Oxidative Stress, Central Hypothyroidism, Autism and You

   Warsaw University of Life Sciences, Source: Wikipedia

Regular readers of this blog will have noticed there are some strange things going on related to endocrinology in the autistic brain; in effect there are low levels of certain critical hormones.

We saw in research from the Harvard Medical School that it seemed that oxidative stress in the brain affected the level of a key enzyme D2 (iodothyronine deiodinase type 2).  D2 has an important role; it converts the passive thyroid pro-hormone T4,  into the active thyroid hormone T3.  Without enough T3, you are said to be hypothyroid.  When the brain is affected, it is called central hypothyroidism.

As T3 is essential for cellular metabolism, growth and differentiation, and thus critical for brain development, thyroid deficiency during embryonic or early postnatal periods would likely lead to developmental abnormalities, including autism.

Now we have some follow up research from Harvard and Warsaw University.  The paper is more readable than many scientific papers, so click on the full version below.

DISRUPTED BRAIN THYROID HORMONE HOMEOSTASIS AND ALTERED THYROID HORMONE-DEPENDENT BRAIN GENE EXPRESSION IN AUTISM SPECTRUM DISORDERS

“While the mechanism responsible for the decrease in brain T3 levels in ASD is unclear, the relationship between T3 and Hg (mercury) should not be that easily dismissed.

Our recent animal study of perinatal mercury exposure in rats supports the possibility that the environmental toxicants can affect brain deiodinases and thus affect brain TH (thyroid hormone) status even in absence of systemic hormonal deregulation

Total Hg levels were determined in human postmortem cerebellar and brain stem samples derived from both male and female ASD cases. The results of this analysis, presented in Fig. 4 as the male and female combined data, indicate no significant difference in Hg levels between control and ASD cases in either the brainstem or the cerebellar samples.

Thus, changes in oxidative stress levels reported here could also modulate D2 activity. It is of interest that TH regulates GSH levels in the developing brain and treatment of astrocyte cultures with TH results in increased GSH levels and improved antioxidant defense, suggesting that TH plays a positive role in maintaining GSH homeostasis and protecting the brain from oxidative stress. Thus lower T3 levels in ASD brain may exacerbate the oxidative stress.

The results presented here suggest that putamen is the brain region that exhibits not only an increase in oxidative stress and a decrease in T3 levels, but also most prominent changes in gene expression in ASD. Interestingly, the putamen's main function is to regulate movements and influence reinforcement and implicit learning, processes that rely on interaction with the environment; abnormal sensory reactions are part of autistic pathology. Thus, present study further implicates this brain region in autistic pathology.

Decreased brain TH levels and changes in gene expression in ASD brains, suggested by the present study, are likely to impact the developing brain and have clinical implications. It has been previously observed that deficiency of T3 during early postnatal periods impacts basic stages of development i.e. neurogenesis, cell migration of, and synaptogenesis that could contribute to downstream functional and structural damages observed in ASD brains. At this point, because the instability of D2 in the postmortem tissue and lack of detectable D3 activity we can only speculate on the molecular mechanisms involved in decreased TH in ASD brains. However, present data suggest that the role of TH in ASD pathology should not be dismissed prematurely and certainly requires further study, especially since correction of TH deficiency may offer new therapies.

Our results showed, for the first time, brain region-specific decrease in TH levels in the cortical regions of ASD male cases. Data reported here, although derived from a limited sample size, suggest the possibility of brain region-specific disruption of TH homeostasis in autistic brain. Furthermore, brain region-specific changes in TH-dependent gene expression reported here suggest disruption of gene expression that could possibly impact the developing brain and contribute to the autistic pathology. While the postmortem instability of brain deiodinases precluded further molecular studies, the role of TH in ASD pathology and TH-based new therapies warrant future studies.

The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism. “

Conclusion

We know that T3 is reduced in the autistic brain.  This may be because oxidative stress has reduced the level of the enzyme D2, but we cannot be sure, because the brain samples are old and D2 will decay with time.

The authors clearly hope that thyroid hormone-based therapies for autism will emerge.  Autistic people are likely to be euthyroid, so in their blood the thyroid levels are just fine; it is just in the brain the level of T3 is low. A successful therapy would raise the level of T3 in the brain, without affecting the level of T3 in the blood.

Reducing oxidative stress (if present) can only do good.  This is easily done with N-acetylcysteine (NAC).  If giving NAC reduces stimming/stereotypy, then the odds are that you have oxidative stress.  Oxidative stress appears to be chronic, it never goes away; you can treat it, but you cannot cure it.  We also saw this is the asthma research, where smokers were resistant to asthma drugs.  Even decades after ceasing to smoke, oxidative stress lingered and reduced the effectiveness of drugs.  In asthma the treatment for oxidative stress is NAC.

