If you need some woo, and you need it fast, who ya gonna call? HuffPo!
Yes, as I've pointed out since its very inception, if there's one thing The Huffington Post is good at doing, it's butchering medical science and serving up regular heapin' helpings of the purest woo. Be it the anti-vaccine pseudoscience that has dominated its pages from the very beginning (including posts by our old friend Dr. Jay Gordon), the quantum woo favored by Deepak Chopra, or the rank quackery that's been showing up on HuffPo's pages more and more frequently over the last two years or so, there's no "respectable" news outlet that lays down pure pseudoscience and antiscience on as regular a basis as HuffPo does. If you want a concentration of woo more powerful than the "Lifestyle" or "Health" sections of HuffPo, all that's left is NaturalNews.com, Whale.to, and Mercola.com.
One of the denizens of HuffPo who's provided me copious blogging material is one Dr. Mark Hyman, he of the "Ultrawellness." Every time I read the term "Ultrawellness," I always think of A Clockwork Orange and wonder if Ultrawellness has anything to do with the ol' ultra-violence. It doesn't, really, at least not violence violence. It does appear to have a lot to do with engaging in a bit of "ultra-violence" against science, reason, and logic, though. Through an elaborate bit of woo known as "functional medicine," Hyman and his droogs regularly do to science and medicine what Alex and his droogs did to an elderly vagrant and later to Mr. Alexander and his wife in A Clockwork Orange. It's hard for me, while reading one of Hyman's articles, not to visualize him dancing about as he sings "Singing in the Rain" between kicks to science's solar plexus perfectly timed to the song.
So it was, as I read Hyman's latest, entitled Autism Research: Breakthrough Discovery on the Causes of Autism. It's a perfect example of how Dr. Hyman so frequently takes a recent study, and then goes right off the deep end with it. It's also proof positive that an idea that anti-vaccine loons had taken and run with a begining nearly two years ago, namely that autism is caused by mitochondrial disorders (never mind how rare such disorders are) is very likely a permanent addition to the anti-vaccine canon. First we had the Hannah Poling case. Then, instead of autism being a "misdiagnosis for mercury poisoning," as Age of Autism used to claim when it claimed constantly that mercury in vaccines cause autism, suddenly autism was a "misdiagnosis for mitochondrial disorders"--exacerbated by vaccines, of course. Because in the end, whether it's mitochondrial disorders or vague "susceptibilities," it's the vaccines. It's always about the vaccines.
In any case, the whole "mitochondrial diseases as the cause of autism" had faded into well-deserved oblivion as an interesting hypothesis that doesn't seem to be panning out, except perhaps in a very few children; that is, until a new study provided the impetus to dig up its corpse for the first time, and Hyman's got the shovel:
Many studies have illuminated the causes and possible treatments for autism, but mainstream physicians or scientists ignore most of this data. This new study, breaks new ground because it was published in one of the world's major medical journals.
In it researchers from UC Davis examined children two to five years of age from the Childhood Autism Risk From Genes and Environment (CHARGE) study in California -- a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. What they discovered was the aforementioned mitochondrial dysfunction that lead to problems with energy. Interestingly, these abnormalities were not found in neurons on a brain biopsy but from examining white blood cells called lymphocytes. This means the energy deficit was a systemic problem -- not one residing solely in the brain.
This study forces the question: How do children acquire energy deficits that affect their whole system, not just the brain?
Don't you just love the mavericky-ness of it all. Damn those short-sighted conventional doctors! They just can't see what Hyman can see, because, well, they're so...cautious! I mean, think of it. Here we have a pilot study of 20 children, ten autistic children and ten neurotypical children, by investigators at the MIND Institute. This was an observational study using data collected from the Risk From Genes and Environment study in California, which is a population-based, case-control investigation that includes confirmed autism cases and age-matched, genetically unrelated, typically developing controls children. The study began in 2003 and is still ongoing. Basically Giulivi et al recruited their subjects as follows:
For this study, we selected 10 individuals who met criteria for full syndrome autism on both the ADI-R and ADOS and 10 typically developing control children. Children were recruited consecutively and examined during the time windows when our laboratory staff was available to conduct assays of mitochondrial function; this was necessary to ensure fresh biological specimens. Scheduling of examinations in the clinic is essentially random, depending only on a match between the parent's availability and a clinic slot, with all children being seen by clinical staff having identical expertise. Because ASD represents a fairly diverse phenotype, we studied children meeting criteria for full syndrome autism and neurotypically developing children (controls) without a clinical diagnosis of full syndrome autism, ASD, or developmental delays.
So what we have here is clearly a very small study intended as a pilot study. It's not prospective, and it's not randomized. Although case-control studies can identify risk factors for various conditions, selecting a tiny number of children out of a large case-control study can only provide very preliminary results. That doesn't mean that it's not worth doing. Such studies can be useful in that they can generate hypotheses that can be tested later in larger studies. However, any results from such a study are highly provisional, very likely wrong, and desperately need confirmation from a more rigorously designed study before one can have any confidence in them.
That being said and reemphasized, what did the investigators find? Basically, they drew blood from these children and meaured mitochondrial-dependent oxygen consumption, mitochondrial DNA copy number and deletions, and mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate, the latter three all surrogates that can be used to estimate mitochondrial activity. The results indicated that mitochondrial oxygen-dependent oxygen consumption was impaired in the lymphocytes from children with autism when compared with those from neurotypical children. In addition, when all the results were taken into account, children with autism were more likely to have mitochondrial dysfunction and/or either overreplication or deletions in mitochondrial DNA. Basically, this study suggests that mitochondrial disorders might be relatively prevalent in children with autism, although the study does have a number of limitations, described by the authors themselves:
First, the number of individuals in which mitochondrial activities were assessed was relatively small, although the sample size (based on statistical power for discovery of effects) was adequate. Nevertheless, caution should be exercised with regard to the generalization of findings in a larger population. Second, the possibility of type I errors should be considered. Of the analytes reported in Table 2, 8 of 10 participants were significantly outside the 99% CI of the mean for controls for NADH oxidase, as were 8 of 10 for succinate oxidase, 6 of 8 for PDHC activity, 6 of 10 for adenosine triphosphatase, and 4 of 10 for cytochrome c oxidase. Such findings are highly unlikely to occur by chance alone, although the interpretation of findings with both higher and lower activities is more complex than when values are consistently in one direction. Similarly, for the mtDNA analyses, 5 of 10 participants showed significantly higher copy numbers than controls, although the ratio of CYTB to ND1 was significantly reduced in 2 of 10 participants. Ten group comparisons were made in this study; of these comparisons, 6 were significant at the α level of .05 and 2 were significant at the α level of .005 (ie, using the conservative Bonferroni correction).
Translation: This may be a false positive, due to multiple comparisons and numbers in the autistic children both higher and lower. As I pointed out before, this is a pilot study. It's impossible to conclude much from it. Not that that stopped Age of Autism and others in the anti-vaccine movement from going wild on it. It certainly doesn't stop Mark Hyman from mixing these results with his Ultrawellness ultra-violence to science and proclaiming:
The causes of mitochondrial dysfunction are well known, specifically as it relates to metabolism and the brain, and I have documented them in my books "UtraMetabolism" and "The UltraMind Solution." They include environmental toxins (iv) -- mercury, lead and persistent organic pollutants(v) -- latent infections, gluten and allergens (which trigger inflammation) sugar and processed foods,(vi) a nutrient-depleted diet(vii) and nutritional deficiencies.(viii) These are all potentially treatable and reversible causes of mitochondrial dysfunction that have been clearly documented.
Uh, no. they haven't been "clearly documented," at least not directly in the peer-reviewed scientific literature, although woo-meisters like Mark Hyman are very good at torturing scientific results like the results of the current study into seeming to support their idea that their woo can "recover" autistic children or even cure autism. That's exactly what Hyman does as he describes an anecdote about a child named Jackson, a child with autism, whom Hyman claims he "recovered":
I found all these problems in Jackson, and over a period of two years we slowly unraveled and treated the underlying causes of his energy loss which included gut inflammation, mercury, and nutrient deficiencies. Over time, the tests for his mitochondrial function and oxidative stress (as well as levels of inflammation and nutrient status) all normalized. When they became normal, so did Jackson. He went from full-blown regressive autism to a normal, bright beautiful six-year-old boy.
