Showing posts with label T4. Show all posts
Showing posts with label T4. Show all posts

Thursday 17 May 2018

Statins, SLOS and Hypocholesteraemia – Going Nowhere Fast

Today’s post is about cholesterol, statins and autism. There is a well-documented condition associated with autism called SLOS (Smith-Lemli-Opitz Syndrome). It is caused by mutations in the DHCR7 gene encoding the enzyme that catalyzes the final step in cholesterol biosynthesis.

Toe syndactyly (webbed toes), one symptom of SLOS

Reduced activity of the enzyme 7DHCR typically leads to low levels of cholesterol, but markedly increased levels of precursor 7DHC (and its isomer, 8DHC) in blood and tissues. Typical SLOS manifestations include intellectual disability, growth retardation, minor craniofacial anomalies, microcephaly and 2-3 toe syndactyly (webbed toes).
SLOS is rare, but some cases do get missed because you can have a DHCR7 mutation and have normal levels of cholesterol and have normal cognitive function.

Cholesterol and the blood brain barrier (BBB)
You do have a lot of cholesterol in your brain, but it does not cross the blood brain barrier (BBB), it was made in the brain.  Eating more cholesterol can have no direct effect on cholesterol levels in the brain.
The standard treatment for SLOS has long been oral cholesterol supplementation, but there is no conclusive research to show it helps. There is plenty of anecdotal evidence.

Simvastatin and SLOS
Simvastatin is a drug widely used drug to treat people with elevated cholesterol.
There has been anecdotal evidence that Simvastatin improves SLOS and recently a very thorough study was carried out to establish whether or not it really has a benefit.
In reality the study was comparing:

Simvastatin + cholesterol supplement  vs  cholesterol supplement

The study was carried out by researchers including Dr Richard Kelley (“Dr Mitochondria”) and Dr Elaine Tierney (“Dr Cholesterol”)

Currently, most SLOS patients are treated with dietary cholesterol supplementation. Although cholesterol therapy reduces serum 7-DHC concentrations to a degree, significant amounts of 7-DHC persist even after years of therapy.  Anecdotal case studies and case series support the idea that cholesterol supplementation benefits the overall well-being of SLOS patients; however, the effects of dietary cholesterol supplementation on cognitive or behavioral aspects of this disorder have not been reported by others or substantiated in a limited controlled trial. The efficacy of dietary cholesterol supplementation is probably limited by the inability of dietary cholesterol to cross the blood–brain barrier. Moreover, increased concentrations of 7-DHC or 7-DHC-derived oxysterol could have toxic effects. Specialists have hypothesized that, in patients with mild to classic SLOS, many aspects of the abnormal behavioral and cognitive phenotype could be the result of altered sterol composition in the central nervous system. Thus, interventions that ameliorate the central nervous system biochemical disturbances in SLOS are critical to understanding the pathological processes that underlie this inborn error of cholesterol synthesis and to developing effective therapies to treat the neurological deficits.

Expression of DHCR7 is regulated by SREBP2, which, when activated by low levels of cholesterol in the endoplasmic reticulum, increases the transcription of most genes of the cholesterol synthetic pathway. Having shown that DHCR7 expression is increased in SLOS fibroblasts treated with simvastatin,31 we hypothesized that the paradoxical increase in serum cholesterol could be the result of increased expression of a DHCR7 allele with residual enzymatic function, and we demonstrated that many DHCR7 alleles encode an enzyme with residual activity. Furthermore, both in vitro experiments with human  fibroblasts and in vivo experiments using hypomorphic Dhcr7T93M/delta mice support the hypothesis that increased expression of DHCR7 alleles with residual enzymatic activity can significantly improve plasma and tissue sterol concentrations. Because residual DHCR7 activity varies among patients with SLOS, this hypothesis could explain the paradoxical increase in cholesterol in some patients and the adverse reactions observed in others.

In this study we also evaluated the potential of simvastatin to alter specific aspects of the SLOS behavioral phenotype. Our secondary outcome measures were the CGI-I and ABC-C irritability scores. Although we observed no significant effect on the CGI-I, we did observe significant improvement in the ABC-C irritability score (Figure 4). This article therefore represents the first controlled study to demonstrate improved behavior in subjects with SLOS in response to a therapeutic intervention.

In summary, this study represents the first controlled trial of simvastatin therapy in SLOS and the first controlled trial demonstrating the potential of drug therapy to modulate sterol composition and to improve behavior in SLOS. We have established that treatment with simvastatin is relatively safe, can decrease DHC levels, and can improve at least one aspect of the behavioral phenotype. These data support continued efforts to identify and rigorously evaluate potential therapies that may have clinically meaningful benefits for patients with SLOS.

Plasma sterol levels

Cholesterol and dehydrocholesterol (7DHC + 8DHC) levels were measured at baseline (B), washout (W, 14 mo) as well as at 1, 3, 6, 9 and 12 months in both the placebo and simvastatin treatment phase. Plasma cholesterol levels (A, B) and DHC (C, D) decreased significantly during the simvastatin phase compared to the placebo phase. The plasma DHC/Total Sterol ratio (E, F), which was the primary outcome measure of this study, also decreased significantly. Data expressed as mean ± SEM.

