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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. Given how often the vicious circular cycle thing works, I was wondering if sleep apnea and other physical problems can be caused by some of these issues? I have a host of them (sleep apnea, overweight, high cholesterol, high blood pressure, tendonitis, arthritis, chronic pain, allergies, etc.) It would be wonderful to find a better starting point than “lose weight” given fatigue, pain, etc interferes so much with that.

    • Hi Chris,

      I like Pam have sleep apnea, and I have been wondering if it could be the result of some of these mentioned? However, being tested it looks like my airway is very shallow (my lower jaw is too far back) and I’m not overweight or anything else. All conventional ways like CPAP and oral appliences have not worked. It looks like surgery is only option….unless it could be from one of these guys above??

    • Yep, it would be very interesting to know what impairs central nervous control of breathing during sleep for sleep apnea. Haven’t found any helpful information yet. Losing weight seems to be a starting point that makes a difference for some people. My father had no weight problems and 2 things have helped him get from severe sleep apnea to mild sleep apnea (he’s pissed he didn’t get it away completely yet ;-):
      – Making sure to not lie on your back (he uses a selfmade positional device)
      – Tongue, mouth and throat exercises

    • Pam, I know for a fact, that if you are working on your feet, losing weight helps. I’m not trying to convince you of anything. I’m just stating a fact.

  2. Hi Chris
    As a colon hydro therapist I have worked with many people over the past 15 years struggling with ill health and un-wellness. I have seen many do all of the things you have suggested in your posts and while many feel better and empowered for a period of time I have not seen success in the long term (10 years). Often times, my clients will report that it is because they have not “adhered” to the sometimes pretty extreme or radical protocols, however most of these protocols are suggested as short term interventions, not as ways of living (because they are unsustainable and have lead to deficiencies later on). What is your personal experience for your own health and that of your clients after 5 years and then going into 10 years? I am a firm believer in the human potential and integrative medicine but have witnessed real life limitations when it comes to using complementary alternative therapies as a cure. I’m also beginning to wonder if we are confusing cause and effect when it comes to some of these new tests and their results ie. parasites, bacteria, and fungi in people not feeling well. The only reason I have this doubt is because of the inconsistency I see in the results of treating them. And lack of long term stable wellness. Would love to hear your thoughts on this. Love your work.

    • Matter is not everything. We are multidimentional beings.There is mind, emotions, spirit that comes into play, too. What we believe, what we can’t accept on an emotional level or our Spirit (soul, inner child trauma) is trying to get our attention through bodily symptoms (somatic) = all must be considered when it comes to healing. Healing is a journey to wholness.

      • Thank you. Couldn’t agree more. We must look at the whole person including emotions, spiirt, etc.

      • Spot on Simona, thanks for the reminder. Can I get that reminder at the end of each work day please and thank you:)

        • Thank you. ladies. As it stays here: “The soul always knows what to do to heal itself. The challenge is to silence the mind”

          ― Caroline Myss

    • Kate, let’s keep it simple. If you are low on energy, you have to add energy. If you have problems after doing that, then maybe you should investigate some of what is mentioned here.

  3. Hi Chris,

    You and I have worked together and picked away at the various challenges to my health and vitality. CIRS, Lyme, methylation issues, etc are all part of my picture. I’m so happy you’re sharing more information about CIRS here and in an upcoming podcast. For people like myself who have been digging and unable to get to the bottom of their health challenges, this is a crucial area to look at, I believe. I was not making any of the expected progress with so much of the good I was doing for myself. Thank you for your work and continuing to shed light on topics like this.

  4. I have been diagnosed with CFS/ME. I have found that changing my diet to paleo and taking a number of supplements inc VitB12, vitD3 and magnesium have made the biggest impact on increasing my energy levels and reducing my pain levels

  5. While I thought the article was great, the question “So, to whom to to now?”. Does a physician know where I can be tested to find out which factor is relevant?

  6. Chronic fatigue sufferer living in the UK. Do you know how I get tested for gut parasites?

    • You could try looking up Breakspear Clinic in Hemel Hempstead, Hertfordshire. Might be able to help you with this testing but not totally sure.

    • Hi, I have had the Doctor’s Data GI tests done by my Functional Medicine GP (Dr Chatterjee, I see him privately). If you just want access to the test (rather than further help/diagnosis) I think there are quite a few nutritionists who can help and might be cheaper… Good luck! Eva

    • Check out Dr. Sarah Myhill’s (U.K.) website, she has a lot of information about testing (she has treated many clients in the U.K. for CFS).

  7. It would be great to hear more about chronic infections. I have often a sore throat or ear but no other symptoms. My doctor always wants to give me lozenges but that’s just fighting symtpoms. I wonder whether these are “flare ups” of something. Since I’ve stopped eating gluten it has become massively better but lately it has become worse again (I am still off gluten and eat mostly primal). No gluten intolerance or anything has ever been found though.
    Further they’ve found Borrelia burgdorferi but appearently they are not “active”. I never understood what that means and have it now monitored annually. Nothing has ever come out of that.

