Always Tired? An Integrative Approach to Fatigue

Dr. Bethany Mattson, ND

Fatigue is a common yet vague complaint that often presents in the healthcare setting. Causes of fatigue are often multifactorial and require thorough history, physical exam, and lab evaluation to work up. Comprehensive evaluation is indicated due to the wide variety of underlying conditions ranging from lifestyle factors, such as sleep disturbance, to severe disease, including cancer. Being mindful of the red flag symptom presentations, in addition to fatigue, is key to keeping patients safe. 

Common red flag symptoms to watch for include unexplained bleeding, bone pain, and unexplained fever. 

When starting to evaluate fatigue, a wide net should be cast. This blog will overview common conditions that present with fatigue, lab work and functional testing to consider, and lifestyle factors that may be contributing to fatigue in the absence of disease. 

1) Conditions to Investigate:

Anemia and iron deficiency without anemia:

Anemia and iron deficiency are very common causes of fatigue due to iron’s key role in hemoglobin production, which delivers oxygen to tissues. When iron is low, oxygenation decreases and fatigue results. Although iron deficiency anemia is a common type of anemia, there are many other types of anemia including macrocytic/megaloblastic anemia, anemia of chronic disease, and hemoglobinopathies such as thalassemia that also need to be evaluated for. 

Hypothyroidism: 

Thyroid imbalance is a common cause of fatigue, as thyroid hormones regulate metabolism, energy production, and mitochondrial function. When thyroid function slows, metabolic rate slows as well. When hypothyroidism is caused by an autoimmune reaction (Hashimoto’s thyroiditis), resulting inflammation and increased immune action also contribute to fatigue. The presence of autoimmunity signals the need for deeper root cause evaluation that often includes comprehensive gut testing. 

Blood sugar/Insulin imbalance: 

Conditions including prediabetes, type 1 and type 2 diabetes, and insulin resistance should always be ruled out in the presence of fatigue. Impaired glucose uptake into cells leads to chronic fatigue and fluctuating energy levels, as blood sugar levels spike and crash. Insulin resistance may also be present before there is any known blood sugar imbalance. Hyperinsulinemia begins when insulin goes above 8 mIU/mL, and indicates that cells are desensitized to the action of insulin. This can cause sugar to circulate in the blood stream, but results in cells becoming starved for energy from glucose, as that sugar cannot enter the tissue for utilization and processing. As glucose acts as a primary energy source in the body, blood sugar balance is a large goal in fatigue management. 

Vitamin deficiencies:

Vitamin B12 and folate support energy metabolism, DNA synthesis, and red blood cell formation. Vitamin D supports bone and muscle function, immune regulation, and mitochondrial function. Deficiency in any of these vitamins can worsen fatigue. 

Hormonal imbalance:

Hormone balance can greatly impact energy. Some key hormones that affect energy include low testosterone or DHEA and low estrogen levels. Both testosterone and DHEA support energy metabolism and athletic performance. Low estrogen can worsen fatigue through neurotransmitter and blood flow imbalance. Additionally, hormone imbalance can worsen cortisol dysregulation, melatonin production, and overall sleep quality.  

Chronic infections:

Chronic infections can contribute significantly to fatigue by disrupting the immune system and inflammation levels. Conditions to screen for include chronic reactivation of the Epstein-Barr virus, Lyme disease, infectious hepatitis, and long-COVID. 

Respiratory/Cardiovascular: 

It’s important to rule out contributing cardiovascular or respiratory conditions, as impaired blood flow and decreased oxygenation can significantly impact energy levels. Conditions such as congestive heart failure pr chronic obstructive pulmonary disease (COPD) are common causes of fatigue. 

Other conditions: 

Many other conditions can cause fatigue and should be evaluated for when indicated including autoimmune conditions such as Lupus, Rheumatoid arthritis, and autoimmune hepatitis. 

Additional considerations include fibromyalgia, chronic fatigue syndrome, Celiac disease, mold exposure, and depression or other mental health conditions. Additionally, sleep disorders should be investigated such as insomnia, sleep apnea, and other sleep disorders such as restless leg syndrome. 

2) Lab Work and Functional Testing Options:

There are many options for lab work to investigate fatigue. The integrative approach to fatigue often includes many tests that range from conventional to functional.

Complete blood count (CBC):

Used to uncover imbalances like asymptomatic infections with elevated white blood cells, and to determine subtype of anemia. Anemia may present as microcytic or macrocytic, or hypochromic versus normochromic.   

A neutrophil-lymphocyte ratio (NLR) can also be examined and can reflect cell-mediated inflammatory activity. An ideal range is 1-1.70, with higher activity suggesting bacterial infection, inflammation, metabolic dysfunction and may even implicate worsening of cardiovascular disease. A lower ratio suggests chronic infection or viral infection.  