Naturally, there's a video:
Once again, as has been emphasized here and elswehere time and time again. Autism is not a condition of developmental stasis. It's a condition of developmental delay. Autistic children can and do develop, sometimes dramatically. Some of them develop to the point where they no longer meet the criteria for autism spectrum disorder. That's why testimonials like that of Jackson can appear on the surface to be so compelling. The unspoken underlying assumption behind Jackson's testimonial is that, without all the "Ultrawellness" voodoo that Hyman do so well, Jackson would have stayed nonverbal, as he was at 22 months. In addition, like their neurotypical counterparts, autistic children often develop in spurts, with periods of rapid change alternating with periods of slower or even imperceptible change. Hyman states in his testimonial about Jackson that he worked on him for over two years. How do we know that Hyman's various "biomedical" interventions had anything to do with Jackson's improvement? We don't.
That's the reason that randomized clinical trials are so critical. One story of improvement from a condition characterized by a highly variable course and a subset of children who develop to the point where they lose their diagnosis means very little. To try to account for this and determine whether any intervention is actually doing something requires a randomized, double-blind clinical trial. In fact, figuring out what treatments work in autism is damned hard even with randomized clinical trials. Trying to do it in retrospective studies or nonrandomized studies is damned near impossible. Trying to draw conclusions from single patients like Jackson that can be generalized comes close to futility. In the meantime, Hyman falls for anti-vaccine propaganda and blames vaccines for a significant number of cases of autism.
Based on this new study, I fully anticipate that there will be a new round of promotion of mitochondrial disorders as The One True Cause of autism, or at least the One True Reason why some children are allegedly susceptible to "vaccine injury" tha turns them autistic. Never mind that the investigators themselves have said quite emphatically that their study says nothing about vaccines and autism. Never mind all that. Dr. Hyman knows his clientele, and he knows that they like their woo to sound all science-y, preferably based on recent research. Because this study has managed to achieve a fairly high degree of publicity since it was released, it's perfect for Hyman to use and abuse, and use it and abuse it he does.
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Hey, speaking of mitochondrial damage:
Acetaminophen Induces Apoptosis in Rat Cortical Neurons
Thoughts?
As you say, "Once again, as has been emphasized here and elswehere time and time again. Autism is not a condition of developmental stasis. It's a condition of developmental delay.". Autism is a symptom, not a disease. And it seems clear that one cause of delay, probably of many, is mitochondrial disorder. In the case of my grandson, the mitochondrial disorder was detected FIRST, based on physiological and genetic evidence and confirmed by a range of tests; the realization of severe developmental delay (manifesting as autism) came later. No vaccines involved.
Maybe, maybe not.
There is intriguing evidence implicating mitochondrial dysfunction in some children with autism, but it's not at all clear whether it's the underlying disorder or simply a consequence of the underlying disorder. It's certainly not at all clear that somehow correcting the mitochondrial disorder (which much of this biomedical woo favored by Hyman doesn't really do anyway) would reverse autism. As I said, it's an interesting little study but it's impossible to make any hard conclusions, given that it might well be wrong. I'll certainly say that further study is warranted.
Linking this to vaccines, as the anti-vaccine movement does, is also highly dubious, because it's fever, not anything about the vaccines, that can cause problems in children with severe mitochondrial disorders. That's why it's generally recommended that children with mitochondrial disorders receive their vaccines.
Jen in TX@1
Very preliminary finding regarding adverse effects of high dose (or overdose) of acetaminophen.
-JP
The video is interesting. There's a cut in the middle, and it's quite clear that the boy really only wants to be there so he can say what his favorite sport is. His father barely acknowledges him through the video, and the boy waits patiently, with only a little fidgeting. Not bad for a six-year-old. But when the boy finally gets to say his piece, the father barely gives him time to do so before dismissing him to go play.
I also noticed that the way the boy announced his favorite sport was highly reminiscent of the way my seven-year-old PDD-NOS daughter would (and completely different from the way my neurotypical three-year-old would). I question whether the boy was ever "cured" or whether he simply matured.
One thing that infuriates me about the biomedical movement is how it discourages parents from attributing improvement to the child's own natural gifts.
As far as the mitochondrial stuff goes, I find it a little interesting because I recently finished re-reading "A Wind At the Door". It's aimed at young readers, and it's rather surreal, but much of the action revolves around mitochondria -- evil beings called Echthroi are attempting to kill Charles Wallace by subverting the farandolae which live inside of his mitochondria, stopping them from maturing and producing energy to keep him alive.
Charles Wallace is an odd boy. He's positively brilliant, but he doesn't talk much (though when he does, it's at a very high level) and so the townsfolk and his classmates all think he's an idiot. He's also completely inept, socially, and I can't help but think that if he were a real person, he'd be diagnosed with Asperger's or something similar. There is a sort of irony, then, that "A Wind At the Door" portrays a probably autistic boy about to die of a mitochondrial disease -- but his social problems are not regarded as anything to be cured but rather as an essential (if rather trying) part of who he is.
The big part the study is (inherently) missing, it's not capable of distinguishing between autism is caused by mitochondrial disorder and autism and mitochondrial disorders are part of the same developmental aberration.
There was an article about brain scans being able to pick autistic kids with 95% accuracy out of a control group, to me this mitochondrial study is just another block in the "autism has a physiological basis" theory.
The AoA people naturally haven't caught up to this yet, but, if enough physiological signs of autism can be identified, they might be identified so early as to definitely exclude the vaccine theory. In that case, expect to find the goal posts in a surprising new position at third base.
Thank you! I know that many who post here could probably figure this one out on their own, but although I spotted the science-y stuff and identified the woo easily, I couldn't take apart the study as thoroughly as you. Now I can! This is the great service that you perform here. Now I can pass this information on in simple enough terms to the next wooster I run into. In this way, I think we can start to make a dent in the gullibility of the often unsuspecting public. Not all will listen, of course, but some will and each one is a victory for reason and science.
Hyman's "treatment" sheds light on the explosion of "gluten free" products now seen even in regular supermarkets. You would think that people aged 40 or so could by now spot a "food fad" when they see one!
Having gone through some of the stages of woo-susceptibility myself (kids with ADHD), I can understand how it happens--and I can very much appreciate that I came across voices of reason along the way.
Nice deconstruction. Kim Wombles also wrote about this at Countering, as did Kev at LBRB.
The primary point all of you made? Preliminary study, preliminary study, preliminary study! Thanks for hammering on this point. Hopefully it will get through to at least a few people.
I noticed this too. The hand gestures were very familiar (although you really couldn't get a good sense one way or the other since the father didn't let him finish). My five-year-old daughter with PDD-NOS could easily sit still that long, but there is no way my son with autism would.
Interesting pilot study for sure. However, the effects of true systemic mitochondrial dysfunction are not limited to the brain. Those with mitochondrial disorders (including me) have a whole range of systemic effects, and most are not on the autistic spectrum. There was no mention of any of these other systemic effects of mitochondrial dysfunction in the JAMA article, and only one child met the criteria for a respiratory chain defect based on the blood assays performed.
There's certainly reason to suspect that there is an underlying cause that impacts mitochondrial function in autistic children, but I strongly suspect that mitochondrial dysfunction itself is not a cause, but rather, an effect.
Orac, great job! ( Or as Alex might say, " Horrorshow!** ) Why do the woo-providers always reduce complex conditions / illnesses to *vitamin deficiency", *toxins*, *allergens* i.e. something easily reversible *if* you can acquire the right supplements, diet, or treatment ( usually chelation), provided sympathetically by said woo-provider? Similarly, we have the Feingold diet (ADHD), Orthomolecular psychiatry - schizophrenia and other SMI as a niacin deficiency... This "simple cause/ simple treatment formula" only reveals the perpetrator's simplified misunderstanding of neuro-developmental conditions and SMI. Usually, I've found, any genetic influence is summarily dismissed *because* that would be more difficult as a selling point for supplements ( although at least one woo-meister talks about " reversing genetics" through nutrition). Not so much on therapy as treatment either.
** derived from the Russian "horosho" meaning " good", as "droog" from "druga" meaning "second", friend.
Mitochondrial issues in individuals with ASD may well be a result rather than a cause of ASD.
