Genetics, the mono virus, gut bacteria, and even hormones have all been blamed for chronic fatigue.
But what if we are getting too specific? Maybe the root cause of fatigue is something more generalized.
I believe chronic fatigue is a consequence of inflammation. Out of control inflammation that affects multiple body systems.
The last time you sprained your ankle, it became red, hot to touch, swollen, and painful didn’t it?
This is the inflammatory process at work. And when it occurs in a localized area (like an ankle), the process of inflammation works wonders. Inflammation is absolutely essential for your body to heal that ankle sprain. Inflammatory cells (macrophages) release a hormone called insulin-like growth factor 1 (IGF-1). IGF-1 helps your muscles and other damaged tissue in the area to heal.
When you ice an ankle sprain, you send away those macrophages, which suppresses your body’s ability to heal the injury. This is why I never recommend to ice an injury. New research suggests icing an injury actually makes things worse.
But Chronic Fatigue Syndrome is a much more complex process than an ankle sprain. That’s why CFS affects many different areas of your body, from your brain to your immune system. And inflammation may be what’s at the root cause of all your problems.
What exactly is inflammation?
Inflammation is the complex biological response your body uses to respond to harmful stimuli.
Your body has two immune systems that respond to intruders:
- Innate immune system
- Adaptive immune system
The innate immune system is a generic immune system response that relies on inflammation. As soon as your immune system identifies an intruder, it creates inflammation, which is a physical barrier between the intruder and itself. It’s a generalized means to eliminate invaders.
The adaptive immune system is much more specific. Adaptive immunity occurs after an initial exposure to some type of intruder, like a virus or bacteria. Remember chickenpox (varicella virus)? The reason you can’t catch that virus more than once is because your adaptive immune system remembers it. When you encounter the intruder again it is easily neutralized. The adaptive immune system is a targeted approach to eliminate invaders.
One theory of the cause of chronic fatigue is that for some reason the innate immune system can’t turn off. This causes inflammation to run rampant. And constant inflammation is tied to fatigue.
The chronic fatigue & inflammation connection
Many chronic fatigue patients report that their symptoms began after infection. Sometimes the infection was a bad flu virus. Others report their fatigue began after catching mono.
As far as inflammation goes, this makes sense. Flu viruses, mono viruses, and any other infectious agents all require your body to create inflammation in order to neutralize the attack. What if the infection prevents your innate immune system from turning off?
What confuses most doctors is that conventional inflammatory markers are rarely elevated in chronic fatigue syndrome. These conventional markers include:
- C-reactive protein (CRP)
- Erythrocyte sedimentation rate (ESR)
But these usual suspects do not cause the inflammation found in Chronic Fatigue Syndrome.
Multiple studies (and a meta-analysis) have found there are two inflammatory markers commonly out of range in chronic fatigue. These two markers are:
- Transforming growth factor beta (TGF-β)
- This marker is commonly higher in chronic fatigue.
- Resistan
- This marker is commonly lower in chronic fatigue.
Transforming growth factor beta (TGF-β)
It is commonly thought that TGF-β is an anti-inflammatory cytokine. When your body is dealing with an infection or inflammation, it releases TGF-β to help lower the levels of inflammation. This explains the high levels of TGF-β in CFS – your body is trying to lower inflammation, and there’s a lot of inflammation in CFS. So, TGF-β levels rise.
But new studies are suggesting that TGF-β can alter its role depending on its location in your body. In conditions like inflammatory bowel disease (IBD), TGF-β contributes to inflammation in the gut. If this is the case in chronic fatigue as well, TGF-β could be the cause of the high levels of inflammation within your body.
Resistan
Resistan has been shown to have a significant effect on promoting inflammation. That is to say, it is a pro-inflammatory cytokine. People suffering from autoimmune conditions like lupus (SLE) and Crohn’s disease have high levels of resistan.
However, when looking at patients suffering from chronic fatigue, resistan is a bit more confusing. Patients with mild-moderate levels of fatigue show increasing levels of resistan. But resistan levels decrease in patients with moderate-severe levels of fatigue. At the time of this writing, researchers are unsure why resistan levels fluctuate as chronic fatigue gets worse.
Resistan and TGF-β are two of the inflammatory markers that are usually out of range in Chronic Fatigue Syndrome. With all this inflammation going on, could Chronic Fatigue Syndrome be closely related to an autoimmune condition?
Is Chronic Fatigue Syndrome an autoimmune condition?
The autoimmune-fatigue theory came about by accident. In 2008, an oncologist in Norway treated one of his cancer patients with a drug called rituximab, a drug that treats autoimmune disorders. Shortly after receiving rituximab, the patient’s chronic fatigue was gone. This sparked a small research trial into the effectiveness of rituximab on CFS.