  8. This is an excellent article for sharing with clients. Thank you for writing such a clear concise piece that, I’m sure, will help so many people find and answer to their chronic conditions.

  9. Hi Chris,how about heart issues? Guess weak heart will also lead to chronic fatigue.

  10. Chris, have you experimented with high dose thiamine for fatigue? There are at least 9 really interesting studies with wonderful results, although most are just case studies, but still.
    Here they are: http://www.ncbi.nlm.nih.gov/pubmed/?term=Costantini+A%5BAuthor%5D+thiamine

    I have SIBO, H. Pylori(hopefully, I got rid of it with last Abx course) and likely mild IBD, and I have found HUGE improvement in fatigue with sublingual methyl-B12 supplementation, hopefully high dose thiamine will help as well and give me strength to fight these problems until they’re solved.

      • Too bad the studies don’t state what amount exactly is “high-dose” — not very helpful.

        • Actually they do state the exact amount, and that is from 600-1000mg thiamine per day depending on your weight

    • My functional DC has put me on an “Active” B1 (thiamine). The deficiency made me jittery and raised my blood pressure. She said there are some people (mostly women) who cannot convert regular B1.
      The link to the B1 studies did not find anything.

    • Hi Simas,

      Thiamine plays an important role in aerobic energy production, so it makes sense that it would help with fatigue. We do use it occasionally for this purpose.

  11. Greetings from Australia! Your article is spot on Chris. Major turning point for me was an accurate parasite test for D fragilis. Eradicated with antibiotics, antiparasitic herbs, healed leaky gut, went AI Paleo, continue with good pre & pro biotics, corrected low stomach acid, mthrfr supps and feel a new woman. Being diagnosed with a parasite and clearing it was a major turning point for me 🙂 strong gut health is the basis of all health. big fan of yours. another great article thanks 😉

      • Any chance that this type of testing is available in the UK, Emma? I live in London.
        I know my fatigue is gut-related, but it’s impossible to have tests like these on NHS (our health system). Doctors just look at you blankly and say there’s no funding.

        • HI Terry, the test uses PCR which is a DNA test so it picks up parasites whether dead or alive. Austrlalia invented it so I am not sure if it’s available in the UK. Best to go to Dr who is a parasite expert. Or phone up some pathology labs and ask them if they do it. it has been very helpful for us. I hope its available elsewhere as it changed our lives. After 7 years of bad health i finally got an answer. good luck ; )

        • Try Breakspear Clinic in Hemel Hempstead, Hertfordshire but you do need to be able to pay quite a lot, might need to postpone your next holiday to pay for the treatments. A holiday lasts two weeks, good health is going to last much longer! Regards, get well soon. Christine

      • VIVA BRAVO Australia,
        Discovering H. Pylori, FODMAPs, FAILSAFE, Fed UP,
        And now an accurate Parasite test!
        WOW ~ Beyond Hat Trick!
        We love you, Keep up all that great GE work…

      • this service by QML pathology is only available in their area,ie,QLD/northern NSW,which is only a small part of Australia;eg,Sydney and Melbourne,the 2 largest population centres of Australia,can’t access this service.

  12. I’ve had chronic daily headaches with no known cause or trigger for 18 years- since I was 15. They began after a trip to Zimbabwe. I was on a flight that was grounded in Chicago where I had tons of tests and almost passed away from several complications. The only tests that showed anything were a sinus infection and slightly elevated Ebstein Barr titers.
    The pain is now mainly in my occipital nerves. Neuro said these were damaged from the severity of the infection. It also gives me fatigue and occasional dizziness.
    I’ve tried alternative therapies like chiropractic, accupunture, etc. I would love any kind of solution!

    • I also a healthy eater, exercise regularly, never smoked etc. I vaguey remember one doctor discussing heavy metal toxicity with my parents so I had metal fillings replaced with amalgam.

      • Rule out Salicylate induced reactions, migraines, hypo-glycaemia? Try the Failsafe diet with qualified supervision?

        “How many people are salicylate intolerant and don’t realise it? Research shows that about 20% of adults with asthma(1), 60% with of people with food-induced itchy rashes, headaches or migraines, 70% of people with irritable bowel symptoms(2) and 75% of children with behaviour problems(3) may be sensitive to salicylates. In my experience, most people with salicylate intolerance have no idea what could be affecting them. How many people are salicylate intolerant and don’t realise it?”<<<

    • A few weeks ago another letter writer recommended books by Dr. John E. Sarno, MD. Since then I have read “The Body Mind Prescription” and “The Divided Mind”. Research lead me to a work book by Howard Schubiner,MD. I am very impressed with their research and the results I am experiencing. Your case sounds similar to case studies detailed in these books. Best wishes. I hope you find relief! And even if this is not the answer to that particular need this research is definitely worth knowing about.

