One of the theories that comes up again and again in the study of autistic spectrum disorders (and other chronic mental and physical disorders as well) is the theory that these disorders are a problem of too few antioxidants. Sounds simple, but as always, the biochemical processes can get complicated.  

When we burn fuel and various other biochemical things, we create toxic byproducts. These toxins can damage DNA and make systems inefficient and ragged, and call up our inflammatory army to clear the damage, which can cause its own problems. Since our body is a tiny little ecosystem, we have our own chemical clean-up crew that should be johnny-on-the-spot to sop up free radicals and other untoward elements.

We can measure how good our clean-up crew is in various ways, and a couple of very small studies have demonstrated that kids with autism don't seem to be very good at dispensing with toxins.  In this Egyptian paper (1), kids with autism have lower rates of superoxide dismutase and glutathione peroxidase than matched control children (this could mean they make less or are dealing with more oxidation than other kids, so the enzymes are used up faster). These two enzymes clean up superoxide and the resultant hydrogen peroxide, reducing them to less dangerous downstream products, cleaning up the body’s environment, as it were. I have also reviewed a study showing inefficient and dirty mitochondria in children with autism compared to controls.

(A free radical courtesy Flickr Creative Commons)  

Children under three not only grow at a rapid rate, they also seem to have naturally low glutathione levels, making them among those particularly vulnerable to oxidant injury (2). Glutathione is a major part of the body's detoxifying systems and is the major antioxidant in the body. Children who have genetic inefficiency in the antioxidant system will therefore be even more vulnerable. The brain, being a high energy and relatively delicate organ (the liver has an astonishing capacity to regenerate cells, whereas the brain has almost no capacity to regrow cells but can modulate connections to bypass injured systems to some extent) will be especially susceptible to oxidative damage.  

Another area vulnerable to lack of glutathione? Our delicate airways—one of the reasons perhaps some children eventually "grow out" of asthma. Once they get older, their glutathione levels become more robust, and oxidative damage stops in the airways, so decreased symptoms of asthma.

One scary fact to contemplate is that the commonly used over the counter painkiller, acetaminophen (brand name Tylenol), is well-known for rapidly depleting the body’s glutathione stores. I know. The link seems silly. Tylenol is for babies, right? Far safer than aspirin for fever, after all.  Pediatricians recommend acetaminophen (Tylenol) all the time. My point is that acetaminophen is known to gobble up glutathione like gangbusters, and some of us will be more vulnerable to this glutathione destruction than others.   

Let me not mislead you, for everything I am about to write about has not been proven in randomized controlled trials, but the biologic mechanisms make sense and the epidemiology matches. I would say most doctors will have a wrinkle-nosed reaction to acetomenophen, simply because if you overdose on the stuff, even in small amounts, you run the risk of dying a horrible death. Tylenol breaks down to NAPQI which breaks down the master antioxidant of the body, glutathione, in large amounts, and kills the liver and kidneys and brain and lungs. Fortunatlely the liver can usually repair itself at a rapid rate—what about the lungs? Or the brain? "Real" antioxidants are more than a vitamin pill. We need to make our own.

In autistic spectum disorders, there is an increased level of inflammation (2):  

There are an increasing number of reports that anomalies in the immune system may play a role in autism. This has been found at the molecular, pathological, and epidemiological level. Altered levels of immunoglobulins, cytokines and inflammatory markers have been identified in the serum, cerebral spinal fluid, and autopsy brain tissues of autistic patients. Gastrointestinal inflammation in autism as well as pathological evidence of neuroinflammation involving activation of brain microglia has been shown. An increase in head circumference in autistic children, a consistent finding in autism, may involve neuroinflammation.

In addition, the rise in childhood asthma does correlate with the disuse of aspirin (due to deadly Reyes syndrome) and increases in the use of Tylenol starting from the 1980s.  There is a compelling paper written by a pediatric pulmonologist in the December 2011 edition of Pediatrics discussing the relevant evidence linking acetaminophen use to childhood asthma.  As aspirin use can be deadly in children and ibuprofen might also be problematic for children with asthma, pain and fever control in asthmatic children can be a difficult situation that warrants a frank discussion with your pediatrician.  However, only one dose of acetaminophen per month in children over a year was associated with a 3-fold increase in risk of having asthma, and if the correlation is in fact causative, stopping the use of acetaminophen in pre-teens could cause a 40 percent reduction in asthma cases.

