One of the questions that came up in the comments on my first post of the series was why are researchers (and celebrities) stuck on gluten-free, casein-free diets to treat autism? The whole idea is based on the idea that the exorphins (dietary opiate proteins) found in gluten and casein somehow cause or exacerbate the neurological issues in autism spectrum disorders (ASDs). Also, it is well documented that kids with ASDs seem to have more gut and dietary issues than other kids, so a dietary culprit was an obvious place to look.
A weakness to these theories is that we have been eating gluten and casein for a long time (the beta casein A1 is found in about 50% of cows of European descent, which are also the cows who make American, Australian, and New Zealand milk at least), and the autism rates have been (possibly) escalating only recently. Or have they?
Back in 2003, JAMA released a study and editorial on the rates of autism. At the time, most studies were showing that rates were somewhere around 1 per 1,000 children. Since previous studies (from the 60s and 70s) usually estimated around 4-5 per 10,000 children, that means a doubling of prevalence from the 1970s to the 1990s and early 2000s. (There are many issues with trying to put a reliable number together- I recommend you read the editorial I linked as it seems to be a very fair presentation of the data - the main issue being that the definition for autism spectrum disorders widened considerably between 1960 and 1990, which could certainly explain an increase in prevalence in studies without an actual increase in prevalence in the population). Then a number of very large survey studies were done in 2006-2009, including 78,000 parents in the National Children's Health Study (1), and another multi-site study in the Autism and Developmental Disabilities Monitoring (ADDM) Network (2). These were all big news last year, as several of these studies came out at the same time, and the rate had jumped to approximately 110 per 10,000 children. I'll let the second study speak for itself at this point:
"Approximate range: 1:80--1:240 children [males: 1:70; females: 1:315]. The average prevalence of ASDs identified among children aged 8 years increased 57% in 10 sites from the 2002 to the 2006 ADDM surveillance year. Although improved ascertainment accounts for some of the prevalence increases documented in the ADDM sites, a true increase in the risk for children to develop ASD symptoms cannot be ruled out. On average, although delays in identification persisted, ASDs were being diagnosed by community professionals at earlier ages in 2006 than in 2002."
A 57% increase in four years. That sounds really, really bad. However, much of this increase was felt to be due to increased awareness, and recognition that early intervention and treatment could help kids with ASDs, so kids were being diagnosed earlier, and the diagnosis would be made more readily so kids could be eligible for early intervention services. In fact, the latest studies may be the ones that actually have a more realistic estimate of the number of kids affected, and previous studies grossly underestimated the number of cases. In my opinion, the best evidence that autism may not be increasing at all is a report from the Adult Psychiatric Morbidity Study from the UK in 2007 (3). They found that approximately 1% of adults living in households have symptoms consistent with ASDs. Since that is pretty close to the 1 in 110 number we have for today's children, it suggests that the enormous increase in diagnosis in kids may be due to increased outreach and widening of diagnostic categories. However, a more recent increase can't entirely be ruled out.
In any event - that means that we don't necessarily have to look for something brand spanking new or rapidly changing in our society to explain the increase. We can take a broader view. So back to gluten and casein and those pesky exorphins.
Couple of interesting tidbits. Really, the theorized mechanism of wheat and casein exorphins causing neurotoxic events that are expressed as our brains develop is quite similar to the same theory in schizophrenia. It's probably coincidence, but schizophrenia and autism both affect about 1% of the population. Some of the same genetic chromosomal deletion syndromes are implicated in both autism and schizophrenia.
And, frankly, the exorphin question is an easy one to test, at least indirectly. We have naltrexone, after all, a readily available, relatively inexpensive opiate blocker in pill form. Once taken, it will sit on our opiate receptors like a lock on a door, blocking exorphins from casein and gluten just as readily as heroin or morphine, and keep the opiates from activating our opiate receptors. So if dietary exorphins worsen autism in those of us with vulnerable phenotypes, naltrexone should help.
Fortunately, there are several studies of naltrexone and autism (4)(5)(6). And, overall, the studies lean towards naltrexone being a useful treatment for some kids. It seems most effective in decreasing self-injurious behavior (interesting in light of the findings I wrote about in this post, linking alterations in the opiate symptoms and self-injurious behavior), like self-picking, finger-biting, and head-banging. It also seems to help some kids with improved attention and eye contact, hyperactivity, agitation, stereotyped behaviors, social withdrawal, and temper tantrums. (Naltrexone is not FDA approved for use in autistic disorder in kids, but due to the limitations of therapeutic alternatives, it is mentioned often in review papers as a useful medicine that might be worth giving a try).
