What does Cancer Risk and Autism tell us?

Today’s post is a short one.

As you look deeper into how the body functions you come across many, only recently understood, pathways.  In reality these are still “works in progress”, but some will eventually lead to a better understanding of diseases like cancer, diabetes, Parkinson’s, Alzheimer’s and, eventually, many types of autism.

Within this blog we have seen how many common diseases share some underpinnings with autism.  As a result these diseases appear more commonly in people with autism, and so they get called comorbidities.

Some comorbidities get talked about quite a lot, things like epilepsy and MR/intellectual impairment.

For me the really interesting ones and the ones that might actual lead you to some therapeutic implication.  In this respect, allergies (food and airborne) have proved to be the most useful.

Not far behind are heart disease, diabetes and cancer.

In Paul Whiteley’s blog he recently highlighted a study showing how heart disease was increased in autism.  This has been noted before and I believe leads back to calcium channels, known to be dysfunctional in autism.  One particular channel is called Cav1.2 and it is widely expressed in the brain and the heart.  In earlier posts I have covered this channelopathy from the point of view of autism.  Not surprisingly, if you have Cav1.2 dysfunction in the brain, it might very well occur elsewhere.

There are little genetic errors called Single Nucleotide Polymorphisms, or SNPs.  In the CACNA1C gene there are 12,932 known SNPs.  Some of the most common ones are associated with autism, bipolar and schizophrenia.

You can look up this gene, or any other one, and see for yourself.

Genecards database

If you read the gene description above, the idea that heart disease is comorbid with autism is no surprise. 

The lower red arrow points at hypokalemic periodic paralysis.  This has appeared many times on this blog, along with Hypokalemic Sensory Overload.  I discovered long ago that there is a potassium ion channel dysfunction in autism; it appears to be behind the odd sensory overload experienced by many with autism and also in some people with ADHD.  What is interesting is that this dysfunction co-occurs with CACNA1C dysfunctions.

Cancer and Autism

The science behind cancer is complex and so as not to research it in vain, it is useful to know that there is solid evidence linking autism and cancer.

The following study of 8,438 people with autism, compared their incidence of cancer with the incidence in the general population

To understand the jargon first read this excerpt from a fact sheet on cancer statistics:

Fact Sheet: Explanation of Standardized Incidence Ratios

How an SIR Is Calculated

The expected number is calculated by multiplying each age-specific cancer incidence rate of the reference population by each age-specific population of the community in question and then adding up the results. If the observed number of cancer cases equals the expected number, the SIR is 1. If more cases are observed than expected, the SIR is greater than 1. If fewer cases are observed than expected, the SIR is less than 1.

Examples:

60 observed cases / 30 expected cases: the SIR is 60/30 = 2.0

Since 2.0 is 100% greater than 1.0, the SIR indicates an excess of 100%.

45 observed cases / 30 expected cases: the SIR is 45/30 = 1.5

Since 1.5 is 50% greater than 1.0, the SIR indicates an excess of 50%.

30 observed cases / 30 expected cases: the SIR is 30/30 = 1.0

A SIR of 1 would indicate no increase or decrease.

Here is the autism study:-

Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder

Objectives

To investigate whether individuals with autism have an increased risk for cancer relative to the general population.

Study design

We enrolled patients with autistic disorder from the Taiwan National Health Insurance database in years 1997-2011. A total of 8438 patients diagnosed with autism were retrieved from the Registry for Catastrophic Illness Patients database. The diagnosis of cancers was also based on the certificate of catastrophic illness, which requires histological confirmation. The risk of cancer among the autism cohort was determined with a standardized incidence ratio (SIR).

Results

During the observation period, cancer occurred in 20 individuals with autism, which was significantly higher than a total number of expected cancers with a SIR estimate of 1.94 (95% CI 1.18-2.99). The number of cancer in males was greater than the expected number with a SIR of 1.95 (1.11-3.16), but no excess risk was found for females with a SIR of 1.91 (0.52-4.88). Cancer developed more than expected in individuals age 15-19 years with the SIR of 3.58 (1.44-7.38), but did not differ in other age range groups. The number of cancers of genitourinary system was significantly in excess of the expected number (SIR 4.15; 95% CI 1.13-10.65), and increased risk was found in ovarian cancer with SIR of 9.21 (1.12-33.29).

