No unique patterns of gut issues in autism? Headline fail...

"This study supports the observation that children with autism who have symptoms of gastrointestinal disorders have objective findings similar to children without autism. Neither non-invasive testing nor endoscopic findings identify gastrointestinal pathology specific to autism, but may be of benefit in identifying children with autism who have atypical symptoms."

So concluded Rafail Kushak and colleagues [1] (them of "Lactase deficiency not associated with intestinal inflammation or injury is common in autistic children and may contribute to abdominal discomfort, pain and observed aberrant behavior" [2]) who undertook some important work around the topic of gastrointestinal (GI) issues being over-represented in cases of autism (see here). Some media on their recent findings can be read here (see here).

Looking at the results of 61 children diagnosed with autism and presenting with GI issues and data from 50 non-autistic individuals also being assessed for GI problems, researchers examined whether there were any differences between the groups on a range of measures including disaccharidase activity, intestinal inflammation and gut permeability (the so-called 'leaky gut'). They reported finding some discrepancies between the groups - including "mild levels of mucosal inflammation on intestinal biopsy" for some of those with autism -  but nothing that seemed to point to a 'GI fingerprint' specifically relevant to just autism. They concluded that where GI issues appear alongside autism, the same level of assessment and care should be afforded as it is when GI issues are present outside of autism. Tim Buie, one of the study authors, had said as much quite a few years back.

I would draw attention to a few important points included in the Kushak study. First, are the participant groups. This was a study comparing children with and without autism who were both under investigation following the presentation of GI issues. They were not comparing children with autism with GI issues with non-autistic children without gut issues. I say this just in case anyone assumes that the findings point to no significant gut issues being identified in those with autism. That is absolutely not the case. Headlines might need some adjustment.

Second, the results reported are to some degree at odds with other findings published by independent groups - specifically those reported by Stephen Walker and colleagues [3] (see here for my take). Although perhaps not exactly overlapping in terms of methods and outcomes, Walker et al concluded that their data was evidence that "ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease." I might add that at the time of writing this post and despite the Walker findings being published some 3 years ago, no-one has taken up the research gauntlet to try and replicate/challenge the Walker publication. That IBD might be over-represented when a diagnosis of autism is received is also an important point to make (see here).

Finally, mention of the words "leaky gut" in the Kushak report are a continued welcome sign. That measurement via "rhamnose/lactulose test and measured by HPLC-MS" did not appear to differentiate kids with autism with GI issues vs, kids without autism with GI issues is an important addition to the debate in this area. I know discussions of intestinal permeability with autism in mind can furrow brows in certain quarters but there is a growing recognition that (a) this is a real phenomenon (see here) and (b) for at least some people on the autism spectrum, gut permeability issues are present (see here). That gut permeability issues might be a 'later life event' when detected in 'some' autism (see here) is also worth re-iterating as is the idea that 'treating' gut permeability might be something that many people are already doing without even knowing it (see here).

Now, about that study on the use of dietary intervention for children with autism WITH bowel issues...

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[1] Kushak RI. et al. Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms. J Pediatr Gastroenterol Nutr. 2016 Feb 20.

[2] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

[3] Walker S. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013; 8: e58058.

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Kushak RI, Buie TM, Murray KF, Newburg DS, Chen C, Nestoridi E, & Winter HS (2016). Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms. Journal of pediatric gastroenterology and nutrition PMID: 26913756

Gastrointestinal comorbidity for World Autism Awareness Day

Today (Tuesday 2 April 2013) is World Autism Awareness Day (WAAD).

I don't exactly know how one is supposed to communicate this message ('Happy world autism awareness day' just doesn't roll off the tongue). So I guess all I will say is to reiterate the subtext of this blog on what the spectrum - the very wide spectrum - means: "To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities."

Onwards. Having discussed the latest paper from Drs Stephen Walker and Arthur Krigsman on bowel pathology in cases of autism potentially denoting a distinct condition from other inflammatory bowel diseases and stumbling upon the paper by Peeters and colleagues* on functional defecation disorder and autistic traits, I thought it appropriate to pop into the DeLorean and revisit a paper which never really received the recognition it deserved.

