Sunday, February 24, 2013

Some Thoughts on Chronic Disease: Part 2

See Part 1
 
This post is just some of my current thoughts on chronic disease and is quite speculative at times

The Common Soil Hypothesis and Positive Feedback

The common soil hypothesis suggests that similar mechanisms (such as oxidative stress) promote T2D and CVD.


I agree, but we can take this further: 

1) Several mechanisms of disease promote more than just one disease.  Inflammation, immune dysfunction, immune suppression, nutrient deficiencies*, mitochondrial dysfunction, chronic infections and chronic stress are some common causes of most chronic disease**.


 2) Some diseases promote other diseases and several of the underlying pathologies above promote other pathologies (and then indirectly perpetuate themselves).  For example: 

  • Autoimmune diseases are highly inflammatory and this inflammation can promotes osteoporosis and cancer
  • Inflammation causes oxidative stress and oxidative stress causes inflammation.  Also, inflammation can causes immune dysfunction and immune dysfunction increases inflammation
  • Inflammation from atherosclerosis can promote osteoporosis and the released calcium can form calcified arteries 

3) Many chronic diseases perpetuate themselves directly, which is an example of positive feedback.  For example: 

  • oxLDL promotes endothelial dysfunction, which in turn makes LDL more vulnerable to oxidation
  • Mitochondrial ROS inhibit the electron transport chain, which in turn increases mitochondrial ROS.  And oxidative stress can damage mtDNA, which disrupts mitochondrial function, which can result in more oxidative stress 

4) Somewhat unrelated but worth mentioning is that some of the mechanisms that promote chronic disease aren’t sufficient to cause chronic disease.  For example: 

  • Genetic susceptibility, exposure to an autoimmune-inducing antigen, immune dysfunction and intestinal permeability seem to all be necessary but none are sufficient for autoimmune disease
  • High LDL-P and infections/elevated CRP can promote CVD but alone don’t seem to be sufficient for CVD 

All four points are bad news for people with chronic disease.  The first two points can explain why chronic diseases have high comorbidity: if you have one chronic disease you likely have, or will get, another.  The second and third points can explain why they are called chronic diseases and are thought to be incurable.  It takes a major lifestyle change to steer one’s health in the opposite direction***.  And the last point suggests people with chronic disease have at least one underlying pathology. 

But there’s some good news in all of this.  If you have more than one chronic disease or health problem it’s likely they share some underlying pathologies and can be dealt with simultaneously.  If one biomarker is bad, but the rest are fine it might be unlikely that you would develop a chronic disease (which isn’t to say you should ignore the bad biomarker or risk factor). 

* Vitamins A, D and K2, coenzyme Q10, zinc and LCO3s are some of the nutrients that seem to be highly therapeutic for a specific chronic disease and/or therapeutic for many.  I’m not going to suggest that some nutrients are ‘better’ than others, but rather that many of these nutrients come from animal foods and that people eating a SAD aren’t getting enough of them.  On the other hand, if everyone was eating a diet low in plant foods I would expect to see nutrients like magnesium, copper, manganese, folate and vitamins B1, C, E and K1 to be very therapeutic 

** You could probably group these underlying pathologies into two main categories: 

1) Mitochondrial related: (the metabolic syndrome nutrient deficiencies related to mitochondrial function and mitochondrial related oxidative stress and inflammation) 

2) Immune/GI related: (immune dysfunction, immune suppression, metabolic endotoxemia, intestinal permeability, chronic infections nutrient deficiencies related to immune function and immune related inflammation and oxidative stress) 

Mitochondria and the immune system/gut bacteria seem to be some of the more delicate systems in the body, so they will likely be the first to fail in a hostile environment and be the systems involved in aging and chronic disease. 

Problems in these systems (mutations in mtDNA, bacterial composition, etc) are probably somewhat transferable from mother to child, which may partly explain how each generation of Pottenger’s cats became less healthy and may also explain some of the massive increases in chronic disease over the last century. 

