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5 Causes of Fatigue Your Doctor May Not Be Looking For


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Fatigue is one of the most common health complaints, but its cause is not always easy to determine. Read this article to discover five little-known causes of fatigue that should be ruled out if you’re eating right and getting enough sleep, but still feel tired all the time.

causes of fatigue
There are many factors that can cause chronic fatigue. CentralITAlliance/iStock/Thinkstock

Fatigue is one of the most common symptoms that patients report to health care practitioners. In fact, one recent study found that nearly 40 percent of U.S. employees experienced significant fatigue in the previous two week period. (1)

This shouldn’t come as a surprise, given the diet and lifestyle that most people living in the industrialized world follow. The average American gets almost 70 percent of calories from flour, sugar, industrialized plant oils, alcohol, and dairy products. One-third of Americans get fewer than 6 hours of sleep per night, despite a mountain of evidence indicating that we need 7-8 hours to function properly. And according to the American Institute of Stress, 77 percent of people regularly experience physical symptoms—with fatigue at the top of the list—due to chronic stress. (2)

Poor diet, lack of sleep, and chronic stress are undoubtedly the most common causes of fatigue. But what about those who eat right, get enough sleep, manage their stress, and still feel tired all of the time?

In a conventional medical setting, these patients are often diagnosed with depression or anxiety and prescribed antidepressants. This is a fallback position that doctors resort to when they either don’t know what to do next, or don’t have time to do the necessary investigation.

Unfortunately, antidepressants are rarely successful because they fail to address the real underlying causes of fatigue in these patients. In a recent article called Why We Get Sick—and How To Get Well, I argued that there are 8 core pathologies at the root of most symptoms and diseases. Identifying and then addressing these pathologies is the key to successfully treating all health complaints and concerns, and fatigue is no exception.

With this in mind, let’s look at 5 lesser-known causes of fatigue that should be ruled out if you’re doing everything right but still feel tired.

#1: Chronic Infections

Several studies have found that patients complaining of chronic fatigue have lab markers consistent with active pathogen activity and infection. (3) These include stimulation of lymphocytes (a type of white blood cell involved in fighting infections), abnormal patterns of CD4+ and CD8+ T cells (which are also involved in fighting infections), and lymphadenopathy (an enlargement of the lymph glands consistent with infection).

These infections may be either viral or bacterial. For example:

  • In one study of patients with chronic fatigue, nearly 80 percent had markers of reactivated Epstein Barr Virus (EBV), and almost 50 percent had increased antibody titers to Human Herpes Virus (HHV). (4)
  • HHV has been proposed as a causal factor in several diseases that are commonly associated with significant levels of fatigue, including Sjogren’s syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis. (5, 6)
  • A review of studies found that 50% of patients with chronic fatigue and fibromyalgia were infected with Mycoplasma (an intracellular bacteria), compared to 10 percent of controls. (7)
  • Severe fatigue is a common presentation in patients who have been infected by Borrelia burgdorferi, the bacterium that causes Lyme disease, even many years after apparently successful antibiotic treatment. (8)

It is important to note that the presence of these pathogens alone is likely not sufficient to cause disease. 95 percent of the population has been exposed to EBV, and Mycoplasma and HHV infection are not uncommon—yet the vast majority of those infected are not sick.

Tired all the time despite eating right and sleeping enough? Find out why.

There are several explanations for this discrepancy. First, there may be differences in the various strains or subspecies of each organism. Second, genetic differences may predispose some people to be more affected than others. (9) And third, differences in diet, lifestyle, and other environmental factors affect susceptibility.

Unfortunately, diagnosing these chronic infections is challenging and fraught with controversy. This is in large part because these organisms are experts at evading our immune system, and thus difficult to test for. I will be discussing chronic infections in more detail in future posts.

#2: Biotoxin Illness (And Chronic Inflammatory Response Syndrome)

A biotoxin is a poisonous substance produced by living organisms. They can be further classified into fungal biotoxins (e.g. mycotoxins), microbial biotoxins, plant biotoxins, short phytotoxins and animal biotoxins. These biotoxins are found in water-damaged buildings, marine or freshwater environments, and in microorganisms that infect humans.