The subject matter for today is the paper by Karoly Horvath and colleagues** published in 1999 as we begin another trip down the autism research memory lane, same as I did when covering the the Mary Goodwin paper from 1971 on the gut-brain axis and autism (see here) and the John Money autism and autoimmunity paper also from 1971 (see here).

Hadrian's Wall @ Wikipedia  

Remember my name
The name Karoly Horvath will probably be familiar to quite a few people who've been on the autism research scene for a while. Another of Dr Horvath's papers*** created a bit of stir a while back based on some very preliminary findings on the use of the digestive hormone, secretin for cases of autism.

Following some initial reports of "transient, marginally significant improvements in autistic behaviors" in some cases as per studies like the one from Coniglio and colleagues****, a whole slew of subsequent trials have painted a rather less positive picture on the use of secretin for autism as per the review by Krishnaswami and colleagues***** (open-access) which quite emphatically stated that "secretin as a treatment approach for ASDs warrants no further study".

I'm not one to normally challenge paper conclusions - particularly systematic reviews - but will perhaps contrast that quote with the closing remarks made by the Cochrane Library review of Williams and colleagues******. They left the secretin research door slightly ajar for those who were potentially able to  identify "important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing". I'm a great believer in subgroups when it comes to autism, or rather the autisms, and how a diagnosis of autism is seemingly protective of nothing when it comes to other conditions/states, so you can perhaps assume which quote was my preference.

Factoids
Anyhow, back to the Horvath 1999 paper. A few interesting factoids from their report:

• Thirty-six children all diagnosed with an autism spectrum disorder (ASD), mean age 5.7 years, formed the participant group. Children were all referred to the gastroenterology (GI) clinic where the authors worked following the presence of various GI symptoms ranging from abdominal pain to chronic diarrhoea and various other presentations.
• As well as quite a bit of review of participants' medical history, various clinical investigations were undertaken which included a "full upper gastrointestinal workup", analysis of digestive enzyme function in the small intestine and some histological examination.
• Results: quite a few important findings. Reflux esophagitis was present in nearly 70% of participants (25/36). Chronic inflammation of the gastric mucosa was determined in 15 children. Reduced disaccharidase activity was present in approximately 60% of children, and in particular low lactase levels. Following administration of secretin, participants with autism and diarrhoea comorbid showed signs of increased pancreatico-biliary fluid output potentially indicative of "upregulation of the secretin receptors" itself potentially related to "either a defect in secretin production or a problem of release from the intestinal S cells".
• "There was no evidence of either fungal or bacterial overgrowth in the duodenum" was another finding.

I know there is a lot to take in from those results so I'm going to try and put them into some kind of perspective with some of the other related literature in the peer-reviewed domain.

Lactose intolerance
I'll start with the disaccharidase activity side of things. The Horvath results were in some respects ahead of their time with their findings in this area. I've talked previously about the Rafail Kushak paper and their findings of the frequency "of lactase deficiency was 58% in autistic children ≤ 5 years old and 65% in older patients". Notice the similarity in the percentages between Horvath and Kushak. Indeed, this whole area of carbohydrate malabsorption present in cases of autism was very nicely continued by the Brent Williams paper looking at enzyme activity and autism. I know a few people have talked about how some of these findings might overlap with for example, the various reports on the use and effectiveness of a gluten- and casein-free (cereal grains and mammalian dairy free) diet in some cases of autism. Certainly, I wouldn't rule out a possible overlap to account for any results.

Reflux and GERD
Gastroesophageal reflux and reflux esophagitis - states pertaining to inflammation of the esophagus - were also commonly reported in the participant group and indeed also correlated with various behavioural manifestations noted in some cases (nighttime wakening, signs of irritability, abdominal discomfort) which are "typically reported by non-autistic children with esophagitis". A little reading around this topic suggests that many cases of such esophagitis are tied into things like GERD - gastroesophageal reflux disease - which is basically about stomach acid rising up instead of staying where it should be and causing damage. That being said, other explanations have also surfaced to potentially account for the damage done during GERD (see the paper by Souza and colleagues*******) highlighting a possible role for cytokines in this process. I'm also conscious of the findings of eosinophilic esophagitis being reported in individual cases of autism (see here). In terms of management options and without heading down any medical advice giving path, I was very interested to see a body of work appearing supporting the use of baclofen for cases of GERD********, a derivative of which - arbaclofen - has recently been touted as a potential intervention option for cases of autism. One has to wonder whether kum-ba-arbaclofen might be doing so much more than just affecting GABA receptors?