If you want a diagnostic test to establish central hypothyroidism (without any injections), this is easy.  Just give a small dose of T3 for a few days.  Before the thyroid has time to reduce its natural thyroid output, there will be a temporary increase in brain T3 levels.  If behavior improves notably for a day or two and then reverts, you have established a case of central hypothyroidism and seen how it affects behavior.

The scientific method of determining central hypothyroidism uses a test called the TRH stimulation test; but you do not get to see how behavior changes when T3 increases in the brain.

Also, note again that while mercury is definitely very bad for you, the study showed that the brains of people with autism had no more mercury than the control group.

We also see that while oxidative stress may cause a reduction in brain T3 levels, low T3 levels promote further oxidative stress.  So it is a self-perpetuating process.  This brings us back again to my venn diagram, where everything is inter-related. 

Autism Phenotypes

Hardly a week goes by without somebody mentioning to me a wonder treatment or even “cure” for autism; the latest one being the GAPS diet.

I think all such reports are worthy of investigation, but many lead to nowhere.

Why is this?




  

·       Medical science has failed to adequately define autism, so we are not all talking about the same autism

·        Many people putting forward theories have not read even the most basic (and not contested) autism research.  Some are even, apparently, qualified “doctors”.
 

Autism Phenotypes

What is not disputed is that autism has many sub-types (phenotypes). Researchers tell us 10-20% of cases referred to as autism have a known genetic defect (Fragile X, SLOS, Timothy syndrome etc.).  80% do not have a known genetic marker/cause.

Autism can be subdivided into regressive (when a child loses speech and other learnt skills) and non-regressive (early onset).  Even this can be a subjective judgment, since it effectively relies on parents to determine it, after the event.

Then you have cases of autism which clearly have nothing to do with Kanner’s classic version.  In this blog I showed how even cerebral malaria in a child can lead to the onset of autism.  This clearly is a case of brain damage caused by malaria; but to the observer, months later, it would probably be classed as regressive autism or childhood disintegrative disorder.

 

Testing for Autism

Researchers and doctors keep repeating that there is no test for autism.  This is not strictly true, but it does explain why so many different conditions are all lumped together as “autism”.

In fact, if you read the research closely, you will see that there are many tests for autism; although they may not be perfect.

The only way to know for sure that it is genuine autism is to examine the brain itself.  The only way to do this 100% accurately is via post-mortem analysis of the brain.  Recently, non-invasive methods have been developed to confirm the same findings of brain malformation that occurred prior to birth.

So the kind of autism that relates to tissue held in brain banks is best understood.  But what kind of autism would that be?  Well, it refers mainly to children and young adults who died prematurely.  They died from things like seizures or drowning.  What does that tell us?  This tells us that these people were most likely severely affected by autism.  The mild, social difficulties, type of autism is, fortunately, hardly likely to make it to the brain tissue bank.

If the person interpreting the MRI of a child’s brain knows what to look for, they may very well be able to identify this type of autism.  The expert here is Eric Courchesne.

A similar approach can followed using Electroencephalography (EEG) to identify autism; but it would be smart to cross check this with Eric.

Regressive vs. Early-Onset

Then you have the difference between regressive and non-regressive autism.  Here again, from my Dean’s List of researchers, we look at Paul Ashwood’s research to see that kids with regressive autism have HIGHER levels of inflammatory markers in their blood.  These include cytokines like interleukin 6, which can be inexpensively measured in most laboratories.  This tells us that perhaps regressive autism is an entirely different condition from non-regressive/early onset autism.  As I would expect, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. 

Elevated plasma cytokines in autism spectrum disorders provide evidenceof immune dysfunction and are associated with impaired behavioral outcome

 

Lab Testing

We have seen earlier in this blog that some very expensive lab tests exist for autism, but their usefulness and integrity is highly disputed.  There are, of course, many hundreds of other tests that are entirely validated by medical science.  Many of these tests are cheap and available all over the world.

Hormonal Screening

We know from the research that about 30% of people with autism have high blood serotonin. A standard lab test is required.

We know that many have high levels of insulin-like growth factor (IGF-1).  A standard lab test is required.

Thyroid hormone levels and in particular a blunted response of TSH to TRH (i.e. central hypothyroidism) can help define further phenotypes.

The TRH test is now not widely used, but TSH, FT3 and FT4 are cheap tests.

