large percentage of these patients, mental health problems and fibromyalgia have been also recognised [[3], [4], [5]]. Interestingly, many patients could experience severe fatigue in a clinical setting of myalgic encephalitis/chronic fatigue syndrome (ME/CFS), even several months after SARS-CoV-2 infection [6]. In this context, low level inflammation and hypoperfusion have been recently proposed as potential pathomechanisms of occurrence of ME/CFS [7].

On these bases, possible predictors of ME/CFS have been recently investigated in 234 patients with post-COVID-19 syndrome [8]. To date, almost 60% of evaluated patients had fatigue symptoms, and 21.4% met classification criteria for ME/CFS. The authors performed a deep assessment of laboratory features of included patients, stratifying the results in 3 groups, namely patients meeting classification criteria for ME/CFS, patients with fatigue but not reaching the classification criteria for ME/CFS, and patients without fatigue.

Open access, https://www.sciencedirect.com/science/article/pii/S0022399923000880

 

[SNT Gatchaman]

Coronavirus disease 2019 (COVID-19) has provoked a catastrophic medical emergency worldwide. ... long-term effects in patients suffering from COVID-19 have been increasingly recognised.

Know what else has provoked this catastrophic medical emergency worldwide?

Still, on the plus side, it's an editorial in J Psychosomatic Research that discusses biological underpinnings of ME/CFS. Also the CSF-to-CFS ratio is a quite restrained 3:21 in this corrected proof.

On the minus side —

Despite a moderate increase, patients with ME/CFS had significantly higher serum ferritin levels when compared with patients with fatigue not reaching the classification criteria and patients without fatigue. Interestingly, serum ferritin levels also correlated with the severity of the clinical picture, assessed by fatigue assessment scale and self-rating depression scale. Finally, serum ferritin levels were significantly higher in female patients with ME/CFS.

In addition, the finding of the association between serum ferritin levels and ME/CFS is somewhat surprising as low, rather than high, values of this molecule have been historically associated with fatigue in both anaemic and non-anaemic individuals and iron supplementation may improve fatigue in more than 80% of iron deficient patients.

Gonna need some emojis for that one.

High serum ferritin levels may be used as clinical feature to timely identify patients with ME/CSF. Consequently, an early recognition could improve the management of these patients by using a feasible biomarker, which is easily and widely used in clinical practice.

You guys ... this is the March 15th edition, you're two weeks early.

 

[Hutan]

(cross post with SNT Gatchaman)
Editorial in the Journal of Psychosomatic Research

On these bases, possible predictors of ME/CFS have been recently investigated in 234 patients with post-COVID-19 syndrome [8]. To date, almost 60% of evaluated patients had fatigue symptoms, and 21.4% met classification criteria for ME/CFS. The authors performed a deep assessment of laboratory features of included patients, stratifying the results in 3 groups, namely patients meeting classification criteria for ME/CFS, patients with fatigue but not reaching the classification criteria for ME/CFS, and patients without fatigue. Despite a moderate increase, patients with ME/CFS had significantly higher serum ferritin levels when compared with patients with fatigue not reaching the classification criteria and patients without fatigue. Interestingly, serum ferritin levels also correlated with the severity of the clinical picture, assessed by fatigue assessment scale and self-rating depression scale. Finally, serum ferritin levels were significantly higher in female patients with ME/CFS [8].

Reference 8 is:
Y. Yamamoto, Y. Otsuka, K. Tokumasu, N. Sunada, Y. Nakano, 6 HondaH, Sakurada Y, Hasegawa T, Hagiya H, Otsuka F.
Utility of serum ferritin for predicting myalgic encephalomyelitis / chronic fatigue syndrome in patients with long COVID
J. Psychosom. Res. (2023)
(IN PRESS)

 

[FMMM1]

Not sure what to make of this publication e.g. I would have expected this to have emerged a long time ago.

If iron transport/metabolism is relevant, in a large proportion of cases, then I'd expect seething to turn up in the GWAS study.

 

[Kitty]

I would have expected this to have emerged a long time ago.