*** Which is why 80/20 or 90/10 might be fine for most people, but often not good enough, and usually not recommended, for those with severe health problems 

A Homeostatic Model of Disease and Negative Feedback 

If the points two and three above are true then the slightest problem would escalate us into poor health and disease.  Fortunately that’s not the case as our body is regulated by homeostasis.  Homeostasis is a process involving negative feedback that keeps the body’s internal environment relatively stable.  Some things regulated by homeostasis include body temperature, body pH, circadian rhythms, blood glucose, etc.  Chronic disease could be described as a departure from homeostasis, which can be caused by: 

  • The homeostatic mechanisms being compromised
  • The homeostatic mechanisms being overwhelmed 

This suggests you could cause obesity (for example) by: 

  • Changing the regulation of appetite so as to increase appetite without a sufficient compensatory increase in energy expenditure (compromised)
  • Changing the regulation of energy expenditure so as to decrease energy expenditure without a sufficient compensatory decrease in appetite (compromised)
  • Consistently overeating beyond the ability of regulatory mechanisms to burn off extra calories (overwhelmed)* 

And suggests you could resolve obesity by: 

  • Supporting the systems that regulate appetite and energy expenditure (leptin, other satiety hormones, food reward, etc)
  • Eating within a physiological range - the range where homeostatic mechanisms aren’t being overwhelmed (for example your basal metabolic rate ± say, 100 calories?) 

This homeostatic model doesn’t directly advance understanding, but I think it’s an ok theoretical framework and is a good way to begin asking questions.  For example:  Disease A is a result of the breakdown of regulation of B.  What regulates B?  What can go wrong in the regulation of B?  What causes the dysregulation of B? 

* I’m not suggesting you need to calorie count, just that eating 10,000 extra calories everyday will make you fat (which shouldn’t be too objectionable).

Sunday, February 17, 2013

Some Thoughts on Chronic Disease

This post is just some of my current thoughts on chronic disease and is quite speculative at times 

Underlying Pathologies Cause Disease 

Why is the topic of chronic disease important?  Chronic diseases are widespread and cause a lot of suffering: most people (7/10) will die from a chronic disease, nearly a half of adults have from at least one chronic disease and about a quarter of those with chronic disease experience significant limitations in daily activities (US figures from the CDC) [1] 

Following from a previous post, despite chronic diseases being so common, it seems the default human condition is to be healthy*, seeing as hunter-gatherers, traditional cultures and wild animals have near population wide freedom from chronic diseases, such as obesity, type 2 diabetes, autoimmune diseases, cardiovascular diseases and cancer. 

Chronic disease doesn’t ‘just happen’.  Everything in science has an explanation.  Unfortunately, overwhelmingly the explanations generally given for chronic disease are genetics (you got X due to family history), other non-modifiable risk factors (age, sex, ethnicity, etc), environmental factors that are obvious (drinking, smoking, no exercise) or vague (poor diet) or related to triggers (proximal causes), like a stressful period or an injury.  While some triggers are quite relevant, they will generally not cause the disease or its symptoms without what some underlying problem/s (the ultimate cause/s) (which I refer to as the underlying pathology) 

As a result of these limited explanations, someone who is health conscious, yet has a chronic disease feels powerless.  They tried, but they still ended up fat and/or sick.  At this point some people, including observers, give up, while others keep trying, but with limited information.  The way the medical system treats chronic disease doesn’t help either.  Despite a perception of drugs solving a problem, the drugs used for chronic disease often have limited efficacy and some adverse side effects. 

What aren’t discussed are the ultimate causes, the underlying pathologies behind the disease in question.  I got into blogging about chronic disease because I saw that in the literature there was a lot of information that fairly consistently pointed to various underlying pathologies causing diseases (like mitochondrial dysfunction in type 2 diabetes), information that you don’t generally hear about.  This should make a lot sense since the body has many homeostatic processes to regulate things and function.  Therefore underlying pathologies are required to disrupt homeostasis and diseases are a condition where function is impaired and has signs and symptoms. 

Understanding the underlying pathologies is important for understanding how lifestyle and drugs have their effects, and also to make educated guesses on what to research in the future.  However, there was much less information on how lifestyle can lead to underlying pathologies, which is fair enough because that step is much harder.  Seeing as chronic disease is almost always caused by an underlying pathology I think we should be more interested in getting rid of the stuff that promotes pathology rather than adding in dietary/health gimmicks and obsessing over things like some obscure compound in a vegetable that reduces the risk of cancer (or whatever) by 10%. 

The Jaminets propose that malnutrition, toxins and infections are the main causes of chronic disease, which I agree with.  You might be able to add a few things to that list such as chronic stress (is that a toxin though**?), but otherwise it’s pretty complete.  Seeing as malnutrition, toxins and infections often cause chronic disease through underlying pathologies a basic flowchart of chronic disease may look like this.


