Shock, Hypoxia & ME/CFS: Part II

Summary

Numerous lines of evidence implicate problems with blood flow or oxygen delivery in ME/CFS. HIF-1 is the master regulator of the body’s response to diminished oxygen delivery and is upregulated under low oxygen conditions. HIF-1 downregulates mitochondrial energy production and upregulates glycolysis in an effort to protect cells from the adverse effects of oxygen deficit. In a chronic low oxygen state, chronically elevated HIF-1 could account for a low metabolic state resembling hibernation, could account for “deconditioning” and could account for post-exertional malaise (PEM). We will take a look at models of chronically elevated HIF-1 as well as genetically reduced levels of HIF-1.

In addition, chronically elevated HIF-1 could potentially be related to increased rates of cancer and autoimmunity in ME/CFS.

Ron Tompkins, HIF-1 and Trauma

Dr. Ron Tompkins, MD, ScD, is one of our researchers on the scientific advisory board of the Open Medicine Foundation (OMF). He is chief of the Trauma, Burns and Surgical Critical Care Service at the Massachusetts General Hospital, chief of staff at the Shriners Hospitals for Children in Boston and a professor of surgery at Harvard Medical School.  We are so incredibly blessed to have people like Dr. Tompkins working to find answers for ME/CFS patients.

Dr. Tompkins specializes in finding new ways to treat patients who have suffered burns and major injuries. These critical injuries are collectively known as trauma. Interestingly, he thinks there may be a connection between trauma and ME/CFS. On his OMF page, it says: “There seems to be a relationship between trauma and ME/CFS, possibly being triggered by or putting the body into a constant state of trauma.”

This is an interesting statement because trauma involves bodily injury, but also involves circulation problems and increased inflammation. Dr. David Bell, who is also on the scientific advisory board of the Open Medicine Foundation, has compared ME/CFS to sepsis, which also involves circulation problems and inflammation. 

I compared ME/CFS to shock in my last article. Shock is defined as “the state of not enough blood flow to the tissues of the body as a result of problems with the circulatory system.”  I had symptoms consistent with shock, like palor, profused sweating, confusion, weakness and a rapid heart rate when I first got really sick. ME/CFS has connections to multiple causes of shock, including sepsis, loss of blood volume and mast cell activation.

Trauma induces shock in a way that is very similar to the way sepsis causes shock. In sepsis, inflammation from infection degrades the function of the circulatory system.  In trauma, inflammatory molecules released from dead and dying cells causes similar inflammation and problems with blood vessels.

Here and here you can find more of my thoughts on circulation and ME/CFS.

Recent research about burn trauma from Dr. Tompkins has focused on a molecule called HIF-1. He and colleagues have found that HIF-1 is elevated in burn patients.  In an interview with Cort Johnson, Dr. Tompkins says that he expects HIF-1 to be high in ME/CFS patients as well.

HIF-1 stands for hypoxia-inducible factor-1 and as discussed in my last article, “Shock, Hypoxia & ME/CFS”, it is the master regulator of the body’s response to low oxygen levels.

Burn patients, like other kinds of trauma patients and like ME/CFS patients, have a kind of metabolism that involves trouble using oxygen to make energy in the mitochondria coupled with excessive production of energy through an alternative pathway called glycolysis.

HIF-1 increases whenever there is a disruption in blood flow, as in shock, but also is stimulated by inflammation and oxidative stress, both known features of ME/CFS.

HIF-1 is a possible cause of the “cellular hypoxia” talked about by Dr. Bell. When comparing ME/CFS to sepsis, Dr. Bell had observed that the particular energy production problems in the illness seemed to resemble a situation in which cells have a puzzling inability or unwillingness to use oxygen to make energy.

Elevated HIF-1 is also a logical cause of the observed high levels of glycolysis identified in cells from ME/CFS patients by Dr. Xinnan Wang’s Stanford lab. Dr. Wang remarked that the metabolism of these cells most resembled the metabolism of cancer cells, a metabolic state called the Warburg effect.  The Warburg effect is orchestrated by HIF-1.

