Why Does ME/CFS Look Like Sepsis?
- ME/CFS looks like sepsis. Sepsis on the surface is an illness caused by massive inflammation. At its core, however, sepsis is an illness of blood vessels. In sepsis, inflammation wreaks havoc with the function of our tiniest blood vessels, impeding blood flow and interfering with the delivery of oxygen to tissues.
- Nitric oxide is a tiny molecule that helps hold small blood vessels open so that blood can flow through them. My ME/CFS and autism symptoms improve with agents that increase nitric oxide. Other patients have also seen improvement.
- I developed Mast Cell Activation Syndrome at the same time that I developed ME/CFS. Mast cells are located in and around blood vessels and can be activated by changes in blood flow and blood flow deprivation. Is this the cause of MCAS? Mast cells can cause blood vessel damage that resembles the blood vessel damage in sepsis. Can chronic mast cell activation look like chronic, mild sepsis?
- At the level of blood vessels, hemorrhage, the sudden loss of blood, causes damage that looks like the damage that sepsis causes. ME/CFS patients have chronic low blood volume. Does having chronic low blood volume cause chronic, mild damage to the blood vessels in a way that could give rise to an illness that looks like chronic, mild sepsis?
- Glycocalyx is a material that lines the blood vessels. Glycocalyx helps keep small blood vessels open by releasing small amounts of nitric oxide. Inflammation causes it to dissolve during sepsis, causing the blood vessel problems that you find in sepsis. Glycocalyx can be destroyed by mast cell activation, systemic inflammation, psychological stress, blood volume loss, and major injuries. All of these events have been linked to ME/CFS.
- ME/CFS and sepsis look like hibernation at a cellular level. Our cells aren’t dying, but they are in a state of chronic low energy production. A molecule called HIF-1 can cause hibernation in heart muscle cells upon oxygen deprivation. HIF-1 governs responses to low oxygen in the body and suppresses mitochondrial energy production while increasing glycolysis. Low mitochondrial energy production and high glycolysis are found in ME/CFS and sepsis. HIF-1 is known to be elevated in sepsis and Dr. Ron Tompkins mentioned that he expected to find an elevated level in ME/CFS as well. Does HIF-1 cause a state of hibernation in ME/CFS patients?
The Unknown Of Unknowns
I was sixteen when I developed ME/CFS. I have had it for twenty years. The most obvious symptoms of ME/CFS are an unrelenting fatigue and a flu-like malaise that worsens after exercise or even after normal daily activities. Most people who develop ME/CFS do so after an infectious illness. People get sick and simply never recover.
A physician named Steven Hatch wrote a book on medical uncertainty called Snowballs in the Blizzard. He stated in an interview about the book that, in terms of illnesses, ME/CFS is the “unknown of unknowns”.(1) It is an illness that is disabling to millions across the globe but whose cause remains relatively impervious to investigation.
After getting sick and before we completely give up on receiving help from doctors, we tend to show up at doctors offices with a giant file of records hoping that this doctor, unlike the previous ten, will be able to find order in the chaos of our symptoms. In the absence of objective markers for this illness, doctors spy our giant file of records and often conclude that we don’t have a physical problem. Instead, they think we have a have a mental problem.
About twenty-five percent of people with ME/CFS either can’t leave their bed or can’t leave their house. Despite its severity, ME/CFS has been denigrated by the medical system for fifty years as either not real or psychiatric in nature. In part, this is due to the fact that medicine distinguishes and researches illnesses based on which part of the body or which system is affected.
ME/CFS is hard to define in this way. It is an illness that seems to pervade the body diffusely, causing problems with the cardiovascular, endocrine, gastrointestinal and nervous systems. ME/CFS seems to be everywhere in the body and nowhere at the same time.
What if there are in fact clues embedded in the specific ways that you got sick and in the specific ways that I got sick? Certain symptoms and sequences of events. If we look closely enough, if we do not dismiss symptoms as unimportant or permanently inexplicable, if we listen to patients and their self-reports, what if we can find order in the chaos?
The Open Medicine Foundation is a group of world-class researchers dedicated to sharing their data freely and finding treatments for ME/CFS as quickly as possible. At the Open Medicine Foundation Symposium this year, one of the researchers held up a book by Dr. David Bell, a physician who treated ME/CFS patients for decades. The researchers suggested that Dr. Bell was ahead of his time, that Dr. Bell really knew what he was talking about.
Dr. Bell was the first to point out that ME/CFS looks an awful lot like a deadly illness called sepsis. While ME/CFS may be the mystery of mysteries, much more is known about sepsis. If we can figure why exactly ME/CFS looks like a chronic, non-deadly version of sepsis, this quite possibly expands the ways we might be able to treat ME/CFS.
When I first got sick, a few things happened in sequence. I got hives from my knees to my waist, I stopped sleeping, I started sweating profusely, I started flushing all the time in my cheeks, nose, and ears, I became allergic to everything I was eating and I developed a blood vessel condition called Raynaud’s phenomenon. The sleeping and the sweating we’ll get to in an upcoming article. The flushing, the hives, the allergies and the Raynaud’s phenomenon we’ll cover in this article. We’ll look at how these symptoms might be connected to a process that resembles sepsis.
