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).

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