Does that mean that dietary exorphins are definitely the cause of the problem, or at least piece of the cause? Not so fast. The whole reason scientists studied naltrexone in autism in the first place had nothing to do with wheat or casein. Turns out a paper in 1979 hypothesized a link between derangements in the opiate systems of autistic children and the symptoms of autism, and later naltrexone studies showed that some kids with autism seem to produce an excess of beta-endorphin (our own, natural opiates). Theory goes like this - flooding the immature brains of kids with beta-endorphins may delay or hamper maturation in some way, causing the brains of autistic kids to stay in an infantile stage of development, particularly with regards to social interaction and sensory response. Kids who responded best to naltrexone had the biggest decreases in the amount of their own beta-endorphins.
All right, let's bring it all together. A large subset of autistic kids seem to have leaky guts (remember - no robust link between the amount of leakiness in the gut and either positive celiac markers OR gastrointestinal symptoms such as diarrhea, bloating, or abdominal pain - you can't tell if a kid has a leaky gut using these kinds of criteria or tests!). Another subset of autistic kids have elevated levels of their own natural beta-endorphins and seem responsive to an opiate blocker, naltrexone. Gluten and casein have exorphins (opiates) which can hypothetically wriggle through that leaky gut and may have an effect on the central nervous system.
There, finally, a plausible link between gluten, casein, and autism. Not as necessarily a cause, and certainly not a cure, but perhaps as an exacerbating factor. But, before April 2010, the dietary studies were crap. And too small. Enter the ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Published in Nutritional Neuroscience in April 2010, this study combined a lot of nice features. It had a decent sample size - 72 Danish kids with ASDs (established by standard diagnostic criteria), and it was long - two years. It had a sort of modified cross-over design. It was honest about being single blind - meaning the researchers (except the nutritionists) didn't know which kids were getting the special diets, but the parents (of course) knew. The kids' urine was tested for any abnormal metabolic byproducts.
Here's what the researchers did - for the first year, they put about half the kids on a gluten-free, casein-free diet and monitored their progress for 8 months. If the improvements in the kids on the diet were significantly better than the kids off the diet, they would extend the trial and put everyone on the GF-CF diet at 12 months, and monitor them for a total of 24 months (this is what happened in the actual trial - there was significant improvement in the study diet kids, and a worsening in the kids on the standard diet, so everyone was put on the study diet for the last 12 months). The researches used a battery of different tests, measuring a bunch of different subsets of autistic behaviors and ADHD symptoms at points along the trial. The results?
"Introducing a gluten-free, casein-free diet had a significant beneficial group effect at 8, 12, and 24 months of intervention on core autistic and related behaviors..." The improvement was less dramatic after the first 8 months, and could represent a plateau effect. Attentional and communication symptoms seemed to improve the most. About half the kids dropped out in the second year, perhaps the kids that didn't benefit. The researchers note that there aren't long-term safety studies of gluten-free casein-free diets in kids, and that a knowledgeable nutritionist should be consulted.
Whew.
One last little thing. The leaky gut study I wrote about extensively in my first post on diet and autism had a very interesting component I didn't mention then. Some of the kids in that study, turns out, were already on a gluten-free, casein-free diet. The leakiness of the gut was measured via the IPT test - two sugars, lactulose and mannitol, are given orally to fasting kids, and their urine is collected for the next five hours. Mannitol is small and absorbed via the cells of the gut, and the amount absorbed reflects the "absorptive capacity of the gut." Lactulose is too large to be absorbed directly by the cells, so it has to squeeze in between the cells, and if a lot can squeeze through, the gut is "leaky" and the ratio of lactulose to mannitol in the excreted urine goes way up. A "normal" ratio is less than 0.03, and the higher the number is, the more leaky the gut is. Control kids in that study had ratio average of 0.023. In the autistic kids overall, the ratio was an average of 0.041. But in the autistic kids who were on the gluten-free, casein free diet, the ratio was less than 0.02, and when only data from the autistic kids not on the special diet was used, the average ratio jumped up to approximately 0.055. And, once again, the leakiness measured in these kids had no relation to GI symptoms or positive celiac marker testing.
