Let’s Talk About Fatigue (part 2)

In part 1 of this series, I discussed fatigue or low energy in broad terms and then briefly explained how hormones may play a role. If you remember, I commented that I’ve observed in clinical practice that most people’s fatigue is due to one of these three underlying causes:

  1. Hormone abnormalities
  2. Oxidative stress
  3. Nutrient deficiencies

What is Oxidative Stress?

Oxidative stress is another vague term, just like fatigue, that refers to a significant inflammatory load on the body’s antioxidant and detoxification systems, which produces an imbalance of free radicals and antioxidants that would normally neutralize those free radicals.

Antioxidants donate a free electron to a free radical in order to ‘neutralize’ it, which keeps it from searching for extra electrons in places like your DNA, cell membranes, and other important nutrients you need.

What are free radicals?

Free radicals are a class of chemicals that are the byproducts of both normal human metabolism and cellular waste generation, as well as toxic elements that the body is exposed to such as bacterial toxins, environmental pollutants, and other inflammatory particles.

Under normal circumstances, the body has plenty of antioxidants that it both makes and absorbs from food to bind these free radicals and make sure they do not cause damage to cells, tissues, and organs.

However, under circumstances such as a major illness, prolonged physiological or emotional stress, inadequate dietary intake or absorption of certain nutrients, serious medical conditions, or other inflammatory disorders, some or all of these antioxidant systems are impaired — they’re redirected to deal with the illness, inflammation, stress, or just depleted because there are not enough building blocks available.

This causes a build up of inflammatory free radicals.

What are antioxidants?

Antioxidants include some of our vitamins, like A, C, and E. They also include plant-derived compounds referred to as phenolic compounds, or polyphenols.

And, we make some of them, including the ‘master antioxidant,’ glutathione (GSH). GSH is made in our own cells from the amino acids cysteine, glycine, and glutamine, as well as the vitamin B3 (niacin), in the form of NADPH.

Normally our antioxidant GSH gets recycled or regenerated in the body, as long as we have enough of the building blocks available. But in times of increased illness or physiological stress, such as greater demands from the liver to remove something toxic, the amount of GSH being regenerated cannot keep up with the amount the body needs.

This leaves free radicals and other toxins unbound, and they can build up in quantity.

They can bind to cells, cell membranes, DNA, and other structures in the body, damaging them and leading to even more inflammation.

The liver also accumulates many of these free radicals during this deficit of GSH and other antioxidants, which will often lead to elevated liver enzymes on laboratory testing, as well as impaired liver detoxification pathways.

When there are more free radicals being produced than there are antioxidants to neutralize them, you have oxidative stress.

Conditions or disorders in which oxidative stress is a major mechanism of inflammation include:

  • Autoimmune disorders
  • Cancer
  • Metabolic syndrome
  • Insulin resistance
  • Heavy metal toxicity
  • Mold toxicity
  • Pathogenic infections
  • Neurodegenerative diseases
  • Environmental toxic exposures and pollutants
  • Intense exercise
  • Infertility
  • Also occurs as part of the aging process, but can be accelerated in these conditions

These are the main categories in which oxidative stress appears, but there are certainly others, and within each of these we could get even more specific.

The important thing to note is that in each of these cases, something toxic is being produced or absorbed and there are not enough defense mechanisms to effectively dispose of whatever that is.

What happens next depends on the underlying cause, but one of the most common symptoms experienced by individuals in all of the above categories is: fatigue.

Let’s Not Forget Nitric Oxide…

A growing body of research is beginning to support the recognition of the role that nitric oxide (NO) plays in antioxidant function, cell membrane function, energy generation, and immune stability.

Nitric oxide is a normal gas, produced by cells to communicate with each other. It is made from L-arginine, oxygen (O2), and NADPH as substrates; and FMN, FAD, heme, and tetrahydrobiopterin as cofactors. [1]

It influences cardiovascular function through effects such as vasodilation (opening up the blood vessels, which also lowers blood pressure), immune function, and nervous system function.