While most people get ME/CFS after an infectious illness like a nasty virus or mononucleosis, I got ME/CFS after a bout of food poisoning and a period of high emotional stress. The emotional stress was the nail in the coffin for me. Yet my illness looks just like someone who got their ME/CFS after an acute infection. People can also get ME/CFS after accidents and injuries. One of the big mysteries about ME/CFS is how people can end up in the same place from so many different causes. We will explore how this could be.
A Slow, Chronic Sepsis
Dr. David Bell treated ME/CFS patients for decades after an infectious illness broke out in his town of Lyndonville in upstate New York. Hundreds of residents contracted the illness and subsequently developed ME/CFS.
In 2007, after years of observation, Dr. Bell published a short book laying out a case that ME/CFS might be like a mild, chronic version of an illness called sepsis.(2)
Sepsis is a dangerous illness that can develop after a severe bacterial infection. Forty percent of people with sepsis die.(3) ME/CFS patients don’t die, but like sepsis patients, they feel like they are going to die. Other similarities between the two conditions are striking.
Sepsis arises after an overwhelming bacterial infection. ME/CFS most often develops after an infection, sometimes viral and sometimes bacterial. A more severe infection increases the risk of developing sepsis and the same seems to be true for ME/CFS.
Like sepsis patients, ME/CFS patients tend to have strikingly low blood pressure. My most frequent measurement has been 84/54. That is extremely low blood pressure for someone who is walking around and not hospitalized. Normal blood pressure is about 120/80.
Dr. Bell notes that the type of low blood pressure ME/CFS patients have would set off alarms in an intensive care unit where doctors are keeping an eye out for things like sepsis and extreme blood loss.
In sepsis, low blood pressure results from a combination of issues. One cause is an increased amount of nitric oxide.
Nitric oxide is a tiny gaseous molecule that is found all over the body in both useful and deleterious roles. Under conditions of inflammation, it is released as part of a purposeful response to infection.
In sepsis, a gigantic immune response triggers an equally gigantic level of nitric oxide release. Excess nitric oxide makes blood vessels soft and floppy, making it difficult to maintain blood pressure. It’s as though the pipes in the plumbing in your house were suddenly made out of flexible rubber instead of metal or hard plastic. In a house with ballooning rubber pipes, you would be hard pressed to actually get water to come out of your shower head.
In a similar way, a body with a great deal of nitric oxide release has trouble pushing blood around the body effectively. Various body parts may end up with inadequate blood flow and inadequate amounts of the oxygen and nutrients that blood carries.
Elevated nitric oxide has also been found in ME/CFS. In fact, a longstanding theory about the cause of ME/CFS holds that elevated nitric oxide is at the center of the mystery.(4) High levels of nitric oxide can not only lead to floppy blood vessels and low blood pressure but also to high levels of cellular damage in the body caused by a molecule downstream of nitric oxide called peroxynitrite. If you keep up with ME/CFS research, you may have heard of the peroxynitrite theory of the illness. ME/CFS patients have evidence of the particular type of damage that peroxynitrite causes.(5)
Dr. Bell built on the nitric oxide theory of the illness in his book to explain a possible connection between sepsis and ME/CFS: he proposed that both sets of patients have trouble making enough energy at a cellular level because of excess nitric oxide.
Nitric oxide inhibits energy production by mitochondria, our little electrical plants inside each cell.(6) With low mitochondrial function, total energy production is slashed since the majority of energy in the body originates in this pathway. Mitochondria use the oxygen we breathe in to make energy. When mitochondria aren’t working, it is rather like there is not much oxygen around.
In sepsis, oxygenated blood is present, but cells for some reason don’t make use of it. Sepsis researchers had previously proposed the idea that cells don’t make energy in sepsis precisely because of the excess nitric oxide in the condition. Dr. Bell suggested that the reason for low mitochondrial function in ME/CS is also excess nitric oxide.
Autism is also linked to low energy production. New research suggests that my two conditions, ME/CFS and autism, may, in fact, be closely related.(7)
Some evidence suggests that the picture with nitric oxide and ME/CFS may be more complex than simply too much nitric oxide. We seem to have an overall heightened level of nitric oxide, but at the same time administering agents that increase nitric oxide can be helpful, which suggests to me that excess nitric oxide may not be the core problem with our illness.
In sepsis, you find a paradox of simultaneously having too much overall nitric oxide production, which is definitely problematic, but also too little nitric oxide production in crucial regions of the body: the smallest blood vessels.(8)
It is at the level of these smallest blood vessels where the core illness process in sepsis occurs Perhaps will find problems affecting these smallest blood vessels in ME/CFS as well.
Norwegian researchers Oystein Fluge and Olla Mella burst onto the ME/CFS research scene in 2009 with a finding that some patients might experience remission from ME/CFS by taking a drug called Rituximab. Rituximab is normally used to treat cancers or autoimmune disease. We are still trying to determine for certain if Rituximab is a viable treatment for ME/CFS and if so, what kind of patient will benefit.
We learned something interesting, however, from one of their patients who benefitted from Rituximab but relapsed after getting off the drug. This patient wound up in the hospital with unrelated heart problems. Her doctor prescribed a drug called Imdur which releases nitric oxide in the body to dilate blood vessels that are constricted. This provides more blood flow to the heart, relieving issues there, but also increases blood flow all over the body.