Biotoxins are not a problem for most people. When we are exposed, the toxin is “tagged” and identified by the immune system and broken down and removed from the body by the liver.

However, several years ago Dr. Ritchie Shoemaker, a family physician in Maryland, identified a subset of the population that is not able to properly detoxify biotoxins. They have a particular set of HLA-DR genes that cause defects in antigen presentation. In laypersons terms, their bodies are unable to recognize biotoxins as toxins, and thus they are not tagged and removed as they should be.

The persistence of these biotoxins in the body then sets off a chain reaction of biochemical events, leading to a continuous upregulation of multiple inflammatory pathways, reduced blood flow, a dysregulated immune system, hormone imbalances, intestinal permeability, and disrupted neurological function. Dr. Shoemaker has termed this constellation of biotoxin-induced signs and symptoms “Chronic Inflammatory Response Syndrome”, or CIRS.

A full discussion of CIRS is beyond the scope of this article. For a concise description, see this page on Dr. Shoemaker’s website, Surviving Mold. There is a wealth of information available there, and Dr. Shoemaker is going to be a guest on my podcast in a couple of weeks, so make sure to catch that interview if you’d like to learn more.

In my clinical work, I’ve found that CIRS is extremely common in my patient population, which consists largely of people struggling with complex and difficult-to-diagnose chronic illnesses. I believe this is likely one of the most significant—yet least often explored—causes of fatigue and other chronic health problems.

#3: Impaired Methylation

If you’ve been following my work for the past couple of years, you’re already familiar with methylation and its role in human health and disease. I’ve dedicated two podcast episodes to it thus far, and I’ll be writing and speaking about it more in the future.

Methylation is a complex biochemical process. Rather than dive deeply into how it works, I’m going to focus here on its role in chronic fatigue. If you’re new to methylation, listen to my Methylation 101 podcast (or read the transcript) to get some important background.

There are several reasons why impaired methylation can cause chronic fatigue:

  • Methylation is required to produce CoQ10 and carnitine, which are essential for producing cellular energy.
  • Methylation regulates gene expression (it turns genes on or off). Genes code for proteins, which are the building blocks of neurotransmitters, hormones, enzymes, and immune factors that are necessary for normal function.
  • Methylation strongly influences detoxification, and problems with detoxification can lead to fatigue.
  • Methylation regulates folate metabolism, and folate is needed for the synthesis of new DNA and RNA.
  • Methylation promotes normal immune function. Weak immune function and autoimmunity are both associated with fatigue.

Thus it should come as no surprise that studies indicate that genetic mutations which affect the methylation pathway are associated with chronic fatigue. (10)

Defects in the methylation cycle can lead to both low levels of the active forms of folate and B12, and changes in folate and B12 metabolism. B12 and folate deficiency cause fatigue, and supplementation with B12 has been shown to have a positive effect in patients with fatigue. (11)

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#4: Mitochondrial Dysfunction

Mitochondria are known as the “battery” or energy powerhouse of the cell. They are organelles inside of cells that take in nutrients, break them down, and create ATP (adenosine triphosphate), which is the fundamental energy unit of the cell.

In addition to their role in energy production, mitochondria are also involved in the production of reactive oxygen species (ROS), regulation of amino acids, metabolites, and enzyme co-factors, neurotransmitter synthesis, insulin secretion, and pyrimidine and lipid production.

Because of these numerous and important roles, any defect in the function of the mitochondria will have widespread consequences.

Mitochondrial dysfunction has been linked not only to fatigue, but to a wide range of health conditions like cancer, diabetes, fibromyalgia, and serious mental disorders like schizophrenia and bipolar disease. (12, 13)


For many years mitochondrial disease was thought to be rare, and limited to serious and potentially fatal forms that manifest during infancy or childhood. However, we now know that a full spectrum of mitochondrial dysfunction is possible, ranging from relatively mild to life-threatening.