Decreased production or low levels of NO is actually considered to be one of the earliest warning signs of many chronic illnesses. [2]

illustration from “Nitric oxide in mucosal defense: a little goes a long way.” John L Wallace and Mark J Miller, 2000. Gastroenterology, 2000, vol 119: 2, pp512-20

Low levels of NO are seen in autoimmune diseases, cardiovascular disease, and neurodegerative diseases. [2]

The main theory surrounding NO’s antioxidant activity, and why many people who suffer from chronic illnesses have lower levels of this critical gas is that NO is also a scavenger of free radicals and reactive oxygen species (ROS), which are produced in high quantities during oxidative stress. [3]

Why Does Oxidative Stress Cause Fatigue?

There are a few ways that this symptom manifests in these cases.

During an infection, for instance, immune cells rush to fight the invading pathogen (virus, bacteria, fungus, or parasite). When doing so, these immune cells produce free radicals that target the infectious organisms.

This is normal, but when it occurs in a prolonged manner, over months or years, or the body is unable to fully fight the infection, such as in the case of biofilms in the body, these free radicals are being produced for longer and at higher concentrations than the body’s own antioxidant reserves can keep up with.

figure from Niemann et al (2017). Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution. Journal of the American College of Cardiology
Volume 70, Issue 2, July 2017 DOI: 10.1016/j.jacc.2017.05.043

If oxidative stress has occurred first, such as in the case of a toxic exposure to lead paint in your home, the immune system will be triggered by the initial oxidative stress, and then can create even more free radicals in the process, further increasing inflammation and decreasing available antioxidants.

You can see how in either case, the body’s own internal antioxidant stores and production can become overwhelmed either very quickly, in the case of an acute exposure to something very toxic, or gradually, in the case of a chronic infection. [4]

The feeling of fatigue, or tiredness and low energy, comes from a lack of GSH, but may also be caused by depleted intracellular nutrients.

Intracellular nutrients are depleted when there is greater demand from the liver and internal organs to fight inflammation, to keep the immune system functioning, and when nutritional intake or digestion and absorption may be impaired.

These nutrients include everything from our vitamins, minerals, co-factors, protein/amino acids, fats, carbohydrates, and more.

When there are not enough nutrients to fuel muscle contraction, breathing, heart beat, cognitive function, and basic movement, the body and major muscles will feel fatigued, as it tries to prioritize basic functions (breathing, heart rate, and digestion) over movement.

Sometimes our lack of some of those nutrients also makes it harder for us to carry enough oxygen to certain cells, such as when we have an infection that reduces our available iron, causing us to become anemic, and reduces how much oxygen we can carry in our blood to our heart, lungs, and muscles.

We can also lack a nutrient because we don’t eat enough, and then the oxidative stress makes that primary deficiency worse.

Or, we can lack a nutrient because we have genetic influences that make it more difficult for us to absorb that nutrient in our gut or into our cells, or even to activate or use that nutrient, once its in our body. Added to oxidative stress, this can continue to make a bad situation worse.

Why Do Some People Experience Oxidative Stress More Easily or Intensely Than Others?

Now we’ll get into the questions that I hear posed by people who are skeptical of why some people seem to be more sensitive to toxicity and infections than others.

First, every one of us is different. Even identical twins, who have the same DNA, will have different environmental exposures, different nutrient intake patterns, and therefore, can have vastly different genetic expression sometimes, and different abilities to adapt to stressors and exposures.

These factors below can affect how well you either fight off an infection or toxic exposure or not:

  • Genes
  • Environment (pollution, noise, radiation, air quality, etc)
  • Diet/Nutrient density
  • Microbiome diversity
  • Microbiome plasticity (how easily does your microbiome adapt to changes)
  • Immune system adaptation and robustness
  • Lifestyle (stress management, sleep, exercise)
  • Detoxification efficiency (how well does your body get rid of toxic waste on its own)
  • Prior toxic exposures

As you can see, figuring out why someone is experiencing fatigue from oxidative stress in the first place is a combination of piecing together their history, their lifestyle, their nutrient intake, their genetic influences on nutrients and biological function, their environmental exposures, and overall, how well their body can handle all of this over time.

I will share a personal example to illustrate:

I recently had a concentrated exposure to black mold about 9 months ago. Toxic molds produce mycotoxins, which, in the human body, are extremely inflammatory, causing sudden fatigue, anxiety, depression, body aches, cognitive and mental decline, and quite a few more unpleasant symptoms or side effects, including autoimmune diseases and cancer.

I was lucky enough to catch this before I got really really sick, but I still got really sick. I will make a totally separate post that explains this particular medical problem in more detail, don’t worry.