Rett syndrome, an ASD-like syndrome that can cause profound disability following 6 to 18 months of apparently normal postnatal development, is caused by mutations in the MECP2 gene. Rett syndrome is commonly associated with apparent mitochondrial dysfunction, including âultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity.â [Am J Med Genet. 2002 Aug 15;111(3):238-42]
The MECP2 gene product is a regulatory protein that affects the expression of myriad other genes, including genes affecting neurodevelopment as well as some mitochondrial genes such asCO1 (cytochrome oxidase subunit 1). [Mol Cell Biol. 2006 July; 26(13): 5033â5042; BMC Neurosci. 2010; 11: 53.]
Although mutations in MECP2 are a rare cause of ASD, MECP2 gene expression is commonly abnormal in the brains of individuals with ASD. [Epigenetics. 2006; 1(4): e1â11; Hum Mol Genet. 2004 Mar 15;13(6):629-3] The number of postmortem brain from individuals with ASD assayed for MECP2 expression or the MECP2 gene product is smallâbut most of the samples have shown abnormal results. Thus the majority of ASD samples assayed show abnormal expression of a critical regulatory gene that affects neurodevelopment and also affects mitochondria.
The role of MECP2 in neurodevelopmental disorders is reviewed in Curr Psychiatry Rep. 2010 April; 12(2): 127â134; the role of MECP2in Rett syndrome and ASD was reviewed in Epigenomics. 2009 October 1; 1(1): 119â130.
ORAC:
Not ANYTHING about the vaccines? And can't vaccines cause fever with anorexia?
Linking this to vaccines, as the anti-vaccine movement does, is also highly dubious, because it's fever, not anything about the vaccines, that can cause problems in children with severe mitochondrial disorders. That's why it's generally recommended that children with mitochondrial disorders receive their vaccines.
Vaccines sometimes trigger high fevers, do they not?
Hyman's site prominently features, "Ask Dr. Mark"- where a curious mar.. uh, *client* queries, " Can I overcome a family history of disease, or is it my fate?" ( other questions involve "stress" and "de-tox") Guess what he answers.
Vaccine preventable diseases sometimes trigger high fevers too, much more frequently than vaccines do.
Well if you have got Orac's words of wisdom you certainly have got some tortured, peer reviewed science! But try this, when all is said and done about this and that piece of science - there are no unvaccinated autistic people. None whatsoever and there should be, but there are not. Categorically there are not. It is simple, autism is the world's first shelf life disorder that affects millions of kids. It was invented in America and when the rest of the world understands this there will be almighty hell to deal with. It will leave the coming muslim conflict standing because it was done knowingly by intelligent people who said you could inject mercury into tiny bundles of humanity without harm. In fact it would be good for them and prevent disease etc. They were wrong, wrong, wrong and it has blighted a generation of kids whose lives have been stolen from them on the temple of the mighty US dollar and its deaf blind pharmaceutical industry. Unvaccinated is unautistic! It is simple!
Tony Bateson, Oxford, UK.
Good point Science Mom@13
I have a follow up to Jen in TX's question @11. Does vaccination have anassociation with lifetime or childhood probability of "high" fever?
@Science Mom:
Sometimes fevers can't be controlled, and how do we know that attempts at controlling fever aren't contributing to the problem? (See new evidence @1.)
Science mommy
Anticipated how? By forcing the issue with a vaccine? Controlled how? By taking acetaminophen and risking a reduction in immune response?
Post-Vaccine Acetaminophen May Harm Immune Response
http://www.medpagetoday.com/PrimaryCare/Vaccines/16458
They far more commonly prevent them.
Anthro @ 7:
It's definitely a fad, but one which has been appreciated by my family. While the faddishness of it annoys me, I have a cousin with severe celiac sprue, and the fad has been helpful in raising awareness. But it's got a dark side too -- you cannot trust the label "gluten free", it turns out, because few of the people pushing this diet realize just how extensive the dietary restrictions really are for true cases of gluten intolerance -- and because in the US, the term is not regulated. Simply being wheat-free is not sufficient. Problems of cross-contamination exist, and there is also the problem that a great many of these things are flavored with various extracts, particularly vanilla extract. Vanilla extract is 35% grain alcohol, and depending on the source of the alcohol, may be a potent trigger of celiac symptoms. Made from rice would be fine. Made from potatoes would be fine. Made from corn would be fine. (Assuming no cross-contamination, of course.) Made from wheat or barley, as much of it is, would not be so good. The doctors were particularly emphatic about vanilla extract when my cousin was diagnosed, because it's so easily overlooked. She even has to be careful about ice cream.
OHHHHHHH, gimme one o' them purple pills,
I want it to cure all my ills,
Gimme perfect answers, perfect cures,
Don't want uncertainty, I wanna be sure!
Research is so complicated,
Docs and scientists leave me frustrated,
But I'll spend my cash on a quickie fix
That Sumdood says will do the trick(s)!
So gimme one o' them purple pills,
And I'll shell out the biggest bills!
Is my autism gone yet, Doc???
Most always, fevers can be controlled and the risk of vaccination, in most cases, outweighs the risk of the corresponding infection for children with mitochondrial disease/disorders. Your link is with regards to high and overdose AAP, not what is within the prescribed limits. I see that that has been pointed out to you, why do you fail to acknowledge this?
re: #7 Gluten free may be a fad for autism, but it IS the treatment for celiac disease. That is most likely why there are so many more products, more easily available.
Tony Bateson, have you made good on your offer and written a one thousand dollar check to AoA's Kim Stagliano yet, since her third child with ASD (that's the unvaccinated one, as you know) disproves your point?
Seriously, claiming that autism was âinvented in Americaâ seems to come from the wacky Olmsted-Blaxill notion that a condition does not exist until it has been reported in the medical literature, so autism did not exist until it was describedâdonât you wonder how people managed to die of heart disease, cancer, or other medical problems before there was a medical literature?
As usual Augie, you come cluelessly blazing in with a minutia of evidence for something without regards to the whole picture. Yes there is evidence of Acetaminophen interfering with antibody production in vacinees, which is why it should be avoided in normal healthy children. There are also other NSAIDS which may be used that may not have the same interference. I sincerely doubt that you are equipped to consider all of these factors as a mito specialist would. So unless you care to argue that a case of pertussis is safer than the vaccine, STFU you witless dolt.
@Tony Bateson
Good to see you're still a stupid bastard. Come back in again in a month or two for your regular checkup.
Okay, lets say that "mitochondrial disorder + oxidative stress" is a common cause of autism. Then what's the connection with vaccines? Vaccines can cause oxidative stress, but so can other things. Unless there's not just different degrees of oxidative stress, but different qualities of oxidative stress, and oxidative stress from vaccines has a quality to it which mitochondrial disorders are more sensitive to. I'm not a biologist, but from my understanding of mitochondria, there can only be a difference of degree, not quality (except for a "differences in degree become a differences in quality" type thing).
I wonder if Mr. Bateson ever gets tired of being so phenomenally wrong? If he actually paid any attention and did some reading of the literature, he would find that autism was not something coined in the U.S. In fact, the term "autism" was coined by a Swiss psychologist, Paul Eugen Bleuler way back around 1911/1912. I wrote a bit about it over at Silenced, including a follow-up article looking at the diagnostic precursors to autism, dementia praecocissima and dementia infantilis.
And, as brian and others have reminded Tony countless times before, Kim Stagliano's youngest daughter refutes his claims.
From OP:
To be accompanied by cheesy 80s theme music, no doubt.
Calli @ 18:
I don't know if the regulatory régime in Canada ensures that gluten-free really does mean gluten-free, but I can sympathize with being glad that gluten-free foods are more of an option these days (and also with worries that the term is weakened on account of the fad), since I am on good terms with several people who are celiac (one whom my fiancée and I had over for dinner just the other day).
@Science Mom:
"Your link is with regards to high and overdose AAP, not what is within the prescribed limits. I see that that has been pointed out to you, why do you fail to acknowledge this?"
"The data presented here establish, for the first time, a direct neurotoxic action by AAP both in vivo and in vitro in rats at doses below those required to produce hepatotoxicity and suggest that this neurotoxicity might be involved in the general toxic syndrome observed during patient APP overdose and, possibly, also when AAP doses in the upper dosing schedule are used, especially if other risk factors (moderate drinking, fasting, nutritional impairment) are present."
Don't make the assumption that parents always use acetaminophen properly. And don't assume that everyone's tolerance to acetaminophen is exactly the same. Furthermore, when kids are feverish, they tend to not want to eat or drink, thus increasing the risk for acetaminophen toxicity. (See above mention of fasting and nutritional impairment.)