That was my first thought, but might it be something that could easily be overlooked? 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. It probably wouldn't even be noted in some ME studies.

 

[Amw66]

Know what else has provoked this catastrophic medical emergency worldwide?

Still, on the plus side, it's an editorial in J Psychosomatic Research that discusses biological underpinnings of ME/CFS. Also the CSF-to-CFS ratio is a quite restrained 3:21 in this corrected proof.

On the minus side —





Gonna need some emojis for that one.



You guys ... this is the March 15th edition, you're two weeks early.

My aunt who is severely affected has humongous ferritin levels . No problems on iron panel and no haemachromatosis. Ferritin us an inflammatory marker .
Her sister , who dosn't have ME developed very high ferritin levels too . Again iron panel ok.
Recently diagnosed ( after bring fobbed off re back pain ) with osteo arthritis - so inflammation high .

Ferritin isn't only about iron.

 

[John Mac]

When I first became ill in 2002 with extreme fatigue (the beginning of my ME I believe) I went to the doctors and they found my ferritin levels were high, 760, normal range 30-330, and remained high so they sent me to the blood specialists who tested me for hemochromatosis (negative) and checked my liver etc (all ok). In the end they gave up and said they didn't know what was causing it but suggested that high ferritin levels can be a sign of inflammation. They said that 760 is not that high and it probably wasn't the cause of my fatigue. They mentioned that donating blood was one way of reducing high ferritin levels. The levels eventually came down under the 330 mark and the fatigue went away for a while and no blood test since has as far as I know has ever shown it to be high. But it is a bit suspicious that the level was high when my ME started.

 

[Mij]

My ferritin levels dropped below 6 soon after M.E onset and kept dropping. I had to take iron supplements regularly for decades.

 

[Hutan]

For what it's worth, my measured ferritin levels have been very normal during my illness. My son's ferritin level was actually low, below the normal range, when he first got ME/CFS. He was prescribed an iron supplement; his measured levels have been normal since.

 

[SNT Gatchaman]

Ferritin isn't only about iron.

To expand a little on this, ferritin biology is not fully understood. It's considered an acute phase reactant in which it may be a marker of cell damage. Serum ferritin levels can be used to estimate body iron stores but it's not so straightforward. Liver biopsy or MRI are often used to try and get a better estimate in iron-overload conditions.

There was a special issue on Advances in Iron Metabolism and Anemia in Metabolites in 2022, containing —

The Role of Ferritin in Health and Disease: Recent Advances and Understandings (2022)

And from Chemistry and biology of ferritin (2021, Metallomics) —

Initially, ferritin was considered predominantly a cytosolic protein with a general iron storage function. Ferritin can also be found in other cell compartments such as the nucleus, mitochondria or lysosomes where it may play various different roles depending on the cellular context. Mitochondrial ferritin can protect cells against ROS and thus against ferroptosis. The expression of L-ferritin and H-ferritin can differ between different cellular compartments. In liver and spleen cells, it was shown that H-ferritin is mainly found in the nucleus, whereas L-ferritin is predominantly found in the cytosol. In addition, specific receptors can take up exogenous ferritin via endocytosis. Further studies are required to investigate how exactly this affects iron homeostasis of cells and how this relates to receptor-mediated iron endocytosis of transferrin or hyaluronates or iron uptake through membrane iron channels. In iron-depleted conditions, ferritin can be found in lysosomal compartments, more specifically in autophagosomes and autolysosomes during a process called ferritinophagy, which generates labile iron from the ferritin stock.

Ferritin can also be secreted by cells and be found in the serum, where it comprises mostly of L-ferritin subunits. L-ferritin is mainly involved in iron storage and mineralization. Thus, serum ferritin may carry iron, but not load labile iron that is present outside of the cell. [...] It is also unknown whether iron is bound to ferritin during the secretion process or whether iron can be loaded onto ferritin in the serum, which poses the question to what extent serum ferritin levels are indicative of serum iron concentrations. These questions remain to be answered to better understand the role of serum ferritin as an iron carrier, delivery, or storage system.