So far I’ve written about obesity, osteoporosis, autoimmune disease, depression, cancer, cardiovascular disease, hypertension and acne (remember to check out the links in the summary posts, which direct you to the more in depth posts); and to some extent on insulin resistance, type 2 diabetes, Parkinson’s disease and Alzheimer’s disease 

* Angelo Coppola also broadcasts this message, and like me believes it to be a major piece of the evolutionary/Paleo approach:“To me, Paleo is and always has been about “Human beings are not broken, by default.”" - Angelo Coppola 

** Glucocorticoids have some very important functions, but they have many undesirable effects if chronically elevated
 
See Part 2

Sunday, February 10, 2013

Evolutionary Psychology

Not to be confused with Emily Deans’ blog Evolutionary Psychiatry. 

Evolutionary psychology (EP) uses evolution to help understand human behaviour, personality traits, cognition, etc.  I think it’s an excellent theoretical framework to understand psychology, as I see psychology as being a subset of biology, and as has been quoted to death (but needs to be repeated): 

“Nothing in biology makes sense except in the light of evolution”
-          Theodosius Dobzhansky 

The point of this post is that EP has its own explanations for several mental illnesses that suggest mental illness could be a good thing, or at least not necessarily a bad thing and/or are evolutionary adaptive for a variety of reasons.  For example: 

Major Depressive Disorder 

EP has proposed many different explanations for depression, such as: 

  • Avoiding sources of stress because current stressors are exceeding the capacity to cope (psychic pain or distress as a motivator)
  • Rumination to facilitate problem solving towards long term goals, purpose and meaning
  • Signalling suffering/unmet needs to others (cry for help)
  • Avoiding others to prevent spread of infection
  • To lower the demeanour of animals who have lost rank to minimise harm 

Feeling ‘depressed’ is not the same as major depressive disorder (MDD).  Feeling depressed may be adaptive, but MDD is not.  While MDD can be caused by infection and stress, EP can’t explain the following: 

  • How things like LCO3s, zinc and exercise are therapeutic
  • Low serum BDNF in people with MDD
  • Evidence supporting the role of MDD as an inflammatory disease
  • How LPS can trigger MDD symptoms in those susceptible
  • Immune dysfunction being associated with MDD (high CD4+:CD8+ ratio and simultaneous inflammation and immune suppression)
  • Glucocorticoid resistance 

Some of the explanations don’t add up: 

  • People with MDD are not in an ideal position to problem solve as some of the symptoms of MDD include logical fallacies (see part 1, 2 and 3)*
  • Having MDD for months/years is unnecessarily long when yielding rank quickly is sufficient to minimise harm 

On top of that, the two strongest bits of evidence against EP’s explanation for MDD are hippocampal atrophy (suggestive of pathology and why would that be necessary, adaptive or good?) and suicide. 


* Many of the logical fallacies could perpetuate MDD.  I suspect that for many people a significant portion of time in cognitive behavioural therapy is spent dismantling them. 

Postpartum Depression 

Postpartum depression affects 15-20% of women during the first year after giving birth [1].  The EP has two main explanations for postpartum depression (PPD): 

  • PPD informs the mother that she has undergone a fitness loss in having a child and so it’s a cry for help and/or a driver to focus on the mother’s wellbeing
  • To reduce investment in offspring who would have been unlikely to survive to adulthood (mainly due to a lack of support from others, not because the child was deformed). 

Social support predicts PPD and is very therapeutic for it, which supports the second point.  Though just like MDD there are biological factors that haven’t been accounted for: 

  • LCO3s increase BDNF [2], are anti-inflammatory and are therapeutic for MDD [3].  Low plasma levels of DHA are associated with more depressive symptoms [4].  PPD may be due to low LCO3s as they in high demand during early development (potentially depleting the mother) and PPD is associated with low fish intake and low DHA levels [5]
  • During pregnancy pro-inflammatory cytokines are lower and the mother is immune suppressed to inhibit potential immune responses against the foetus*.  Very shortly after delivery the mother switches to a pro-inflammatory state to deal with the aftermath of childbirth.  While the PP period is pro-inflammatory, women with PPD have 3 times more IL-6, which may be caused by glucocorticoid dysregulation (not producing enough or resistance) [1]
  • Women who have anti-thyroid antibodies are more likely to get PPD.  Among women with anti-thyroid antibodies administration of T4 reduced PPD from 50.6% to 17.2% [6]
  • A low selenium diet can cause mood disturbance [7] and selenium decreases with pregnancy [8].  Women with low intakes of selenium (<8.9µg) were 2.95 times more likely to experience post-partum depression [9] and each 10µg of supplemental selenium reduces the risk of PPD by 24% [10]
  • Lower serum zinc (but not magnesium) is associated with PDD [11] and combined treatment of zinc, magnesium and vitamin B1 improved depressive symptoms in postpartum period in an animal model of PPD [12].  Other minerals may also have a role [13] 