Mitochondrial dysfunction can be classified as primary or secondary. Primary mitochondrial dysfunction results from mutations in mitochondrial DNA (mtDNA), which are inherited from mothers. Secondary mitochondrial dysfunction results from the influence of environmental factors (such as toxins, poor diet, etc.) that can damage the mtDNA.

Since mitochondria are responsible for cellular energy production, fatigue is a hallmark of mitochondrial disease. (14) Studies of patients with myalgic encephalitis (aka Chronic Fatigue Syndrome) are more likely to have mitochondrial dysfunction than controls. (15, 16)

#5: Gut Dysfunction

There are numerous pathologies related to gut health that are associated with fatigue, including small intestinal bacterial overgrowth (SIBO), chronic infections (bacterial, viral, parasitic), dysbiosis and fungal overgrowth, intestinal permeability, and food intolerances—to name a few.

There are several mechanisms that explain this connection:

  • Decreased absorption of nutrients required for energy production and normal physiological function
  • Abnormal immune function or response caused by disrupted gut microbiome
  • Chronic inflammation and oxidative stress
  • Impaired detoxification

For example, one study showed that infection with a parasite called Giardia lamblia is associated with an increased risk of chronic fatigue that persists for at least 5 years after the infection has been treated. (17) Another study found that patients with chronic fatigue had abnormally elevated levels of a yeast called Candida albicans in their stool. (18) Finally, intolerance of gluten and other food antigens is associated with fatigue. (19)


The problem with fatigue is that it’s such a non-specific symptom; it has numerous potential causes, and often requires a lot of investigation to determine the primary driver.

Unfortunately, the conventional medical system is not set up for this. It is based more on disease management or symptom suppression with drugs than it is on identifying the underlying cause of disease.

This is where a functional medicine approach can be so helpful, and why I am so passionate about and focused on training a new generation of clinicians in this framework. (If you’re interested in learning more about this training, check out this page.)

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Join the conversation

  1. I’ve discovered the main cause of fatigue is the frequencies in our air today. These weren’t prevalent in years past, so we don’t have the genetics to deal with it. I suspect 5.0 GHz, and worry that 6.0 GHz is even worse. These make our environment much more entropic(i.e. disorganized, a falling apart) than before, and the cure is to add energy to the system(i.e. your body). Distance is your best defense against strong emitters.

  2. I’m hoping to get a little guidance here. I have been struggling with fatigue for about 4-5 years. I’m 25 and I live a healthy and active lifestyle. I will get anywhere from 7.5-9 hours of sleep per night and feel tired until about 3pm after waking up at 7am. I have talked to doctors about fatigue but I feel they think it’s just all in my head. I’m not sure where to go from here. Are there specific tests I can request to help me get to the bottom of this?

    • Please take a food and allergy test. I eat an exceptionally good diet. I follow the Weston A price foundation Plan but was exhausted to the point I would just lay in bed and stare at the walls. I was too tired to get out of bed but yet still too tired to watch tv. I’ve always been a very energetic person. Anyway test results came back allergic to milk quit right away felt better right away. The raw milk is awesome for my husband and three young children just not for me.

  3. My Aunt and I suffer from extreme fatigue- I sleep 12-16 hours daily and she sleeps 20-24 hours at a time. She is 55, I am 30. Had a sleep study done- I’m healthy and ‘normal’. She and I have had blood tests, thyroid examinations, autoimmune tests, antidepressants, neurologist appointments, lifestyle changes, etc. Nuvigil worked temporarily for me and not at all for my Aunt. Does anyone have any ideas?

    My career is suffering- and I’d like to have children soon. We are both feeling discouraged.

    • Take a food and allergy test. Mine was milk as soon as I gave it up my energy came back and my brain fog lifted. Be very cautious with supplements. Always try to get your vitamins from whole lightly cooked Foods and raw fruit. You literally are what you eat.

    • I ended up inventing something that added energy to my body. My sleep and rest are rejuvenating. I also discovered that some fatigue is due to not eating something(I know!). The theory is that our environment is much more entropic than it used to be, and the way you deal with that is to add energy to the system(i.e. your body). I used to deal with some of it through herbs, vitamins, and homeopathic hormones. I then dealt with it with stones(rotating them). Through sheer luck, I discovered the invention I made(you still have to do your proper work, just to get that luck.).

