Fatigue is one of the most common complaints people bring to their doctors, yet it’s also one of the most frustrating. “You’re just tired” doesn’t feel like an answer when exhaustion is affecting your work, your relationships, and your quality of life.

Here’s what makes fatigue so challenging: it’s a symptom, not a diagnosis. Dozens of different conditions can cause persistent tiredness, from thyroid problems to nutritional deficiencies to blood sugar dysregulation. The same symptom — exhaustion — can have completely different underlying causes that require completely different solutions.

This is why “get more sleep” or “reduce stress” often fails as advice. If your fatigue is caused by an underactive thyroid, no amount of sleep will fix it. If iron deficiency is draining your energy, stress reduction won’t help. You need to identify the actual cause.

Blood testing is one of the most powerful tools for uncovering why you’re fatigued. It can reveal thyroid dysfunction, anemia, vitamin deficiencies, blood sugar problems, and other conditions that cause persistent tiredness — often before other symptoms become obvious. Finding the cause is the first step toward actually feeling better.

When Fatigue Is More Than Just Tiredness

Everyone feels tired sometimes. A late night, a stressful week, a period of intense work — these cause temporary tiredness that resolves with rest. That’s normal.

But fatigue that persists despite adequate sleep, that doesn’t improve with rest, that interferes with daily life — that’s different. That kind of fatigue often signals that something is wrong.

Normal tiredness versus fatigue that warrants investigation:

Normal tiredness:

• Has an obvious cause (late night, busy period, travel, jet lag)
• Improves with rest and recovery
• Comes and goes based on circumstances
• Doesn’t significantly impair daily functioning
• Energy returns after a good night’s sleep
• You can push through when needed

Fatigue that suggests an underlying cause:

• Persists for weeks or months without clear explanation
• Doesn’t improve significantly with rest or sleep
• Present even after what should be adequate sleep (7-9 hours)
• Interferes with work, relationships, or daily activities
• Accompanied by other symptoms (discussed below)
• Represents a change from your previous energy baseline
• Requires increasing amounts of caffeine or stimulants to function
• Includes “crashing” at certain times of day
• Makes activities you used to enjoy feel like too much effort
• Affects both physical and mental energy

If your fatigue matches the second description, investigating the underlying cause is essential — not just for energy, but because fatigue can be an early warning sign of conditions that need attention.

Accompanying symptoms that provide clues:

Fatigue rarely occurs in isolation. The symptoms that accompany it often point toward specific causes:

• Fatigue + feeling cold + weight gain + constipation: Suggests thyroid dysfunction
• Fatigue + shortness of breath + pale skin + rapid heartbeat: Suggests anemia
• Fatigue + energy crashes + hunger + carb cravings: Suggests blood sugar dysregulation
• Fatigue + muscle weakness + bone pain + frequent illness: Suggests vitamin D deficiency
• Fatigue + numbness/tingling + memory problems + balance issues: Suggests B12 deficiency
• Fatigue + low mood + loss of interest + sleep changes: Suggests depression
• Fatigue + muscle aches + joint pain + brain fog: Suggests chronic inflammation or autoimmune conditions
• Fatigue + snoring + morning headaches + daytime sleepiness: Suggests sleep apnea
• Fatigue + excessive thirst + frequent urination + blurred vision: Suggests diabetes
• Fatigue + hair loss + dry skin + brittle nails: May suggest thyroid or iron issues
• Fatigue + decreased libido + mood changes + muscle loss: Suggests hormonal imbalances

These patterns aren’t diagnostic by themselves, but they help guide which tests are most important to pursue.

The gradual onset problem:

One challenge with fatigue is that it often develops gradually. Your energy declines slowly over months or years, and you adapt. You drink more coffee. You go to bed earlier. You stop doing some activities because you’re “too tired.” You may not even remember what normal energy felt like.

This gradual adaptation makes it hard to recognize how much energy you’ve lost. Many people don’t seek evaluation until fatigue becomes severe — but by then, an underlying condition may have progressed significantly. If you suspect your energy isn’t what it should be, it’s worth investigating even if you’ve “learned to live with it.”