Growth Hormone (GH) is also implicated in autism, along with IGF-1; there is a lab test to measure pituitaryfunction to see how well GH is being produced.

By screening for hormonal dysfunction, it would be possible to identify phenotypes that would most likely benefit from therapies targeting those defects, like NNZ-25266.

Pancreatic Dysfunction

It is reported by Joan Fallon, of Curemark, that 50+% of kids diagnosed with “US autism” seem to have a pancreatic dysfunction.  This can be tested for by measuring fecal chymotrypsin level.  The test measures how well your pancreas is working, and is a standard test for people with cystic fibrosis.  Since the US diagnoses far more kids with autism than other countries, it seems highly plausible that “US autism” includes many more phenotypes than, say, “French autism”.

I was quoted about $8 for a chymotrypsin test.

Ion-Channel Diseases (Channelopathies)

Many diseases like Parkinson’s disease, Spinocerebellar Ataxia and Timothy Syndrome are caused by faulty calcium ion-channels.

The Bumetanide autism therapy, undergoing trials in Europe, is based on another channelopathy, this time a faulty chloride transporter NKCC1.

It is clear from reports I have received, that Bumetanide therapy is totally ineffective in some children with ASD, but in other children, like my son, it is effective.

So some types of autism have certain channelopathies and other types have different ones or, quite possibly, none at all.  

Conclusion

My conclusion today is pure conjecture.  I imagine that possibly as few as a quarter of cases of “US autism” are actually “real” autism, that is with all the brain damage/malformation that is identified in those post mortem brain studies and which forms the basis of 90% of autism research.

The other three quarters may be something entirely different, just like the case of the mosquito that bit the child, produced cerebral malaria and then later the full symptoms of autism.  Within the three quarters may be food allergies, digestive enzyme deficiencies, gut disorders, mastocytosis, blood brain barrier defects, undefined calcium ion-channel diseases etc.

This would account for those occasional amazing “recoveries” and the apparent success, in some cases, of diets like GAPS.  Sadly, diet is unlikely to 100% fix brain damage.  If you are lucky enough to totally “recover”, you cannot have had brain damage in the first place.  It is evident that in some phenotypes of autism, diet can reduce autistic behaviours.  This can only be proved in trials, if biomarkers are established for that specific phenotype.

Most likely the only biological thing all these “autisms” have in common is oxidative stress and neuroinflammation; but only a non-medical scientist, like me, can say such a thing.

 

 

Central Hypothyroidism or Low Brain D2 Levels in Autism

I am returning to an old theme of mine, which is my hypothesis that the thyroid releasing hormone (TRH) may be of therapeutic value in autism.  I have been reading up on what some endocrinologists are doing the US and also looking a bit deeper into the underlying biology of the related hormones and thinking about my research sample of one, Monty aged 10 with ASD.   My original hypothesis was argued in an earlier post.

The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism

Since none of the TRH researchers care to reply to my emails, I decided to refine and document my hypothesis further and then plan to go and see a child endocrinologist for myself.  In most countries, the doctor does the talking and the patient does the listening, so I know that I need something unusual; I called it “an open minded endocrinologist”.

Peter’s TRH & Central Hypothyroidism Theory

Research has documented which parts of the autistic brain are often damaged.  The Purkinje cell layer and the cerebellum in general has been a focus of my blog; but the hypothalamus, which is very close by, is also known to be different in autistic people.   It has been shown that diminished grey matter exists in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin.  My pet hormone “TRH” is also produced in the hypothalamus.  The pituitary gland is a protrusion off the bottom of the hypothalamus at the base of the brain. The pituitary gland is functionally connected to the hypothalamus via a small tube called the pituitary stalk. The pituitary gland secretes nine hormones that regulate homeostatis; one of these is TSH (thyroid stimulating hormone). 

In summary, TRH from the damaged hypothalamus travels down to the pituitary gland where it triggers the release of TSH.  TSH travels a bit further to the thyroid gland where two important hormones, T3 and T4, are produced.

When the levels of T3 and T4 are low a condition called hypothyroidism exists.  T4 is a so-called pro hormone of T3.

I have already noted that when Monty was a young toddler he was tall for his age, about the 90^th percentile; aged 10 his is now about the 25% percentile.  When I started this blog, I saw in the old autism literature there are lots of studies about head circumference in autism.  In summary they found that in autism the head (and by inference the brain) grows very fast in the first couple of years and then by 3 or 4 years of age the brain has prematurely reached adult size.  The brain grew faster than normal and certain parts developed abnormally.  I did not see any research into abnormal development in height.  It would be very easy to study this, since in most countries a child’s height is regularly recorded.