In addition to having increased glycolysis and decreased mitochondrial energy production, ME/CFS patients show a reduction in the function of an enzyme called pyruvate dehydrogenase or PDH.  Inhibiting PDH is central to how HIF-1 inhibits mitochondrial function.

Pseudohypoxia

In trauma patients, mitochondrial energy production is downregulated and glycolysis is upregulated in a more exaggerated way than you would expect from a simple loss of oxygen delivery to tissues. This is known as cytopathic hypoxia, which is synonymous with the Warburg effect, and very likely synonymous with Dr. Bell’s cellular hypoxia. Dr. Tompkins work with burn patients clearly related elevated HIF-1 to this type of metabolism.

This change in metabolism is thought to contribute to the elevated lactate levels you find in trauma. Lactate is a byproduct of elevated glycolysis.  Elevated lactate has also been found in ME/CFS.

HIF-1 organizes the body’s response to hypoxia but when elevated causes symptoms of hypoxia.  In this way, elevated HIF-1, even if the cause is inflammation, creates certain symptoms of hypoxia, whether oxygen is available or not.  If HIF-1 is highly elevated, your metabolism will function like there is little oxygen around.

By suppressing mitochondrial function and elevating glycolysis, HIF-1 elevation protects cells by preventing the explosion in oxidative stress that mitochondria would produce under low oxygen conditions and allows us to have an alternative source of energy.

Pseudohypoxia is especially useful and HIF-1 is especially elevated under conditions in which oxygenation is repeatedly blocked and then reintroduced. By remaining elevated beyond the time frame of any specific low oxygen incident, HIF-1 protects against repeated and ongoing disruptions in oxygen.

Shock is, by its nature, a state of dynamically changing blood flow. Small blood vessels, crucial to delivering oxygen to cells, have variable and changing levels of blood during shock (here and here) successively denying blood flow to cells and then reintroducing it.  HIF-1 is elevated in diverse shock states.

HIF-1 and Hibernation

Pseudohypoxia can save your life under low oxygen conditions.

Elevated  HIF-1 can protect heart tissue from damage during a heart attack, a situation in which oxygenation in the heart muscle is reduced. If you have an interrupted flow of blood to your heart, in many circumstances HIF-1 can organize a response to suppress your heart muscle’s energy production to protect the muscle in a state of metabolic hibernation until blood flow returns. If successful, the muscle will start contracting again, virtually unharmed.

ME/CFS patients are sometimes described as if they are also in a state of hibernation. Energy production is low, but under the right circumstances, it appears that we can come fully come back to life. We are, perhaps, sleeping beauties. It looks as though whatever is making us sick is not causing permanent damage.

Is a persistent state of low state of energy production in ME/CFS akin to hibernation and is this caused by a chronic elevation in HIF-1?

A Model of Chronic HIF-1 Elevation

Elevated HIF-1 can save your life in situations of short term oxygen deprivation, but what would chronically elevated HIF-1 look like?

Interestingly, we have a model of chronically elevated HIF-1 production in a genetic condition called Chuvash Polycythemia (CP).  CP is named after a region in Russia called Chuvashia where the inhabitants have an increased incidence of the condition.

People with CP aren’t exactly like people with ME/CFS.  One of the key features of CP is a pathologically increased amount of red blood cells, whereas in ME/CFS red cell mass tends to be reduced along with total blood volume, but the metabolic peculiarities of CP are eerily similar to ME/CFS and researchers think that these changes are related directly to elevated HIF-1 rather than red blood cell alterations.

When exercising, patients with CP produce much more lactate than normal people much earlier in the course of exercise. This is a finding also seen in ME/CFS, particularly on the second day of an exercise study in ME/CFS at a time when post-exertional malaise has set in.

