"It's all just in your mind" – Cereal Grains edition

Dr. Briffa on Gluten Sensitivity:

… The authors of the piece refer to a study (due to be published) in which 920 patients with symptoms of irritable bowel syndrome (e.g. abdominal discomfort and bloating) have wheat (as well as other foods including cow’s milk) removed from the diet [2]. On blind challenging with food (participants did not know what food they were being challenged with), a full third of patients responded adversely to wheat and not with placebo. As the authors say:

The evidence therefore suggests that, even in the absence of coeliac disease, gluten based products can induce abdominal symptoms which may present as irritable bowel syndrome.

As a result of this and other evidence, non-coeliac gluten sensitivity was recognised earlier this year by a group of 15 international experts [3]. Common symptoms that are attributed to this condition include “intestinal symptoms such as abdominal discomfort, bloating, pain, and diarrhoea (also consistent with irritable bowel syndrome) or with a variety of extra-intestinal symptoms such as headaches, “foggy mind,” depression, fatigue, musculoskeletal pains, and skin rash.”

The authors conclude:

For patients who report wheat intolerance or gluten sensitivity, exclude coeliac disease… and wheat allergy…. Those patients with negative results should be diagnosed with non-coeliac gluten sensitivity. These patients benefit symptomatically from a gluten-free diet. They should be told that non-coeliac gluten sensitivity is a newly recognised clinical entity for which we do not yet fully understand the natural course or pathophysiology.

I am almost speechless at the balanced and honest nature of this account of gluten sensitivity: it recognises the limitations of medical testing and admits there’s things we simply don’t know or understand. I have a feeling there’s going to be plenty of people reading this who will feel inclined to shove these findings in the face of a practitioner who told them their tests were negative and that their wheat sensitivity is imagined and ‘all in their mind’.

References:

1. Aziz I, et al. Does gluten sensitivity in the absence of coeliac disease exist? BMJ published 30 November 2012

2. Carroccio A, et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol (forthcoming).

3. Sapone A, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med2012;10:13

Treat Fatigue with Iron Supplements?

Fatigue can be caused by an array of conditions.

Iron deficiency is a common cause, though whether iron supplements offer benefit in the absence of anemia remains to be established.

Children and women, particularly pregnant women, need adequate iron in their diet.

While low-dose supplements are considered safe and may be helpful in meeting daily requirements, specific supplementation isn’t necessary or advisable in the absence of a clear deficiency.

And just because it’s a supplement doesn’t mean it can’t be harmful.

Iron supplements can be toxic in children, and should be stored like any other potential poison.

What is true for iron as supplement, should be taken as guideline for other (mineral or vitamin) supplements as well: Low doses may be OK, but high doses of (some) supplements can harm you – and any supplement might mainly give you expensive urine.

--

And personally, my advise to increase iron is:

• Ditch cereal grains
  (see Loren Cordain' Cereal Grains: Humanity's Double-Edged Sword for details how grains hinder mineral absorption)
• And eat more beef

"At least two subgroups of patients with CFS can be identified by gene expression changes following exercise"

A follow up to their previous studies by "The Lights".

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC.

Department of Anesthesiology The Brain Institute Department of Neurobiology and Anatomy Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT 84132, USA.

Abstract

OBJECTIVES:

To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise.

DESIGN:

Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate).

Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise.

Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen.

Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise.

Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments.

RESULTS:

No gene expression changes occurred following exercise in controls.

In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h.

These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered.

History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup.

FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls.

CONCLUSIONS:

At least two subgroups of patients with CFS can be identified by gene expression changes following exercise.

The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine.

The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A.

FM-only patients can be identified by baseline increases in three genes.

Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

Sinusitis associated with fatigue and pain

I found some older studies (warning: they try to push endoscopic sinus surgery), but they are interesting nevertheless:

ScienceDaily (Aug. 14, 2003) — Washington, D.C. – A new study published in the August 11 issue of the Archives of Internal Medicine demonstrates a possible link between unexplained chronic fatigue and sinusitis, two conditions previously not associated with each other. Also newly noted was a relationship between sinusitis and unexplained body pain.
…
Through his private internal medicine practice, Chester questioned 297 patients, noting unexplained chronic fatigue in 22%, unexplained chronic pain in 11%, and both in 9%. While these numbers are consistent with previous studies, Chester observed an unusual connection between patients with chronic pain or fatigue: prevalent sinus symptoms. Sinus symptoms were nine times more common on average in patients with unexplained chronic fatigue than the control group, and six times more common in patients with unexplained chronic pain. In addition, sinus symptoms were more common in patients with unexplained fatigue than in patients with fatigue explained by a mental or physical illness, suggesting the syndrome of unexplained fatigue is more closely associated with sinusitis than are other types of fatigue.
…
15 out of the 65 patients in Chester's study met criteria for chronic fatigue syndrome (CFS), a severe form of unexplained chronic fatigue associated with body pains and other symptoms. Most CFS patients had sinus symptoms and many noted a sudden onset of their illness, similar to people with sinusitis. "We clearly need to do more research to see if sinus treatments alleviate fatigue and pain. This study does, however, offer hope for possible help in the future." said Chester.

ScienceDaily (Sep. 23, 2008) — A new analysis led by researchers at Georgetown University Medical Center suggests many patients with sinusitis have aches and pains similar in severity to people in their 80s and those with arthritis or depression. …  "We found that the daily experience of bodily pain was much more common in patients with sinusitis than in the overall population," explains Chester. "Confirmation that aches and pains occur with sinus disease is a relief to many patients who thought they had two separate illnesses."

So what did the meta analysis find?

