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Sunday, 22 September 2013

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 90th 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.


 


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.

 
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.  

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. 


5 comments:

  1. hi, my sons Lab test shows Triiodothyronine-T3(low)0.770ng/ml(1.27-3.8ng/ml) T4 -(normal)7.08ug/dl(5.26-14.8ug/dl) TSH-(normal)2.23uiu/ml(0.7-5.0uiu/ml) shall i start giving thyroid medication?

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  2. Most thyroid medication is just T4. Most doctors do not believe they ever need to give T3, since the body is SUPPOSED to convert T4 to T3 all by it self. This would appear not to be working in your son. I would go and see an endocrinologist and ask about trying T3. It depends where you live, in the US it is easy to get T3, in Europe it is hardly ever prescribed.

    ReplyDelete
  3. Hypothyroidism impairs chloride homeostasis and onset
    of inhibitory neurotransmission in developing auditory
    brainstem and hippocampal neurons
    http://www.bauing.uni-kl.de/fileadmin/tierphys/publikationen/Friauf_et_al_EurJNeurosci_2008__13286_01.pdf

    Very relevant I think, especially regarding the Ben Ari and Lemmonier (sp?) stuff.
    And...
    http://www.ncbi.nlm.nih.gov/pubmed/10426574
    "In conclusion, nicotine increases D2 activity probably via nicotinic acetylcholine receptors, and may influence brain function, at least in part, by affecting thyroid hormone metabolism."
    My son (23, Asperger's Syndrome, dyslexia, dyspraxia) is just coming out of another catatonic episode (which has repeated almost exactly from last year at the same time, right down to cancelled holidays. It was preceded both times by tooth pain and visit to dentist. I think this is a marker for the GABA dysfunction starting vis: http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0704325/pdf
    GABA function in trigeminovascular nociceptive neurotransmission.

    I think you are very much on the right track with your research, we need a network of friendly gps to help run trials of diuretics and such

    kind regards
    janet

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    Replies
    1. All very interesting. It is hard to generalize since without any diagnostic tools it is very hard to know what dsyfunctions any person has.

      In your case if the visit to the dentist is the trigger, is it inflammation or what the dentist did that is the trigger? If it is the inflammation, it could even be some mitochondrial issue. If you thought that might be the case you may be able to prove it.

      Autism (or Asperger's) secondary to Mitochondrial Disease (AMD) has a therapy:-

      Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

      L-Carnitine 50 mg/kg/d Alpha Lipoic acid 10 mg/kg/d
      Coenzyme Q10 10 mg/kg/d Pantothenate 10 mg/kg/d
      Vitamin C 30 mg/kg/d Nicotinamide 7.5 mg/kg/d (optional)
      Vitamin E 25 IU/kg/d Thiamine 15 mg/kg/d (optional)


      Apparently some people respond very quickly to L-Carnitine. If they do then it is almost certain they have (AMD) any kind of inflammation would make AMD worse.

      I had one lady with Asperger's write to me telling me how well L-Carnitine worked for her. In my son L-Carnitine did nothing, so I guess his mitochondria are not affected.

      Nicotine patches are easy to try and can be cut into small pieces.

      GPs are not interested. My sister is a GP and said she would not prescribe anything to her patients. She suggested I write a case study for the BMJ (British Medical Journal). I did email the editor and ask if they were interested, as expected, she did not reply.

      I actually think Verapamil is the most potent element of my therapy. I keep finding new reasons why it could be effective. I think bumetanide will only help a sub-set of people with autism. I think Verapamil may help almost all of them.

      Delete
  4. There are other potential problems with other drugs including iron-containing vitamins http://www.dospalosradio.org

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