The take-away point? Once again, I think there is enough scientific evidence to suggest that some kids with ASDs will, in fact, benefit from a gluten-free, casein-free diet, and while it is no cure and may not be a part of the original cause (some known teratogens that cause autism seem to work at around 8 weeks gestation (7)), it may be worth a try. It shouldn't be attempted without some professional nutritional advice, especially in a picky kid. And it's clearly no holy grail.
Another point - gluten is (once again) creepy. Gliadin and zonulin do not a good combination make. No one wants a leaky gut. Just something to think about.
Showing posts with label casein. Show all posts
Showing posts with label casein. Show all posts
Thursday, September 9, 2010
Tuesday, September 7, 2010
Diet and Autism 1
Let's begin with the Harvard Mental Health Letter (April 2010 page 4). HMHL just loves to rain on my "diet and mental health" parade:
"Researchers have long disagreed about whether gastrointestinal problems may underlie some symptoms of autism spectrum disorders. This has not stopped some researchers and celebrities from promoting theories and special "autism diets" with no scientific support. Yet these unfounded recommendations might appeal to grieving and vulnerable parents who are heartbroken about a child's sudden developmental regression."
Wow. That's harsh. I hope to use the next several posts to explore some of the theories behind what might be causing austim and to see just how wacky and dangerous these diets really are.
Autism spectrum disorders (autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified, together known as "ASDs") seem to impair a child's ability to communicate and interact with other people. ASDs are also characterized by ritualistic or repetitive behaviors, such as tapping fingers or head banging, or picking. Autistic children in general are more picky than children without ASDs, and temper tantrums around unsatisfactory meal times can be extreme. (A decent point is that restricting a picky child's menu by going gluten and casein free could be a nutritional issue.) Constipation is also more common among kids with autism, and it seems that kids with ASDs frequently experience abdominal pain, stool leakage, bloating, and reflux (1).
The Harvard Mental Health Letter is blunt, at this point: "There is not enough evidence to support special "autism diets" that eliminate casein... or gluten." Previous studies were not properly done, or too small, or didn't even use standard measures to diagnose autism in the first place. There is only one double-blind, crossover trial of casein and gluten free vs. regular diets (not sure how you really double-blind that but okay), of 15 children with ASDs, and after 12 weeks the diet seemed to have no effect (2). Some of the parents felt the intervention trial was more successful than the independent reviewers.
All right, all right, we get the picture, Harvard Mental Health Letter. But let's step back a bit. What is autism, and what causes it? Well, there is no universal theory, no consistent genetic findings (though autism does seem to run in families sometimes), and no agreed upon biological mechanism for what causes autism (3). Some researchers feel it is a brain development problem. Others wonder if autism is a set of disorders similar to phenylketonuria (where an inability to metabolize a certain amino acid can lead to progressive mental retardation, brain damage, and seizures, but can be averted by not eating that amino acid, phenylalanine).
The whole idea that gluten-free casein-free diets might be useful for autism is based on theories that exorphins (protein fragments that act as opiates) from gluten and casein might make it through the intestinal barrier and go on to act on the brain, causing harm. A similar theory is at work in gluten-free diets and schizophrenia. One very interesting tidbit of information: kids with autism and their family members seem to have leakier guts than families without autism (4). (Here's a finding which makes the Harvard Mental Health Letter's statement that researchers are promoting "autism diets" with no scientific support, seem, well, cranky. To be fair, the largest and best gluten-free casein-free diet trial was published in April of 2010 too, and the leaky gut study I'm looking at is epublished ahead of print, meaning it doesn't seem to even be officially published yet.)
Wait a minute. Back up. How does one measure a leaky gut? Well, to test the gut integrity, one can drink a solution of metabolically inert sugars, like lactulose and mannitol, and in a person with a leaky gut, those sugars will end up in the urine (this is called an IPT test). In addition, a leaky gut tends to be an inflamed gut, and one can skip intestinal biopsies and check fecal calprotectin (FC), a protein produced by intestinal granulocytes. Lots of FC in your poop apparently means you probably have an inflamed bowel. Of course celiac disease is associated with inflamed, leaky guts, so the researchers in the study took 90 kids with autism spectrum disorders and 146 of their first-degree relatives, and also 64 children and 146 adult controls. Everyone was given an IPT test, some were checked for FC, and all the kids with autism were screened for celiac (using anti-tTG antibodies, IgG anti-gliadin antibodies, and IgA anti-gliadin antibodies, anti-endomysium antibodies, and the genetic testing for HLA DQ2 and 8). Relatives and controls with abnormal IPT and FC tests were similarly screened for celiac.
Sounds interesting! What are the results?