Lastly, I am not disagreeing with you that a febrile response to a natural infection wouldn't cause the same problems, and I've even tried pointing this out at Age of Autism (they don't listen to me either). I'm not convinced that fevers alone are the problem, but rather, the way in which they are managed.
For those who are interested, the FDA actually has a proposed rule (I didn't see a final rule, yet) on gluten-free labeling. You can see the Q&A here.
Hello friends -
It's too bad to see this study used by either side, either to sell stuff, or primarily as an exposition on the limitations as acknowledged by the authors.
Why not focus, instead, on what this study can actually teach us?
This is the second study to found highly, highly increased rates of fully diagnosable respiratory chain disorders in an autism population; not to mention several other biomarker studies that consistently show metabolites consistent with mitochondrial dysfunction in autism.
Orac found time to copy in the entire section regarding the limiations as noted by the authors (including confirmation that care was taken to avoid the potential confound of multiple comparisons), but there is no mention of the fact that besides oxygen consumption differences, rates of hydrogen peroxide production was higher in the autism group; indicating limitations in removing ROS. The authors state:
Thus, lymphocytic mitochondria in autism not only had a lower oxidative phosphorlyation capacity, but also contributed to increased cellular oxidative stress
There is no mention of the fact that other experiments have shown increases in mtDNA copy number and/or overreplication in instances of increased oxidative stress. This would be consistent with the premise that problems in detoxification systems (i.e., glutathione) can particpate in process that exaberbates mitochondrial dysfunction. In fact, the authors state:
Differences in mtDNA parameters between control children and those with autism could stem from eitehr higher oxidative stress, or inadequate removal of these harmful species. The increased reactive oxygen species production observed in this exploratory study is consistent with the higher ratio fo oxidized NADH to reduced glutathione in lymphoblastoid cells and mitochondria from children with ASD, supporting the concept that these cells from children with autism present higher oxidative stress. Increased reactive oxygen species production induced by dysfunctional mitochondria could elicit chronic oxidative stress that enhances mtDNA replication , and possibly mtDNA repair.
I'm starting to learn enough to understand that our arrow of causality can't be aimed from this study, but while focusing on the problems with this study is a fun undertaking if our goal is to bash Mark Hyman,it is largely a disservice; and an intellectually honest reading tells us that if these findings are due to chance, we need to start rethinking a slew of more basic science regarding the interactions of oxidative stress on mitochcondrial function, and indeed, a dozen or more papers that consistently show increased oxidative stress in autism.
This isn't healthy skepticism, it is faux skepticism.
Finally, I ran across this paper the other day, which may shed some light on one possible mechanism by which a state of persistent mitochondrial dysfunction; chronic inflammation, and in this particular case, early life immune activation. Dopaminergic neuronal injury in the adult rat brain following neonatal exposure
to lipopolysaccharide and the silent neurotoxicity was published a few months ago, wherein neonatal rats (day 5) were given LPS to stimulate an immune response. The authors found that 65 days later, animals injected with LPS were characterized 'a sustained increase in microglial activation and inflammatory responses', persistent changes to the dopaminergic system, and salient for our purposes, significantly reduced mitochondrial complex 1 activity Nice.
- pD
@pD
Before you jump all over Orac, note his comment:
Composer99
On the Ghostbuster theme . . .
When ya read some woo
on the internet
who ya gonna call
HuffBusters!
When Mercola types
and ya get upset
who ya gonna call
HuffBusters!
Please, someone musical run with this.
Jen in TX, the PLoS ONE study was not in humans. You must be cautious about overgeneralizing the results of a very preliminary study.
-JP
Science Mommy
How about a little less mommy and a little more science, dear.
rates of hydrogen peroxide production was higher in the autism group; indicating limitations in removing ROS. The authors state:
Thus, lymphocytic mitochondria in autism not only had a lower oxidative phosphorlyation capacity, but also contributed to increased cellular oxidative stress
Did the authors actually isolate the mitochondria free of other microbodies, specifically peroxisomes? Peroxisomes are the primary organelle for the production (and degradation) of hydrogen peroxide.
Jen, please do yourself a favour and calculate the dosages used in the rat study and dosages used in children to see the differences. Also, consider the route of administration. If parents overdose their children, and I know some do, that's the fault of the parents and not the medicine. Did you miss this from the PloS study?
Again, please do those calculations and put them into context.
@1
Be careful about results obtained from rats. Certain products are not metabolized the same in rats as in humans - a stiking exemple is tamoxifen, which kills rats at much feebler doses than in humans.
Rats have very big livers compared to humans, in which the main metabolic pathways for the same substances may differ greatly with those in humans. What is not hepatotoxic for rats may be for humans, and vice-versa.
In humans, toxic doses of acetaminophen result in hepatic damage, and sometimes in kidney damage, which may be accute or chronic. The doses given in this study are quite high (250-500 mg/kg) and corresponds to a 17g to 35g dose in an average 70 kg human. The highest lethal dose reported for acetaminophen is 20g, the lowest around 4g. At these dosages, it has killed mainly by destroying the liver (not a nice death, it will take 2-3 weeks).
This study is about a huge overdose (as in attempted suicide or maybe accidental poisoning in children), not normal, even if heavy, use.
Denice Walter @11
Did anyone notice the title of the video:
"A young buy>/b> cured of autism"
Accidental typo or subconscious revelation?
Arrgh - HTML fail.
Just in case Jen in TX wants to dodge the point:
The acetaminophen doses in the rat study were 250mg/kg and 500mg/kg. Standard pediatric dosing is 15mg/kg.
Standard dose of 160mg/5mL oral liquid for a 10kg child is about 5ml. To hit the doses in the study, you'd be looking at a minimum of about 80mL. I think that even the most ignorant parent isn't going to make that grave an error.
Hi catalse -
Did the authors actually isolate the mitochondria free of other microbodies, specifically peroxisomes? Peroxisomes are the primary organelle for the production (and degradation) of hydrogen peroxide.
This information does not look to be available in the paper I have, in many places it states that the eMethods section of jama.com has more in depth details on the methodology used for hydrogen peroxide detection, and other pieces. Unfortunately, I do not have requisite access to view the data there.
- pD
Yakivegas -- I would suspect the most common overdosing error would be in double-dosing (father gives a dose, mother unwittingly gives the dose as well half an hour later) or in substituting a tablespoon for a teaspoon (which, in the US at least, would triple the dose). Of course, that's still way less than the 80mL you calculated as equivalent to the dose in the rat study.
I think we do overtreat fevers, especially since *high* fevers (the ones that are actually dangerous) are not commonly associated with vaccines. It's low fevers that are most commonly associated, and even they are an infrequent occurrence. My children never got fevers from any of their vaccines that I can recall, and we never did the prophylactic acetominophen thing.
I'm formulating my own review of this preliminary report, but a couple of points right off the bat:
[1] For a large number of the parameters, there is no known "normal range", so the control group (actually, the 99% confidence interval of the control group) was assumed to represent the "normal range" and any deviation from this was considered "abnormal". This is a good "first approximation", but it still doesn't make any deviation from this range "abnormal" in a physiological sense.
[2] No mention was made of any of the autistic subjects showing clinical signs of mitochondrial dysfunction. The "abnormal" numbers may represent yet another case of "statistically significant but physiologically irrelevant".
[3] It seems odd that 80% of the autistic subjects (and 0% of the control subjects, but see [1] above) showed "mitochondrial abnormalities". In fact, if you look through the tables, 100% of the autistic subjects showed some "abnormal" result on the parameters tested.
Given that mitochondrial disorders are considered to be rather rare (1 in 4000 or 2.5 per 10,000 in one article), finding that 80% of autistic children have them would imply that the true prevalence of mitochondrial disorders is at least 53 per 10,000 or 1 in 188 (assuming 1 in 150 children are autistic - that goes to 80 per 10,000 or 1 in 125 if you use the "1 in 100" autism prevalence).
I could possibly imagine that "mainstream medicine" might miss a quarter or even half of children with mitochondrial disorders, especially if they are mild, but missing over 95% (or 97%, if you use the "1 in 100" autism prevalence) of mitochondrial disorders? That seems a bit high to me.
And that's just counting autism. What if it turns out that other developmental disorders have a similar rate of mitochondrial dysfunction? Mitochondrial "dysfunction" might be as prevalent as left-handedness.