The biological factors would somewhat agree with EP in that the mother has undergone a fitness loss and perhaps the child might be less likely to survive due to malnourishment, but the degree of fitness loss of the mother and malnourishment of the infant or the mother isn’t supposed to happen. 

Others 

EP has explanations for other mental illness as well, I’m aware of EP’s explanations for bipolar disorder (BD) and schizophrenia*, which suggests the two mental illness could be/have been beneficial because they enhance creativity [14] and also schizophrenia because it promotes hypervigilance of danger. 

However, BD and schizophrenia are associated with lower brain volumes in several brain structures [15], people with BD [16] and schizophrenia [17] have a high suicide rate, even by mental illness standards** and people with schizophrenia have fewer children [18] [19]. 

As for the underlying pathologies I’ll leave that to Emily Deans, a psychiatrist who has done a lot of research on the biological causes of mental illness. 

* Most people think only of the psychotic symptoms (hallucinations and delusions) of schizophrenia, which are called ‘positive symptoms’, but more common and more debilitating are the ‘negative symptoms’, which are similar to MDD and don’t respond well to the standard anti-psychotic medications. 

** At least 25-50% of people with BD have attempted suicide at least once [20] and people with BD have a suicide rate of about 1% per annum, compared with 0.015% in the general population.  (People with BD are also more likely to have successful suicide attempts (1/3 vs 1/30) [16].  In other words BD causes a lot of suffering that no one should have to experience. 

Summary 

Not all of EP’s proposed explanations for mental illness are evolutionary adaptive, some are psychologically adaptive, but all share the view that ‘mental illness could be a good thing, or at least not necessarily a bad thing’, which I think is a wrong and dangerous approach.  One slippery slope that an evolutionary psychologist could take is to block the treatment or not make it as effective in order for the ‘adaptive’ elements of MDD (for example) to manifest. 

“Finally, I disagree that psychotherapists should "seek to alleviate their [patients'] suffering, adaptive or not." By that logic, doctors should always alleviate physical pain, adaptive or not. Yet physical pain often helps prevent further injury and promotes healing—if you have an injured limb, refrain from using it! Similarly, sadness is almost certainly a healthy response to adversity that may limit losses and promote healing.” [21] 

Evolutionary psychologists often seem to confuse normal human emotions such as depression and anxiety with mental illness such as MDD and anxiety disorders.  Depression and anxiety have a function, MDD and anxiety disorders are dysfunctional and are often caused by an underlying pathology (hippocampal atrophy for example). 

You’ve got to wonder whether the evolutionary psychologists have had first hand or second hand experience with mental illness.  Because in addition to impairing function and causing suffering, mental illness is inherently irrational and maladaptive.  I think the only benefit of mental illness is just improving your understanding of them, allowing you to have more compassion for those who are afflicted by them.

Sunday, February 3, 2013

The Carnivore Connection Hypothesis: Part 2

Read part 1 here

Chris Masterjohn’s AHS 2012 Presentation 

Chris Masterjohn’s AHS 2012 presentation is excellent on so many levels.  It’s highly relevant to this post and I consider it to be required viewing.  He makes the following points: 

  • Most humans (>95%) have many duplications of the salivary amylase (SA) gene, whereas chimpanzees have no duplications
  • Populations consuming a higher starch diet tend to have more copies of the SA gene on average (7 copies) than populations consuming a low starch diet (5 copies), but both groups have more copies than chimpanzees (2 copies)
  • The number of copies of the SA gene correlates with SA activity.  Humans have ~4 times more SA activity than gorillas and ~10+ times more SA activity than other primates
  • During a ‘starch tolerance test’ people with high SA activity have a lower AUC for blood glucose and insulin due to a greater pre-absorptive insulin release
  • But during a glucose tolerance test there is no significant difference between people with high SA activity and people with low SA activity
  • Insulin resistance can be caused by energy overload and oxidative stress 