When I recently checked to see what are the effects of hypothyroidism in typical children, I found interesting reading:-

Effects of Hypothyroidism During Infancy. Transient hypothyroidism is common among premature infants. Although temporary, severe cases can cause difficulties in neurologic and mental development.

Infants born with permanent congenital (inborn) hypothyroidism need to receive treatment as soon as possible after birth to prevent mental retardation, stunted growth, and other aspects of abnormal development (a syndrome referred to as cretinism). Untreated infants can lose up to three to five IQ points per month during the first year. An early start of lifelong treatment avoids or minimizes this damage. Even with early treatment, however, mild problems in memory, attention, and mental processing may persist into adolescence and adulthood.

Effects of Childhood-Onset Hypothyroidism. If hypothyroidism develops in children older than 2 years, mental retardation is not a danger, but physical growth may be slowed and new teeth delayed. If treatment is delayed, adult growth could be affected. Even with treatment, some children with severe hypothyroidism may have attention problems and hyperactivity.

Hypothyroidism is usually caused by a failure of the thyroid gland.  TRH is being released to the pituitary, which the produces TSH.  The problem is in the thyroid.  The cure is usually to give T4 in tablet form.  The body is usually able to produce T3 from the T4.

Role of D2 and D3 & Oxidative Stress

Both T3 and T4, are produced in the thyroid gland. The ratio of T3 to T4 released into the blood is 1:20.  Both T3 and T4 then reach the individual body organs, where the prohormone T4 is converted to the biologically active hormone T3. The organ/tissue levels of T3 are regulated locally primarily by the activity of two different selenoenzymes, deiodinases type 2 (D2) and type 3 (D3), although deiodinase type 1 is also involved. In the CNS, approximately 70-80% of T3 originates from intracerebral T4 to T3 conversion, while the plasma contribution amounts to 20-30 %  and D2 is responsible for most of the T3 supply within the brain.

The major source of the biologically active hormone T3 in the brain is the local intra-brain conversion of T4 to T3, while a small fraction comes from circulating T3.

As evidence derived from in vitro studies suggests, in response to oxidative stress D3 increases while D2 decreases (Lamirand et al., 2008; Freitas et al., 2010).  As we know in the autistic brain we have a lot of oxidative stress.

Furthermore, in ASD, the lower intra-brain T3 levels occur in the

Absence of a systemic T3 deficiency (Davis et al., 2008), most likely due to the increased activity of D3.

 

Central Hypothyroidism

There is a supposedly rare condition called Central Hypothyroidism, which occurs when the pituitary gland does not produce enough TSH in response to TRH.  In the research jargon they call it “a blunted response”.  Note that blood levels of TSH, T3 and T4 can be normal in cases of central hypothyroidism.

Research has long ago shown that in autistic children often have a blunted response of TSH to TRH.  Interestingly in many psychiatric conditions, like depression, research also shows a blunted response.

Reduced thyroid-stimulating hormone response to thyrotropin-releasing hormone in autistic boys.

 

The Blunted TSH Responseto TRH — What Does It Tell Us? Biological Monitoring During Psychopharmacological Treatment

Panic, suicide, and agitation: independent correlates of the TSH response to TRH in depression

In the US, psychiatrist have longed prescribed the hormone T3 for depression.  I cannot find much in the way of explanation by psychiatrists of this, other than that some endochronologists do not seem to approve.

In theory if you are low on T3 and T4, the therapy is to give just T4. But as we learned above, if D2 and D3 are misbehaving T3 will not be produced as required.

In the “rare” cases of central hypothyroidism the researchers report being able to correct T4 quite easily but not T3.  So their bodies are not converting enough T4 into T3, because D2 and D3 levels are out of balance.

So the Peter theory has to evolve

In autism there is very likely to be central hypothyroidism, a deficiency of D2 in the brain causes low T3 and I conjecture that there is also a reduced level of TRH being produced in the hypothalamus.  Both the hypothalamus and the pituitary gland are under-responsive.  As a result many hormones are going to be reduced including TRH, TSH, oxytocin, arginine vasopressin and others.

Because TRH also has secondary, only recently understood, behavioral effects, the central hypothyrodism symptoms fits nicely with my earlier TRH theory.

In the US some “holistic” doctors specialized in autism have long been claiming that the majority of kids with ASD are hypothyroid.  They claim that the modern T3 and T4 blood tests are “inaccurate” and that the old TRH stimulation test is more “accurate”.  They then end up prescribing supplementary T3 and T4.  This always looked odd to me; in fact it is yet another case of getting the right answer, but for the wrong reason.