I'm going to stop there with the Horvath paper and its quite important observations. Once again it is a good example of how, just because we see a rising tide of new findings on autism or any other condition or state, we shouldn't neglect the older literature (published pre-social media) and the valuable insights that it has provided. Indeed, I am going to champion the paper by Horvath et al as an important one; particularly when it came to the assessment of carbohydrate digestive enzyme activity because it was truly ahead of its time and very possibly something that you might hear more about in the coming years of autism research.

Importantly for WAAD, the Horvath paper is a stark reminder that awareness of the autism spectrum should extend beyond just the triad (very soon to be dyad) of core symptoms and into the range of often very pronounced comorbidities which can also exist and affect quality of life. And just in case you need a more recent example of this, have a look at this paper from Francisca van Steensel and colleagues********* (open-access) and their findings on the over 50% rate of psychiatric comorbidity reported in their pediatric cohort. Their focus on 'anxiety disorders' does not need any more chatter from me.

To close, something musically, a little more contemporary. Bruno Mars and Locked Out Of Heaven.

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* Peeters B. et al. Autism spectrum disorders in children with functional defecation disorders. J Pediatr. March 2013.

** Horvath K. et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999; 135: 559-563.

*** Horvath K. et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys. 1998; 9: 9-15.

**** Coniglio SJ. et al. A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism. J Pediatr. 2001; 138: 649-655.

***** Krishnaswami S. et al. A systematic review of secretin for children with autism spectrum disorders. Pediatrics. 2011; 127: e1322–e1325.

****** Williams K. et al. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 4: CD003495.

******* Souza RF. et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009; 137: 1776-1784.

******** Cossentino MJ. et al. Randomised clinical trial: the effect of baclofen in patients with gastro-oesophageal reflux - a randomised prospective study. Aliment Pharmacol Ther. March 2012.

********* van Steensel FJA. et al. Psychiatric comorbidity in children with autism spectrum disorders: a comparison with children with ADHD. J Child Fam Stud. 2013; 22: 368–376.

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Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, & Tildon JT (1999). Gastrointestinal abnormalities in children with autistic disorder. The Journal of pediatrics, 135 (5), 559-63 PMID: 10547242

Disaccharidase levels in coeliac disease

It tends to happen. You have a particular study or topic on your mind and all of a sudden other related material seems to magically appear alongside it. Take for example my recent posts on carbohydrate metabolism and autism. Following on from some other related work published a few months back, the digestion (or problems with the digestion) of carbohydrates seems to be a rising point of interest in relation to some cases of autism. One would by the very least expect more research to be done in this area.

Then yesterday (22/09/11) this paper by Mones and colleagues* appears looking at the levels of disaccharidases in people with coeliac (celiac) disease (CD). I must admit that I don't have the full-text of the paper at present so am very much working on the summary abstract. What I gather from that information to hand is that disaccharidase deficiency seemed to be a fairly common issue in pediatric cases of CD examined by Mones; where the degree of damage to the villi, as scored using the Marsh criteria, is perhaps not as severe as partial or full villous atrophy. Indeed Mones and co. reported significant reductions in lactase, sucrase, maltase and palatinase in Marsh I/II categorised patients with CD.

Mones presented cases where the level of immunopathology was relatively slight (compared with the nuclear wasteland of Marsh IV pathology) yet overall carbohydrate metabolism was significantly impaired.  It has long been known that CD shows more than a passing relationship to disaccharidase deficiency and that the level of deficiency seems to increase according to the level of mucosal damage.

It is also fast becoming recognised that outside of what might be called 'classical' CD, there seems to be a 'spectrum' of gluten sensitivity which does not follow normal CD diagnostic markers yet still may benefit from the implementation of a gluten-free diet. The intestinal pathology accompanying these gluten spectrum conditions remains a little bit of a mystery but on the basis of what is being seen in CD and also in recent days, autism, perhaps there are a few clues as to what and where we should be looking.

* Mones RL. et al. Disaccharidase deficiency in pediatric patients with celiac disease and intact villi. Scandinavian Journal of Gastroenterology. September 2011.