Even though this is a "rapid communication" type of article, it seems strange that the editors of JAMA didn't kick it back to them to explain how 80% (or 100%) of their test subjects have what has been up until now a relatively rare disorder. Of course, JAMA isn't the journal it used to be, so their editorial standards may have slipped.
Still, it is odd that the authors discussed - at length - how mitochondrial dysfunction could contribute to the autism phenotype without once (that I found) discussing how it came to be that be that so many of their autistic subjects have it.
I have numerous other "quibbles" with this article, but these are my major concerns.
Prometheus
I think the mitochondrial disorder hypothesis is very appealing on a number of fronts, and it is still being actively pursued by a number of researchers. One of the mysteries of autism is that the twin concordance is very, very high, indicating that autism is mostly genetic. Yet genome wide studies have not identified the genes responsible; the forms of autism with identified genetic causes are things like Rett Syndrome and Fragile X, which are not "pure" autism, and account for a tiny fraction of autism cases. If there were a straightforward Mendelian cause, it would have been found by now. So it's beginning to look like there probably multiple genetic causes of sporadic autism, perhaps even a combinatorial situation in which the individual genes don't cause much harm, but their are "bad" multigene combinations. On the other hand, postmortem studies of autistic human brain have found strong evidence of neurochemical commonalities, suggesting that there is some kind of "final common pathway" to autism. Neuronal electrical activity uses a lot of energy, and it is plausible that there might be critical points in embryonic brain development that place a high demand on energy metabolism, and mitochondrial dysfunction arising from a variety of defects could lead to a failure of the brain to correctly "wire" itself.
Of course, none of this has anything to do with vaccination. The Hannah Poling case is in its own way as atypical as Rett or Fragile X--she had numerous other symptoms, and is not at all representative of typical autism. If mitochondrial dysfunction has anything to do with autism, it is probably a developmental mishap that occurs in utero. And there is really no plausible reason to expect vaccination to play a role.
How did Dr Hyman pass the science courses in med school?
I agree with you, Orac: http://healthforhumans.blogspot.com
"The acetaminophen doses in the rat study were 250mg/kg and 500mg/kg. Standard pediatric dosing is 15mg/kg.
Standard dose of 160mg/5mL oral liquid for a 10kg child is about 5ml. To hit the doses in the study, you'd be looking at a minimum of about 80mL."
To be fair, it's not a direct translation. Dose translation guidelines between species. I leave all that to the PK dudes, though. I'm more concerned that Jen is dosing her kids IP instead of giving it orally, m'self. :p
Even more than that - those 250-500 mg/kg were given intravenously. The rule of thumb for estimating equivalent oral dosage is to multiply by 10. Therefore, to get around the blood concentration in that paper we're talking about 800mL of oral liquid.
Acetaminophen at these dosages is clearly hepatotoxic in humans, where adult lethal doses run between 4 and 20g - which kill largely with liver damage. You simply cannot reach these concentrations in the human brain without extensive liver damage.
@ Militant Agnostic : Hahahaha! Actually, I'm certain that there are ( more likely, *were*) freudians who might argue that there aren't *any* accidents and that *all* typos are indeed revelations of the subconscious. Be that as it may, woo-meisters' motives are usually so transparent that revelatory typos are superfluous.
@49a
I think I just found my woo. I just have to figure out how to capitalize on it. Expect to see me on Oprah in a couple of years explaining how I can tell you how to achieve happiness by following the advice I give you based on your typo's and shilling my self help book.
"Yes, as I've pointed out since its very inception, if there's one thing The Huffington Post is good at doing, it's butchering medical science and serving up regular heapin' helpings of the purest woo..."
The only mistake in that statment was the word "medical." PuffHo serves up the woo on ALL science.
Pehaps juxtamitochondrial illness ---- I don't suppose something like coxiella, bartonella, borrelia or rickettsia would enhance cellular function in any way. Look at NK counts and ASO titers --- immune suppression rules the day.
One wonders how many parents of autistic children will get sucked into new, costly and useless treatments for their kids as the result of breathless overhype by people like Hyman.
It's worth mentioning again that the authors of this pilot study certainly do not herald it as a "breakthrough discovery" and do not claim that the metabolic defects they found cause autism, or that if they're reversible that will sucessfully treat the problem.
And yes, the toxin shouters will be quick to blame every conceivable component of vaccines for mitochondrial disorders, independent of logic and evidence.
pD gloms onto a study in which: "...neonatal rats (day 5) were given LPS to stimulate an immune response. The authors found that 65 days later, animals injected with LPS were characterized 'a sustained increase in microglial activation and inflammatory responses', persistent changes to the dopaminergic system, and salient for our purposes, significantly reduced mitochondrial complex 1 activity Nice."
Nice? Oh, perhaps you're extrapolating from this rat study to conclude that getting sick with a number of vaccine-preventable diseases likely exposes children to hazardous amounts of LPS from disease organisms, and thus vaccinating them would reduce the risk of their developing mitochondrial dysfunction. A bit of a stretch based on this limited evidence, but possible... Or would you be hinting that the much smaller potential LPS exposure from vaccines is what we need to worry about?
Knowing pD and her belief that infantile infectious disease is negligible and that immune system effects of such diseases are inconsequential in comparison to the effects of those nasty vaccines, I suspect we know where she's trying to go with this.
@Calli #23 and Zen #26
I am well aware of celiac disease (and there's a related dermatological condition as well) and know someone who has it. That is what makes the faddishness of the kind of thing Hyman and many other woomeisters practice so annoying--it belittles the real medical problem of celiac disease. The explosion of products has been to cater to people with supposed "allergies" diagnosed by these quacks on a regular basis as a source of "inflammation" that is responsible, supposedly, for an enormous range of ailments--not for the relatively small number of people with true celiac disease. Even at the co-op, the staff admit that its a fad--one that has done well for them. Most of these people who supposedly can't "tolerate" gluten eat it when they really want to; then they blame anything that occurs in the following month (such as feeling "depressed" or "fatigued" ) on the ingestion of gluten. People with sensitive skin blame gluten for every rash or chapped skin that befalls them. As these things come and go anyway, they are bound to coincide with eating certain things sometimes--and this is all it takes for people to start blaming the evil gluten for any little thing.
I have every sympathy for anyone who actually has celiac disease or anything like it, but that is not the vast majority of people I see at WF and the coop filling their carts with (as you point out) gluten-free products that may not be so at all. I was biopsied last year for the dermatological condition that is related to celiac disease (can't remember the name now) and was truly daunted at the idea of being required to avoid all gluten. I was extremely relieved when the biopsy was negative and even happier when the condition cleared up on its own eventually. Even happier that I didn't fall prey to some quack!
I didn't know about the vanilla extract, but I only use real vanilla and avoid anything (including Godiva chocolate) that uses the fake stuff; I'm just a nut about that, it's not for any health reason.
Gotta disagree, Orac. Fox News is even more full of woo and active hatred of science. It's just not limited to medical science.
Thank you Anthro for that hunk of nothing opinion.
Are you also angry at those Aspies jumping on the autism bandwagon? Are they just trying to steal the thunder away from the true autistics?
BTW, you may want to stay away from those co-ops. They aren't scientifically proven to be any better than monsanto derived produce. They are just quacks stealing your money.
In other news, I'm thankful for the scientist that used the scientific method to come up with the idea of insulation. I'm also thankful for the applied scientists that put it into my house.
Bingo. Down Syndrome involves both intellectual impairment and tongue enlargement. Neither is the cause of the other.
Deliberately mixing metaphors is fun, though my favorite is still the inadvertent "what we are hearing is merely the distant rumbling of the handwriting on the wall."
Science mom and Yakivegas:
Is it at all possible that rats are somehow less susceptible to acetaminophen toxicity and that's why the higher concentrations were used? In other words, is what's lethal for a human and what's lethal for a rat exactly the same?
@58
Rats have very big livers (with different metabolisms) compared to humans - sometimes that means drugs will be toxic at higher doses in rats compared to humans.
A good rule of thumb is to consider the doses/kg as 10 times lower in humans compared to rats.
For example, acetaminophen is known to be hepatotoxic (and lethal) to adult humans at oral doses varying from 4 to 20 g (50 to 285 mg / kg). You may expect rats to tolerate doses up to 500mg/kg without liver damage.