This woman experienced a remission like the one she experienced on Rituximab, but this remission started immediately instead of 6 weeks later like Rituximab. Her symptoms returned after she discontinuing Imdur. Fluge and Mella were so struck by this patient’s response and the response of several other patients that they have patented agents that increase nitric oxide as possible treatments for ME/CFS.(9)
Nitric Oxide and ME
One day about seven years ago, I took 4 capsules of potassium at once for the first time.
My skin tends to be pale with nebulous purplish and whitish places. My fingernails tend to be lavender, my hands, and feet cold. When I took the potassium, my skin and nails flushed an even pink color. My hands were warm. They were never warm. I felt good and I never felt good. I went for a bike ride and did not feel sick during the ride or afterward. Normally, people with ME/CFS feel worse with exercise.
Better than good, I felt mentally at ease. With my autism, usually other people make me want to climb out of my skin with anxiety, but I rode bikes with other humans that day and enjoyed the ride and their company. I felt happy. I laughed and smiled. Usually, the only time I was ever at ease was when I was engaged in special interests like studying plants or Amish quilts.
It felt like a miracle. It was temporary, but it was memorable.
Potassium has numerous roles in the body, but one thing that it does is increase nitric oxide release by blood vessels, potentially increasing blood flow in a way similar to the way Imdur worked in Fluge and Mella’s patient.(10)
Rumor is a lot of ME/CFS patients have mutations in an enzyme called MTHFR, which may have a direct bearing on nitric oxide production. Preliminary results from a genetic study suggest that we do have an increased incidence of mutations.(11) I have two different mutations, which together result in a big deficit in the function of the enzyme.
MTHFR turns dietary folates and folic acid into an advanced form of the vitamin called methyl folate. Methylfolate helps increase nitric oxide production in blood vessels in part by increasing a substance in the body called BH4. Low methyl folate levels mean that your BH4 levels will always be in danger of running low and when BH4 is low, you will have reduced production of nitric oxide.(12,13)
Low MTHFR function is also linked to a general susceptibility to blood vessel damage.(14)
Taking a methyl folate supplement makes my skin and fingernails pink, makes me warmer, relieves fatigue and helps me feel more at ease and more social. Methylfolate, by all appearances, increases blood flow.
[A word to the wise, taking methyl folate seems to produce potassium deficiency in many people with ME/CFS, and potassium deficiency can be unpleasant and even dangerous. I encourage you to ask your doctor before trying this.]
Biotin, which I wrote in my last article helps with my fatigue and my autism, increases a substance called cGMP. The way the nitric oxide works on blood vessels to increase blood flow is to stimulate the production of cGMP. Taking biotin thus skips the nitric oxide step but arrives in the same place as nitric oxide. Biotin makes my hands and fingernails pinker and warmer.
In an article on Cort Johnson’s ME/CFS website Health Rising, he writes about a patient’s response to a drug called Mestinon. Mestinon increases the level of a chemical called acetylcholine in the body.(15)
This patient had ME/CFS for 28 years and could not exercise. After starting Mestinon, she felt like going for a run and did. Then she went cross-country skiing. While not totally well, now she works out at the gym, runs three miles twice a week and works full time.
A 2003 case report from a group of Japanese researchers reported that three patients with ME/CFS recovered or had substantial improvement when taking Mestinon.(16)
The generally proposed mechanism of the drug for people with ME/CFS is that it produces a shift in the nervous system away from the stressful “fight or flight” function thought to predominate in our illness back towards a more balanced and restful state. That could be correct, but I will propose another mechanism: by increasing acetylcholine concentration in the body, Mestinon increases the synthesis of nitric oxide and dilates small blood vessels, allowing for increased blood flow.(17)
A possible reason that agents that increase nitric oxide might be effective is that they bring more blood and more oxygen to cells so that mitochondria can make more energy. If so, this supports the idea that excess nitric oxide may not be the most fundamental cause of low energy production. Rather, oxygen delivery may be the core problem.
Oxygen, Autism and ME
I am extremely sensitive to minor decreases in oxygen. This suggests that something about my usage of oxygen is on the edge, close to a precipice of critical dysfunction. Under low oxygen conditions, my ME/CFS gets worse and so does my autism.
I get sicker the day after a plane flight. I feel like I have a bad flu, minus the fever. I have more trouble telling what other people are thinking and more trouble acting in a way that I understand to be normal. Airplanes are low air pressure environments which reduce the amount of oxygen in the blood. A BBC article pegged the amount at a 6% to 25% reduction in blood oxygen levels.(18) Most people don’t notice this minor drop in oxygen.
I also feel much worse simply on low air pressure weather days which also slightly reduce oxygenation in the body. Low-pressure air days include cloudy days, rainy days and often days when the weather is changing. A lot of people who have illnesses like mine feel unusually bad on low air pressure days.
Red Blood Cells
The Open Medicine Foundation, our group of world-class researchers dedicated to finding treatments for ME/CFS as quickly as possible, had a recent discovery about red blood cells. Red blood cells are responsible for delivering oxygen around the body.
