Gulf War Illness May Be Due to Mitochondrial Damage from Toxin Exposures

Beatrice A. Golomb MD, PhD Professor of Medicine Family and Preventive Medicine University of California, San Interview with:
Beatrice A. Golomb MD, PhD
Professor of Medicine
Family and Preventive Medicine
University of California, San Diego What are the main findings of the study?

Dr. Golomb: The main finding is that veterans with Gulf War illness have bioenergetic defects — dysfunction of mitochondria, the energy producing elements of cells — that is evident in comparing affected veterans to matched healthy controls.

An estimated 1/4 to 1/3 of the ~700,000 US veterans from the 1990-1 Gulf War developed chronic multisymptom health problems that entail fatigue, cognitive and other CNS problems, muscle pain, weakness and exercise intolerance, with high rates of gastrointestinal (especially diarrhea) and neurological problems, and other symptoms – as well as autonomic dysfunction. Evidence suggests these problems have not abated with time. Veterans from other nations that have conducted epidemiological studies, including the UK, Canada, and Australia, also show elevated rates of problems. Were any of the findings unexpected?

Dr. Golomb: The findings are unquestionably new, and they will be unexpected to many or most. To my knowledge no prior study has documented (or looked for) mitochondrial dysfunction in Gulf War illness.

I have urged research to examine this at least since 2002, in the earliest meetings of the Research Advisory Committee on Gulf War Veterans’ Illnesses, for which I was the inaugural Scientific Director. At that time, though, only researchers employed by the VA, with at least 5/8 time appointments, were eligible to apply for research funds to study Gulf War illness, which were administered only through the VA. (So, many with promising ideas could not apply for funding.)*

This research was funded through the Department of Defense and their Congressionally Directed Medical Research Program, or CDMRP. Congress appropriated additional funds for research in this area to be administered through the Department of Defense, open to all investigators.  In my view and that of many veterans, that research program has done a superior job in directing funds toward projects that have prospects to actually help understand and treat this condition. Reasons for this include the apparent will to do the right thing; and, in addition to knowledgeable scientific reviewers, their inclusion of a  “relevancy review” by the most important stakeholder — affected Gulf War veterans.

So, the idea that mitochondrial dysfunction might be a major factor if not the key to understanding Gulf War illness was what motivated the study. But one can never be sure whether one’s hypotheses will be borne out. What should clinicians and patients take away from your report?

Dr. Golomb:  This has potential to be a watershed. Findings from this study support a mechanism that accounts remarkably for the accumulated evidence related to Gulf War veterans (as no other hypothesized mechanism has). It fits with information on what exposures relate to Gulf War illness, how the symptoms behave, which objective markers are and are not abnormal, and what other conditions are observed.

I. The exposures that have shown the strongest and most consistent body of evidence connecting them to Gulf War illness, are powerful oxidative stressors that have been shown to confer mitochondrial toxicity in animals. These are acetylcholinesterase inhibitors or “AChEi.”

Veterans were exposedto AChEi via the pyridostigmine bromide nerve agent pretreatment pills given to an estimated 250,000 US troops; which are carbamate AChEis. They were exposed via carbamate and organophosphate pesticides which were used aggressively and in some instances overzealously in efforts to protect against insect vectors of disease (with overexposure for some acknowedged by the DoD). They were exposed via organophosphate nerve gas to which servicepersons were exposed in association with demolition of an Iraqi munitions depot (one for sure, others unconfirmed).

II. The characteristics of symptoms are compatible in numerous particulars with mitochondrial dysfunction, including features that have been deemed paradoxical, or have even been wrongly cited as implying toxic exposures cannot be responsible. These are:

a. Multiplicity of symptom that are protean and span many domains. Around the same number of Gulf deployed and nondeployed have 1 or 2 mild symptoms (as studied by Lea Steele, in Kansas veterans). What is different and “unique” among Gulf deployed personnel, is that there is a large distinctive group who showed symptoms spanning at least 3 of 6 assessed domains (fatigue-sleep, pain, neurological, gastrointestinal, respiratory-breathing, dermatologic), that were of at least moderate severity (not mild), and/or involved more than one symptom within the domain. This multiplicity is also characteristic of mitochondrial illness.

b. The specifics of the symptoms differ from person to person This is also characteristic of mitochondrial illness.

c. Symptoms are dominated by fatigue, cognitive/CNS, and muscle (e.g. pain, weakness, fatiguability), calling to mind classical so-called mitochondrial “encephalomyopathy”. The brain and muscle are highly energy demanding “aerobic” postmitotic tissues, so are especially vulnerable. In both settings, there are high rates of GI and neurological symptoms, recalling mitochondrial neurogastroencephalomyopathy.  Sleep, neurological, psychiatric, dermatologic, shortness of breath, are also common in both. Finally, in both, a range of additional problems are observed in smaller subsets, spanning virtually every organ system (since cell energy is required for every function in the body)

d. There is variable latency to onset of symptoms (that again vary from person to person), as is classical in mitochondrial disease. Symptoms continued to emerge at elevated rates after servicepersons were no longer deployed in the Gulf. This is consistent with mitochondrial phenomena termed “heteroplasmy” and “threshold effects”. (Baseline vulnerability of an organ depends on that organ’s cells balance of mitochondrial mutations, which aren’t the same from organ to organ; and damage can lead to more damage as impaired mitochondria produce oxidative stress, which yields symptoms when a threshold is surpassed, of either cell death or amount of mitochondrial dysfunction — so-called threshold effects.)

III. The profile of other conditions, and of objective markers shown to be altered, are also compatible with mitochondrial disease.

For instance:
a. Routine blood tests are commonly normal.
b. Gulf War veterans showed elevated rates of ALS in three separate studies. ALS is condition tied to mitochondrial dysfunction in a vicious cycle with oxidative stress
c. Other objective markers that are abnormal in Gulf War illness and Gulf War veterans – increased autonomic dysfunction, increased coagulation activation, increased autoimmune markers, etc — are each expected sequelae of intertwined mitochondrial dysfunction and oxidative stress.

Clinicians should also take from this report that these veterans’ suffering is real and due to “organic” causes, not in any way “all in their heads.”
It is a tragedy that cannot be undone that many affected veterans attest they have been subjected to derision rather than compassion, and dismissiveness rather than help. But perhaps armed with better information, physicians may do better in the future.

Also, these findings suggest that treatment approaches targeting bioenergetics and oxidative stress (and downstream sequelae of these) may confer benefit to those who are affected. What recommendations do you have for future research as a result of this study?

Dr. Golomb: Replication is always desirable, and is currently planned..
A randomized trial of coenzyme Q10 (vs placebo) should be published this year.

More research will be needed to continue to understand the secondary mechanisms involved; and to identify and test promising treatments to mitigate the ongoing suffering and impaired function of these veterans.


Mitochondrial Dysfunction in Gulf War Illness Revealed by 31Phosphorus Magnetic Resonance Spectroscopy: A Case-Control Study

Hayley J. Koslik, Gavin Hamilton, Beatrice A. Golomb

Published: March 27, 2014

DOI: 10.1371/journal.pone.0092887