Thyroid Dysfunction: The Energy Regulator

The thyroid gland is essentially your body’s metabolic thermostat. It produces hormones that regulate how quickly every cell in your body uses energy. When the thyroid underperforms, everything slows down — including your energy production.

Hypothyroidism (underactive thyroid) is one of the most common — and most commonly missed — causes of persistent fatigue. It affects approximately 5% of adults, with many more cases going undiagnosed for years because the symptoms develop gradually and are often attributed to “just getting older” or “stress.”

How thyroid dysfunction causes fatigue:

Thyroid hormones (T4 and T3) affect energy production at the cellular level. They regulate:

• Mitochondrial function — mitochondria are the “power plants” of cells, producing ATP (cellular energy). Thyroid hormones directly influence how efficiently mitochondria work.
• Oxygen consumption — how efficiently cells use oxygen to generate energy through aerobic metabolism
• Metabolic rate — the overall pace of energy-producing chemical reactions throughout the body
• Protein synthesis — including enzymes needed for energy metabolism pathways
• Neurotransmitter function — affecting alertness, mental energy, and cognitive function
• Cardiac function — affecting how efficiently the heart pumps blood and delivers oxygen
• Body temperature regulation — reduced heat production contributes to the cold intolerance common in hypothyroidism

When thyroid hormone levels are low, all of these processes slow down. Cells produce less energy. The result is a profound, pervasive fatigue that doesn’t improve with rest — because the problem isn’t lack of sleep, it’s impaired energy production at the cellular level.

Characteristics of thyroid-related fatigue:

• Exhaustion that sleep doesn’t relieve — you wake up tired
• Feeling like you’re “running on empty” or “pushing through mud”
• Needing significantly more sleep than before (10-12 hours and still tired)
• Difficulty getting going in the morning — a profound morning sluggishness
• Energy declining over months or years (gradual onset)
• Fatigue affecting both physical and mental function equally
• Reduced stamina and exercise tolerance
• Mental fatigue — difficulty concentrating, brain fog, slow thinking

Other symptoms that accompany thyroid-related fatigue:

• Feeling cold when others are comfortable (cold intolerance)
• Unexplained weight gain or difficulty losing weight
• Constipation
• Dry skin and hair
• Hair loss, including characteristic thinning of the outer third of eyebrows
• Brain fog and difficulty concentrating
• Depression or low mood — often misdiagnosed as primary depression
• Muscle weakness, aches, stiffness, or cramps
• Slower heart rate (bradycardia)
• Puffy face, especially around the eyes
• Hoarse voice
• Heavy or irregular menstrual periods in women
• Elevated cholesterol (thyroid hormones affect cholesterol metabolism)
• Slow reflexes

The more of these symptoms you have alongside fatigue, the more likely thyroid dysfunction is contributing. Many people are surprised to discover how many of their symptoms resolve once thyroid function is addressed.

Hashimoto’s thyroiditis:

Hashimoto’s thyroiditis — an autoimmune condition where the immune system attacks the thyroid — is the most common cause of hypothyroidism in developed countries. It’s important to identify because:

• It’s progressive — thyroid function typically declines over time as more thyroid tissue is damaged
• Antibodies can be detected years before TSH becomes abnormal, providing early warning
• Early detection allows monitoring so treatment can begin at the optimal time
• It’s associated with other autoimmune conditions that may also cause fatigue
• Understanding that it’s autoimmune may influence lifestyle and treatment decisions

Subclinical hypothyroidism and fatigue:

Some people have “subclinical” hypothyroidism — TSH is elevated but thyroid hormones are still in the normal range. Whether this causes fatigue is debated in medicine, but many people with subclinical hypothyroidism report significant tiredness that improves with treatment.

If your TSH is in the higher end of “normal” (some experts consider TSH above 2.5 worthy of attention, especially with symptoms) and you’re fatigued, it may be worth discussing with your healthcare provider. What’s “normal” statistically may not be optimal for you individually.