Another rule of thumb is to consider an injected dose (which is what is used in this study) as able to reach a concentration 5 to 10 X superior to the same as oral dose. This would bring the equivalent dose in a human, as per hepatotoxicity, to around 5g/kg - definitely lethal, and definitely hepatotoxic.
What this means is that a human will be quite dead, or will have significant liver damage, before acetaminophen has any effect on his neurons as per this study.
Anthro @ 54:
I am well aware of celiac disease (and there's a related dermatological condition as well) and know someone who has it. That is what makes the faddishness of the kind of thing Hyman and many other woomeisters practice so annoying--it belittles the real medical problem of celiac disease.
Belittles and confuses. I totally agree. Very glad to hear you tested negative for celiac disease! My cousin was diagnosed young enough that she never learned what she was missing, food-wise; she was diagnosed at 6 months. She didn't show the dermatological symptoms, and had one atypical symptom -- high fever -- that briefly had them thinking she could be suffering from meningitis. When they realized she had an ileus, they started to zero in on the real problem, and eventually did a biopsy of her intestines, which revealed the characteristic lesions.
Me too. Actually, it is real, honest-to-gosh vanilla extract I'm talking about, made from vanilla beans, not vanillin. I also much prefer real vanilla, and when possible, vanilla beans. However, using the beans is not always practical in a recipe. Luckily, there is one brand of vanilla extract which has been certified gluten-free by a celiac sprue group. Madagascar Vanilla, IIRC, which as it happens is also a high-end vanilla extract made from Madagascan vanillan.
The brand of vanilla ice cream that my cousin eats is Bryer's. Old-fashioned ice cream. It really is better, and you can tell they didn't use vanilla extract -- the ice cream is dotted with little vanilla seeds. ;-)
Jen in TX:
Absolutely that's possible, in the absence of information to answer the question. They don't test LD50s in humans, after all. This is the essential weakness of animal models. Mind you, it's important to point out that the reverse could also be true -- rats may be *more* sensitive to acetominophen than humans are, especially given their rapid maturation. Since of course nobody (or at least nobody sane) tests LD50 in humans, it's hard to say.
I cannot believe how many comments and strong sentiments over such a tiny study. Parents of children with autism are often too busy with the daily realities of life to bother with the latest studies. Medicine has and continues to fail them badly. I am all for research that examines early diagnosis and cure, but there is so little money for treatment. Behavioral treatment, GOOD behavioral treatment programs are underfunded all over the country. Applied Behavior Analysis has the most empirical support but there are others. If only some of the research dollars could go directly to serve families. The MDs want to study the pills, the psychologists want to advance their own nuanced behavioral method, Medicaid and private insurance want to avoid paying for any of it, and early intervention programs and schools keep hoping they will get more funding so they can come up with a definitive way to help these children and their families in a timely fashion. It is very hard for families to access and then pay for behavior programs. So they take a vitamin, change a diet or join a support group. Would you fault a cancer patient for trying alternative treatments if there was an 8 month waiting list and no way to finance effective therapy for his problem? If medicine offered REAL help, there would be no demand for the QUACKS
www.pensivepediatrician.blogspot.com
dr_som,
To be honest I would fault a parent for trying certain treatments. If they are going to use something potentially dangerous on their children, like feeding them chelators I would be worried. If they were going to try something pretty harmless, perhaps changing diet somewhat, I would not have that much of a problem. I do not think it would really do much but they can try it.
But I do not think you will get a lot of disagreement here over the lack of funding to help parents. In fact, I doubt many people here are really trying to focus on "fixing" and "curing" autistic children either. That really is something more in line with the view of those over at AoA and similar places who seems to view those with autism as being broken, it being the worst thing possible, worse than death.
To do the measurements they report, they had to have isolated mitochondria.
This is not a smoking gun or any similar breakthrough type research. It is a tiny study, they used blood cells which are very different than any other type of cells in the body, and these particular blood cells are acutely regulated by cytokines in the blood. A âsnapshotâ of what these particular mitochondria are doing at an instant of time doesn't tell much about a chronic condition which extends over years.
Mitochondria in every tissue compartment are different. Mitochondria in every tissue compartment are regulated to be different and to do different things. These blood cells are âsupposedâ to make H2O2. That is part of what they do in the immune response, make H2O2 so that myeloperoxidase in the extracellular space can take that H2O2 and kill bacteria with it.
The differences they report might still be ânormalâ and not of clinical significance. The differences may be statistically significant but not clinically significant.
Mitochondria are really really complicated. They have a couple of thousand proteins, only 13 are coded by mitochondrial DNA. All the rest are made from DNA coded in the nucleus. Mitochondria in nerves are a lot different than mitochondria in every other tissue compartment. The mitochondria in nerves are a lot more resistant to âtoxinsâ than mitochondria every where else.
If there were mitochondrial toxins in vaccines, then when a vaccine is injected IM, the dose of those toxins on the mitochondria where the vaccine is injected would be thousands of times higher at the site of injection than in the tissues remote from that site. Thousands of times higher dose of mitochondrial toxins means even more certain mitochondrial destruction, which would cause a necrotic spot where the vaccine is injected. A necrotic spot is not observed in every single vaccination, therefore vaccines do not contain mitochondrial toxins that can affect the mitochondria in neurons. This is not a close call.
All aspects of mitochondria are regulated. Mitochondria have a finite lifetime and there are regulated pathways that clear out old ones and replace those old ones with new ones. This is known as mitochondria biogenesis. A long term problem with mitochondria can only be due to a problem in the long term regulation of mitochondria biogenesis. Mitochondria biogenesis is regulated by nitric oxide.
Kemist@42
"This study is about a huge overdose (as in attempted suicide or maybe accidental poisoning in children), not normal, even if heavy, use."
No, it is not, and the authors were quite clear about that.
Kemist@52
"Acetaminophen at these dosages is clearly hepatotoxic in humans,"
Right. In humans!
The LD50 for acetaminophen in rats is...(?)
typed "The LD50 for acetaminophen in rats" into yahoo and this is from the first page it returned:
Toxicity
Oral, mouse: LD50 = 338 mg/kg; Oral, rat: LD50 = 1944 mg/kg.
(http://www.druglib.com/activeingredient/acetaminophen/)
The LD50 of rats for acetaminophen is ~1.9 g/kg. Caffeine is ~0.19 g/kg.
http://en.wikipedia.org/wiki/Median_lethal_dose
In any case, the mitochondria in the liver are much more sensitive to the toxicity of acetaminophen than are the mitochondria in the brain. That is why people die of liver failure from acetaminophen poisoning and not neuropathy.
The reason liver mitochondria are more sensitive is because they are a lot more complex, and the liver is what does all the toxin disposal. Often the metabolites of a toxin are more toxic than the toxin itself. The liver mitochondria crap out if they make too much toxic byproducts and so stop making them. Then either you can get rid of the toxin another way more slowly and your liver can regenerate, or you die. That is a âfeatureâ that keeps your brain alive while your liver takes the hit. If your liver is too badly damaged, you die, but you don't die because the toxins made your brain crap out so a predator could eat you.
Jen in TX I just posted a comment with a link to the LD50 in rats, but 1 link was enough to send me to the spam filter so daedalus2u got it first :(
Oh, perhaps you're extrapolating from this rat study to conclude that getting sick with a number of vaccine-preventable diseases likely exposes children to hazardous amounts of LPS from disease organisms, and thus vaccinating them would reduce the risk of their developing mitochondrial dysfunction. A bit of a stretch based on this limited evidence, but possible... Or would you be hinting that the much smaller potential LPS exposure from vaccines is what we need to worry about?
LPS is popular for research studies because it induces extremely robust immune and inflammatory responses. In fact, sometimes animals given LPS die of toxic shock. Human vaccines use safer adjuvants. So your first interpretation makes a lot more sense, although I'm sure it is not what pD had in mind.
The authors may express that opinion, but it does not mean that it is a fact.
When is a human going to gobble 17g to 35g (17 000 to 35 000mg) of acetaminophen in less than one hour, which is what 250 to 500mg/kg represent in an average adult (neglecting the parenteral to oral ratio), the doses at which acetaminophen showed neurotoxicity in this study ?
