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  • Dr Laura Stix

The Top 5 causes Of Persistent Fatigue

There is always a reason for why you are chronically tired and have no energy -- sometimes it just takes some sleuthing!

Chronic persistent fatigue

We all know what it feels like to be tired and dragging our butts. But sometimes that fatigue lingers on, day after day, and it may not be clear why it's happening.

Additional symptoms that commonly occur alongside persistent fatigue can include:

  • brain fog or a "heavy head"

  • not feeling rested even after many hours of sleep

  • inability to concentrate

  • poor memory

  • muscle fatigue or weakness

And we all know that diet, exercise and sleep are very important, so it can be frustrating when it feels like you're doing everything right but you're still not making headway on boosting energy levels. You see the medical doctor and they run blood work and tell you everything is "normal" but you still feel crummy.

There's a reason for everything, so it's just a matter of knowing how to sleuth through your health profile, ask the right questions and run the right lab tests to ultimately figure it out.

It's also important that lab work has a more nuanced interpretation to it, because falling inside a reference range does not mean everything is necessarily ok or optimal, and some reference ranges are huge (like ferritin).

For example, I commonly see blood work for Vitamin D where people are in the low end of the range but still "normal" (the range is 75-250). Optimal levels are around 150-200 and the older an individual becomes, the less natural vitamin D they produce in the sun. Supplementing and supplementing at the appropriate level (most are far too low) requires professional guidance and supervision. Testing and proper test interpretation is essential -- especially when vitamin D plays such an important role in the body including immune function, mental health, calcium absorption and bone health. Low levels of vitamin D can cause aches and pains and fatigue as well.

Here are the top 5 (of about 13 or so) key underlying issues that cause persistent fatigue. Often it's a combination of more than one:

1) Thyroid Problems - These are incredibly common (particularly hypothyroidism) and are under-diagnosed.

It makes for very difficult weight loss even when someone has "subclinical" hypothyroidism (meaning that lab values are still within the range, but are not optimal). Conventionally, only TSH is typically run to assess thyroid function, however in order to get a complete understanding of how the thyroid is functioning and what may be impacting it, a full thyroid panel must be run including TSH, free T3, free T4, TPO and TG antibodies (and sometimes Reverse T3 can be helpful too).

Added to this problem are common nutrient deficiencies that the thyroid needs to function well or heavy metals or toxins that can negatively impact the thyroid.

2) Anemia - This could be due to low iron, B12, folate, genetic conditions, or a result of chronic disease and inflammation.

The "normal" reference range is massive for ferritin (the storage form of iron) and is far too low for both ferritin and B12. In Canada, you're considered "normal" for B12 if levels are above 110, while in Japan you are considered deficient if below 500.

Checking markers for inflammation can sometimes be important with this because ferritin does not only tell us about iron stores - it is also an indirect marker for inflammation. This is why an iron panel should be run alongside ferritin, as well as other markers for inflammation and a CBC, in order to accurately interpret ferritin results.

3) Cortisol Imbalance (or what is termed "HPA Axis Dysfunction") - This is very common and various stressors on the body and mind can impact this. This means not only psychological stress, but ANY stressor on the body, like toxins from the environment, inflammation, lack of sleep, etc.

Being stressed all the time puts strain on the body where, over time, the brain begins to dial down the signaling to the adrenal gland which means less cortisol is made (and this can mean less energy).

A single morning blood draw does not capture the rhythm of cortisol release, nor is it a reliable measure for more subtle cortisol issues. The most accurate way to capture the cortisol rhythm (and what is used in research) is salivary testing. Taking 4 or 5 samples across the day allows us to observe the cortisol trend across the day.

A normal cortisol curve shows a sharp increase on waking and then a gradual decline across the rest of the day. That initial rise in cortisol within the first hour of waking is called the Cortisol Awakening Response (CAR) and is of particular interest as it is suggested to play an important role in the link between stress and health.

