Gulf War Illness: Unifying Hypothesis for a Continuing Health Problem (2018) Mawson and Croft

Milo

Senior Member (Voting Rights)
Gulf War Illness: Unifying Hypothesis for a Continuing Health Problem

https://www.mdpi.com/1660-4601/16/1/111

Abstract:

An estimated 25%–32% of veterans of the 1991 Gulf War continue to experience multiple unexplained health problems known as Gulf War Illness (GWI).

GWI encompasses chronic pain, musculoskeletal weakness, headache, fatigue, cognitive deficits, alterations in mood, and numerous multi-system complaints.

Most potential exposures implicated in GWI were not well documented but included varying levels of several neurotoxicants as well as the anticholinergic drug pyridostigmine bromide (PB), which was routinely taken as prophylaxis against the nerve agent soman.

While some veterans also took chloroquine as an antimalarial agent, the literature suggests an association between receipt of multiple vaccinations prior to or during the conflict (perhaps combined with other exposures), and GWI.

In-theater exposures may account for any single individual veteran’s ill health but many veterans of the same era who were not deployed overseas also suffer the same or similar symptoms.

The features of GWI also overlap with those of fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity, in all of which liver dysfunction has been documented, suggesting a unifying hypothesis.

It is proposed that multiple vaccinations, with concurrent or subsequent exposure to PB or additional chemical insults of a liver-damaging nature, plausibly explain the pathogenesis and the observed chronicity of GWI.

The suggested mechanism for GWI is thus a chemically-induced impaired liver function, with the spillage of stored vitamin A compounds (“retinoids”) into the circulation in toxic concentrations, resulting in an endogenous chronic form of hypervitaminosis A.

Implications of the hypothesis are briefly reviewed. View Full-Text
 
Thank you for the mention @ScottTriGuy !


The hypothesis is a bit oversimplified but this may be an important step so that ME/CFS Researchers look at liver function more closely.


Some comments :


1) We note the mention of "Cholestatic Liver damage" disruption after accumulation of Vitamin A in the liver :


ijerph-16-00111-g001-550.jpg



2) from the paper :


Liver damage is common to most if not all of these syndromes, as evidenced by increased liver enzymes and clinical diagnoses of liver disease [24,25,26,27]. In the study of Australian male Gulf War veterans [27], those with multisymptom illness were significantly more likely than the control groups to have been diagnosed with obstructive liver disease, defined as alkaline phosphatase >110 U/L and γ-glutamyl-transferase >60 U/L.


Here are the references 24,25,26,27 respectively:


  1. Fostel, J.; Boneva, R.; Lloyd, A. Exploration of the gene expression correlates of chronic unexplained fatigue using factor analysis. Pharmacogenomics 2006, 7, 441–454. [Google Scholar] [CrossRef]
  2. Rogal, S.S.; Bielefeldt, K.; Wasan, A.D.; Szigethy, E.; Lotrich, F.; DiMartini, A.F. Fibromyalgia symptoms and cirrhosis. Dig. Dis. Sci. 2015, 60, 1482–1489. [Google Scholar] [CrossRef]
  3. Al-Harthy, N.; Kumagi, T.; Coltescu, C.; Hirschfield, G.M. The specificity of fatigue in primary biliary cirrhosis: Evaluation of a large clinic practice. Hepatology 2010, 52, 562–570. [Google Scholar] [CrossRef] [PubMed]
  4. Kelsall, H.L.; McKenzie, D.P.; Sim, M.R.; Leder, K.; Forbes, A.B.; Dwyer, T. Physical, psychological, and functional comorbidities of multisymptom illness in Australian male veterans of the 1991 Gulf war. Am. J. Epidemiol. 2009, 170, 1048–1056. [Google Scholar] [CrossRef]


This paper could be a huge step forward.

Recall that despite extensive testing on ME/CFS patients, to this day no research effort has considered performing a simple test called Total Bile acids to check for cholestasis / Bile acids disruption.
 
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https://www.biolab.co.uk/index.php/cmsid__biolab_test/Bile_Acids_Total
It's interesting to read here that bile acids can affect energy cellular signalling. Have I understood this correctly @mariovitali ?

Correct, apparently they also play a part on innate immune system, Gut dysbiosis, glucose control and other important functions.


An example for innate immunity :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099188/

EDIT : Unfortunately TGR5 / GPBAR1 is not being analysed by 23andme. Seems to be a very interesting research target

EDIT2 : Bile acid metabolism is extremely complex. Having a normal test for total bile acids doesn't mean that all is fine. Bile acids composition (there are many types of Bile acids) is also of importance and unfortunately this test is only available in Universities (to the best of my knowledge)
 
Just as an n=1 anecdote, my level of functioning still remains higher than it has been for years since my bile duct was unblocked and expanded by a stent. I've recently wondered about the effect of an improved flow of bile on my gut microbiome composition, it would seem logical that there must be some effect.
 
https://www.biolab.co.uk/index.php/cmsid__biolab_test/Bile_Acids_Total
It's interesting to read here that bile acids can affect energy cellular signalling. Have I understood this correctly @mariovitali ?

@obeat i think this deserves a mention as well. Bile acids are required for the conversion of T4 to T3. This paper gives a great explanation of the connection between Liver, Bile acids and Thyroid. I wonder how many ME/CFS patients have also thyroid issues, especially hypothyroidism. In the same paper observe the mentions on topics previously being identified by Machine Learning / Network Analysis (FXR,LXR, PPARs, CYP7A1, ABCA1) and were mentioned in my presentation in London :


https://www.s4me.info/threads/presentation-at-euromene-london-uk.5760/

@Andy in one of the slides on my first post of the EUROMENE presentation Thread it is interesting that "cholecystectomy" was picked up by the algorithms ;-)


screen-shot-2018-09-13-at-08-56-33-png.4132
 
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I understand that to be the term for removal of the gall bladder? I am due to have that done but just clearing and widening of my bile duct seems to have resulted in personal improvement.