ME/CFS Patients have red blood cells that are too stiff.(19) Red blood cells are a bit too big to fit through our smallest blood vessels, our capillaries, and so they are normally a little squishy. Healthy red blood cells deform or change shape, to squeeze through tiny blood vessels to deliver oxygen. If these cells are too stiff, blood flow through capillaries is impaired.(20)
In sepsis, red blood cells are also stiff and have trouble deforming to fit through capillaries. A decrease in red blood cell deformation, or squishiness, in sepsis is linked to problems with microcirculation, the blood flow through the smallest blood vessels in the body.(21) Problems with microcirculation are at the heart of what goes wrong with the body in sepsis and might be crucial for the illness process in ME/CFS.
The tiny vessels of the microcirculation are responsible for bringing oxygen to individual cells in the body. When microcirculation is not working, it doesn’t matter how much oxygenated blood you have in larger blood vessels, cells and tissues will still starve for oxygen.
In sepsis, this is exactly what you find: oxygenated blood, but tissues starving for oxygen.
When the tissues are lacking in oxygen, they turn off oxygen-using mitochondrial energy production and switch to a different process called glycolysis that does not use oxygen. Glycolysis is less efficient. Various studies have found abnormalities in ME/CFS involving increased glycolysis and trouble making energy in the mitochondria.(22-24)
What Is Sepsis, Really?
Sepsis begins with an infection, but it is actually an illness of the blood vessels. In 2015, a panel at the U.S. National Institutes of Health (NIH) redefined sepsis as an injury to the endothelium, a tissue that lines blood vessels. The damage to the endothelium causes severe harm to the microcirculation, the blood flow through our smallest blood vessels.(25)
Central to this process of injury is a material called glycocalyx.
Glycocalyx is a fragile, fuzzy, jelly-like substance that lines the interior of blood vessels all over the body. Inflammation causes glycocalyx to disintegrate and slough off blood vessel walls.
The ubiquity of glycocalyx inside blood vessels throughout the body explains how a bacterial infection in one part of the body turns into a devastating bodywide illness in sepsis.(26)
Substances that degrade glycocalyx travel through the blood triggering the same damage all over the body.
Glycocalyx damage provides a second reason for low blood pressure in sepsis. When glycocalyx is lost from blood vessel walls, water from the blood leaks through them and into surrounding tissue, producing edema, or swelling, and a drop in the total amount of blood in circulation.
This loss of glycocalyx is closely associated not only with blood volume loss but also with the harmful changes to microcirculation that are typical of sepsis.
Glycocalyx makes nitric oxide and production of nitric oxide by intact glycocalyx in small blood vessels keep these vessels open so that blood can flow through them.(27) Keeping blood vessels open is actually an active, dynamic process that the glycocalyx performs.
With the loss of glycocalyx in sepsis, a very peculiar pattern of blood flow develops.(28) This is difficult to visualize in tissues from living human beings, but we have seen this phenomenon in numerous animal studies as well as from studies in which researchers took images from the thin membranes underneath the tongue in sepsis patients.
Instead of a webwork of tiny vessels with blood flowing through every vessel, what we see is capillaries with blank patches where a steady flow of red blood cells should be. Instead of a regular road map, it looks like a roadmap with sections of the roads washed out. The slowdowns and stoppages occur in a dynamic process: sometimes blood flows through certain vessels, sometimes it doesn’t.(28)
This pattern of blood flow causes remarkable difficulty in cells being able to use oxygen for energy, consistent with what we find in both ME/CFS and sepsis patients. Plenty of oxygen in the blood, but a decline in cells actually using oxygen to make energy.
Both glycocalyx loss and the hardening of red blood cells are able to trigger problems in microcirculation. The relationship between these two processes is still mysterious, but it is conceivable that, among other effects, red blood cells that are unable to fit through capillaries deny oxygen to the blood vessel walls themselves, damaging them and triggering inflammation and the loss of glycocalyx. We also know that the loss of glycocalyx limits nitric oxide production by blood vessel walls and increases inflammation and damaging free radical production. The loss of nitric oxide and the increase in oxidative stress under these circumstances can trigger red blood cell hardening. Thus, conditions created by glycocalyx loss can contribute to the hardening of red blood cells. (29,30)
It remains to be seen whether hardened red blood cells are causative in ME/CFS, whether they function more as a marker of overall blood vessel dysfunction, or whether they have some other cause. Perhaps these altered cells are both a cause and a result of microcirculation problems.
A vascular problem called Raynaud’s phenomenon is very common in ME/CFS patients. In Raynaud’s, small blood vessels in the fingers and toes constrict in response to changes in temperature. The skin there looks white or blue-ish while the phenomenon is occurring.
I have Raynaud’s and I did not have Raynaud’s until I developed ME/CFS. Raynaud’s doesn’t usually cause permanent damage, so it is remarked upon occasionally, but generally considered unremarkable and unimportant. What if it is actually an important sign of broader blood vessel dysfunction in the illness?
In Raynaud’s, we have evidence of red blood cell hardening.(31) We also have evidence of a deficit of nitric oxide in blood vessels in people with the condition.(32) My Raynaud’s resolves with the nitric oxide promoting supplements that I take.
In an interesting if preliminary bit of evidence, a series of published case studies from an Italian doctor reported that Raynaud’s patients improved with a supplement called mesoglycan.(33) Mesoglycan is made up of the same stuff as glycocalyx and is known to work to thicken the glycocalyx layer in blood vessels.