It's important we stop using the term "Adrenal Fatigue", as it perpetuates the false belief that the adrenal gland gets tired and stops producing cortisol. That is not at all what happens, but rather it's a hormone feedback loop that slows the production of cortisol. It is a complex system that researchers are still trying to figure out and cortisol production can vary greatly not only between people, but in the same person. This is why, in an ideal world, a 7-day salivary CAR would be performed but this just isn't practical. We must be cautious when interpreting salivary or urinary metabolite testing for this reason.

4) Nutrient Deficiencies - Even fresh, organic foods are depleted in the levels of nutrients they once held decades prior. I discuss this in my magnesium article you can check out here if you like.

The millions of reactions that take place in our body require specific vitamins and/or minerals to do the job, so if something is missing, a whole chain of reactions get back-logged, like a jammed conveyer belt. I discuss how challenging magnesium is to test and unfortunately many nutrients are not very straightforward. The reason is because what we find in the blood is not a reflection of what is actually found in the tissue.

Some lab tests are useful (like testing serum vitamin A or Vitamin D) but many are not. A hair mineral analysis can be a useful tool that captures both the minerals, as well as a variety of heavy metals in the body (no vitamins though). No test is perfect and this test assumes we are excreting well and it's showing up in the hair (and that there isn't environmental contamination).

The most common significant vitamin and mineral deficiencies are magnesium, zinc, iron, copper, vitamin E, B vitamins, and vitamin D (technically it's a hormone, not a vitamin). Other important nutrients that are commonly inadequate and can lead to fatigue include things like L-carnitine, choline, creatine, and various antioxidants.

5) Blood Sugar Dysregulation - Many people are insulin resistant due to ongoing elevations in blood sugar (and therefore insulin), and this commonly leads, not only to weight gain, but to fatigue as well. This is because the body is not able to readily make use of carbohydrates as an energy source, since glucose is not able to make it's way into the cells. Insulin helps provide a "doorway" for the blood sugar to get inside cells, but when someone has insulin resistance, the doorway stays locked.

Additionally, when someone has a meal, a snack, a meal, a snack, etc where blood sugar quickly rises, there is a constant yo-yo-ing of blood sugar and insulin (and some inflammation). When blood sugar goes up, so does insulin. When blood sugar drops down, we can feel weak, lethargic, fuzzy headed, trembly, cravings -- which often causes us to want to reach for another snack to help resolve the symptoms. It's not a good roller coaster to be on.

Because carbohydrates play such a large role in our everyday lives (sandwiches, pizzas, buns, muffins, pasta, potatoes, grains, crackers, cookies, etc) most people are not metabolically flexible. This means that their body relies on carbs for energy and does not use fat stores well. You know you are metabolically flexible if you can go several hours without food (and function well, sometimes better, doing so).

I use to have what's called "Reactive Hypoglycemia" from my "healthy" high carb diet. Even though I wasn't overweight, if I didn't have some sort of a carb snack/fruit handy I would get shaky and lightheaded, sometimes even cold sweats! Thankfully I can now say I am very metabolically flexible and can go many hours without food and not have any issues.

When testing for blood sugar issues (and insulin resistance) I like to see HbA1C (your average blood sugar over the last 2-3 months) as well as a fasting glucose & fasting insulin, to calculate the HOMA-IR (an estimate of insulin resistance).

Keeping blood sugar in check is important when looking for ways to improve energy levels.


It's frustrating to feel fatigue day after day when you feel like you're doing everything right. Fortunately, with some solid health detective work, the answers can typically be found and corrected for - the key is to know what to look for.

The 5 main causes of persistent fatigue include thyroid dysfunction, anemia, cortisol issues, nutrient deficiencies and blood sugar dysregulation.


Nida Ali, Hannah Tschenett, Urs Markus Nater. Encyclopedia of Mental Health (Third Edition). Biomarkers of stress and disease. 2023, Pages 221-231.

Nina Smyth, Elena Rossi, Carly Wood. International Review of Neurobiology. Chapter Nine - Effectiveness of stress-relieving strategies in regulating patterns of cortisol secretion and promoting brain health. Volume 150, 2020, Pages 219-246.


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