-> severe accidental overdose / attempted suicide
@ Jen, yes it's possible, but as Cali (I believe) pointed out, they could also be more susceptible. In any event, they appear to be a reasonable surrogate for toxicity studies and AAP. As she also pointed out, there is no way to establish an LD50 in humans so toxicity data is accrued from accidental or intentional overdoses. What these authors attempted to do is knowing the range for hepatoxicity, asking the question of what do doses below that range do. I think the more data we can establish on such a widely used (and abused) medication such as AAP, for a safety/toxicity thresholds, the better, don't you?
People are not understanding the basic facts about mitochondria. Mitochondria have a limited lifetime. They wear out and need to be replaced. Sort of like blood cells, but on a shorter time frame. âToxicityâ to mitochondria can only occur in the presence of the toxin. There can be no residual effects of âtoxicityâ on mitochondria because any damaged mitochondria are replaced. If mitochondria cannot be replaced, then the person dies.
If someone is alive a year after some event, that event did not irreversibly damage their mitochondria because they are alive. If their mitochondria had been permanently damaged, they would be dead.
It is sort of like blood cells, if your blood cells were not at all replaced, when the ones you have get tired and crap out, then you get anemia that is irreversible and you die.
Kemist,
Do you really believe that the authors of this study would be so stupid as to not realize that acetaminophen dosed in humans at 250-500mg/kg would be lethal?
Really?
As was pointed out already, the LD50 for acetaminophen in rats is 1.9 GRAMS/kg. That's quite a hefty dose, that would most certainly kill even the heaviest human many times over, if we're dosing by weight. Since it was pointed out already that LD50 data on acetaminophen in humans is not possible due to obvious ethical dilemmas, we have to go by what information has been gleaned from accidental and intentional overdoses, and those ranges are much, much smaller than 1.9g/kg, usually around 150-250mg/kg.
So...to fry a rat liver, you need around 1.9g/kg of acetaminophen. To fry a human liver, you need >150mg/kg of acetaminophen (possibly even less if you have other comorbitities).
It appears to this google trained "scientist" that it takes a much higher concentration of acetaminophen to fry a rat liver, and that's why the authors used the concentrations that they did.
Do I have that right?
"Dr. Som" asks:
If I understand this argument, if a patient is unable to obtain real treatment for their condition, it is better that they spend their time, money and energy on treatments that won't work (or, to be absolutely fair, hasn't been shown to work) rather than do nothing?
This argument fails on several levels, not the least of which is that the problem with real autism treatments isn't that they are unaffordable or in short supply. The problem is that none of the treatments which have been proven effective in autism are able to provide the degree of "cure" that the quack (excuse me, I meant "alternative") treatments promise.
Of course, another difference between the proven and "alternative" treatments is that the "alternative" treatments don't appear to work when they are rigorously tested. That might explain why the "alternative" practitioners are so reluctant (excuse me again, I meant "too busy") to test them.
Prometheus
The problem with the rat study is that it is not acetaminophen that is toxic, it is a metabolite of acetaminophen that is toxic. When formation of that metabolite is blocked, so is the toxicity. What is being looked at is the relative metabolic capacity of rat liver to clear acetaminophen vs the relative metabolic capacity of cortical neurons to make the toxic metabolite.
They cite other data showing that if a lower dose is given, that the acetaminophen is actually protective. That is at a lower dose (~100 mg/kg) acetaminophen protects neurons. That lower dose is still toxic to humans and causes liver toxicity.
What is the trade-off in humans between metabolism and clearance by the liver of acetaminophen and the metabolic capacity of cortical neurons to make the toxic metabolite? Do human cortical neurons even have that cytochrome P450 enzyme? When you give acetaminophen to a human, how does the dose/response in liver vs cortical neurons change? Is the 100mg/kg that is protective in rat cortical neurons also protective in human neurons? Or does the toxic dose to cortical neurons scale with the toxic dose in the liver?
The type of cell death that was observed is apoptosis. That is programmed cell death, the same kind of cell death that occurs in any type of excitotoxicity. The death rates of cortical neurons in vitro look funny to me. The smallest dose tested, 0.5 mM/L had maybe 5% LDH release. A 10 times higher dose, 5 mM/L had maybe 13%? 10 times more only kills 2.5 times more cells? I notice they don't report results for doses less than 0.5 mM/L except from the literature (where they are protective). According to the data they cite, 0.1 mM/L should have been better than their control which was just vehicle and which killed about half as many as did the 0.5 mM/L dose.
I don't think this paper tells us much of anything about toxicity of acetaminophen in humans, or which tissue compartments will be affected first. Presumably it is the liver. They don't show any data that suggests otherwise.
Jen in TX asks:
Short answer: no.
We don't know the LD50 in humans for most compounds, largely because it isn't ethical to do the testing. The best we can do is - based on deliberate and accidental overdoses (where, I might add, the actual dose is often in question) - the probably toxic dose.
For acetaminophen, the LD50 in rats is 1944 mg/kg, for mice it is 338 mg/kg and the "probably toxic dose" in humans is anything above 140 mg/kg.
Comparing the LD50 to the probably toxic dose is comparing apples and orangutans. In adults, doses above 25 grams (~350 mg/kg) are considered to have a "high risk of lethality", which even then doesn't equal a 50% chance of death (i.e. the LD50).
In humans, there are three pathways for acetaminophen metabolism: glucuronidation, sulfation and N-hydroxylation. The first two account for the bulk of acetaminophen metabolism (60 - 100%, depending on dose) and have no toxic intermediates.
N-hydroxylation, on the other hand, produces a highly toxic intermediate (N-acetyl-p-benzo-quinone imine or NAPQI) which must be conjugated with glutathione immediately or it will cause oxidative damage to the cell.
There are people (and species, e.g. cats) that have more extensive or rapid N-hydroxylation of acetaminophen; these people (and species) are more susceptible to acetaminophen toxicity, especially at higher doses. Also, when a very large dose of acetaminophen is taken/given, the glucuronidation and sulfation pathway can become "saturated", shunting more of the acetaminophen into the N-hydroxylation pathway.
In overdosage (or in species where N-hydroxylation predominates), the production of NAPQI can consume glutathione more rapidly than the cell (especially liver cells, where the bulk of the metabolism is done) can produce it, leading to oxidative damage. Enough oxidative damage leads to apoptosis (cell death).
Further complicating the issue is the fact that the glucuronidation and sulfation pathways are inducible, meaning that if they are being heavily used, more enzyme is produced. The result is that people who routinely use large amounts (but not toxic amounts) of acetaminophen can eventually tolerate doses that would be certainly lethal in a typical person.
Since the bulk of the metabolism of acetaminophen is done in the liver, the liver is usually the organ that fails in fatal acetaminophen toxicity. However, lesser amounts of acetaminophen are metabolised in other tissues (kidneys, lungs, white blood cells, etc.) and isolated cultures of these tissues can show acetaminophen toxicity as well. However, in the intact organism, it's usually the liver that fails first.
It's worth noting that in those cases where acetaminophen caused permanent liver failure and the patient promptly received a liver transplant, there has not been significant brain, kidney or lung damage attributable to acetaminophen. Of course, liver failure of any duration can by itself cause brain and kidney dysfunction (and probably lung damage, as well), muddying the waters more than a bit.
Now, I have no illusions that this will do anything to get "Jen in TX" off of her acetaminophen crusade, but I wanted to provide a bit more information for anyone else reading along.
Prometheus
Ugh. This makes me mad for several reasons. One, my kid has a bona fide mitochondrial disorder and now folks are gonna think I'm a loony toon if I mention it. Two? They keep preying on the hopes and fears of parents and claming recovery. I get so jealous when I hear those stories. Jealous because I want my kid to recover and I know it isn't going to happen. I love him very much and I want what's best for him. But recovery? Cure? Nope. Not gonna happen. Stop teasing us, woo doctors.
@77
They used that dosage to bring the rat cerebrospinal fluid concentrations up to the level that they saw in their in vitro study (0,5 to 5mM). These concentrations are huge for a pharmaceutical (especially considering that we're talking about crossing the blood-brain barrier), on the scale that are used in screening studies. The purpose of using such high doses is to see if a given substance has any effect at all.
Luckily for their in-vivo study these concentrations won't kill rats, but they would certainly kill a human.
So these results have very little significance in humans, since a human cannot tolerate these dosages without severe liver/kidney damage.
It seems to me that if you want to study the subtoxic and toxic effects of acetaminophen in a rat model, you need to be giving your rats concentrations of acetaminophen that actually approach the area of hepatotoxicity. For rats. Otherwise, you might as well just be giving them plain old water.