Does restoring glycocalyx with mesoglycan resolve the deficit of nitric oxide in small blood vessels, relieving the condition? If Raynaud’s is related to a deficit of glycocalyx, is the prevalence of Raynaud’s in ME/CFS a sign that we have a problem with glycocalyx and does this deficit result in changes in our blood flow?
In sepsis, the patchy and ever-changing delivery of blood flow results in a lack of oxygen and nutrients reliably reaching cells. Blood vessels keep opening and closing, denying blood flow and then reintroducing it.
Different than simply cutting off oxygen indefinitely, this pattern of blood flow reminds me very much of a phenomenon called ischemia-reperfusion.
Ischemia is blood flow deprivation and reperfusion is when blood flow returns. In a stroke, for example, the brain is deprived of blood flow and then it is restored.
The injury caused by Ischemia-reperfusion is much more destructive than oxygen deprivation by itself. While the oxygen deprivation of ischemia slows down normal energy production in mitochondria, the return of blood flow causes an explosion of oxidative stress. During oxidative stress, cells emit more toxic free radicals than the body can control and these free radicals trigger inflammation and damage. Prominent among these free radicals is peroxynitrite, that damaging chemical long implicated in ME/CFS.(34)
In sepsis, the peculiar alterations in blood flow may produce a situation like ischemia and reperfusion.(35,36)
- Do we look like sepsis patients because our blood flow is like sepsis patients and is this because of glycocalyx disruption or other microcirculatory damage?
- Do we have chronically elevated peroxynitrite because of this pattern of blood flow that resembles ischemia-reperfusion?
- If we have this pattern of blood flow, what might be some of the other implications?
One possible consequence of such a pattern of blood flow, if it does resemble ischemia-reperfusion, is that it might cause an illness that does not end. The damage arising from ischemia-reperfusion is very effective in causing glycocalyx to disintegrate.(37) Damaged glycocalyx would then further prolong alterations in blood flow patterns.
Mast Cell Activation Syndrome
In sepsis, the disease process goes off like a bomb. In ME/CFS it is more like a soft rumble that goes on forever. An ongoing, non-fatal dysfunction.
Dr. Bell wrote of a patient in his town whom he saw a few days prior to his developing a full-blown infectious illness that would leave him with ME/CFS. This patient had remarkably red cheeks.(2)
Bell thought that maybe an unusual parvovirus variant might have infected people in his town because parvovirus can cause a red rash on the cheeks by causing inflammation in blood vessels. In his book, Bell proposed that people with ME/CFS have a vasculopathy, which I think was a quite prescient observation about blood vessel function in the illness. Vasculopathy means that something, we don’t necessarily know what, is wrong with the blood vessels.
I don’t know if Dr. Bell’s patients truly had parvovirus or some other event that caused a change in blood vessel function, but when I first got sick, my cheeks and ears and nose flushed like crazy. There was nothing subtle about the flushing. It looked and felt like a sunburn. It was embarrassing.
When I first got sick, I also developed hives from my knees to my waist. I had never had hives before. Both the flushing and the hives are signs of an immune system event called mast cell activation. (38,39)
Like many ME/CFS patients, I have a disorder called mast cell activation syndrome (MCAS) that either developed or markedly worsened when I got sick at sixteen. Mast cell activation syndrome is a condition in which mast cells activate frequently and in an exaggerated way.
Mast cells are immune cells. They are a little weird and not completely understood. Mast cells are often hard to find and quantify under a microscope and this is one reason we have had difficulty understanding their role in illness. They are also multifunctional, kind of like the Swiss army knife of immune cells. These cells carry within them a vast diabolical tool kit of inflammatory substances and destructive enzymes. They are stationed at the surfaces of the body, in the skin, in the gut, in the lungs, and in the blood vessels and serve as first responders to various signs of danger. Their purpose is to return the body to homeostasis, our normal state of health, but prolonged activation or errant activation can cause inflammatory illness because they are found in so many places and release so many potentially damaging substances.
The symptoms of MCAS overlap heavily with ME/CFS and related disorders and include severe fatigue, cognitive problems, widespread pain, food intolerances, sleep difficulties, migraines, irritable bowel syndrome and more.(38-46)
Dr. Theoharis Theoharides, MD, Ph.D., a researcher at Tufts University who studies mast cells, has connected mast cell activation to at least certain subsets of autism.(47) My food allergies trigger not only flushing but autistic symptoms like an intensified inability to take the perspectives of others, irritability, anxiety, and rigidity. A bad food allergy reaction looks quite a bit and feels quite a bit like an autistic meltdown.
Nancy Klimas is a physician beloved among ME/CFS patients for her compassion, intelligence and humble devotion to illuminating the cause of this illness. I saw her at her office about 15 years ago. She wasn’t able to help me then, but perhaps five years ago her office called me to ask what I thought was the cause of my own illness. I think that her office was doing a project of calling numerous old patients and asking them the same question. Bless her for listening to us.