Hypocholesterolemia (low cholesterol) and some Autism
Ten years ago, Tierney and Kelley published research showing that about 20% of autism is associated with very low cholesterol levels (less than the 5th centile for typical young people) but in their sample of 100, none had an abnormally increased level of 7DHC consistent with the diagnosis of SLOS or abnormal level of any other sterol precursor of cholesterol.

Tierney went on to patent cholesterol as a therapy for autism.

The present invention relates to the field of autism. More specifically, the present invention provides methods for treating individuals with autism spectrum disorder. Accordingly, in one aspect, the present invention provides methods for treating patients with autism spectrum disorder. In one embodiment, a method for treating an autism spectrum disorder (ASD) in a patient comprises the step of administering a therapeutically effective amount of cholesterol to the patient. In more specific embodiments, the ASD is autism, Asperger's disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), Rett's syndrome and childhood disintegrative disorder. In one embodiment, the patient has autism. 

Tierney has a clinical trial registered that was to start in 2009.

Three sites (Kennedy Krieger Institute [KKI], Ohio State University [OSU], and the National Institutes of Health [NIH]) will collaborate to accomplish the objectives of this study. In addition to defining the frequency of altered cholesterol homeostasis in ASD, 60 youths (20 at each site) with ASD plus hypocholesterolemia will enter a 12-week, double-blind, placebo-controlled trial immediately followed by a 12-week open-label cholesterol trial to test the efficacy of dietary cholesterol supplementation. Outcome measures will include standard tests of behavior, communication, and other autism features.

It appears that the study has not been completed.

Dr. Elaine Tierney and her colleagues are studying different metabolic disorders that can present with autism spectrum disorder through the Autism Metabolic Research Program at Kennedy Krieger. In 2000 and 2001, this group of researchers identified that Smith-Lemli-Opitz-Syndrome (SLOS) is associated with autism spectrum disorder. Since SLOS is known to be caused by a defect in the body's biosynthesis of cholesterol, SLOS may provide clues to the biochemistry of other autism spectrum disorders (ASD).

Dr. Tierney and colleagues published a paper in 2006, in the American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), in which they describe finding that a subgroup of children with ASD have abnormally low cholesterol levels. The children's low cholesterol levels were apparently due to a limited ability to make cholesterol. This finding, in concert with their work with SLOS, has led them to believe that cholesterol may play a role in the cause of some cases of autism spectrum disorder. Dr. Tierney and colleagues at Kennedy Krieger, the National Institutes of Health and Ohio State University are performing a double-blind placebo-controlled study of cholesterol in individuals with ASD.

Cholesterol as a marker of inflammation
Nowadays, hypercholesterolemia and inflammation are considered as “partners in crime”.  Statins do lower bad cholesterol, but they also have broad anti-inflammatory effects.

Arteries do clog up with cholesterol, but a big part of why this happens is inflammation. Cholesterol deposits are initially a protective mechanism, like a band-aid. Treat the inflammation and cholesterol will not need to be deposited.
An altered immune response is a feature of many people’s autism, and you can measure it.
As Paul Ashwood’s research has shown, there are different immune sub-groups that people with autism fall into, and so you could treat each cluster with a specific therapy.

Cholesterol and Thyroid Hormones
Your thyroid produces hormones that control your metabolism. Metabolism is the process your body uses to convert food and oxygen into energy.

Your body converts the circulating pro-hormone T4 into the active hormone T3 locally. So, in your brain T4 has to be converted to T3. If you lack enough T4 coming from your thyroid gland or the special enzyme called D2 you are going to feel lethargic.
Your body needs thyroid hormones to make cholesterol and to get rid of the cholesterol it doesn’t need. When thyroid hormone levels are low (hypothyroidism), your body doesn’t break down and remove LDL (“bad”) cholesterol as efficiently as usual. Elevated LDL cholesterol will show up in your blood tests.
Hyperthyroidism has the opposite effect on cholesterol. It causes cholesterol levels to drop to abnormally low levels.
So best to check thyroid function and cholesterol levels.

My main interest is autism with a tendency to big heads (hyperactive growth signalling pathways) and an overactive immune system. This is the opposite of SLOS and hypocholesterolemia (low cholesterol).
For the 20% with low cholesterol, I think this is a very important biomarker.

.Is supplemental cholesterol the answer? I am not so sure it is.
Hopefully one day soon Dr Tierney, at Kennedy Krieger, will publish her results of cholesterol as a therapy for people with autism and low cholesterol.
For me it is good to see that Simvastatin was well tolerated in a 12 month long trial in children from 4 to 18 years of age. I have the very similar drug, Atorvastatin, in my Polypill.
Interestingly, in a paper that I will cover in later post, increasing HDL (good cholesterol), a feature of Atorvastatin and Simvastatin, was one marker of behavioral improvement in the Ketogenic Diet.

Thursday 8 May 2014

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.

“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. “


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.