The T4-to-T3 conversion issue:

Some people have normal TSH and T4 but still experience thyroid symptoms. This can occur when the body isn’t efficiently converting T4 (the storage form) to T3 (the active form). Factors that impair conversion include chronic stress, inflammation, selenium deficiency, and certain medications. Testing Free T3 in addition to TSH and Free T4 can help identify this pattern.

What to test:

TSH is the primary screening test. Elevated TSH indicates the pituitary is working harder to stimulate an underperforming thyroid.

Free T4 measures circulating thyroid hormone. Low free T4 with elevated TSH confirms hypothyroidism.

Free T3 measures the active thyroid hormone. Some people have adequate T4 but low T3 due to conversion problems — this can cause fatigue even when TSH and T4 look normal.

TPO antibodies identify Hashimoto’s thyroiditis. Positive antibodies indicate autoimmune thyroid disease, even if TSH is currently normal.

Thyroglobulin antibodies are another marker for autoimmune thyroid disease that can be positive in Hashimoto’s.

Iron Deficiency and Anemia: The Oxygen Connection

Iron deficiency is one of the most common nutritional deficiencies worldwide, affecting an estimated 2 billion people globally. Fatigue is often its first and most prominent symptom. Even mild iron deficiency — before it progresses to full anemia — can cause significant tiredness that impairs quality of life.

Understanding the iron-energy connection:

Iron plays several critical roles in energy production:

• Hemoglobin: Iron is the central component of hemoglobin, the protein in red blood cells that carries oxygen from lungs to tissues. Less iron means less hemoglobin, which means less oxygen delivery. Since oxygen is essential for aerobic energy production, reduced delivery directly impairs energy.
• Myoglobin: Iron-containing protein in muscles that stores oxygen for immediate muscle use during activity. Low iron impairs muscle function, endurance, and exercise capacity.
• Mitochondrial enzymes: Iron is essential for cytochromes and iron-sulfur proteins in the electron transport chain — the final step of cellular energy production. Without adequate iron, cells can’t efficiently produce ATP regardless of oxygen availability.
• Neurotransmitter synthesis: Iron is a cofactor for enzymes that produce dopamine, serotonin, and norepinephrine — neurotransmitters that affect energy, motivation, mood, and cognitive function.
• DNA synthesis: Iron is required for the enzyme ribonucleotide reductase, essential for DNA synthesis and cell division. This affects rapidly dividing cells including red blood cell precursors and immune cells.

This is why iron deficiency causes such profound fatigue — it impairs oxygen delivery AND cellular energy production AND brain chemistry AND immune function simultaneously.

Iron deficiency without anemia — the hidden epidemic:

Here’s something important many people don’t realize: you can be iron deficient and significantly fatigued without being anemic. Standard screening that only checks hemoglobin misses these cases entirely.

Iron deficiency progresses through stages:

1. Stage 1 — Iron depletion: Iron stores (measured by ferritin) drop, but functional iron and hemoglobin are still normal. Fatigue may already be present.
2. Stage 2 — Iron-deficient erythropoiesis: Iron supply to developing red blood cells is compromised. Transferrin saturation drops. Hemoglobin is still normal but red cell production is affected. Fatigue often significant.
3. Stage 3 — Iron deficiency anemia: Hemoglobin drops below normal. Red blood cells become small (microcytic) and pale (hypochromic). This is when most cases are finally diagnosed — but it represents late-stage deficiency.

Waiting for anemia to develop before treating iron deficiency means waiting until the problem is severe. Many people suffer from treatable fatigue for months or years because their hemoglobin was “normal.”