I told her office without a doubt it was the food allergies. The food allergies that triggered insomnia, exhaustion, confusion, forgetfulness, and pain. The food allergies that were not the type of nuisance allergies that allergists treat with medications and allergy shots, nor the type of food allergies that cause deadly anaphylaxis. These were a different type of food allergy, a type that medicine does not research or acknowledge and left me utterly alone to deal with. An onslaught of allergies too numerous to escape that made me too ill to function each day for decades.
At my workplace, I don’t talk about my autism, though I will help people if they or their kids need it without explaining how I know what is wrong and how to fix. A few years ago, word got to me that a coworker’s 4-year old son had Aspergers. He wanted some help and I suggested to his dad for him to stop eating what many people with MCAS find to be their worst foods: dairy, wheat, corn, soy, and eggs. All it took was dairy. This coworker sent me a video of his son a few days later, talking like any four-year-old: bubbly, cheerful, asking for a hot dog and ketchup. Cured, apparently.
What causes this mysterious syndrome of chronic mast cell hyperactivation? Why the suddenness of the onset? When I was sixteen, I had a sudden explosion in mast cell activity What happened?
Perhaps the answer lies in changes to the microcirculation.
Mast cells lie in close proximity to blood vessels all over the body and situations of ischemia and reperfusion trigger the activation of mast cells and the release of their vast array of inflammatory substances and enzymes. If we have a chronic pattern of blood flow similar to ischemia and reperfusion, it could be enough to trigger chronic mast cell activation.
Mast cells are not only triggered by ischemia-reperfusion, they are crucial to the damaging effects of ischemia-reperfusion.(48-51) Part of the damage that mast cells cause is to destroy glycocalyx.(52)
Mast cells release an enzyme called heparanase and an inflammatory mediator called TNF-alpha when activated and both are efficient at destroying glycocalyx.(53) In this way, chronic mast cell activation might be able to produce damage to blood vessels and circulation in a way that resembles a slow, rumbling sepsis-like condition.
I take a mast cell inhibiting drug combined with the common antihistamine Benadryl to control mast cell activation. This combination is globally and enormously helpful. People with MCAS take a variety of drugs to contain the mast cell activation and like me receive relief for numerous seemingly disparate symptoms.
The idea that mast cell activation could have effects on blood vessel function all over the body is not new. According to the research of Nicholas Kounis, MD, mast cell activation is capable of triggering heart attacks by disrupting the function of small blood vessels in the heart and is capable of disrupting the function of blood vessels all over the body, including in the brain. Dr. Kounis named this phenomenon Kounis Syndrome, and he considers it to be relatively common but vastly underrecognized. (54,55)
Heparanase & Heparan Sulfate
In ME/CFS, we have a chronic inflammatory condition, often begun by an infection, but without evidence of ongoing infection. We are probably looking for a non-infectious perpetuator.
Heparanase, that enzyme released by activated mast cells, liberates heparan sulfate, the major component of glycocalyx, into general circulation where it acts a powerful immune activator by interacting with a receptor called TLR4. This is the same receptor activated by disseminated bacterial infection in sepsis, the same receptor that begins a sequence of events that ends in glycocalyx loss and microcirculatory dysfunction.(56) Thus, a condition in which circulating heparan sulfate is elevated stands a good chance of looking rather like sepsis.
The release of heparan sulfate into circulation has been proposed to serve as a cause of systemic inflammatory response syndrome (SIRS). SIRS is essentially just like sepsis but can be triggered by a range of infectious and non-infectious causes. Sepsis is actually one kind of SIRS, SIRS triggered by bacterial infection. Like sepsis, SIRS is an overwhelming inflammatory event that triggers a devastating microcirculatory dysfunction.
At the 2017 Open Medicine Foundation Symposium at Stanford, Wenzhong Xiao, Ph.D., presented evidence that the gene expression in ME/CFS resembled SIRS more than any other illness.(57)
Might chronic mast cell activation cause a constant release of heparan sulfate and could this contribute to a condition that looks like low-grade sepsis or SIRS?
Endothelin-1 and Nitric Oxide
One molecule that comes up over and over again in my searches about mast cells and glycocalyx is endothelin-1.
Endothelin-1 both activates mast cells and destroys glycocalyx.(58,59) Its release is triggered by various events, but one cause ischemia and reperfusion.(60,61) Endothelin-1 is elevated in sepsis. Infusion of endothelin-1 replicates many of the vascular changes that occur in sepsis and endothelin-1 antagonists have reversed the microcirculatory changes in sepsis.(62)
Endothelin-1 and nitric oxide have a special relationship. They inhibit one another.(63) In a situation of glycocalyx loss, where less nitric oxide is produced, one effect could be a chronic increase in endothelin that triggers chronic mast cell activation and blood vessel damage.61
Raynaud’s phenomenon is related not only to a deficit of nitric oxide but also to an increase in endothelin. Treatments that block endothelin are effective in Raynaud’s and I wonder what the effect would be in ME/CFS.(64)
Low Blood Volume
Like people with sepsis, people with ME/CFS have low blood volume, sometimes extremely low blood volume.(2,65) Perhaps some of this volume loss is related to blood vessel damage and a chronic leak of water from the blood into surrounding tissues. I know I have quite a bit of edema, or swelling, much more than you would expect for someone as young, thin and ostensibly healthy as I am.
Dr. Bell talks about patients who are as much as 50% low in the amount of blood in circulation.1 It is rather remarkable that such people are living, but because the blood loss is not fast, the body somehow finds a new normal. You feel terrible, but you don’t die.