Ferritin: 

Used to determine iron storage levels and optimally range from 50-70ng/mL. When ferritin is elevated, it may also be acting as an acute phase reactant due to elevated inflammation, so an iron panel can help distinguish iron overload from increased inflammation. 

Iron panel:

An iron panel can provide further detail into anemia or suspected iron deficiency. An iron panel includes iron levels, transferrin saturation, and total iron binding capacity. 

Reticulocytes: 

This test is not often included in initial screening panels but can be added to help further work up anemia. This test is generally used to generate the corrected reticulocyte count to help differentiate between high or low bone marrow production of RBCs. Reticulocytes are often low in megaloblastic anemia but may be elevated in other causes of macrocytic anemia. 

Comprehensive metabolic panel (CMP):

A metabolic panel is used to assess fasting blood sugar levels, liver and kidney function, and electrolyte balance. Understanding liver health is key to understanding potential detoxification issues, metabolism imbalance, energy production, and overall systemic health.  

Full thyroid panel:

A full thyroid panel typically includes TSH, free T4, free T3, reverse T3, and thyroid antibodies including both thyroid peroxidase (TPO) and thyroglobulin (TG) antibodies. Full thyroid testing can help to diagnose exact thyroid imbalance, including subclinical hypothyroidism, Hashimoto’s thyroiditis, and Grave’s disease. 

Blood sugar/Insulin balance:

Key blood sugar testing including fasting glucose, Hemoglobin A1c, and fasting insulin. Labs should be completed after a 8-10 hour fast and in the morning ideally before 10am for the most accurate fasting insulin. Insulin and glucose levels can be used to determine a HOMA-IR insulin resistance score, with an ideal index of 0.75-1.25. 

Inflammatory markers:

Chronic inflammation can affect mitochondrial health and significantly contribute to fatigue. Increased inflammation can also be a result of an underlying condition or gut imbalance. 

Typical inflammatory markers to check include c-reactive protein (CRP), homocysteine, and sedimentation rate (ESR). Elevated CRP and homocysteine are associated with increased cardiovascular disease risk. Homocysteine often elevates in the context of vitamin B12/folate deficiency, or when there is a genetic variation in the MTHFR gene. CRP, as well as the more sensitive inflammatory marker, hs-CRP, will elevate when the liver is exposed to a higher level of IL-6, and can suggest an underlying immune dysfunction. Elevated IL-6 can result in atherosclerosis, which is why this marker is often associated with heart disease. 

Vitamins and nutrients: 

Key vitamins and nutrients to test for include vitamin B12, folate, and vitamin D. It’s important to remind patients to stop taking any B vitamins about a week before the blood draw to get most accurate results. 

Hormone testing: 

Hormone testing often includes serum markers, such as testosterone, DHEA and estradiol. For reproductive aged-women, follicle stimulating hormone (FSH), luteinizing hormone (LH), and anti-mullerian hormone (AMH), collected on cycle day 2-4, could be considered as well, to determine HPO-axis activity. FSH and LH in men can suggest hypogonadal response from primary or secondary cause. 

Autoimmune testing: 

Autoimmune disease often has a component of fatigue due to increased inflammation and immune activity.  Antinuclear antibody (ANA) testing can be used to help diagnose lupus, rheumatoid arthritis, or other rheumatologic conditions. A Celiac disease panel should also be considered in though with known or suspected gluten sensitivity or other gut imbalance. 

Pregnancy test:

Urine or serum pregnancy testing should be considered in all reproductive aged women with unexplained fatigue. Even in the presence of contraception use and regular cycling, pregnancy can be possible and should be ruled out. 

Fecal occult blood: 

Important to rule out more serious causes of fatigue such as unknown bleeding and cancer. 

Functional testing: 

Functional testing is a common addition to fatigue work up for integrative practitioners and offers deeper evaluation than is possible with serum testing alone. 

Urinary hormone testing 

Urinary hormone testing can reveal metabolites of imbalance, that can shed light on underlying metabolic dysfunction. For example, a higher preference for 5a-reductase metabolites of testosterone and DHEA (Androsterone, 5a-DHT and 5a-Androstanediol) can suggest insulin resistance or metabolic disease. Low 2-Methoxy E1 compared to 2-OH E1 can indicate poor methyl activity, which can lead to fatigue. And higher metabolized cortisol compared to free cortisol can suggest metabolic syndrome, insulin resistance or inflammation, leading to less free cortisol for energy, and a “wired but tired” symptom presentation, while high free cortisol with a low metabolized cortisol pattern suggest hypothyroid imbalance. 

Urine metabolite/salivary testing for cortisol

Hypothalamic pituitary adrenal (HPA)-axis dysregulation is a common cause of fatigue and can lead to significant cortisol imbalance. The benefit of urine metabolite testing is the ability to distinguish total metabolism cortisol compared to free cortisol throughout the day. Both low metabolized and free cortisol can cause fatigue, as discussed above. Additionally, a cortisol pattern that does not follow a diurnal pattern can interfere with sleep and cause daytime fatigue. 

