Professor Marios Hadjivassiliou: neurologist, gluten ataxia and Gluten Related Disorder specialist
Prof Hadjivassiliou co-founded the Sheffield Institute of Gluten-Related Disorders (GRDs) in 2013; the world’s first clinic to specialise in the neurological manifestations of gluten-related disorders.
Neurological, Not Gut
Research suggests symptoms of GRDs are 7-8 times more likely to be outside the gut than within it and much of that is neurological. Prof Hadjivassiliou’s research found that about 57% of patients with unexplained neurological conditions, including ataxia and neuropathy, have high gluten antibodies and respond well to a GFD (gluten free diet). People with idiopathic chronic headaches and peripheral neuropathy should get tested too as they have also responded well in GFD trials.
NCGSs Not Making It Up!
No-one yet knows the exact trigger for NCGS or non-coeliac GRDs generally - the gliadin, other gluten peptides, something else in wheat or not wheat at all. Neither do we yet have a reliable marker to confirm NCGS. But, NCGSs are not making it up and it’s not all in their mind: they invariably improve on a GFD. In his clinics, if they can’t find a cause for a condition, they trial a GFD automatically.
Markers: GADs, Transglutaminases and Genes
Prof Hadjivassiliou has found GAD antibodies turn up a lot in NCGSs rather than coeliacs. GAD stands for Glutamic Acid Decarboxylase antibodies, found high in Type 1 diabetes, stiff person syndrome and some neuro diseases. They come down significantly on the GFD, so he feels it could turn out to be a good lab marker in future. He feels, if present, they suggest multiple autoimmune diseases could be going on.
The other really interesting discussion was about the different transglutaminases found in GRDs. In summary, tTg2 (tissue Transglutaminase 2) is linked with CD gut, although also proven to react with brain and nervous tissue which is less well-known, tTg3 with skin (eg. dermatitis herpetiformis) and tTg6 with non-gut, especially the brain. He thinks tTg6 could turn out to be the neurological gluten marker, especially since they have found more than 30% of idiopathic ataxia patients have it.
This is not an exact science, though: he makes the point that sometimes in neurological GRD people with CD enteropathy, you only find TG6 where you might expect to find tTg2. In other words, it is important to look for all the transglutaminases. This might even point to the fact that the damage doesn’t start in the gut; that maybe in some people it is the blood brain barrier that is affected first, no-one yet knows.
Lastly, but very importantly – and making me feel more than a little smug as I have been fighting for this for 4 years now – he suggests that NCGSs may have their own DQ gene, not just the DQ2 and DQ8 we currently look for in CD. He has found 20% of his ataxia patients have DQ1 and says this may be the gene related to gluten neurological disorders but we just don't know yet. This concurs with my own clinical testing. I find a lot of neuro GRDs have DQ1 – and in fact DQ3, which has yet to be acknowledged - but I’m confident!
Prof Hadjivassilou gives a GRD if DQ2, 8 or 1 genes are positive and he finds antibodies, then re-tests 6 months and 12 months later to check antibody levels are reducing. If not enough progress is seen, they assume hidden gluten ingestion.
Gut patients feel better much more quickly than neuro ones – well over a year usually because of the continued inflammation, he assumes. Neuros have to be more vigilant, too: even one exposure can set them back months, not days.
Key Practical Message
If you have an idiopathic neurological (or any unexplained) problem, check for a GRD. Test all the transglutaminases, include DQ1 in gene testing and look for GAD antibodies as a general marker for multiple autoimmune disease. Neuro GRDs must be extra vigilant if they are to heal.
Dr Umberto Volta: Cardiology, internal medicine, immunology, focus on gluten illness and malabsorption syndromes
Dr Volta is colloquially known as ‘Mr NCGS.’ He was the first to identify the Elisa IgA and IgG gliadin antibody and transglutaminase markers for CD, then five years ago began investigating NCGS because they were finding so many gluten sensitives with no wheat allergy or coeliac diagnosis but a clear gluten problem. His clinic team is currently following two thousand NCGS patients closely to determine more about the condition.
NCGS So Far
The prevalence of NCGS is much higher than published figures suggest - around 6% of the population, not 0.6%. In his clinics, they see double the number of NCGS cases than CD. Average age of CD is 35 and NCGS 45 and he thinks NCGS starts suddenly, mostly with no previous symptoms and is more likely to develop in susceptible people after 40. More females than males get NCGS – a rate of 4-5:1 compared to 2-2.5:1, so always more women but double in NCGS.
