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Saturday, March 5, 2011

Leaky Gut and Chronic Fatigue Syndrome

Jen linked another Maes leaky gut paper from the comments in the Depression and a Leaky Gut post.  This paper is a case report of a 13 y/o girl with chronic fatigue syndrome.  In January 2005, the girl had a sore throat.  Thereafter she began to have progressive weakness, increasing fatigue, unrestorative sleep, abdominal bloating, headaches, a 22 pound weight loss, and poor concentration to the point where the girl was in a wheelchair and no longer able to study for school.  From the beginning, after nothing too obvious was found by the internal medicine doctor, the patient's parents were urged to take the girl to a psychiatrist.  Instead, the parents took her to a specialist in chronic fatigue syndrome, who checked a number of inflammatory markers, finding many highly positive.  In addition, the girl had high levels of circulating antibodies to the lipopolysaccharide on the outside of some gram negative gut bacteria - suggesting a "leaky gut."

The girl was treated with antibiotics, but steadily worsened, until she was admitted to the hospital to normalize her nutrition.  Then she was sent to neurology where they checked her muscle fibers, finding some abnormalities, but nothing major.  The senior neurologist felt the patient had a symptom of a psychogenic "conversion" disorder, "la belle indifference."  If the girl exhibited this symptom, she would have been oddly unconcerned about her impaired condition.  The term "conversion disorder" is a Freudian one, meaning that anxiety symptoms are being converted into physical symptoms.  Classically, "la belle indifference" is described in cases of hysterical blindness, where someone can't see and doesn't seem too bothered by the fact.

Problem is, people with chronic fatigue often have a depressed affect, so their emotional responses are muted.  They are suffering a great deal, and certainly feel that suffering, but the face and voice might not quite show it.  However, the content of the discussion is telling.  And Maes (a psychiatrist) was angry with the neurologist who diagnosed la belle indifference.  Maes says he detected no sign of unconcern - instead he saw "a young lady who was very ill and suffered from her illness and not being able to go to school and meet with her friends."

Maes continued the work-up and started her on a whole slew of nutritional supplements and the "leaky gut diet."  The corresponding author email bounces, but this paper (after several teases) gives up the following information about the diet:  "consisting of milk allergic, gluten-free and low carb diet." (Thank you, Jen). 

The nutritional supplements had some basis in thought (not surprising, from Maes, who seems to account for everything except for relying on experience from evidence-based medicine - but you can't turn your back on a 13 y/o girl in a wheelchair if you think you can get her to walk out of it.)  First off, the girl's labs showed signs of an increased immune response in some respects, and decreased immune response in others.  They were consistent with lab findings of other people with symptoms of chronic fatigue syndrome, though there are no official lab findings for CFS.  Maes is quite specific, however, in noting each of the innumerable abnormalities she had, and how they link to issues with disparate parts of the gut, nervous, and immune systems. 

He surmises that the activation of immune cytokines and autoimmunity is related to the increased transfer of the bacterial lipopolysaccharide (LPS) across the gut.  He thinks there is a trigger factor, such as exhaustion, emotional stress, or an infection (perhaps the sore throat in this girl's case - she was also found to have a mycoplasma infection, which was treated), that will cause the inflammatory system to fire up.  Some elements of this system seem to help LPS cross over from the gut into the bloodstream.  Then the immune system mounts a response against the LPS - resulting in further inflammation and the acceleration of the symptoms of CFS.  Once again, Maes is exceedingly specific, defining a large cast of immune characters and the responses. 

So, the supplements - L-carnitine, CoQ10, lipoic acid, and taurine (one might recognize these as some of the compounds that are suggested to help mitochondria run more efficiently - and several of them are absent in entirely plant-based diets.)  In order to deleak (sounds better than plug up, I think) the gut, the girl was given L-glutamine, gamma oryzanol, zinc, "etc" along with the gluten-free, casein free, lactose free low carb diet.  