Yes, cholecystectomy is the removal of gallbladder. The system i use has been identifying issues with the Liver / Gallbladder and the "cholecystectomy" entry here indirectly suggests that Gallbladder -and as a consequence- bile acid issues may be responsible for ME/CFS symptoms.


It will be very interesting to see also how you will feel after the operation @Andy , please keep us posted.
 
My cholecystectomy preceeded most of my ME symptoms. It was done 5 months post EBV infection. But like @Trish said, especially from the work of Dr Broderick, seemingly Gulf War and ME are different illnesses. However we know that a hih percentage of PWME has gallbladder problems.
 
Vitamin A toxicity deserves a much closer look i believe. As many of you know by now , i i've been trying to bring the attention of Researchers to a hypothesis that GWI, Post-accutane Syndrome, Post-finasteride syndrome, ME/CFS , Fibromyalgia and Post-treatment Lyme disease syndrome have the same biological basis.

I wonder if the following can be regarded as simply two more coincidences :


a) Looking at Post-accutane syndrome : Accutane is a form of Vitamin A (13-cis-retinoic acid). In a paper we read the following :


Electron microscopic examination revealed changes characteristic of vitamin A toxicity: hyperplasia of the perisinusoidal (Ito) cells with evidence of their activation and transformation, increased storage of lipids and vitamin A, perisinusoidal fibrosis, damage of the sinusoidal wall, partial necrosis in hepatocytes and an increased number of lysosomes, megalysosomes and smooth endoplasmic reticulum (SER), the signs of cholestasis as well as an increased number of Kupffer cells in the lobules etc. Histochemical examination showed a high content of vitamin A in the transitional (Ito) cells and in hepatocytes. These data led to further questioning of the patient who disclosed that he had acne conglobata which had been treated with Isotretionin, 20 mg/day

Link : https://www.ncbi.nlm.nih.gov/pubmed/14978883

Fatigue is being mentioned by many Post-accutane sufferers, examples :

https://www.acne.org/forums/topic/350720-post-accutane-fatigue/


-On the "Members-only" section on PR :

Link : https://forums.phoenixrising.me/ind...me-chronic-fatigue-illness.54073/#post-929294

-User AB, Phoenix rising :

I was also taking accutane at the time of illness onset. I'm still ill 18 years later.

https://forums.phoenixrising.me/ind...sted-research-on-cfs.51283/page-2#post-849618

So it is interesting that Vitamin A is relevant to both the paper quoted in this thread and also Post-accutane. I hypothesise that the main factor here is impairment of bile acids metabolism.


Moving on to Post-finasteride syndrome (which also has fatigue as a symptom) : Finasteride is an inhibitor of 5-alpha reductase (5AR). Interestingly, 5 alpha reductases are required for bile acid metabolism :


5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isoenzymes of 5α-reductase, SRD5A1, SRD5A2, and SRD5A3, which vary in different tissues with age.


I also believe (which was mentioned on my presentation in London) that for ME/CFS we have a similar situation of liver function disruption which affects bile acid metabolism (among others). We have potential evidence of liver issues according to Maureeen Hanson, bile acid disruption , phospholipids disruption as well. Interestingly RBC deformability relies hugely on phospholipid availability. Yet one more coincidence? We shall see.

In yet one more coincidence (?) F-Actins and cytoskeleton are part of the required machinery for RBC deformability :

The biconcave disk shape and deformability of mammalian RBCs rely on the membrane skeleton, a viscoelastic network of short, membrane-associated actin filaments (F-actin) cross-linked by long, flexible spectrin tetramers.

Link : https://www.pnas.org/content/115/19/E4377

Machine Learning has also identified Actin Cytoskeleton and F-Actins. More in this post in my blog :

http://algogenomics.blogspot.com/2017/08/new-findings-myosin-d3-actins.html

As @Trish rightly put it, i've been making a huge mistake to rely on researchers to look at this theory whereas i should be trying to talk to ME/CFS organisations instead. Lesson is learned and now we are moving forward with a different approach.
 
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Newish website:
Welcome to our new website – www.kcmhr.org
by Prof Nicola Fear & Prof Simon Wessely 3 months ago

Welcome to our new website. We, the King’s Centre for Military Health Research (KCMHR), are the leading civilian UK centre of excellence for military health research. We are part of King’s College London, and for the last 25 years our research has provided evidence on the health and well-being of serving and ex-serving personnel and their families.

Basically, this new website is to help us further disseminate what we do, which is to provide easily accessible evidence for policy makers, the public, parliament, the media, our fellow academics, charities and most of all, serving and ex serving members of the Armed Forces, not just in the UK, but around the world.
https://kcmhr.org/welcome-to-our-new-website-www-kcmhr-org/

About KCMHR
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Impact and dissemination

Findings from the studies conducted at KCMHR are regularly published in high-impact journals such as the British Medical Journal (BMJ) and the Lancet series. The high-quality of this research is regularly cited by leading medical research organisations in the UK and used as impact case studies within academia. We also strive to ensure that our research is disseminated widely throughout academia but also to military providers, medical professionals, policy makers, charities, and serving and ex-serving personnel and their families.
strange that a "centre of excellence for military health research" and no mention of GWI research being done abroad........but then as SW says GWI doesn't exist...
see also KCL
https://www.kcl.ac.uk/search/search#/all?term=gulf war syndrome
 
At this rate, every single GWI sufferer will be dead before there's any chance of progress. Problem "solved". Which appears to be the whole point, frankly.
 
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