5 Causes of Fatigue Your Doctor May Not be Looking For


    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.

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    Originally posted on The Chris Kresser Blog
    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.

    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 lambliais 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.)

    Now I’d like to hear from you. Are you suffering from chronic fatigue that has not resolved despite eating well, sleeping enough, and managing your stress? Have you investigated any of the causes I mentioned in the article? What did you find out? Let us know in the comments section.