Conclusions

Our study demonstrated that patients with autistic disorder have an increased risk of cancer.

So, overall, the risk of all cancers is about twice as high if you have autism.  

Certain cancers are particularly high risk and understanding why this is the case might lead to a better understanding of the “pathways” leading to some types of autism. Due to the rarity of some cancers, like ovarian, one might need to validate the result; note the (1.12-33.29) range for ovarian cancer.

Rather than worry about this risk, we should use these observations to understand and treat autism.

Just as we can counter the elevated risk of heart disease we can do the same for cancer.

Clearly the cancer pathways that will soon be appearing in this blog are relevant to autism.  But in the meantime anyone can reduce their cancer risk by ensuring a high level of antioxidants in their body.  People at higher risk are those with low levels of antioxidants, which include almost all older people and people of all ages with autism.

A vast wealth of information already exists showing the chemo-protective effect of antioxidants.  Cancer clearly generally results from multiple hits, and you may be unlucky to have a single gene that “ups” your risk.  By upping your antioxidant intake you can slash one risk, in this multiple step process.

It does not seem to matter which potent antioxidant you take, but you do need enough of it.  They are all slightly different and most likely a mix of several will yield the best result.

My current favourites are:-

·        NAC (N-acetyl cysteine)

·        ALA (Alpha lipoic acid) - Nrf2 activator

·        Sulforaphane – Nrf2 activator

·        Cocoa Flavanols

·        Lycopene (cooked tomato)

These should reduce both the risk of cancer risk and heart disease.

Other antioxidants mentioned in this blog include:-

·        L-Carnosine

·        Silibinin – Nrf2 activator

·        Selenium

One should be aware that avoiding cancer and treating an existing cancer are different tasks.  Once a cancer has developed, some antioxidants can interfere with the body’s own response mechanism.

My focus is preventative “medicine”.

We saw in an earlier post how children at risk of developing asthma could be identified by their atopic dermatitis.  By treating these children with a cheap mast cell stabilizer called Ketotifen, a trial showed how it was possible to avoid the onset of asthma.

I suspect that the same thing might be possible with epilepsy.  We saw in an earlier post that the first epileptic attack make a (epigenetic?) change, and thereafter there is a greatly increased risk of future seizures.

Other interesting preventative interventions, include statins to avoid Parkinson’s disease and Verapamil to avoid the onset of Type II diabetes.

I did explain all this to the European Medicines Agency some months ago, the idea of treating the comorbidities of autism BEFORE they occur.  Perhaps an idea before its time?

Asthma-Autism Hypothesis and Immunomodulatory Therapy for Autism

You may be aware that about a third of people with autism also have asthma; this is not a coincidence, just as the finding that autistic people have elevated cholesterol was not a coincidence. 

Since Monty, aged 10,  has both autism and asthma, I have had to become informed on both conditions.  Having now read the research on both autism and asthma, it is somewhat shocking that there are so  many parallels.  I would now go so far as to make my own hypothesis:-

The causes of Autism and Asthma are overlapping; so much so, that some drug treatments for the core symptoms of one may be effective in the other.

This may sound a strange, even bizarre proposition, but I will show that it is at worst plausible and at best proven.  Note that it was the observation that bumetanide was an effective treatment in neonatal non-convulsive seizures ,that led to the idea of trialling that drug on autistic children.  Many children with autism subsequently develop epilepsy or other forms of seizure.  So investigating the so-called comorbidities is not such a novel idea.
 

Drugs effective in both Asthma & Autism

·         NAC (N-acetyl cysteine) – reduces oxidative stress

·         Prednisone – powerful steroid for short term use to supress immune system

·         Statins – reduce neuroinflammation

·         Ketotifen – mast cell stabilizer and anti-histamine

In case you are not familiar with asthma, there are some remarkable similarities between asthma and autism, just take a look:-

·         Both affects boys much more than girls

·         Both involve neuroinflammation

·         Both are linked to defects in the auto-immune system

·         Exact cause of both is not known, but is seen as a combination of genetic and environmental factors

·         Both were thought of as a psychological disorders and were unsuccessfully treated as such

·         Both are usually lifelong conditions, though functional recovery is much more common with asthma than autism, often occurring after puberty with asthma

·         In recent decades there has been an “epidemic” increase in prevalence of both. 