The perfect solution might have been just to give TRH.  You cannot do this because the half-life of TRH is just a few minutes and it needs to be delivered into a vein.   A nasal TRH spray is being developed with funding from the US military.  TRH has mood changing properties and the military has a big problem with suicide.

My idea of using a TRH analog, such as Taltirelin Hydrate, is practical since it has a long half-life and can be taken orally.  It is licensed as a drug, but only in Japan.  It also has a reduced effect on TSH, so you get the benefit of the behavioural properties of TRH rather than just producing more TSH.  This avoids the patient then going hyperthyroid.

A word from the Harvard Medical School

After interest in the 1970s researching autism and the thyroid, not much has been written for decades.  Recently a paper was published by researchers at the Harvard Medical School showing how oxidative stress in the brain, if present, would disrupt thyroid hormone homeostatis.  It has been a long time coming, but it looks like their thinking is spot on.

Environmentally Induced Oxidative Stress and Disruption of Brain Thyroid Hormone Homeostasis in Autism Spectrum Disorders

 

According to this hypothesis, brain region-specific oxidative stress in autism may be associated with increased D3 and decreased D2 activity resulting in a region-specific T3 deficiency in the brain. Future human studies utilizing the CSF of living ASD individuals or postmortem brain tissue of ASD donors will support its validity. Such findings would have several significant implications. They may result in methods of early ASD diagnosis; detection of high brain D3 levels in postmortem human brains may suggest the benefits of measuring the levels of its product (rT3) in the CSF of living patients to assess the risks, monitor the disease progression and efficacy of ongoing treatment. Furthermore, several tissue-specific and TH receptor (TR)-specific thyromimetics have been developed as potential treatment for atherosclerosis, obesity and Type 2 diabetes and might be able to correct local brain TH deficiency without systemic thyrotoxicity (Baxter and Webb, 2009) and may thus be considered as potential therapeutic agents. Finally, confirmation that autism may be associated with increased D3 and decreased D2 activity resulting in a region specific T3 deficiency in the brain could lead to or reinforce dietary treatments, because D2 activity can be modulated not only by selenium but also by xenobiotic compounds (da-Silva

et al., 2007). In conclusion, TH abnormalities in autism warrant a second look.

This paper from Harvard is encouraging and not only concludes that thyroid abnormalities in autism warrant a second look, but suggests ways to raise the level of D2 and correct local brain hypothyroidism

The xenobioyic compound they refer to is the flavonoid kaempferol.

The flavonoid kaempferol looks interesting and there is also much written about its anti-diabetic effects.  This would be a way to raise the amount of D2 and consequently T3 in the brain.  This might be more effective that just supplementing T3.

By the way, just look at all the other things claimed of this flavonoid:-

Numerous preclinical studies have shown kaempferol and some glycosides of kaempferol have a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anticancer, cardioprotective, neuroprotective, antidiabetic, antiosteoporotic, estrogenic/antiestrogenic, anxiolytic, analgesic, and antiallergic activities.

Kaempferol consumption is also correlated with a reduced lung cancer incidence.

Kaempferol may be a potent prophylactic against NOX-mediated neurodegeneration

If you like natural cures, you will like this paper.  Take a look at page 28.  

A Review on the Dietary Flavonoid Kaempferol

As with other flavonoids, there is low bioavailability – they are absorbed by the body in tiny quantities.  And they are VERY expensive.

 

Conclusion

I wish the Harvard Medical School would follow up fast on its own research, so I do not have to rely on the internet writings of “holistic” doctors.  As the Harvard paper concluded “TH abnormalities in autism warrant a second look”.

Oral T3 clearly does enter the brain in marked quantities, otherwise I suppose US psychiatrists would not keep using it with their depressed patients.  Research shows that most T3 in the brain originates from T4 converted there by D2.  This implies to me that an alternative therapy would be to give something like kaempferol to raise the level of D2.  The problem, as with other useful flavonoids, like Quercetin and Rutin, is low bioavailability – they are absorbed by the body in tiny quantities.  Kaempferol appears to have the basis of being a wonder drug, but let's wait 20 years to see.

In the meantime, I will review all this with my sought for “open minded endochronologist”.  All I can measure is TSH, T3 and T4 in the blood, I cannot even guess at T3 or D2 in the brain.  The old TRH stimulation test involves lots of needles and that is something I have to try and avoid.  Autistic kids don’t sit still for needles.