Showing posts with label Heart disease. Show all posts
Showing posts with label Heart disease. Show all posts

Wednesday 26 November 2014

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.

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:

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.


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:-

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).
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).
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?

Wednesday 5 March 2014

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes


In recent posts we have looked at PPARα (Peroxisome proliferator-activated receptor alpha) and PEA (Palmitoylethanolamide), which activates it.  Both appeared to me to have some very interesting properties.  PPARα has siblings - PPARβ, and PPARγ.  It may not come as a surprise that one of these is currently at the centre on clinical trials for autism.  But is it the right one?
Thiazolidinediones (TZDs) are agonists of PPAR gamma (PPARγ), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. Pioglitazone is currently in Phase 2 trials for autism.

The full version of the earlier study was:-

In view of its established safety profile, the current results provide the rationale or further testing of pioglitazone in autism and other forms of ASD. 
It is interesting that  PPARγ agonists are currently used in type 2 (non-insulin dependent) diabetes because in my earlier post is was shown that activating PPARα could treat a nasty side effect of both type 1 and type 2 diabetes, Peripheral Neuropathy;  this is damage to the peripheral nervous system.  An example is sharp pain in the sole of your feet, even when lying down.
Fibrates are a class of drug identified in the 1930s and are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins. Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.
Although less effective in lowering LDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, they seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes type 2). They are therefore used in many hyperlipidemias. Fibrates are not suitable for patients with low HDL levels.

In the 1990s, the mechanism of action was discovered;  fibrates activate PPARα.
Fibrates are the main PPARα activating drugs in use, but there do seem to be various problematic side effects.  In an earlier post we did discover a naturally occurring PPARα activator that seems to have no side effects or contraindications, PEA (Palmitoylethanolamide).

Heart Disease
Heart disease is the leading cause of death in developed countries and so is very well researched.  What is remarkable is how closely related autism is to heart disease.

Almost all of the ingredients in my autism Polypill are actually drugs normally given to people with heart disease and of course people with autism are known to be prone to heart disease.
Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism.  So is autism.
Let’s look what we can learn from research into PPARs in heart disease.

"Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism. The accumulation of cholesterol-rich lipoproteins in the artery wall results in the recruitment of circulating monocytes, their adhesion to the endothelium, and their differentiation into tissue macrophages. Lipid-loaded macrophages play an important role in the production of chemokines, cytokines, and reactive oxygen species in the early stages of lesion formation. Therefore mechanisms that limit macrophage cholesterol accumulation and/or prevent the production of inflammatory mediators all have the potential to inhibit lesion development.

The PPAR family is comprised of 3 different proteins: PPARα, PPARβ, and PPARγ. Natural ligands for these receptors include fatty acids and oxidized fatty acids. The relevance of PPAR pathways to metabolic disease is underscored by the use of the fibrates (PPARα agonists) and thiazolidinediones (PPARγ agonists) to treat hyperlipidemia and type 2 diabetes, respectively."


"PPAR signaling pathways influence macrophage gene expression and foam-cell formation. Ligand activation of PPARα and PPARγ, but not PPARβ/δ, inhibits the development of atherosclerosis in LDLR_/_ mice. Both systemic and local mechanisms might contribute to these beneficial effects. Previous studies have suggested that PPARα and PPARγ increase LXRα expression in macrophages and promote expression of ABCA1, which mediates cholesterol efflux to apoAI. Results from the study in this issue by Li et al.  suggest that PPARγ may also inhibit cholesterol accumulation in macrophages through direct regulation of ABCG1, which has been implicated in cholesterol efflux to HDL. Activation of each of the PPARs with selective agonists also inhibits the expression of inflammatory markers in the artery wall. These findings reinforce potential use of PPAR agonists as antiatherosclerotic therapies."

"The study by Li et al.  provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both The study by Li et al. provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both PPARα and PPARγ ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. In contrast, the authors did not observe any effect from PPARβ activation. Given the discrepancies between PPARβ agonist effects in mice and primates, however, the possibility that PPARβ ligands may have beneficial effects on cardiovascular disease in humans is not excluded by the present study."

So it would appear that activating PPARα and PPARγ has benefit in heart disease, but likely not PPARβ.
It seems that the traditional PPARα activator drugs, the fibrates, are problematic.  PPARγ activators are widely used in diabetes therapy and there are safe choices.

In autism, a PPARγ activator has already been shown itself to be effective in initial phase 1 trials.  

Heart disease is well researched by clever, very well-funded, people so I am sure they will have figured out to trial PEA instead of Fibrates as a PPARα activator and of course to look at the benefits of Pioglitazone as a PPARγ activator.
Autism is not so well researched.  The PPARγ activator trial is proceeding slowly forward in Toronto.  The PPARα activator trial will commence shortly, but not with Fibrates.