Asthma is much more prevalent among those with autism the general population and is frequently cited as a comorbidity, along with epilepsy and GI disorders.

Left untreated, asthma can easily be fatal, so it has been well studied and numerous drugs have been specially developed.  I thought that perhaps there are insights for autism to be gained by looking at how asthma is treated;   indeed there are.

Asthma Prevalence

There is a lot of research into the prevalence of asthma.  After increasing for several decades, there are some reports of it plateauing or even declining.

Is the prevalence of asthma declining? Systematic review of epidemiological studies

 

It is generally accepted that asthma is a disease of the developed world and the apparently the English-speaking world in particular.

Asthma Statistics

The American Academy of Allergy Asthma & Immunology (AAAAI) has an eye-opening summary of asthma statistics showing:-

·         The prevalence of asthma in different countries varies widely, but the disparity is narrowing due to rising prevalence in low and middle income countries and plateauing in high income countries.

·         An estimated 300 million people worldwide suffer from asthma, with 250,000 annual deaths attributed to the disease.

·         It is estimated that the number of people with asthma will grow by more than 100 million by 2025.

·         Workplace conditions, such as exposure to fumes, gases or dust, are responsible for 11% of asthma cases worldwide.

·          About 70% of asthmatics also have allergies.

·         Approximately 250,000 people die prematurely each year from asthma. Almost all of these deaths are avoidable.

·         Occupational asthma contributes significantly to the global burden of asthma, since the condition accounts for approximately 15% of asthma amongst adults.
 

Asthma Treatment

To learn more about asthma and how it is treated the University of Maryland have a helpful summary, just click the link.

There are generally three lines of treatment.  The well-known first line of treatment is the “rescue” inhaler that children are seen with at school, this is to treat acute attacks.  These are bronchodilators, like Ventolin, that open the airways in moderate to severe attacks.

If acute attacks become frequent, then typically an anti-inflammatory steroid inhaler is prescribed.  Long-term control medications are essential to minimize long-term damage of the inflammatory response, to reduce the risk of serious exacerbations.  This is used daily in the hope of preventing future attacks.

In case of an acute attack that does not respond to the rescue inhaler, an oral corticosteroid can be given .  These are powerful drugs that because they are administered orally will affect the whole body;  the steroid inhaler substantially avoids this drawback.  The corticosteroid  works by deactivating the immune system.
 

There are many other therapies used by allergists, in particular the use mast cell stabilizers and anti-histamine drugs.

Ketotifen

Ketotifen is mast cell stabilizer, which means it blocks mast cells from releasing histamine it is also an H1 antagonist, which means it blocks H1 histamine receptors.  It is primarily used as a long term treatment of asthma.  It will not stop an acute asthma attack, but it should reduce their frequency.  If given to high risk children, its use can avoid the initial onset of asthma.

Prevention of asthma by Ketotifenin infants with atopic dermatitis.

It is used in irritable bowel syndrome and it is by DAN doctors to treat GI problems in autism.  If have read about mast cells and Dr Theoharides, then you can see how mast cells may play a key role in autistic behaviour and as such Ketotifen could be a prime therapy.

Autism and the auto immune system

There is a substantial body of opinion that autism is itself a disease linked to the auto immune system, like asthma and indeed type 1 diabetes.  The over active immune system is destroying certain important body functions.

The logical conclusion would be to find a way to down rate the immune system so that the unwanted affects were minimized, without leaving the body open to attack.  This strategy is indeed followed in asthma therapy where the emergency treatment is oral corticosteroid Prednisone

If all this sounds familiar, it should do.  The hygiene hypothesis has also been used to  link asthma, autism and the overactive immune response. 

In the case of autism at least one therapy is also based on this approach.

There is the case of Stewart Johnson in America, who trawled through the research looking for ways to help his autistic son.  He became convinced that the immune system was the key and looked into ways to down rate it.  He came upon the idea of using the TSO parasitic worms.  These parasites live in pigs(?) and in order to preserve themselves they evolved a method of reducing the immune system of their host so that they would not be expelled.  Treatment with such worms has been tried with other conditions, such as Crohn’s disease.  Mr Johnson ordered some TSO from Germany and fed them to his son.  He found that initially there was no impact on his son’s autism, but when he increased the dose there was a marked reduction in autistic behaviours.