More interesting information (and a related blog post from some time ago):

Numerous studies have attempted to measure the prevalence of autism and asthma in the population. Both asthma and autism have had a similar apparent rise in the number of cases since approximately 1980, over the past 30 years, and in both disorders these have been repeatedly referred to as ‘‘epidemics”. In autism, this apparent rise in cases is highly controversial  and may be whole or in part due to increased disease awareness and/or expansion and reclassification of diagnostic criteria.

The following discussion is not intended to judge the validity of disease prevalence studies in asthma or autism; it is simply to point out interesting minor anomalies in those curves. In disease prevalence curves of both autism and asthma in the US, the sharp rise in cases began in approximately 1980. In the period from 1980 to 1990 there were two slight downturns in the slope of the curves, after 1982 and after 1986. Both curves continue markedly upward after 1988 into the 1990s. In addition, there are similar slight downturns in slopes of the curves at the same times from independent and geographically disparate studies in both asthma and autism including; asthma hospitalizations, autism cases in Minnesota, autism in north east London, and autism in an urban area in Sweden.

Four significant events related to acetaminophen use occurred between 1980 and 1990. The first was the CDC caution in 1980 concerning the relationship of aspirin to the risk of Reyes Syndrome which was followed by a public and professional warning by the United States Surgeon General regarding a possible Reyes Syndrome–aspirin association. These cautions against the use of aspirin as a fever reducer in children were largely responsible for the replacement of aspirin by acetaminophen as a pediatric antipyretic. In 1982 and again in 1986 there were product tampering cases where acetaminophen tablets were laced with cyanide resulting in eight deaths. Acetaminophen sales collapsed after each tampering event, but recovered in less than a year in each case. These dates roughly correspond to the slight downturns in asthma and autism cases.

Personally, I do not give my children acetaminophen and I do not take it myself, but in some cases acetaminophen may be a better choice considering the risks of aspirin (which can be deadly to children)  and NSAIDS (which can cause kidney and gut damage and may also worsen asthma).  The data I present here is definitely preliminary.  I would just caution parents not to be too free with Tylenol. I know that many parents pre-treat their children prior to immunizations, for example, and I think that is a bad idea. Exercise prudence. Fevers happen for a reason. Unless fever is dangerously high or pain is terribly uncomfortable and interfering with sleep, consider not treating it right away.

As for keeping you and your family's antioxidant system humming along nicely, cleaning up all the toxic byproducts of living? Turns out your micronutrient status is exceedingly important in establishing an amazing and efficicient antioxidant system. Copper and zinc need to be topped up in order to make plenty of superoxide dismutase, for example. Children need lots of healthy micronutrient rich whole foods (not processed stuff with spray-on vitamins).

You know who else tends to have a less efficient antioxidant-making system and lower amounts of glutathione? The elderly. It's interesting that the pathophysiology of autism and dementia seem to have some similarities—a similar puzzling and devastating process of inflammation and neuronal cell death occurring at entirely different developmental stages. Could these similarities be due to age-related issues with antioxidant systems? Plausible. Not certain.

These are all complex processes with many players, internal and external. That's why I don't think there is any "one" cause of the autism spectrum disorders (or the dementias, for that matter).  However, combine a genetic vulnerability, low zinc status, maybe some acetaminophen, and inflammatory insult, and ultimately there is a straw that breaks the camel's back.

The good news is that most of us are resilient and can handle a bit of acetaminophen here and a bit of red #5 there, and some of us sail through life smoking cigarettes and chomping on funky fries. The bad news is that some of us aren't as resilient, and one way or another we will all have to pay the piper.

Image Credit

Image Credit

Copyright Emily Deans, MD

Evolutionary Psychiatry

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