Drinking extra water and eating extra electrolytes to increase blood volume is the among the most common and most universally effective treatments for ME/CFS, although the effects are quite temporary.
In an article on Cort Johnsons’ ME/CFS website Health Rising, Dr. Bell shared anecdotes of some of his patients and the effects of blood volume repletion. Two teenage girls had had symptoms of ME/CFS for two to three months, well before the point where they could be formally diagnosed with the illness. Dr. Bell gave them saline IVs for a week. Rather than developing an interminable illness, both appeared to make a complete recovery.(66)
In another patient who had been sick for many years, a single blood transfusion resulted in a recovery for about six weeks for this patient.(66)
In the early phases of sepsis, increasing blood volume with IV fluids restores blood flow through the microcirculation, allowing for better oxygen delivery.(67) When Dr. Bell gave his fluids, maybe he was actually restoring blood flow at the microcirculatory level, cutting short a process that eventually leads to intractable problems with microcirculation.
Conversely, when blood volume is low, this in itself can trigger problems with microcirculation. I think that chronic low blood volume is intrinsically problematic for microcirculation and we don’t yet realize all the implications.
If ME/CFS looks like slow, chronic sepsis, maybe it also looks like slow, chronic hemorrhage. A curious thing about hemorrhage is that, at the level of blood vessels, it looks almost indistinguishable from sepsis and actually constitutes a non-infectious cause of SIRS.(68) Glycocalyx disintegrates with hemorrhage and problems with microcirculation ensue.(69)
It is a testament to how little research funding this illness has received that we have not further investigated why exactly patients have low blood volume, what the effects of this might be and what treatments might be practically employed that are more effective than drinking water and eating salt. Low blood volume seems to be a fact considered unremarkable by mainstream medicine.
What if ME/CFS could be averted in many patients by the administration of saline IV’s, one of the most common and least expensive medical interventions available?
Robert Naviaux, Ph.D., whose work I discussed in my first article, is a researcher at the University of California San Diego. Dr. Naviaux is working with the Open Medicine Foundation to find answers for ME/CFS patients.
In studying the metabolism of patients, Dr. Naviaux identified a class of fatty compounds called sphingolipids as the point of greatest differentiation between healthy controls and people with ME/CFS. Sphingolipids were markedly downregulated in ME/CFS patients.(70)
Albumin is the most abundant protein in the blood and its presence is perhaps the most important protective factor for the health and stability of glycocalyx. The part of albumin that stabilizes glycocalyx is a sphingolipid called sphingosine-1-phosphate (S1P). Without S1P, albumin does not protect glycocalyx.(71)
In a study published in October 2018, researchers found that S1P preserves glycocalyx integrity and function during hemorrhage.(72)
If we have a global reduction in the sphingolipid compounds, is our S1P sphingolipid also low? If we do have low S1P, might ME/CFS patients be unusually sensitive to glycocalyx damage from any cause including inflammation or low blood volume? If this were the case, would intravenous albumin be more effective than intravenous saline for improving microcirculatory function? Intravenous albumin is derived from the blood of other people and would presumably contain normal amounts of S1P.
Many researchers have proposed that cells, tissues, and organs in sepsis assume a hibernation-like state.(73) Organs look like they are dying, but can fully and quickly recover if microcirculation and oxygen delivery is restored in time, kind of like a bear will wake up from winter slumber as long as winter doesn’t last forever.
Humans don’t hibernate seasonally, but we do carry a genetic inheritance from ancient and primitive organisms that reduced energy consumption in order to survive all kinds of adversity. We are, in certain circumstances, able to reduce the consumption of oxygen and other resources during times when these are resources are scarce.
Like sepsis, ME/CFS bears resemblance to hibernation.(70) At a cellular level, energy production remains low for a long period of time, but evidence suggests that our condition may be fully reversible. Somehow, we look close to death, but almost never die.
Fluge and Mella, the researchers who patented nitric oxide agents in ME/CFS, conducted a study with 200 patients in which they found that an enzyme called pyruvate dehydrogenase (PDH) was inhibited in ME/CFS.(74) PDH inhibition is very effective at reducing mitochondrial energy production and, consequently, total energy production.
While the study of hibernation-like mechanisms is preliminary in the human body as a whole, we know quite a bit about hibernation in one part of the human body: the heart. When the human heart has a reduction in blood flow, as happens sometimes in heart disease, sometimes that portion of the heart does not die or even undergo permanent damage. Rather, it hibernates and temporarily fails to contract.(75) When oxygen returns, that portion of the heart will start beating again. Like ME/CFS patients, heart tissue is disabled in function under these conditions, but not permanently disabled.
Key to heart muscle hibernation appears to be a molecule called hypoxia-inducible factor-1 (HIF-1).(76) HIF-1 is the master protein that coordinates the body’s response to hypoxia or low oxygen levels. One of the key effects of HIF-1 is to reduce PDH activity, the same enzyme that Fluge and Mella found a reduction in function for in their group of 200 patients. HIF-1 affects a variety of metabolic components with the overall effect of increasing glycolysis and decreasing mitochondrial energy production, both events seen in ME/CFS.(77)
Could HIF-1 be the cause of chronic low energy production in ME/CFS? Could this be the source of our hibernation-like state? A few observations: states of low oxygen, ischemia-reperfusion, oxidative stress, and inflammation can all cause HIF-1 to increase.