Jo would have in-depth knowledge on this as it's a marker in rheumatoid arthritis and other chronic inflammatory conditions.

 

[Kalliope]

Mine has been low several times. Once it was 2 or 3. I don't notice when it's under the limit due to ME, so have to check regularly and also take supplements. Have any of you had too high levels?

 

[Wonko]

Last time I had it checked it was slightly over 1000.

 

[TigerLilea]

My ferritin levels were always between 27 to 32 until menopause when they went up to 134. Since being diagnosed with MGUS and Sjogren's just over four years ago they have been consistently going down. When they were checked two years ago they were down to 56 and on Monday I get the results from testing done in the ER on Wednesday.

 

[Art Vandelay]

My aunt who is severely affected has humongous ferritin levels . No problems on iron panel and no haemachromatosis. Ferritin us an inflammatory marker .
Her sister , who dosn't have ME developed very high ferritin levels too . Again iron panel ok.
Recently diagnosed ( after bring fobbed off re back pain ) with osteo arthritis - so inflammation high .

Ferritin isn't only about iron.

As I've said elsewhere on the forum, my ferritin has also been very high since I came down with ME/CFS. After tests for haemochromatosis and fatty liver came back clear, doctors just shrugged their shoulders.

My father's ferritin has been similarly elevated for the past 7-8 years without any explanation or much interest from his doctor.

 

[Amw66]

This is quite good re heme/ ferritin functions etc .
Touches on inflammation, signalling etc.

ETA low copper status affects ferritin formation .


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961798/

 

[Jonathan Edwards]

Jo would have in-depth knowledge on this as it's a marker in rheumatoid arthritis and other chronic inflammatory conditions.

I am afraid I never took much interest in ferritin. It mostly seemed to be a red herring, other than in the context of haemochromatosis. Other things more directly reflect inflammation.

 

[Midnattsol]

My ferritin levels have never been an issue. Though I want to point out that ferritin reference ranges have been based on "expert opinion" and some argue the lowest range is too low. Quoting myself from another thread where ferritin levels were discussed:

As @Arnie Pye has pointed out, ferritin <30 might still be deficient. The reference ranges that start at 12-15 have been based on "expert opinion" and not physiology. Another interesting read into that is this Lancet article, which is based on US data (they want a threshold of >25 and not 30 for women, so there are some differences. I haven't looked at the basis for the NICE recommendations). https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00168-X/fulltext

 

[bobbler]

As I've said elsewhere on the forum, my ferritin has also been very high since I came down with ME/CFS. After tests for haemochromatosis and fatty liver came back clear, doctors just shrugged their shoulders.

My father's ferritin has been similarly elevated for the past 7-8 years without any explanation or much interest from his doctor.

Mine can get very low, and are never high, and I also have inflammation

 

[FMMM1]

That was my first thought, but might it be something that could easily be overlooked? 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. It probably wouldn't even be noted in some ME studies.

Any clues re low hemoglobin --- not sure what consequences of marginally low iron would be.

 

[Arnie Pye]

I want to point out that ferritin reference ranges have been based on "expert opinion" and some argue the lowest range is too low.

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" :

In all people, a serum ferritin level of less than 30 micrograms/L confirms the diagnosis of iron deficiency.

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 :

Interpreting a full blood count

• Anaemia is defined as a haemoglobin (Hb) level two standard deviations below the normal for age and sex:
  • In men aged over 15 years — Hb below 130 g/L.
  • In non-pregnant women aged over 15 years — Hb below 120 g/L.
  • In children aged 12–14 years of age — Hb below 120 g/L.
• Mean cell volume (MCV):
  • In adults, microcytosis is when the MCV is less than 80 femtolitres.
    • However, while the probability of iron deficiency in anaemic people increases with decreasing MCV, no specific cut-off point can be used, as even in people with an MCV of 75 femtolitres, only 68% will have iron deficiency.
  • An MCV less than 95 femtolitres has a sensitivity of 97.6% for iron deficiency anaemia.
    • In people with anaemia and an MCV of more than 95 femtolitres, there is a low probability of iron deficiency

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.