5 Causes of Fatigue Your Doctor May be Overlooking

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.

At the California Center for Functional Medicine, we’ve been starting to test and treat CIRS over the past several months. I can tell you that it is extremely common in our 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)

#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.)


Join the conversation

  1. I was fatigued for years. Diagnosed with CVID in 2013. Treatment with IVIG did not help the fatigue. Scans revealed NLPHL. 6 months of ABVD-R increased the fatigue (not surprisingly) Finished chemo in May 2014, but still fatigued from the moment I get up to the moment I got to bed, slowly increasing over the day, with “waves” of intense fatigue at times – unpredictable.

    • My theory still holds true. If you live in a much more entropic environment, you have to add energy to a system(i.e. your body) to prevent it. Yes, it’s hard. Yes, none of what I did completely solved the problem, until I invented something that always adds energy to your body. But my theory still stands.

      • Michael, you keep mentioning your invention but are very vague – are you going to share what it is? I’m certainly curious!

  2. I suffer from. fatigue. Mine is caused from GBS an auto immune disease. I have the ASMAN variant. I take aB complex with vitamin C and D3. These help. I have learned to not over do it. I eat healthy, exercise and get plenty of sleep.

  3. Fluoroquinolone antibiotics – cipro, levaquin, avelox and a few others – can cause debilitating fatigue. Of course they can – as antibiotics that disrupt the DNA and RNA replication process for bacteria (and mitochondria) they are like a nuclear bomb to the gut. Unfortunately, repairing the gut is difficult.

    Also, fluoroquinolones deplete mitochondrial DNA. In their April 27, 2013 Pharmacovigilance Review, “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure,” the FDA notes that the mechanism for action through which fluoroquinolones induce peripheral neuropathy is mitochondrial toxicity. The report says:

    “Ciprofloxacin has been found to affect mammalian topoisomerase II, especially in mitochondria. In vitro studies in drug-treated mammalian cells found that nalidixic acid and ciprofloxacin cause a loss of motichondrial DNA (mtDNA), resulting in a decrease of mitochondrial respiration and an arrest in cell growth. Further analysis found protein-linked double-stranded DNA breaks in the mtDNA from ciprofloxacin-treated cells, suggesting that ciprofloxacin was targeting topoisomerase II activity in the mitochondria.”

    Here is a story of a young woman who has experienced devastating fatigue after taking cipro – http://fqwallofpain.com/2015/08/17/sierras-story-cipro-poisoning/

    Hundreds of research articles about fluoroquinolones can be found here – http://floxiehope.com/fluoroquinolones-links-resources/

    • I have a close friend who is experiencing devastating fatigue and similar symtoms to the young woman’s who’s story is posted above. Originally doctors thought she had a urinary tract and bladder infection. Nothing showed up on test given she suffers from Adisons disease. She was given IV antibiotics for 7 days, 10 day rest period and another 3 days of IV antibiotic treatments. Following that was cystocostopy surgery to view her bladder. Everything turned up negative. Unfortunately the anesthetic from the surgery has now debilitated her. She’s bed ridden and without heavy doses of steroids, she wouldn’t be able to get out of bed just to go to the washroom. She can’t sleep let alone function as a human being. The medical system doesn’t achkowledge Adisons disease so doctors at the hospital typically dismiss her symtoms. Is there any hope?? Anything that she can do or take to get some quality of life back???

    • This rings true as a child into my 30’schedule I was always sick with different infections, from streptococcus throat, to bronchitis pneumonia etc. Finally in 2006 I caught MRSA at work it took over 6 months to clear many I treatments. Along with Cipriani at home as well until finally I had surgery to remove it all. But I never recovered. I just got more fatigued with time. It was similar as when I would get bronchitis or pneumonia, I’d take antibodies be sick 3 weeks than go back to the doctors even worse for them to say it must be viral?
      Only this is like it never gets better?

      • Drop you cell phone usage, if you have fatigue. I fixed my torn meniscus(after they decided, due to risk factors, not to do surgery), and my knee ached until I removed my phone from my pants pocket, and put it 2-3 feet away. Now, I also invented something that fixed my knee.

  4. “#1: Chronic infections”

    Yes, please post more about this.

    It is very difficult (outside the US) to find:

    1) a good functional medicine practitioner who knows how to diagnose and treat

    2) Good books or DIY-hacks on how to find what’s the cause and how to manage it through lifestyle

    I’ve already read:

    – Paleo code, Chriss Kresser
    – Herbal Antivirals, Stephen Buhner
    – Antiviral Agents, Stephen Tyring
    – Herbal Antibiotics, Kasia

    I am usint BHT (butylated hydroxytoluene), various forms of zinc (blood tests come out ok), Lysine (lysine hydrochloride, but it messes up my electrolytes with constant use), wild mediterranean oregano oil, tea tree oil, upped my calcium (based on blood results, for nerve ending health) and even Acyclovir.