Dr. Ron Tompkins helps run the ME/CFS Collaborative Research Center at Harvard University. In an interview on Health Rising, Dr. Tompkins talked about a study he helped conduct with severe burn patients. Burn patients have elevated levels of HIF-1 and Tompkins remarked that he expected that ME/CFS patients would have high HIF-1 levels as well.(78)
The precise parallels between ME/CFS patients and burn patients are not entirely clear but, but burn patients typically develop severely low blood volume due to fluid losses from the injury plus a huge increase in inflammation that disseminates all through the body. SIRS is common after severe burns. I wonder if elevated HIF-1 is common to SIRS no matter what the cause because the relationship between SIRS, disturbed circulation and widespread inflammation.
Glycocalyx & Autism: A Connection?
One theory about autism is that the cause is a deficiency in heparan sulfate. Heparan sulfate is not only the major component of glycocalyx, it is a structural material in the brain and throughout the body. Without enough heparan sulfate, the brain develops differently and functions differently. In animals, a lack of heparan sulfate caused an increase in the generation of neurons during development that seemed to parallel the accelerated growth in the brains of young children with autism. This early growth in brain size is linked to the characteristic larger head size often found in people with the disorder.(79)
Heparan sulfate deficient animals display symptoms similar to autism, including social deficits and repetitive behaviors.(80)
Autistic people have been found to have increased excretion in their urine of heparan sulfate and other molecules that are found in glycocalyx.(81) Interestingly, in a group of autistic children, this excretion of heparan sulfate and similar molecules was reduced by a special diet which excluded milk casein. Dairy is a common allergen for people with mast cell activation syndrome.
Researchers have theorized that people with autism may have problems in the synthesis of heparan sulfate. I wonder if a deficiency could be caused, at least in some cases, by a continual loss of heparan sulfate dislodged from blood vessel walls and other tissues by a process not unlike sepsis and this is why we see elevated amounts coming out in the urine. Perhaps the loss of heparan sulfate is triggered by chronic mast cell activation and the release of glycocalyx degrading substances. When the children in the dietary study avoided dairy, maybe this slowed mast cell activation and this why the children lost less heparan sulfate through their urine.
Sometimes sepsis doesn’t end in death or recovery. It ends in post-sepsis syndrome.(82) Post-sepsis syndrome looks eerily like ME/CFS with severe chronic fatigue, muscle and joint pain, cognitive difficulties and sleep problems. Like ME/CFS, post-sepsis syndrome is just barely recognized by mainstream medicine and the predominant treatment recommendation has been cognitive behavioral therapy, a psychological treatment that has been foisted on ME/CFS patients as well.
I imagine that cognitive behavioral therapy is about as effective for post-sepsis syndrome as it is for ME/CFS, that is, not all effective for the underlying condition and sometimes modestly helpful for coping with a chronic and devastating loss of biological function.
To me, the obvious connection is that sepsis can sometimes not quite resolve and that it can instead turn into something that looks like a slow, chronic sepsis. Sometimes people don’t heal from sepsis and process of sepsis leads to something that looks like ME/CFS.
I propose that any event that has the potential to acutely trigger SIRS, that sepsis-like condition, also has the potential to set in motion or perpetuate something that looks like ME/CFS.
Non-infectious causes of SIRS include hemorrhage, dehydration, surgery, injury, and ischemia-reperfusion. Of these, injury and surgery are known to trigger ME/CFS. The low blood volume that we have is physiologically similar to dehydration and hemorrhage and may also cause a situation similar to ischemia-reperfusion through damage to microcirculatory function.
Question: In ME/CFS, do chronic low blood volume and/or chronic mast cell activation keep us sick by causing continual damage to blood vessels and glycocalyx?
ME/CFS has myriad causes, but somehow we all end up in the same place biologically. The dissolution of glycocalyx and the ensuing problems with delivering oxygen to cells could unite us all.
Stress, supposedly a psychological cause of illnesses that aren’t actually real, causes adrenaline release. Adrenaline can cause severe damage to glycocalyx.(83) Stress also triggers mast cell activation.(39) We classify stress as a psychological event, but stress may cause physical consequences that, in some people, may not be readily reversible simply by removing the initial psychological stressor.
Those who have championed the notion that ME/CFS is a psychiatric disorder have sometimes pointed to the fact that we have not found a lesion: a visible, obvious defect.(84) We have not identified a gross structural problem, a telltale antibody or an ongoing infection. The thinking goes that medicine understands so much that our disease is not likely to be physical because we would know the cause by now.
Patients who have been bed bound for years should be enough for anyone to believe that the illness is physical. We should thus be looking for something scarcely visible. We should be looking for something we don’t quite understand yet, something we can’t quite see clearly.
Microcirculation, the blood flow through our smallest blood vessels, is something difficult to visualize and measure in living humans, and yet deviations from normal have consequences that can affect every organ in the body, can alter metabolism and can increase inflammation. Microcirculation abnormalities could be an invisible force perpetuating a diffuse, mysterious illness.
Let’s look closely here.
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