Abnormal leaky gut - the IPT test (a higher percentage of lactulose and mannitol in the urine)
Adult controls = 4.8%
Child controls = 0%
ASD patients = 36.7%
Relatives = 21.2%
(p<0.0001)
Pathological fecal calprotectin (FC - measure of gut inflammation)
ASD patients = 24.6%
Relatives = 11.7%
(Due to budget constraints, FC was only measured in controls who had an abnormal IPT test - none of them had FC values above the normal range)
ASD patients and celiac testing
Genetic predisposition for celiac (+HLA DQ2 and/or DQ8): 32% of kids with "leaky" IPT test
Genetic predisposition for celiac (+HLA DQ2 and/or DQ8): 35.9% of kids with normal IPT test
Gastrointestinal symptoms: 45.5% of kids with "leaky" IPT test
Gastrointestinal symptoms: 47.4% of kids with normal IPT test.
Positive AGA IgA: 1.6% +/- 2.5%
Positive AGA IgG: 13.8% +/- 24.2%
Positive tTG: 1.04% +/- 0.91%
EMA: all negative
Relatives and celiac testing
Positive AGA IgA: 0.8% +/- 0.4%
Positive AGA IgG:8.4% +/- 5.9%
Positive tTG: 3.0% +/- 3.7%
EMA: all negative
Well! That's a mixed bag. The overall findings - there seems to be a subgroup of kids with autism and their close relatives who have leaky guts. The celiac findings are a little more all over the place. GI symptoms seemed to have no correlation with gut leakiness, meaning the standard recommendation to investigate for celiac or intestinal barrier problems only in autistic kids with GI symptoms seems to fly in the face of scientific findings.
Perhaps more importantly, "gluten itself augments IPT" (in other words, makes gut leakiness worse in cellular models (5)(6)(7)). "We can hypothesize that subjects with ASD are gluten-sensitive.... and hence their intestinal barrier function [abnormalities] will ameliorate with with a gluten-free diet. The well-recognized intestinal mucosal effects of gliadin - the major component of gluten - would justify a treatment with gluten-free diet in ASD."
There is a lot more to discuss. But for now, I'll leave the above information to simmer for a little while.
The bottom line from this post: The clinical trials evidence for gluten-free, casein free diets is poor, so far (though I'll go over what I consider to be the best study later this week). BUT, there is newer evidence of a rather large subset of kids with ASDs who have an especially leaky gut, and the susceptibility to the leakiness seems to be genetic. You are not going to find these kids by looking at patients with celiac markers or by looking at patients with GI symptoms.
"Researchers have long disagreed about whether gastrointestinal problems may underlie some symptoms of autism spectrum disorders. This has not stopped some researchers and celebrities from promoting theories and special "autism diets" with no scientific support. Yet these unfounded recommendations might appeal to grieving and vulnerable parents who are heartbroken about a child's sudden developmental regression."
Wow. That's harsh. I hope to use the next several posts to explore some of the theories behind what might be causing austim and to see just how wacky and dangerous these diets really are.
Autism spectrum disorders (autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified, together known as "ASDs") seem to impair a child's ability to communicate and interact with other people. ASDs are also characterized by ritualistic or repetitive behaviors, such as tapping fingers or head banging, or picking. Autistic children in general are more picky than children without ASDs, and temper tantrums around unsatisfactory meal times can be extreme. (A decent point is that restricting a picky child's menu by going gluten and casein free could be a nutritional issue.) Constipation is also more common among kids with autism, and it seems that kids with ASDs frequently experience abdominal pain, stool leakage, bloating, and reflux (1).
The Harvard Mental Health Letter is blunt, at this point: "There is not enough evidence to support special "autism diets" that eliminate casein... or gluten." Previous studies were not properly done, or too small, or didn't even use standard measures to diagnose autism in the first place. There is only one double-blind, crossover trial of casein and gluten free vs. regular diets (not sure how you really double-blind that but okay), of 15 children with ASDs, and after 12 weeks the diet seemed to have no effect (2). Some of the parents felt the intervention trial was more successful than the independent reviewers.
All right, all right, we get the picture, Harvard Mental Health Letter. But let's step back a bit. What is autism, and what causes it? Well, there is no universal theory, no consistent genetic findings (though autism does seem to run in families sometimes), and no agreed upon biological mechanism for what causes autism (3). Some researchers feel it is a brain development problem. Others wonder if autism is a set of disorders similar to phenylketonuria (where an inability to metabolize a certain amino acid can lead to progressive mental retardation, brain damage, and seizures, but can be averted by not eating that amino acid, phenylalanine).