    I’m still getting constant cold sores, shingles and other symptoms.

    I’m almost 100% clean on my diet and strictly milk, grain and legume free. Have done GI Effects comprehensive profile, all possible IgA, IgG and IgE tests locally availble. I eat insane amounts of green leafy vegetables, all eggs are local and organic, all nuts are organic, as are the oils are use. I eat a limited amount of carbs, mainly from berries and organic fruit.

    I meditate every day. I have good sleep hygiene and sound sleep. I cant’ do strenuous exercise (or my immunity will crash and I will get a break out).

    I’m already living more healthily than 99% of the doctors I meet, but I’m still not feeling well. Better, but only managing.

    So yes please, do write more about these chronic infections and how to DIY hack them. Good ancestral-trained functional doctors are almost non-existent in most parts of Europe (and even more non-existent beyond US and EU).

    We have to rely on ourselves and each other for help…

    • Where you live?

      I’m a european guy and have same problems. EBV and HSV-1 w/ positive IgM e IgG, and high titers for CMV IgG.
      Without any personal help, i started trying some things. I’m feel better, but brain fog still here and some other problems.

      Do you need some prescription to realize the stool test?

    • Do an organic acids test (OAT) and find out what is going on. Great Plains laboratory do them. You may find you are high in oxalates like I did . I was eating what I thought were very healthy foods like nuts, berries and lots of greens including spinach…all very high in oxalates. What I didn’t know was that they were depleting my calcium levels and putting me at risk of kidney stones.

  5. I’ve been on prednisone twice in the last 6 months trying to control severe allergies. In the process I’ve been having bouts of really severe fatigue. When things got really bad, I refused to go back on steroids and figure out what was going on. Over the last month, I’ve removed a lot of inflammatory foods from my diet and finally got my allergies under control and holy cow, it was like a revelation. I love my doctors, but they never looked at my fatigue beyond simple labs. My magnesium was ok, do I was just told to “rest”.

  6. Chris: I am very interested to know if you have additional information about secondary mitochondrial dysfunction. You may not as there doesn’t appear to be a lot of information about it. I would welcome a diagnosis of secondary mitochondrial dysfunction, if this would help engage my health insurance company. I am interested in information about treatment options as there is even less understanding of mitochondria at the health provider level than even C677T. I am open to studies or clinical trials as there seem to be few treatment options.

    The real question in my mind is whether mitochondrial function can be normalized by creating a more mitochondria friendly environment by reducing ROS production through the use of mitochondria targeted antioxidants. I think the answer to this question hinges on the mechanisms used by mitochondria to repair mtDNA, which are quite different from nuclear DNA repair mechanisms.

    • My router used both the 2.4GHz and 5.0 GHz, and I always got so tired, after sitting within 3 feet of it(nowhere can I find out how strong the emitter is, other than it had to be modified stronger, in order to make you hotspot.), that I felt like I had to sleep. This was cured by having the technician bridge my router(which eliminates its WIFI capabilities). That’s my proof.

  7. I have been tested and treated by a functional medicine doctor, who is trained in parasites, biotoxin disease etc. It did not address the underlying problem for me, which was Primary Immune Deficiency: specifically CVID,(common variable immune deficiency). This is what can set the stage for all the issues you mentioned. Until tested and treated by an immunologist with immunoglobulin I did not get better. I would suggest that more people need to have their immune systems checked. 50% of people who are ill with some form of immune deficiency have not been diagnosed, and the average time from onset of symptoms to diagnosis is often up to 20 years. See primary immune.org for more information.

    • Of course I’m depressed! I fall asleep at red lights, on the freeway, in the middle of sentences, at my computer …. all the time! And no one can tell me why! But I don’t think it’s because I’m depressed!

    • I was told I was depressed, turns out I was just suffering from food and environmental/seasonal allergies.

  8. I have been sick all my life. Have seen to many doctors to count. I am still struggling with being ill. I have recently lost 50lbs. I am not trying to lose weight. Sure would love to go at least one day free of pain.

    • People say things like you, and they are unwilling to do things that their minds say can’t work. I suggest you pay attention to anything that makes you feel better, and do those things.