Brain fog is the most common symptom of NCGS he sees, with about 35% of NCGSs having it compared to less than 10% of coeliacs; consequently, he thinks brain fog is a pretty good indicator for NCGS.
Volta says the most common extra-GI symptoms are fatigue (approx. 75%), headache (55%), arthralgia and myalgia (40%), foggy mind, skin diseases, anaemia and mouth ulcers (25%).
Barrier Permeability, Multiple Sensitivity and Malabsorption
Volta’s team has established barrier hyper-permeability is just as much a feature in NCGS as it is in CD. Not surprisingly, then, multiple sensitivity is showing up.
He explained that approximately 50% of NCGSs present with IBS in his clinics and most of those have other food sensitivities. Fascinatingly, he has discovered a link between nickel allergy and corn sensitivity which tends to show as abdominal pain and skin disorders. He finds lactose intolerance in about 40% with nickel and fructose sensitivity also common. I wonder if he has tested histamine; I bet that would show up too?
Malabsorption may be just as clinically significant as in CDs, although it is a form of inflammatory malabsorption rather than villi loss. Around 40% are testing positive for osteopenia and they find low Vitamin D, ferritin, folic acid and B12 regularly. He says NCGSs tend not to tolerate calcium, oddly, when he has given it.
He considers NCGS an inflammatory disorder because there are fewer intraepithelial lymphocytes (IELs) on testing, which suggests less of an immune response. However, I agree with others (eg. Vojdani), who believe that the inflammation damages the linings more and eventually sets up inflammatory or autoimmune pathways, depending on the person. In fact, Volta later gave a list of ‘common NCGS associated autoimmune disorders’, noting alopecia, AI thyroiditis and AI gastritis especially.
Prof. Volta reckons 30% of NCGSs as opposed to 95% of CDs have the DQ2/8 genes, but look at what Prof Hadjivassiliou said about this above – no-one else (besides me and him, it seems) is looking for the DQ1 and DQ3.
CDs have higher IgA anti gliadin antibodies (70%) than NCGSs (7%), probably because CD is a gut disease and most IgA is produced in the gut. In contrast, NCGSs have more IgG antibodies, pointing to a chronic, systemic problem. He has found most NCGSs don’t have positive transglutaminases, although again look at what Prof Hadjivassiliou above said about the tTg6 being the more likely NCGS one and current testing only looks for tTg2, the CD gut marker.
He pointed out, as did many of the experts, that NCGS is a real condition. There are lots of studies already confirming NCGS and he is currently doing a cross-sectional study. I note, though, that he is using rice as the gluten alternative and I have found clinically that many NCGSs cannot tolerate any grain, including rice, so not sure how far that research will get us.
CDs and NCGSs have a different response to the GFD. CDs tend to gain weight and NCGSs tend to lose it because of their different malabsorption syndromes. In CD, patients are not absorbing calories OR nutrients so gain weight when they start getting the calories, whereas in NCGS, they are getting calories mostly; just not the nutrients. For treatment in both, he recommends supplementation especially of iron, magnesium and zinc alongside a general wellness prescription.
Diet-wise, most NCGSs, he says, are hyper-reactive to even tiny exposures and cross-contamination for them is a big problem. He feels NCGSs do not do well on FODMAP foods either and he cautions against using processed GF foods because he has found some people are still reactive, he thinks, to the additives, although I think it is more likely to the other grains, especially corn.
He is not sure yet if NCGS is a permanent or transient condition; he implies permanent, but happily feels the major complications of CD, like lymphoma, are not likely to affect NCGSs.
Key Practical MessageIf NCGS, your diet must be as clean as possible because of the hyper-reactivity common in sufferers. Be aware of the nutrient malabsorption: test minerals and bone density especially, and correct. Also consider other sensitivities especially lactose, nickel, fructose, (histamine?) and FODMAPs.
To read the introduction to the Gluten Summit, see here. Catch up with the mini-series 1, 2, 3, 4 and 5. And to read the conclusion see here
For more from me and on gluten related disorders generally, see my TrulyGlutenFree site. If you are getting confused with all the different advice, don’t worry; I have pulled it all together for you on the site and in the Gluten Plan, plus I will do a summary at the end.
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