On top of these supplements, the girl was given IVIg infusions (gamma-globulin, to clean up inflammation.  This stuff is prohibitively expensive.  I've seen it used with good effect in the very rare, but completely disabling likely autoimmune condition called "stiff man syndrome."  Ironically that case was referred to me for suspicion of conversion disorder.  It is also used in immune deficiencies and Guillain-Barre and Kawasaki's disease.)   The girl got daily infusions (which I find incredible - these treatments are maybe $3000-$10,000 a pop? Each treatment consists of the pooled IgG antibodies from thousands of blood donors. I don't know for sure, but I've seen those kinds of figures thrown around) for a month, then the more typical dose every two weeks thereafter. 

For the first 6 months of treatment, the girl showed no clinical improvement, though Maes tracked her immune response to LPS, and it was dropping and dropping.    At her visit 10 months into treatment, however, she walked into the consultation room, and said she could read books again, had started swimming lessons, and her sleep was much improved.  LPS response slowly improved, and eventually she was able to return to school, and her abdominal bloating went away.  After about a year, she was pretty much back to herself, and the IVIg treatments were stopped, though her leaky gut diet and supplements were continued.   At two years into treatment, she remained well. 

In the discussion, Maes really lets loose.  The only way in which it could be described as civil is that there was no swearing. 
Although these [CFS] diagnostic criteria are now well-established, many specialists... still miss and dismiss this diagnosis.  They rather conclude that patients with this medical disorder suffer - in accordance with Freud's non-scientific theories - from "conversion symptoms with a strong psychogenic component." ...It is common practice... that those patients... are referred to a psychiatrist to undergo the mainstream treatment for that condition, i.e. psychodynamic therapies.  This means that patients with severe medical disorders are being treated as having a mental illness with "a nonsense treatment" that does not treat anything.

He goes on to rail against a prevailing political wind in Europe, where the National Health Services can evidently dismiss those patients who are considered hypochondriacs, thus avoiding the cost of treating these difficult conditions.

Well.  A recent study did come out showing that graded exercise and cognitive behavioral therapy are helpful for chronic fatigue.  I wonder if the possible reduction in stress response from the light exercise and CBT help the condition.  It is still poorly understood (though Maes seems to feel he has a handle on it).  Nor is there the kind of evidence we need for Maes' enormous intervention to recommend his treatment as standard therapy.  Somehow he was able to get the IVIg and convinced the family to keep going though 6 months of no clinical improvement (though the labs were hopeful).  And, as I said before, Maes couldn't turn his back on a 13 y/o girl confined to a wheelchair when he was certain he could help her.  In general, chronic fatigue has a relapsing and remitting course, but Maes has his biomarkers to show the steady biological improvement.  All the papers on the first page of google I found linking chronic fatigue to leaky gut are by Maes.  There are other studies of LPS and chronic fatigue, most via exposing cell cultures to LPS to stimulate cytokine production.

The mechanisms seem plausible, and the case study is compelling.  We need more data.  And you might not be surprised that I don't see much harm in trying a "leaky gut" diet - why not?  I don't know about all the supplements and any long-term effects.  I do of course advocate a nutrient rich whole foods "paleo" diet with plenty of animal protein and fat goodness - which would replace some of those supplements, though perhaps not in the amounts prescribed (which weren't listed in the paper). So, you see, once again, just by going "paleo," we are seemingly a lot of the way to Maes' elaborate reduction of leaky gut and systemic oxidative stress and inflammation.  Thus our overarching theory still seems good, that many of our modern diseases are a result of the modern diet and lifestyle that our paleolithic bodies simply aren't designed for.  Interesting.

* In full disclosure I am the author of a book, Feeling Better: A 6-Week Mind-Body Program to Ease Your Chronic Symptoms, which is based on some research I have participated in with Dr. Arthur Barsky, my co-author.  He is a world expert on somatization disorders, and due to my affiliation, I am often referred "conversion disorder" cases for consultation.  Sometimes the conversions are very classic - these almost always get better with time and things like physical therapy.  When the patient doesn't get better with a conversion diagnosis and a bit of time, or if the symptoms aren't particularly classic, I tend to suspect some unknown serious medical illness.  Often these unknowns are eventually diagnosed. 

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