Every couple of weeks or so, he gave his son another dose of TSO.

A clinical trial is being carried out at the Albert Einstein medical school to test the effectiveness of the treatment.  Mr Johnson created a website to document his experiences.  

It appears that not all people with autism respond to TSO; perhaps this is not surprising, not all people with autism have asthma either.

Perhaps Mr Johnson should see if a mild dose of Prednisone has the same effect as the worms?

Prednisone & Autism

It turns out that some doctors have indeed been prescribing prednisone for autism.  Most are DAN doctors, but not all.

You will even see on autism forums that when kids were given prednisone for their asthma, they suddenly had a big improvement in their autism.

http://www.autismweb.com/forum/viewtopic.php?p=109879

http://www.autismweb.com/forum/viewtopic.php?f=4&t=30238

While extended use of steroids causes side effects, it seems some doctors used them to try to proactively reverse regressive autism and to get non-verbal kids to speak.  This would seem entirely logical.

Immunomodulatory Therapy in Autism

An truly excellent review paper of Immunotherapy in Autism has been written by Dr Michael Chez, a respected mainstream specialist from Sacramento.  He also seems to be endorsing the use of the prednisone steroid in autism therapy

Immune Therapy in Autism: Historical Experience and Future Directions with immunomodulatory Therapy

 Here are two important paragraphs:-

Experience with EEG abnormalities and autistic regression cases that respond to steroids have been described in various case reports. Treatment was usually prescribed with daily prednisone doses of 2 mg/kg/day for 3 to 6 months. Limitations to therapy were usually Cushingoid side effects. As in other chronic conditions requiring steroids, pulse dosing was tried with steroids in the form of prednisone or prednisolone at 5 to 10 mg/kg twice per week. Long-term success with no dependence or minimal Cushingoid effects has been noted in several hundred patients treated in this manner.

 

In summary, among the current studies of immune targeted therapies, the most collective data on steroid effects on autism is probably the largest. Clear clinical improvements are consistent between different groups that had peer-reviewed assessments. In addition, all reported similar outcomes and side effects were made with the use of steroids. As in IVIG treatment, there has been no report of cure or elimination of all autism features. In the majority of cases, steroid effects did not permanently alter an autism diagnosis in these patients. Clinical concerns about steroid dependency and side effects, such as Cushingoid or long-term, well-known steroid effects have limited more randomized or controlled studies of steroid medications in autism. This is unfortunate, as there may be a potential for significant improvement from steroid treatment on cytokine and chronic immune dysregulation in autism.

Oxidative Stress, Nitrative Stress and Inflammation in Asthma

Much has been written about oxidative stress and inflammation in autism, well it turns out these are key issues in asthma.  In asthma, fortunately, they have been looked into very seriously and all is well documented.

Another superb paper, this time by Professor Peter Barnes, from Imperial College in London is:- 

Histone acetylation and deacetylation: importance in inflammatory lung diseases

 This paper should be read from cover to cover, it is full of interesting information.  For example cigarette smoking in asthma causes oxidative stress.  That stress continues even after the patient has given up smoking, so it is chronic.  To treat this oxidative stress, guess what? He uses NAC just like I using for oxidative stress in my son’s autism.

Also, oxidative Stress causes steroid resistance, so steroids that work in asthma do not work well in COPD.

Cytokines in asthma

Because asthma affects so many people and can be fatal, there is a considerable research effort and drug pipeline.

Cytokines play a key role in all inflammation.  The keys ones have been identified in both autism and asthma; the difference is that in asthma they are being studied in great detail.

Also several cytokine modulators are in various stages of development, but tested on asthma sufferers.
 

For the scientists among you, this subject is covered in depth by Professor Barnes, from Imperial College.

The cytokine network in asthma and chronic obstructive pulmonary disease

How Corticosteroids control inflammation

If you are tempted to make a trial of Prednisone, then you should be interested a read how such steroids control inflammation.  Here is an excellent paper that explains how corticosteroids control inflammation:-

How corticosteroids control inflammation: Quintiles Prize Lecture 2005

 

Asthma and statins 

I have established that the anti-inflammatory properties of statins, already applied neuroscientists in other fields, are very helpful in treating autism.