  9. These are some great things to looks for, from a biological point of view. I’d also like to add that fatigue can have a major emotional component too. Not dealing with past issues or feeling blocked in another part of life can take a lot of our energy. As can just being poor at managing the energy we do have – if you’re leaking your energy into a job you don’t like, pursuits that don’t build you up, and relationships that take more than they give, then of course you’re going to be fatigued. A great thing to do is to learn to manage the energy we do have sensibly, then as we work towards having more, we can use it to build a life we love and that will sustain us.

    Thank you for such a thought provoking post.

    • Very well put Samantha. Mental and emotional stress was a huge factor in my daily fatigue and poor sleep. Not to say it’s the only factor for people but it’s a massive one that flies under the radar for most people.

      Chris has stated that his articles on stress management are the least linked to and shared. I think many people assume that if you’re dealing with any emotional stress, that it’s somehow a reflection of your lack of will power or fortitude when in reality I think most people don’t get taught even the most basic stress management techniques.

      • I totally agree, Ian. Stress management and resilience are just so important on our health journey. I think Chris’ stress artcles might also be less linked and shared because dealing with those issues is often a bit harder than taking a supplimemt or getting a test done. Not that suppliments and tests aren’t awesome, but they can’t fix something that has a deeper emotional basis.

        In my opinion, it’s really impotant to be honest with yourself when assessing something like fatigue and explore the emotional/spiritual/mental side of things at the same time as addressing more physical pieces of the puzzle.

  10. I have very high levels of lead and mercury per a 6 hour DMSA urine challenge. I’m sure this is at least one root cause of my issues. What’s, generally, the best way to go about getting rid of these toxins? I don’t hear a lot about treatment for toxic heavy metals. I would love it if practitioners would talk about it more. Thanks

  11. Biolabs or Acumen in the UK do an excellent mitochondrial function test – you definitely need someone who knows how to interpret it for you because it is very complex though. I had mine done with Dr Sarah Myhill who is based in Wales but takes international patients for interpretation by letter. I found it very useful to see there was a real biochemical lesion causing my fatigue. It doesn’t tell you the cause though and this is where the other points are very interesting.

    I definitely had most of the problems on the list from Chris. I’ve tried getting the basics right but had to go radical on a few of them. I’m a poor methylator functionally and have a genetic problem with that too. On top of doing the basics right, I had to take B12 injections for a long time, even weekly IV myers (vitamins) for long periods just to get through the day.

    I’ve suffered with the most intractable gut problems all my life, in spite of paying really careful attention to my diet and supplementation. I recently did a course of fecal bacteriotherapy at the Taymount Clinic in the UK. I think it has helped. I actually had no bacteriodes, which you can’t get any other way than through a person to person transfer. It made me a lot less constipated and a lot more cheerful, which was unexpected.

    I suggest you also look at Chris’s pages on thyroid function as well.

  12. I have suffered from fatigue and fybromyalgia for about 10 years now.Post menopausal and some days I am totally wiped out in evenings.
    I am a carrier for Haemachromatosis but don’t have it.
    Take magnesium and b6, red clover, efamarine, and kiki auperfood and glucosamine but still feeling tired and very achy.My hands even hurt when I grip my steering wheel on my car!
    Any suggestions?

  13. I have EBV, HHV-6, CMV, Lyme, mitochondrial dysfunction, leaky gut, probably SIBO, Hashimoto’s autoimmune, constantly tired and totally brain fogged. I take tons of supplements. I think we are ALL being poisoned to death by the toxic environment, pesticides, chemtrails, EMF pollution, etc. The best thing we can ALL do is protest this government’s corrupt association with big Pharma, etc. and at least save our grandchildren from even worse fates. Americans have become too complacent. Other countries do not put up with this nonsense.

    • How and where can you find out about mitochondrial distinction and the other problems and how to treat it? I am fed up with my doctors.! Thanks for any advice.

    • Please go get tested for CVID from a legit immunologist. I had the exact same profile as you and got better with immunoglobulin. It’s a simple blood test.

  14. I was diaganosed w Lyme and Lupus… Had extreme fatigue for years.. I feel 98% cured – took me many years(7-8). Heres what helped the most: eliminate as much stress as possible, veggie juice cleanse fasting, mega probiotics, armour thyroid, SamE, ginseng, chlorella, rhodiola, oregano oil, and zymactive ( proteolytic enzymes).. Took patience and total self love and surrender. Hang in there and always believe “this too shall pass”. The emotional and spiritual and self love pieces to this are HUGE in the healing.

  15. Dehydration where the body has not or is not absorbing water-eventually depleting hormones and creating disease like cancer

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