"It never gets easier, you just go faster." - Greg Lemond

Friday, July 12, 2013

Gluten intolerance and neurological illness

Gluten containing grains (wheat, rye, barley) make up a large portion of our daily diet, and these grains have become staple foods in the Western world.  Gluten itself is a protein structure that has been shown to elicit an immune response in some susceptible individuals.  Those who are gluten intolerant can be afflicted with what is known as celiac disease in which an immune response against self-enzymes is elicited upon ingestion of even tiny amounts of gluten (1).

Adapted from (6)

Celiac disease is a systemic immunological disease that is most commonly associated with gut dysfunction and gastointestinal symptoms.  Celiac disease is becoming an increasingly commonly recognized disorder, and it is estimated that approximately .75-1.0% of the general population suffers from some degree of celiac disease (1,2).  While the traditional concept is that celiac disease results in gastrointestinal distress, there appear to be a number of symptoms that occur outside of the gastointesinal system.  However, an interesting symptom commonly found in persons who suffer from gluten intolerance or celiac disease are unexplained neurological symptoms. This is actually not that new of a concept, as early as 1966 doctors have associated celiac disease with neurological illness (3).

The biological foundation for this observation is perhaps best evidenced by the fact that the gastrointestinal system actually has its own nervous system which communicates directly with the central nervous system.  There has since been the hypothesis proposed that states:  "Gluten causes symptoms in both celiac disease and non-celiac gluten intolerance, by its action on the nervous system" (1).

Proper neurological function is required for general health and well being; there has been a good amount of investigation into the relationship between gluten sensitivity and neurological function.  Proper digestive activity, including gut motility and gall-bladder function rely on proper nervous system activity.  Thus, the gastrointestinal symptoms reported in celiacs could largely be related to nervous system dysfunction (1,3).   In a report investigating the occurrence of neurological disease in celiacs and non-celiacs it was found that 51.4% of those with celiac suffered some sort of neurological dysfunction, while only 19.9% of those without celiac presented with neurological illness (1).  Other studies paint a slightly less dire picture, with between 10-25% of patients with confirmed celiac presenting with neurological illness of some sort, however the neurological dysfunction that is associated with celiac disease still presents a  large economic and social burden (2).  Similarly, there is a high prevalence (46%) of headache/migraines found in patients with celiac disease compared to those without celiac (29%) (1,4,5).  Taken together, these data suggest that those with celiac are over two-times more likely to have neurological dysfunction, of some sort.

In studies conducted at the Mayo clinic, patients with childhood onset celiac disease suffered from ataxia, peripheral neuropathy and seizures at an abnormally high rate (1).  Dementia has been associated with adult-onset celiac disease, such that dementia began soon after the onset of celiac symptoms, although this appears to be a rather rare phenomenon.  Furthermore, in patients in which celiac disease is associated with neurological dysfunction, cognitive impairment is commonly reported as well as amnesia (1).  The onset of cognitive impairment is also especially found to begin soon after the onset of celiac disease-like symptoms (1).

Adapted from (6)

One of the more interesting concepts regarding gluten sensitivity and gluten tolerance is the differentiation between celiac disease and gluten sensitivity.  I have more or less lumped these two terms together there, which I believe is a practical consideration as our diagnostic methods for these different conditions are constantly evolving and have yet to been unified.  For example, Hoffenberg et al. reported on a large cohort of children who were screened for evidence of celiac disease and found that 724 presented with high anti-gliadin levels (a diagnostic measure of celiac) (4).  However, upon histological examination of these children, 4.3% were define celiac (94% improvement with gluten free diet), 6.6 % were possible celiacs (with 75% improvement on a gluten free diet) and 89.1% were not-celiacs, despite the fact that 53% of these children reported improvement of symptoms with a gluten free diet (1,4).

Interestingly and importantly, neurological symptoms (tiredness, lethargy, irritability, sleep disturbance) were commonly reported in all three of these groups with 71% of the confirmed celiacs, 65% of the possible celiacs, and 51% of the non-celiacs reporting these symptoms (1).

While the association between celiac disease and neurological dysfunction appears to be fairly strong, without understanding of potential mechanisms, I remain unconvinced.  However, there does appear to be a fairly strong mechanistic basis for these observations.  Celiac is an immunological disorder, in which B cell produce auto-antibodies against transglutaminase or gliadin, the enzymes required to digest and absorp gluten or a portion of wheat, respectively (6).  Thus, the current belief is that gluten sensitivity results in auto-antibody production, which in turn damages nerve cells and results in inflammation.  Evidence for this hypothesis consists of the fact that 64% of celiacs who presented with neurological disease also had anti-ganglioside (a nerve cell) antibodies (5,6), in their circulation.  These antibodies have been shown to bind to a number of critical nerve sites that result in immune mediated damage to the nerve.  

Furthermore, studies mapping blood flow in the brains of patients who are gluten intolerant who are on a gluten free diet and those who are not have found that there is significant differences in the perfusion of various areas of the brain between the two groups (7).  While the direct cause of this is unclear, this could be related to inflammation and immunoreactivity, or direct toxicity from gluten.

While alterations in growth and body composition may be expected in persons suffering from gastointestinal illness such as celiac, the concept that this is accompanied by neurological illness as well has significant implications and is possibly less appreciated.  Those with celiac may also suffer from a wide spectrum of neurologic an psychiatric symptoms, including neuropathy, ataxia, migraines, epilepsy, lethargy, irritability, and depression (4,5). 

A search of the literature suggests that gluten can cause neurological harm through a combination of cross reacting antibodies, as well as further immunological damage, or toxicity (6),7. 

Works Cited

1)  Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses 2009;73(3):438–40.

2)  Currie S, Hadjivassiliou M, Clar MJ, et al.  Should we be ‘nervous’ about coeliac disease? Brain abnormalities in patients with coeliac disease referred for neurological opinion.  J Neurol Neurosurg Psychiatry 2012;83:1216–1221 

3)  Cooke W, Smith W. Neurological disorders associated with adult coeliac disease. Brain 1966;89:683–722.

4) Hoffenberg EJ, Emery LM, Barriga KJ, et al.  Clinical features of children with screening identified evidence of celiac disease.  Pedatrics 2004; May;113(5):1254-9. 

5)  Bushara KO.  Neurologic Presentation of Celiac Disease.  Gastroenterology 2005;128:S92–S97
6) Green PHR, Alaedin A, Sander HW, et al.  Mechanisms underlying celiac disease and its neurological manifestations.  Cell. Mol. Life Sci. 2005; 62

7)  Addolorato G, Di Giuda D, De Rossi G, et al. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 2004;116:312–7.

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