The key here, though, was that this was not the first time I had had a concentrated exposure to toxic mold. I had been exposed at least 5 other times that I know of, including twice in childhood (once at a house I lived in for 4 years), and three times as an adult (once in military housing, and the other two times at gyms I worked out at).

Each exposure left me less able to fight off the toxic mycotoxins produced and the fungal biofilms that form in the nasal passages and GI tract, among other places, which is common during exposure in buildings in which you spend a significant amount of time (home, work, gym, relatives/friends, etc).

Each time I’ve been exposed to toxic mold, the exposure was more intense and took longer to get over. There are some genetic things to consider here for me, such as I have reduced GSH production genetically, I have reduced MTHFR activity (so I activate B vitamins required for detoxification and liver transformation less efficiently), I have celiac disease, for which the genes are the same for more intense reactivity to mold (HLA DQ).

So, not only am I more susceptible to mold toxins, I am also less able to fight them off and return to health quickly.

And that is just scratching the surface of risk factors for me.

But you can see how, over time, each toxic exposure can gradually leave someone at risk for additional oxidative stress or inflammatory conditions, if not resolved.

How Do You Know if Oxidative Stress is the Cause of Your Fatigue?

Just like I would test someone’s hormone levels if I suspected that hormones and stress or HPA Axis dysfunction were at the root of their fatigue, I would also test for things that directly indicate oxidative stress or are most likely to cause it.

And there won’t be just one or two things that would point me toward exploring this avenue. Its really going to be looking at a whole pattern and ruling this in as the most likely cause first.

After the fourth time I was exposed to toxic mold, I had just run a thorough micronutrient panel on myself to assess where my extra- and intracellular nutrients were, which is where I noted I had severely low glutathione levels, and that was actually done about 2 months after leaving the second gym I had worked out at that had the toxic mold problem.

This is a direct indication that oxidative stress is occurring, although it is not specific for exactly what is causing the oxidative stress.

Some things that would be obvious causes of oxidative stress, but not the true root cause of the illness in question would be a diagnosis of an autoimmune disease or neurodegenerative condition.

Another angle I would examine is toxic exposure potential:

  • do you work around petroleum-based chemicals?
  • do you work in photography or handle photographic chemicals?
  • do you work in agriculture and handle pesticides and herbicides frequently?
  • do you work with animals and handle pesticides frequently?
  • do you work in an industry that you handle heavy metals such as jewelry, fuel, munitions, smelting, mining, or aviation?
  • are you or have you been exposed to radiation?
  • are you or have you grown up under power lines with heavy EMFs?
  • do you have mercury fillings in your mouth?
  • do you have silicon implants in your body that have leaked or ruptured?
  • do you or have you ever lived near a waste treatment facility or manufacturing facility known to have polluted nearby groundwater?

And then I would also assess infection risk or potential for exposure to pathogenic microorganisms:

  • do you or have you traveled out of the country prior to onset of symptoms?
  • have you had a ‘stomach flu’ lately?
  • have you ever had a tick bite?
  • have you ever lived or worked in a building with water damage or that smells musty or feels damp?
  • are other people you live or work with constantly sick with upper respiratory illness?
  • do you have more than one allergy, including foods and seasonal plants/pollen?
  • do you experience persistent diarrhea and/or constipation?
  • do you have unexplained skin rashes that do not respond to food elimination?
  • have you suddenly started experiencing confusion or trouble finding words?
  • do you routinely swim in lakes or ponds?
  • do you eat food from street vendors, especially outside of the US?
  • do you have pets that have had infections recently, especially parasites or ticks?

The answers to these questions aren’t necessarily going to give you concrete answers, but they would at least narrow down where you’re most likely to find an underlying cause of oxidative stress, so that you can more quickly rule out what is not likely and focus on testing to detect and/or confirm what is more likely.

The last installment of this series will be on nutrient deficiencies, so stay tuned to learn how you can control some of the causes of fatigue that can occur, and manage others through selective supplementation based on symptoms, genes, and diet.

Do you suspect that oxidative stress is the root cause of your fatigue, or have you already been diagnosed with a condition that oxidative stress is commonly implicated in? If you’re interested in working with me on getting to the root of the problem, check out my Work With Me page for more info 🙂

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