The whole idea that gluten-free casein-free diets might be useful for autism is based on theories that exorphins (protein fragments that act as opiates) from gluten and casein might make it through the intestinal barrier and go on to act on the brain, causing harm. A similar theory is at work in gluten-free diets and schizophrenia. One very interesting tidbit of information: kids with autism and their family members seem to have leakier guts than families without autism (4). (Here's a finding which makes the Harvard Mental Health Letter's statement that researchers are promoting "autism diets" with no scientific support, seem, well, cranky. To be fair, the largest and best gluten-free casein-free diet trial was published in April of 2010 too, and the leaky gut study I'm looking at is epublished ahead of print, meaning it doesn't seem to even be officially published yet.)
Wait a minute. Back up. How does one measure a leaky gut? Well, to test the gut integrity, one can drink a solution of metabolically inert sugars, like lactulose and mannitol, and in a person with a leaky gut, those sugars will end up in the urine (this is called an IPT test). In addition, a leaky gut tends to be an inflamed gut, and one can skip intestinal biopsies and check fecal calprotectin (FC), a protein produced by intestinal granulocytes. Lots of FC in your poop apparently means you probably have an inflamed bowel. Of course celiac disease is associated with inflamed, leaky guts, so the researchers in the study took 90 kids with autism spectrum disorders and 146 of their first-degree relatives, and also 64 children and 146 adult controls. Everyone was given an IPT test, some were checked for FC, and all the kids with autism were screened for celiac (using anti-tTG antibodies, IgG anti-gliadin antibodies, and IgA anti-gliadin antibodies, anti-endomysium antibodies, and the genetic testing for HLA DQ2 and 8). Relatives and controls with abnormal IPT and FC tests were similarly screened for celiac.
Sounds interesting! What are the results?
Abnormal leaky gut - the IPT test (a higher percentage of lactulose and mannitol in the urine)
Adult controls = 4.8%
Child controls = 0%
ASD patients = 36.7%
Relatives = 21.2%
(p<0.0001)
Pathological fecal calprotectin (FC - measure of gut inflammation)
ASD patients = 24.6%
Relatives = 11.7%
(Due to budget constraints, FC was only measured in controls who had an abnormal IPT test - none of them had FC values above the normal range)
ASD patients and celiac testing
Genetic predisposition for celiac (+HLA DQ2 and/or DQ8): 32% of kids with "leaky" IPT test
Genetic predisposition for celiac (+HLA DQ2 and/or DQ8): 35.9% of kids with normal IPT test
Gastrointestinal symptoms: 45.5% of kids with "leaky" IPT test
Gastrointestinal symptoms: 47.4% of kids with normal IPT test.
Positive AGA IgA: 1.6% +/- 2.5%
Positive AGA IgG: 13.8% +/- 24.2%
Positive tTG: 1.04% +/- 0.91%
EMA: all negative
Relatives and celiac testing
Positive AGA IgA: 0.8% +/- 0.4%
Positive AGA IgG:8.4% +/- 5.9%
Positive tTG: 3.0% +/- 3.7%
EMA: all negative
Well! That's a mixed bag. The overall findings - there seems to be a subgroup of kids with autism and their close relatives who have leaky guts. The celiac findings are a little more all over the place. GI symptoms seemed to have no correlation with gut leakiness, meaning the standard recommendation to investigate for celiac or intestinal barrier problems only in autistic kids with GI symptoms seems to fly in the face of scientific findings.
Perhaps more importantly, "gluten itself augments IPT" (in other words, makes gut leakiness worse in cellular models (5)(6)(7)). "We can hypothesize that subjects with ASD are gluten-sensitive.... and hence their intestinal barrier function [abnormalities] will ameliorate with with a gluten-free diet. The well-recognized intestinal mucosal effects of gliadin - the major component of gluten - would justify a treatment with gluten-free diet in ASD."
There is a lot more to discuss. But for now, I'll leave the above information to simmer for a little while.
The bottom line from this post: The clinical trials evidence for gluten-free, casein free diets is poor, so far (though I'll go over what I consider to be the best study later this week). BUT, there is newer evidence of a rather large subset of kids with ASDs who have an especially leaky gut, and the susceptibility to the leakiness seems to be genetic. You are not going to find these kids by looking at patients with celiac markers or by looking at patients with GI symptoms.
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