This suggests: 

  • Humans are adapted to eating carbohydrate, specifically starch (somewhat countering the first line of evidence)
  • While there are people who have less adaptation to starch, these people don’t perform significantly worse on glucose tolerance tests, which is a marker of insulin resistance used to diagnose IR/T2D (a very strong counter to the third line of evidence)
  • Insulin resistance can be caused by an underlying pathology 


Underlying Pathologies of IR and T2D 

The carnivore connection hypothesis doesn’t account for the underlying pathologies behind IR and T2D.  To their way of thinking it’s pretty much all about GL, but increasing carbohydrate consumption increases insulin sensitivity, not the other way around [1].  Underlying pathologies of insulin resistance include chronic inflammation and mitochondrial dysfunction, which can be caused by energy overload and other mechanisms* [2]. 

IR and T2D are clinically considered to be on the same continuum, with T2D being diagnosed as a more severe form of insulin resistance, as indicated by elevated fasting blood glucose and impaired glucose tolerance*.  But T2D isn’t just more IR, it requires a reduced insulin release from the pancreas as well.  At least the authors make the distinction between IR and T2D, but they propose that high GL diets cause T2D by exhausting the beta-cells of the pancreas.  If T2D is due to beta cell exhaustion then an animal model like the LIRKO mice (who lack insulin receptors in the liver, have insulin resistance and hyperinsulinemia) would exhaust their beta cells and develop T2D. 

The problem is LIRKO mice don’t develop T2D because they compensate for liver insulin resistance by increasing beta cells, which is mediated by insulin signalling [3].  LIRKO mice who also lack insulin receptors in the beta-cells (βIRKO) don't compensate and develop T2D [4].

This suggests that physiological adaptations to higher carb diets would involve both an increase in insulin sensitivity and beta-cell mass, and that you need an underlying pathology, like mitochondrial dysfunction [5] [6], to impair homeostatic regulation

Seeing as beta cell exhaustion doesn’t occur and those who eat a higher GL diet have a greater physiological adaptation that promotes insulin sensitivity and insulin release, people who eat a high GL diet should do better on standardised tests such as the oral glucose tolerance test 

* Under these circumstances IR can be viewed as a physiological adaptation to energy overload.  But remember that physiological adaptation and evolutionary adaptation are not the same.

Summary 

Remember the four lines of evidence: 

1.      “That during the last two million years of evolution, humans were primarily carnivorous, i.e., flesh-eating hunters consuming a low-carbohydrate, high-protein diet”
2.      “That a low-carbohydrate, high-protein diet requires profound insulin resistance to maintain glucose homeostasis, particularly during reproduction”
3.      “That genetic differences in insulin resistance and predisposition to NIDDM can be explained by differences in exposure to carbohydrate during the past 10,000 years”
4.      “That changes in the quality of carbohydrate can explain the recent epidemic of NIDDM in susceptible populations.” 

The first line of evidence is fairly accurate.  Hunter-gatherers (HGs) generally eat fewer carbohydrates than we do now (~22-40% vs ~50-55%) although this varies widely between HG groups and some eat more carbohydrate than we do.  Though that doesn’t refute the third line of evidence so long as the high carb HGs are less vulnerable to IR/T2D than those of European descent and the low carb HGs are more vulnerable.  The problem is that some high carb HGs/TCs are among the most vulnerable to IR/T2D (Pima, Hawaiians). 

No issue with the second line of evidence.

Even though I have often recently said 'physiological adaptation is not the same as evolutionary adaptation', the third line of evidence is very believable.  I actually thought there would be an effect, just as not large as what the authors were making out.  However, the fact that people with less adaptation to starch perform equally as well on glucose tolerance tests and the Pima/Hawaiians being among the vulnerable to IR/T2D is a strong refutation of the third line of evidence 

The fourth line of evidence suggests high GI/GL diets cause IR and beta-cell exhaustion (in those genetically vulnerable), therefore T2D.  However the opposite is true: carbohydrate consumption correlates with insulin sensitivity, beta cell exhaustion doesn’t occur and insulin promotes beta cell growth/regeneration 

The two main points about the CCH is that vulnerability to IR/T2D can be explained by ancestral carbohydrate consumption and high GI/GL diets cause IR/T2D.  Both points have strong counter evidence against them