  4. My 29 year old son is suffering from fatigue, brain fog, joint and muscle pain and dark circles under eyes — this has been going on for 2 years just after moving from CT to Los Angeles (prior to that he was 100% healthy, rarely sick as a child). We first thought he was suffering from mold exposure which was found when he tested his apartment (spent 5 months there before knowing about it). He moved but symptoms persist to this day (18 months later). Haemachromotosis is in the family, he also has an elevated Ige level of about 800 with no respiratory symptoms. Bloodwork shows: Serum Iron at 135, Ferritin at 205. Had a recent stool test and tested positive for low digestive enzymes and Dientamoeba fragilis. Is on a paleo diet (but now down to 144 lbs, 5’9″), tons of supplements and has even tried colonics.

    Any thoughts or feedback on this health puzzle would be greatly appreciated!

    • In LA it is possible to get what is known as Valley Fever which is caused by a dimorphic fungal species. It is on the weapons list – like anthrax – which means it can be very serious – although many people just get something like a cold. He should get tested. If his insurance or doctor balks one possibility is to go over the border and get tested. Living there it would be wise to learn about it anyway. It took 2 year of agressive treatment to save my daughter and her doctor caught in on the first visit – which is rare.

  5. My 29 year old son is suffering from fatigue, brain fog, joint and muscle pain and dark circles under eyes — this has been going on for 2 years just after moving from CT to Los Angeles (prior to that he was 100% healthy, rarely sick as a child). We first thought he was suffering from mold exposure which was found when he tested his apartment (spent 5 months there before knowing about it). He moved but symptoms persist to this day (18 months later). Haemachromotosis is in the family, he also has an elevated Ige level of about 800 with no respiratory symptoms. Bloodwork shows: Serum Iron at 135, Ferritin at 205. Had a recent stool test and tested positive for low digestive enzymes and Dientamoeba fragilis. Is on a paleo diet (but now down to 144 lbs, 5’9″), tons of supplements and has even tried colonics.

    Any thoughts or feedback on this health puzzle would be greatly appreciated!

    • Sounds like candida overgrowth. I’ve spent many years and thousands and thousands of dollars on every supplement you can imagine. I rarely recommend them. You should always try to get your vitamins and minerals from Whole lightly cooked Foods and raw fruit.

  6. I couldn’t figure out what was making me crash some days. I finally figured out that it happened when I took magnesium and even if I didn’t take it the next two days, I was still exhausted. I’ve since read that you can’t take magnesium when your adrenal glands are exhausted or compromised in some way. Is that true or is there some other explanation? I normally have trouble going to sleep before 3 am even if I’ve only had 3-6 hours sleep for a few consecutive nights, even though I’m quite tired all day. I try not to nap as I won’t get to sleep before 6 am.

  7. I work in a Sleep Lab and see all sorts of sleep disorders. Some made worse by conventional medications. Before you move on to the 5 causes you mentioned it is important to first rule out sleep disorders; snoring – indicates a partial obstruction of the airway during sleep, or sleep apnea – both degrees of breathing disruption. If you are not breathing well your body is under stress at night. Cortisol levels increase, hormones are disrupted, inflammation increases. You also put yourself at a much higher risk for developing high blood pressure, heart arrhythmias, stroke etc. Your blood oxygen levels are affected by pauses in your breathing which wreaks further havoc. There are also other issues occurring during sleep such as periodic limb movements, which keeps your brain more active than it should be during sleep. It can often be addressed by balancing your electrolytes, taking a magnesium supplement often helps to to calm muscle activity.
    Fatigue can easily result from poor sleep quality which these disorders cause. You may sleep 8+hours and still be tired. You can have these issues during sleep and be completely unaware they are occurring. If you are uncertain you can be referred for a sleep study. If your sleep truly is fine and by all measures should be restorative and of sufficient quality, then move on to looking at the issues mentioned in this article.

    Stress during sleep will cause inflammation affecting your gut. If you don’t correctly pinpoint the cause of the inflammation it will continue to occur.