  13. Hi Chris,

    I have been following you, Jordan and Steve for some time now, thanks for your valuable information, I really appreciate it!
    I am 35yo male that has struggled with chronic fatigue, low energy, brain fog, anxiety and depression since about 2006 that just slowly gets worse each year. So it hasn’t been all my life. My mother is the same.
    I have been diagnosed with pyrole disorder and also MTHFR C677T heterozygous. I also had high inflammation markers in a stool test as well as persistent Neutropenia . I am currently waiting on results for a Organic a acids test. I am wondering if it’s worth doing a 23andme gene test? I had very low zinc, B12 and Vitamin D for a Long time. So I’m sure I would have leaky gut too. I also have mold in my house that I am trying to deal with. Is it possible to get a test to see if I am breaking down the biotoxins? If so what is the test called?I also have sinus, and eye irritation Which I know could be gut,inflammation or mold I guess.
    I am trying to take a real functional approach now days, as the tests are expensive, but throwing money at endless supplements aimlessly at my problems in the long run will be more expensive.

    Thanks so much in advance for any reply!


    • I have have Multiple Chemical Sensitivity (MCS) after moving into a brand new home full of chemicals. It has left me chronically ill and has disabled me. Several years later, I had exposure to mold toxins. I can tell you as long as you are in that house with mold, your body will not recover. The sinus and the eye irritation seems consistent with what Suzanne Somers husband experienced when he was exposed to mold after moving into a rental in CA. Her symptomology was distinct from his. My brother was exposed to mold also. He began experiencing heaviness in his legs, sinus, migraines, and then developed mild MCS. He only began to improve when he left the unit with mold problems. Nevertheless, is there a way you can hire a professional to determine how to handle your mold situation? If it can’t be resolved soon, you must leave that place at once for your body to heal. You do not want to get to that point of no return when no matter how many supplements you take, it will be for naught. Finally, I’d take as many antioxidants as you can to support your nervous system/neurological system. Please do not delay re: mold

    • This might be an obvious question but DID you already try to cut out ANY KIND OF GRAIN (Gluten and non gluten) and also ANY KIND OF DAIRY? I would guess it makes a huge huge shift in your health. Me and my mum had similar paths at similar ages as well, just as you described. I managed to go GRAIN FREE and DAIRY-CASEIN-FREE (mostly raw fruits and some cooked vegetable and really turned my health around. It’s so so easy – you just have to know, and my mum did not know, neither did I for many years. All the best.

  14. Sorry forgot to add that I’m from England currently living in New Zealand – Jenny

  15. I was diagnosed with fibromyalgia almost 20 years ago. After years of being told I had depression and anxiety. Since then a number of physical
    Practitioners have told me it doesn’t exist. I should exercise more etc. I had an updated diagnosis when looking to see if I actually had ankelosing spondylitis instead. Came back negative for that but most likely for fibromyalgia. I have experienced chronic fatigue and muscle pain since I was a child and am now 50. I’d like to think that I could still get a handle on this. Any ideas on where to start?

    • A study of 40 women with fibromyalgia and 40 controls found that those with FM had, on average, the same blood levels of mercury, but only one-third the urine level of mercury. This implies that those with FM are less able to excrete mercury, leading to a buildup of mercury in the organs such as the thyroid, adrenal and pituitary glands. Low levels of mercury can affect mitochondrial function, which as Chris points out, is one cause of chronic fatigue.

      Rosborg, I., Hyllén, E., Lidbeck, J., Nihlgård, B., & Gerhardsson, L. (2007). Trace element pattern in patients with fibromyalgia. Science of the Total Environment, 385(1), 20-27.

  16. Following my contracting mononucleosis in 1980, I’ve had what I call ‘recurrent’ fatigue. The most consistent way to bring on a relapse is exercise of an unpredictable frequency or intensity–generally 12 to 36 hours later. (I say unpredictable, because sometimes just walking around the block can trigger symptoms.) Over the last 35 years relapses have gradually become less intense and of shorter duration–but a number of long (8-10 mile) walks earlier this year triggered a relapse that is now in it’s 6th week. It feels like gravity has been turned up, and I can sleep 10-11 hours a night–with a crushing need to take a 2 or 3 hour nap mid-afternoon.

    I’ve been ‘paleo’ since 2010 (vegan for 18 years (!) before that) but doesn’t seem to have had much positive effect on my problem.

    • I too had mono in the 1980’s and it reactivated three years ago when I was exposed to toxins in NY while I worked through hurricane Sandy disaster. I’m also celiac and now have recurring sibo. The biggest help for me, who was bed basically bedridden for three days after any daily activity was using l carnitine. 3G/day divided doses. I was severely deficient.

  17. Hi Chris. Yes, I am one of those ppl who seem to be doing right and are still suffering with extreme fatigue and a slew of other symptoms. I know on thing I didn’t do is check the gut for parasites and bacteria, and after reading this post I think its time. My question is: what do you think of using the Bio Health Lab instead of Genova? Thnx:-)

    • BioHealth 401H is a good panel. We also use Doctor’s Data Comprehensive Stool Analysis and Parasitology.

      • Genova’s GIfx 2200 is quite advanced, identifies many more species than DD’s panel does.