Like ME/CFS patients, patients with CP have low exercise capacity. They also have a drop in muscle pH (an increase in muscle acidity), which is consistent with a finding in ME/CFS patients from Dr. Julia Newton’s work.

Researchers note that patients with CP undergo “substantial” metabolic stress from very small amounts of exercise, such as the light calf exercise employed in one study. ME/CFS also experience high metabolic stress from low amounts of activity.

In the muscles of CP patients, enzymes were altered in a pattern that correlated with elevated HIF-1. Enzymes that increase glycolysis were elevated and enzymes in charge of downregulating the function of the pyruvate dehydrogenase enzyme and decreasing mitochondrial energy production were increased.

Deconditioning

Psychiatrists and psychologists who have pushed the idea that ME/CFS is primarily a psychological disorder have often explained the obvious physical abnormalities in ME/CFS as “deconditioning”. Deconditioning is a loss of metabolic and cardiovascular function that results from inactivity or bed rest.

Saying that ME/CFS patients are deconditioned at once blames patients for their condition and minimizes the condition to something that sounds like the fatigue you might experience from a lack of exercise. This approach to the illness has inhibited biomedical research for ME/CFS and has delayed finding treatments for sufferers.

I want to take a look at how much patients with Chuvash Polythemia look “deconditioned”. Not only is their exercise capacity low, they produce large amounts of lactate while they exercise, indicating markedly low aerobic capacity.  They breathe heavily while exercising and experience exaggerated muscle acidity from light exercise. All of these are symptoms of deconditioning.

Now let’s look at a genetic model in which HIF-1 production in muscle is greatly reduced. In HIF-1 knockout mice, in which muscular HIF-1 production has been genetically eliminated, mitochondrial function is increased while energy production through the glycolysis pathway is greatly reduced. 

These mice have increased exercise times and reduced lactate production.  In fact, the aerobic capacity of their muscles looks like what you would find in exercise-trained mice, without having exercised at all.

In contrast to CP patients, these mice are the opposite of deconditioned.  In fact, at first glance, it looks more like they are pre-conditioned. They look like natural athletes.

The downside of being an HIF-1 knockout mouse is that when your muscles run out of oxygen, low oxygen levels don’t trigger protective HIF-1 and muscle tissue is damaged from repeat exercise.

The Potential Role Of HIF-1 In Post Exertional Malaise

Hypoxia is a relative concept. It is the gap between how much oxygen your cells need for energy and how much oxygen is supplied.

During exercise, even in normal, healthy people, HIF-1 is elevated as muscles increase their need for oxygen in a way that surpasses what blood vessels are able to deliver.

Is post-exertional malaise in ME/CFS patients simply a further increase in HIF-1 in a person with already high HIF-1? Are modest levels of exercise enough to push us off a metabolic cliff by increasing HIF-1 to the point where a devastating inability to make energy with mitochondria takes place?

If we have problems with blood vessels, modest amounts of exercise could increase oxygen use beyond what compromised blood vessel function could supply and could also potentially increase inflammation or oxidative stress in a way that increased HIF-1 levels.

Complications of Chronic HIF-1 Elevation

People with ME/CFS have been observed to have increased rates of cancer as well as an increased tendency towards autoimmune illness.

People with cancer tend to have elevated HIF-1 because of inflammation and because tumors have sections with low oxygen delivery and this causes elevated HIF-1.  We also know that sleep apnea patients, who have elevated HIF-1 due to repeat cessation of breathing during the night and thus repeated low oxygen levels, have an increased cancer risk.

HIF-1 increases anaerobic glycolysis, glycolysis that takes place without oxygen, but it also increases aerobic glycolysis, a type of glycolysis that uses oxygen. Aerobic glycolysis is a slightly different animal and it happens to drive autoimmune processes in the body in a big way.

Conclusion

ME/CFS looks like a state of chronically elevated HIF-1. In an upcoming article, I will talk about some possible ways to affect HIF-1.