Thirty patients were given either rituximab or a placebo. Almost 70% of chronic fatigue patients that received rituximab reported a significant decrease in their fatigue (compared to only 13% of those that received a placebo). It’s effective in the treatment of autoimmunity as it decreases the effectiveness of your immune system.
After this study the researchers proposed that Chronic Fatigue Syndrome was, in fact, an autoimmune condition. New research investigated CFS under the light of autoimmunity. But when a large scale clinical trial was run, it found that rituximab didn’t offer any long-term benefit to CFS patients. The final conclusion at this time is that Chronic Fatigue Syndrome is not an autoimmune disease.
Something autoimmune diseases and chronic fatigue do share in common is inflammation. And new research suggests that there is a connection between fatigue and specific markers of inflammation.
More inflammation, more fatigue?
Thanks to modern testing methods, researchers are now aware of far more inflammatory cytokines than ever before. This means that we can measure even more variables to check for fatigue. You no longer have to depend only on c-reactive protein (CRP) and ESR as the only ways to measure inflammation and immune activation, although most family doctors still rely on them.
The cytokine factor
Cytokines are molecules that aid cell to cell communication in immune responses, and stimulate the movement of cells towards sites of inflammation, infection, and trauma. A recent study looked for a connection between 51 different cytokine levels and Chronic Fatigue Syndrome. This study compared cytokine levels of 186 CFS patients to cytokine levels of 388 people who didn’t complain of fatigue. In this study, there were 17 different cytokines that were strongly tied to severe fatigue.
Of these 17 cytokines, 13 of them were pro-inflammatory, which means that they help your body increase inflammation. Odds are high that it’s these cytokines that contribute to a number of the symptoms commonly associated with CFS.
These 13 inflammatory cytokines had a strange connection to chronic fatigue. We assume if they are inflammatory, and they contribute to fatigue, CFS patients would have higher levels than member of the general population. But that’s not what happened at all.
The cytokine levels of the people who had mild or moderate chronic fatigue were statistically lower than members of the general population. But the levels of these cytokines in people with severe or debilitating fatigue were elevated. This is why so many other studies have been unable to find a strong connection between inflammation and chronic fatigue syndrome.
It’s not a direct relationship between inflammation and fatigue. More inflammation does not always create more fatigue.
A unified fatigue-inflammation theory
No wonder Chronic Fatigue Syndrome is so complicated. Even inflammatory markers don’t follow a “normal” curve in this condition. But there’s a theory as to why that may be.
Those with CFS may have an immune system that functions differently than the general population. Dr. Ritchie Shoemaker believes this genetic difference to be caused by the HLA genes. Approximately 25% of the population has these genes. And these genes may trigger a chronic inflammatory response.
Chronic fatigue patients could have a genetic preponderance to lowered baseline levels of inflammatory cytokines. This has been illustrated through the above study – in general, CFS patients had lower levels of inflammatory cytokines when compared to the general population. The catch here is that this only occurs when the fatigue is mild.
Once fatigue levels increase, chronic fatigue patients have strong elevations of inflammatory cytokines. The levels of inflammatory cytokines in CFS patients levels are far higher than that of the general population (but only when fatigue levels are severe). This cyclical nature of inflammation could come about through the immune system acting on an infectious agent(s).
Mold & fatigue
Take mold for example. Mold illness is a root cause of chronic fatigue. In genetically susceptible individuals, mold (and their mycotoxins) trigger the innate immune system to respond. The response of the innate immune system is always one of inflammation. Those with the HLA genes struggle to expel the mold toxins from their body. This results in a vicious cycle of inflammation. Below, I lay out a proposed mechanism of action:
- Step 1: Immune system is dormant when fatigue levels are moderate
- Possibly why you see low levels of cytokines in CFS patients with mild fatigue levels.
- Step 2: Immune system identifies an infectious agent
- This is the in-between stage. Where in the study inflammatory cytokines were neither high nor low.
- Step 3: Immune system reacts to the infectious agent
- This is when you would see an increase in inflammatory agents in the blood.
- The immune system has identified the infectious agent and is mobilizing a response to fight it off.
- Step 4: Immune system calms down
- After mounting an attack, the immune system down-regulates.
- Step 5: Repeat
- This cycle continues on and on without ever fully resolving the condition.
This cycle of inflammation would explain why your fatigue could be good on some weeks/months (calming of the immune system) yet debilitating the following week/month (activation of the immune system). A more detailed look at the inflammatory process can be found here. And if you want to know more about mold’s connection to chronic fatigue, I have written many more blogs on mold!
To summarize, there is a connection between inflammation and chronic fatigue. But exactly how that relationship exists needs more research.
Now, I want to hear from you!
What have you noticed negatively affects your energy levels?
Do you think it could be because it raises inflammation in your body?
Let me know in the comments section below!