Stool/breath testing

Gut health evaluation is crucial to a fatigue evaluation as the gut synthesizes hormones, regulates neurotransmitters, impacts immune function and inflammation levels, and regulates detoxification. Changes to the microbiome have been shown to impact sleep, mood, cortisol regulation, increase rates of chronic fatigue syndrome, autoimmune conditions, and more. Common gut imbalances to test for include general dysbiosis, small intestinal bacterial overgrowth (SIBO), helicobacter pylori infection, candida overgrowth, intestinal permeability, unknown parasites, Celiac disease, and inflammatory bowel disease. Gut imbalance can cause fatigue directly, or indirectly via nutrient malabsorption and increased inflammation. 

Food sensitivities

Food sensitivities can be tested either through IgG serum testing or through a 6-8 week elimination diet with reintroduction. Food sensitivities can increase inflammation and cause imbalance to immune regulation. Food sensitivity testing can sometimes also indirectly diagnose intestinal permeability.  

Micronutrient testing 

This test may be indicated for patients with suspected intestinal malabsorption, or for those with increased/unique nutrient demand (pregnancy, athletes, or those who follow vegan/vegetarian diets). Uncovering nutrient deficiencies can help guide treatment for fatigue. 

Environmental toxin exposures 

Increased toxic burden from endocrine disrupting chemicals can tax the liver, increase inflammation, damage mitochondrial health and energy production, and impact the nervous system. Panels range from basic heavy metals such as lead and mercury, to full toxicant panels with the optional addition of mold testing. 

Genetic testing

Testing for genetic variations in nutrient status can help guide supplementation and prevent nutritional deficiencies, inflammation, and hormone detoxification. Common genetic variations to test for in the context of fatigue include: 

• Folate-dependent methylation: MTHFR, MTHFD1, FOLR1
• B12: MTR/MTRR, FUT2, TCN2
• Folate-independent methylation: BHMT
• Dopamine clearance and activity: COMT, DRD2
• Omega fatty acids: FADS1/2, FTO
• Iron risk: TMPRSS6, HFE
• Inflammation: TNF, IL-6, IL6R, CRP, VRK2, NRF2, KEAP, NF-KB
• Sleep response: CLOCK, MTNR1B

3) Lifestyle Considerations:

Beyond testing for true disease or health conditions, lifestyle factors can significantly impact energy levels and should be thoroughly evaluated. 

Sleep optimization/insomnia: 

Sleep apnea or other sleep disorders like restless leg syndrome should always be included in a fatigue evaluation. Outside of disease, sleep can be optimized by prioritizing sleep hygiene. Common tips include sleeping in a dark cool room, only using the bed for sleep or sexual activity, utilizing blue light blocking glasses and stopping device use at least 1 hour before bedtime, and minimizing food intake directly before bed. Common sleep complaints include difficulty falling and staying asleep. Careful consideration of circadian rhythm, cortisol balance, blood sugar regulation, and potential for mental health conditions should be made here. 

Diet optimization:

Nutrition and dietary intake can be crucial to energy production. Unknown food sensitivities can increase inflammation and immune action. Helping patients understand their unique dietary needs and eating patterns can significantly improve energy. Optimizing caloric intake to prevent both under and overeating is an important starting place when evaluating diet. Assessing meal timing and spacing throughout the day can help determine length of fasting windows and resulting blood sugar balance. Quality of food intake greatly matters, and helping patients understand the difference between nutrient dense compared to processed, pro-inflammatory foods can further help. Assessing alcohol intake, caffeine use, and other drug use is important to determine energy levels. Finally, adequate hydration and water intake is key to ensure overall diet is optimized. 

Exercise optimization:

Regular moderate exercise has been shown to increase energy levels. If a patient is either under or over-exercising, fatigue may present. Evening exercise can also increase cortisol and interfere with sleep.  

Stress management:

Chronic stress can significantly impact energy levels through cortisol imbalance and HPA-axis dysregulation. When considering stress, it’s also important to rule out depression and anxiety or other mental health conditions that may be presenting with a strong fatigue component. 

Medication use:

Many medications may have fatigue as a side effect and should be carefully evaluated. Common medications with fatigue as a side effect include antidepressants, antihistamines, beta blockers, benzodiazepines, muscle relaxers, and other anti-anxiety medications. 

Conclusion: 

The integrative approach to fatigue includes a wide differential diagnosis list, comprehensive lab testing, and extensive lifestyle support. The goal is to rule out underlying root causes of fatigue that need to be addressed and treated. Although fatigue may be common, it is not always normal, and there are many options to help patients lead an energetic life.