I find that anyone who uses the word "causes" loosely is likely to be full of it.
http://statgirlskewer.blogspot.com/2010/12/autism-cause-identified-no-n…
Jen in TX comments:
Why? As it turns out, rats have a hepatic tolerance of acetaminophen that is much greater than our own - why would we assume that their other tissues have an equally elevated tolerance (hint: it doesn't appear that they do)? Again, by comparison, humans can tolerate roughly as much acetaminophen as mice, less than rats and way more than cats.
As an interesting aside, the toxicity in cats doesn't appear to be hepatic, since exceedingly small amounts of acetaminophen apparently give them fatal methemoglobinemia, not liver failure (caveat: I am not a veterinarian).
The fact is that different species are, well, different. I suppose a better species to use to look at "subtoxic and toxic effects of acetaminophen" (more properly termed acute and chronic toxicity) would be mice, whose hepatic toxicity threshold for acetaminophen is similar to ours.
The reason to not push the dose up to beyond levels humans could survive - the gist of the suggestion from "Jen in TX" - is that all cells have a "toxic threshold" for acetaminophen and will show toxicity at a high enough dose. For that matter, all cells have a "toxic threshold" for table salt, water and even pure, natural cane sugar.
Testing acetaminophen at levels that would be hepatotoxic to humans is pointless - even if acetaminophen does cause brain/lung/kidney/heart damage at those higher dose levels, a real person would already be dead from liver failure (absent the immediate availability of a compatible liver donor).
Again, I harbour no hope that "Jen in TX" will read this and moderate her beliefs that acetaminophen is the scourge of the Earth, but I do hope this will clear up any confusion her assertions have caused.
Prometheus
Over fifty and still on the autistic spectrum, I recently came across a super interesting study (for me) - by Henry Markram, Tania Rinaldi, and Kamila Markram from the Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Switzerland. This study, the "Intense World Syndrome" I feel describes my problems with unbelievable accuracy. I would very much like to have others opinions.
They are investigating "a potentially unifying hypothesis of autism in which a common molecular syndrome causes excessive neuronal information processing and storage in the microcircuits of the brain. Such excessive information handling is proposed to produce hyper-perception, hyper-attention, and hyper-memory, which could become the fundamental cognitive handicap in all cases of autism."
Lots of details here:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518049/
"Prometheus" asks:
"Why? As it turns out, rats have a hepatic tolerance of acetaminophen that is much greater than our own - why would we assume that their other tissues have an equally elevated tolerance (hint: it doesn't appear that they do)?"
Exactly, Prometheus. That was the whole point of the study...to determine what is happening to other cells in the body (in this case, brain cells) before hepatotoxicity occurs.
"Translation: This may be a false positive"
If mitochondrial disorders really are as rare as you've claimed, this would be some false positive!
Jen in TX (#84):
Jen in TX (#88):
Jen, you did see the comments that the LD50 in rats is about six times what it is in mice (and humans)? Did you understand why that was? Rats' hepatic metabolism of acetaminophen is different than ours (and that of mice), so they have less hepatotoxicity. However, as I mentioned above, it doesn't appear that their brains are any less sensitive to acetaminophen than ours (or mouse brains).
So, if you've followed me so far, you'll see that the blood concentrations of acetaminophen needed to cause apoptosis in rat neurons are so high that, in humans, any neuronal apoptosis would be "masked" by the acute liver failure.
Also, the fact that extremely high blood levels of acetaminophen can cause apoptosis of neurons doesn't mean that low levels (like those seen after normal acetaminophen doses) cause a low level of apoptosis - it's not necessarily a linear function. If there is any research showing that acetaminophen has linear-no-threshold toxicity, that would be big news! It would be big news because it would be the first "toxin" that has linear-no-threshold effects.
Of course, if it makes you happy to believe otherwise, don't let a few facts get in the way.
Cheers!
Prometheus
Jake Crosby (#89):
I don't believe that it was Orac who "claimed" that mitochondrial disorders were rare - the United Mitochondrial Disease Foundation "claims" that mitochondrial diseases affect about one in four thousand people. Researchers in mitochondrial disorders make similar "claims".
On the other hand, if 80% of autistic people have mitochondrial disorders, then the real prevalence of mitochondrial disorders (using the "old" 1 in 150 prevalence) would be 1 out of every 188 people (0.53%). That would be a pretty significant jump in mitochondrial disorder prevalence.
If you look at the logical consequences of the findings (i.e. that mitochondrial disorders would be over 20 times more common than they are), it becomes obvious that there is an error somewhere. Either researchers have missed over 95% of all patients with mitochondrial disorders or the CHARGE study is in error. They can't both be correct.
Prometheus
"So, if you've followed me so far, you'll see that the blood concentrations of acetaminophen needed to cause apoptosis in rat neurons are so high that, in humans, any neuronal apoptosis would be "masked" by the acute liver failure."
These concentrations are not "high" for rats. If they were, the liver would have been affected. These concentrations are high for humans. Rats are not humans. But you can't do a study like this in humans, so animals are as close as we can get. I agree that mice might have been a better choice, but that's an issue you'll have to take up with the authors of the study. I'm sure that they would appreciate your insights.
In other acetaminophen related news...
Prenatal Exposure to Acetaminophen Linked to Childhood Wheezing
Add that to the growing pile of evidence that supports my assertion that acetaminophen is the "scourge of the earth" as "Prometheus" so elegantly puts it.
Jen in TX, do you have a reference other than a link to Medscape? I prefer to read the original articles so I don't have a Medscape account. The only recent article I could find was in the journal Thorax and published in Feb 2010 is this the correct paper? Interestingly, I also found a paper in the International Journal of Epidemiology from June of 2009 finding no risk of adverse pregnancy outcomes associated with prenatal acetaminophen use. Additionally, a paper in Obstetrics and Gynecology from Dec 2009 found no increased risk of asthma in children due to prenatal acetaminophen use. How do you interpret these findings in light of your beliefs about acetaminophen?
-JP
I don't have the original article, sorry. It likely hasn't been released yet. I'll keep an eye out for it.
The June 2009 paper only looked at birth complications, such as pre-term birth, low birth weight, etc., not issues like asthma or other allergic disorders, although that paper did find a small association between hypertension and acetaminophen use in the third trimester, and their later worked confirmed that association. See PMID: 19929241
The Dec 2009 paper by Kang et al didn't address acetaminophen use during the second trimester at all. I'm not sure that I understand the point of doing a study on asthma and prenatal acetaminophen use if you're only going to address 2/3 of the pregnancy.
At any rate, the weight of the evidence points to an association between acetaminophen and asthma, at the very least.
Hi Prometheus -
I don't believe that it was Orac who "claimed" that mitochondrial disorders were rare - the United Mitochondrial Disease Foundation "claims" that mitochondrial diseases affect about one in four thousand people. Researchers in mitochondrial disorders make similar "claims".
Is it possible that there is a semantic problem in the distinction between mitochondrial disorder and mitochondrial dysfunction. IIRC, Giulivi only found 1 autism case that could be traditionally diagnosed with mitochondrial disorder. The rest, it would seem, showed biomarkers and/or mtDNA changes that may or may not be physiologically significant, but do not rise to the level that the child would be diagnosed as per UMDF. (?)
Maybe the problem is that there isn't a clearly defined distinction for dysfunction other than it seems abnormal compared to the other group. Are we looking at yet another apples to oranges comparison problem in the autism realm? [not another one!]
Considering a big part of the static rate of autism narrative involves the vast majority of people with autism in the past going undiagnosed, or misdiagnosed, I'm not sure we should express too much confusion at the idea that other disorders are also inappropriately categorized. And, of course, if autism and mitochondrial problems are causally associated, and the rates of these have actually been increasing, then our problems with these numbers aren't as worrisome; at least not in an effort to reconcile them together. [a big if]
- pD
As a mitochondrial researcher, I do have to chime in with the comment that mitochondrial dysfunctions are one of the unusual categories where the tissue being looked at is very important. Due to heteroplasmy, different tissues/cells can have widely varying levels of mutations or dysfuction in the mitochondria. There could be perfectly competent mitos in neurons, while particular blood cells might have higher levels of problematic mtDNA, for example. Or similar levels of mutations could exist in both cell types, but the threshold for pathological dysfunction could be wildly varying.
And personally, I really feel like much of the impact attributed to oxidative stress in many pathologies is a lot of handwaving.