Researchers are also looking to see whether these properties of statins can be helpful in treating asthma.  Here is a recent paper:-

Do statins improve outcomes in patients with asthma on inhaled corticosteroid therapy? A retrospective cohort analysis

The paper concludes -

The findings suggest beneficial effects of statins in asthma management.

 Yet again the same drug has a positive effect in both conditions.

Conclusion

If you have made it this far in my post, congratulations!

So far from asthma, the autism world has taken Prednisone, Ketotifen and NAC.  I suspect that as new anti-inflammatory drugs are developed for asthma, other little gems will become available.  Also new stronger anti-oxidants are likley to be developed for asthma, since they find NAC not powerful enough. 

Prednisone clearly has drawbacks, but in the case of a sudden regression in autism, it might well be a very smart short term intervention.  Perhaps also in kick-starting development where it has stalled/plateaued.

Quite remarkably, statins not only reduce autistic behaviours but also help control asthma.

I think I have proved my hypothesis

The causes of Autism and Asthma are overlapping, so much so, that some drug treatments for the core symptoms of one may be effective in the other.

Also, we learned from Professor Barnes that corticosteroids do not work well in the presence of oxidative stress.  In asthma he reduces this stress using NAC; I do the same in autism with NAC.  This means that if you are going to trial prednisone, it would be very wise to start with NAC first.  It also means that if your child has both autism and asthma, their inhaled steroid will work better if you  are also using both NAC and statins.   

In case you were wondering, prednisone, Ketotifen and statins are all off-patent and very cheap.  NAC is an OTC supplement and inexpensive if you buy it online.


 

Autism flare ups and comorbidities

Anyone familiar with autism will know that it seems to go in waves of good and not so good.  Generally this gets accepted as just the way it has to be.

I chanced upon an unusual paper recently, it was all about comorbidities in autism.  As you may know, comorbidities are other diseases that seem to frequently occur alongside autism.  The main point of the paper and the charity behind it, is that comorbidities should be diagnosed and treated, rather than ignored, just because the person has ASD.

The paper was produced by Treating Autism, a UK charity that follows a biomedical approach similar to the American DAN organisation.  They have a link to a very comprehensive summary of what DAN actually recommends. The DAN paper is by a Dr Jepson.

The idea of treating the comorbidities as they crop up, seems entirely logical to me; but it seems to miss the bigger issue of what the comorbidity might help tell us about the autism itself.

Their list of comorbidities to keep a look at for:-

·         Allergic disorders in ASD: effects of allergies on behaviour, cognition and anxiety. Food and inhalant allergies, allergic rhinitis.

·         Autoimmunity in ASD. 

·         Autonomic nervous system dysfunction (dysautonomia) in ASD

·         Seizure disorders in ASD

Allergic rhinitis was of course the one that caught my eye.  This is the medical name for the itchy red eyes and runny nose caused by summertime pollen and pollution.  This reinforced by own observation that histamine can have a major negative impact on behaviour in ASD.  This was presented in my recent posts on histamine and antihistamine drugs.

Also of note to me was the observation that atopic dermatitis (itchy skin) and asthma are comorbidities.  Asthma was one of the comorbidities I choose to investigate myself.  An interesting observation I came across was that atopic dermatitis is actually a good predictor of developing asthma and, in fact, that by effectively treating it with a particular drug (ketotifen), you can actually halt the progression to asthma.  There is a study investigating exactly this issue; one half of the trial were itchy toddlers with a placebo and the other itchy toddlers had ketotifen.  A year later the group with ketotifen had a far lower percentage that had developed asthma than the placebo group.  I call that interesting but how many family doctors, let alone parents, are aware of that?

 Prevention of asthma by ketotifen in infants with atopic dermatitis

Also, another interesting paper all about childhood allergies is called The Allergic March.

Conclusion

Autism flare ups seem to be common and a little investigation may well lead to a better understanding of your child’s type of autism.  By recording data on bad behaviours, as in an ABA programme, or my preference, by just be keeping a watchful eye, you may well identify the cause and then find a remedy.  It might be a wobbly tooth, or it might be something more subtle like histamine.

I also believe that a detailed understanding of the comorbidities will ultimately lead to some effective therapies for autism itself.  Since it is clear that different people have different types of autism, knowing what triggers your child's flare ups may well help define what type of autism he/she has and therefore what therapies may or may not prove effective.