A subgroup analysis of 11 studies measuring outcomes using the 36-Item Short Form Health Survey (SF-36) demonstrated a moderate-sized combined effect of 0.47 (95% confidence interval, 0.38-0.56; I = 0%), corresponding to a mean +/- standard deviation improvement of 9.7 +/- 3.4 units on the SF-36 vitality domain scores.

A improvement of 10 points on the SF-36 score isn't bad, but it is not a cure to ME/CFS...

Alan Light 2011 Lecture: Gene Expression Biomarkers for Chronic Fatigue & Fibromyalgia Syndromes

As a follow-up to the last post, here is his 2011 lecture (about 1 hour) by Alan Light for OFFER Utah about his very excellent ME/CFS gene-expression study.

This is objective data that there is biological reason for the symptoms [in ME/CFS and Fibromyalgia].

You may want to switch to 1080p HD to best view the slides.
(Part 1 Part 2 Part 3 Part 4 Part 5)

My take-home messages:

1. 70% of ME/CFS patients have Fibromyalgia (FMS) symptoms. And Fibromyalgia gets worse after exercise, even if the definition for FMS does not specify for it. And a majority of FMS patients (but not all) have ME/CFS symptoms.

2. TRPV1 contributes to the body's temperature set point.

3. Alan Light found a sensory definition of fatigue (The nerves at the muscle tell the brain "You are tired") in ME/CFS that contributes to the desire to use the muscles less. It is related to "actual" muscle fatigue ("The muscle is about to fail"), but it is not the same.

4. In both ME/CFS and FMS there is a 40% subgroup, that has a Ad2A (vasoconstriction) decrease. That gene is responsible for preventing orthostatic intolerance (OI / POTS). 70% patients with this gene expression profile have orthostatic intolerance, and 20% without have POTS (it might depend when and how you measure POTS).

5. FMS without CFS patients look like controls after execercise, but have different baseline levels. P2X4, TRPV1 and IL10 are expressed higher at baseline.

6. Gene expression as biomarker for ME/CFS and Fibromyalgia? Specificity 94% (6% of false negatives) and sensitivity of 65% (35% of false positives), good but not excellent biomarker, could be improved. Might be clinically available within 2 to 3 years.

7. The orthostatic subgroup should be treated differently.

8. Pregabalin or Gabapentin decrease the level of pain and of mental fatigue - maybe.

9. The cause could be increase of sensitivity of fatigue and pain, or dysfunction of the sympathetic nervous system.
(My comment, this the only flaw of Alan Light's work I can think of. He is leaving out one possibility: Of course it could be that there is an actual increase of fatigue and pain due to a pathologically increased muscle exhaustion in ME/CFS and FMS patients. If the nerves are sensing something, it could actually be there – doh!)

10. This is objective data that there is biological reason for the symptoms.
(Translated to English: "The psychosomatic school can go and f*ck themselves.")

As an addendum:
Don't miss Christopher Snell's 2012 lecture, which ties in nicely!

Alan Light 2007 Lecture: The Physiology of Chronic Pain and Fatigue

OFFER Utah (warning, their website plays music...) has a lot of lectures regarding ME/CFS on their OFFER Utah Youtube Channel. They have some very good and interesting lectures (and some less so). If you haven't already, you should subscribe to their Youtube channel, add the feed to your RSS-Reader, etc. ...

One very interesting video is this 44 minutes lecture by Alan Light:

"The Physiology of Chronic Pain and Fatigue" Dr. Alan R. Light.

This presentation by Alan R Light was made during the 2007 OFFER Provider's Conference. This lecture shows basically where Alan Light came from and his studies that lead up to the ME/CFS post-exertional gene-expression study "the Lights" (he and his wife Kathleen Light) have done together with Lucinda Bateman.

I had these take home messages:

1. Acute pain and fatigue sensing are protective and evolutionary important to prevent depletion or injury of important systems. If an living being has an impairment in sensing of pain and fatigue, it will usually die quite quickly. So there are multiple pathways in a living being to measure this information.

2. There are many concepts of fatigue. For ME/CFS fatigue is not sleepiness, fatigue is not failure of the muscle, but a sensory event – one could move the muscle with enough willpower.

3. The sensing of muscle-pain and fatigue happens by nerve sensory-endings located between the muscle and the blood vessels. Several metabolites (Lactate, ATP, pH/protons) are measured together by receptors (e.g. P2X4, P2X5, ASIC3, TRPV1) working together.

4. Fatigue and pain share receptors, but are not the same.

5. The sympathetic nervous system can restrict blood vessels to muscles that are not fatigued and increase blood flow to muscles that are.

6. Mononuclear blood cells have these receptors too, as they need to go "where the action is", where damage is, where things are going wrong and they are circulating through the muscles that are used.

7. Enhanced muscle pain is caused by cytokines, and if the blood flow is not increased (if the sympathetic nervous system does not regulate it properly), the metabolites in the muscles build up, and with it fatigue and pain.

8. The NIH (and the medical profession at general) are not interested and it is very difficult to get funding for these studies. All his research depends on the support by the university of Utah. There is some old medical "knowlegde" ("these receptors don't function at physiological ranges" etc.) that needs to be challenged and updated. This research that should have been done 25 years ago and the NIH is dragging its feet.
(I find it ironic that it is Alan Light's research in ME/CFS that improves the understanding in biological and medical sciences of how pain and fatigue work – after all the damage that Strauss et. al. have done with their psychosomatic bullshit, after all the damage Wessely and Sharpe are still doing today)

Don't miss Alan Light's 2011 follow-up lecture!

And don't miss Christopher Snell's 2012 lecture, which ties in nicely!