Characteristics of iron deficiency fatigue:

• Exhaustion, especially with physical exertion — activities that used to be easy now leave you breathless and depleted
• Feeling winded or short of breath with activity
• Reduced exercise tolerance and endurance
• Fatigue that worsens through the day
• Profound weakness and lack of stamina
• Difficulty recovering from physical activity
• Feeling like you need to catch your breath after climbing stairs
• Heavy legs during exercise

Other symptoms of iron deficiency:

• Pale skin, especially noticeable inside lower eyelids, nail beds, and palms
• Shortness of breath, especially with activity
• Rapid or irregular heartbeat (the heart compensates for reduced oxygen-carrying capacity)
• Dizziness or lightheadedness
• Cold hands and feet (blood flow prioritized to vital organs)
• Brittle nails, spoon-shaped nails (koilonychia)
• Restless legs syndrome — an irresistible urge to move legs, especially at night
• Pica — unusual cravings for ice (pagophagia), dirt, starch, or other non-food items
• Frequent infections (iron affects immune cell function)
• Hair loss and slow hair growth
• Difficulty concentrating and poor memory
• Headaches
• Sore or swollen tongue (glossitis)
• Cracks at corners of mouth (angular cheilitis)

Who is at risk for iron deficiency:

• Women with heavy menstrual periods — the most common cause in premenopausal women. Each menstrual cycle can lose 15-30 mg of iron or more with heavy flow.
• Pregnant women — iron requirements increase dramatically to support fetal development and expanded blood volume
• Vegetarians and vegans — plant-based (non-heme) iron is absorbed only 2-20% as efficiently as animal-based (heme) iron
• People with GI conditions affecting absorption — celiac disease, inflammatory bowel disease, H. pylori infection, gastric bypass surgery
• People taking proton pump inhibitors (PPIs) long-term — stomach acid is needed for iron absorption
• Regular blood donors — each donation removes approximately 250 mg of iron
• Endurance athletes — increased iron losses through sweat, GI bleeding, and hemolysis (destruction of red blood cells)
• People with chronic bleeding — GI bleeding (ulcers, polyps, cancer), heavy periods, frequent nosebleeds
• Older adults — reduced stomach acid and dietary changes
• Children and adolescents during growth spurts — increased iron requirements

What to test:

Ferritin is the most important test for iron status — it reflects iron stores. Low ferritin indicates iron deficiency even before anemia develops. A ferritin in the “low-normal” range may still be associated with symptoms — many experts consider optimal ferritin to be higher than the lower end of reference ranges. However, ferritin is also an acute phase reactant that rises with inflammation, infection, or liver disease, so it should be interpreted in context.

Serum iron measures circulating iron. It fluctuates significantly throughout the day and with meals, making it less reliable than ferritin for assessing overall status.

TIBC (Total Iron Binding Capacity) measures the blood’s capacity to transport iron. High TIBC suggests iron deficiency — the body is making more transferrin (iron transport protein) in an attempt to find and carry scarce iron.

Transferrin saturation (iron ÷ TIBC) indicates what percentage of iron transport capacity is being used. Low transferrin saturation confirms iron deficiency.

Hemoglobin and hematocrit detect anemia — but remember, these can be completely normal in early and even moderate iron deficiency.

MCV (Mean Corpuscular Volume) — low MCV indicates small red blood cells (microcytosis), characteristic of iron deficiency anemia, though this is a late finding.

RDW (Red Cell Distribution Width) — elevated RDW can be an early sign of developing iron deficiency, showing increased variation in red cell size.

Vitamin B12 Deficiency: The Nerve and Energy Vitamin

Vitamin B12 is essential for energy production, red blood cell formation, DNA synthesis, and nerve function. Deficiency is surprisingly common, especially in older adults (affecting up to 20% of those over 60), those following plant-based diets, and people with absorption issues. Fatigue is often the first and most prominent symptom.

How B12 affects energy:

• Red blood cell production: B12 is required for DNA synthesis during red blood cell formation. Deficiency leads to fewer, larger, dysfunctional red blood cells (megaloblastic anemia) that carry oxygen less efficiently. The result is reduced oxygen delivery to tissues and fatigue.
• Cellular energy metabolism: B12 is a cofactor for enzymes in the citric acid cycle — a key pathway for cellular energy production. Without adequate B12, cells can’t efficiently convert food into usable energy.
• Myelin synthesis: B12 is essential for producing myelin, the protective sheath around nerves that allows rapid signal conduction. Deficiency impairs nerve function, affecting everything from muscle coordination to cognitive function.
• Neurotransmitter production: B12 is involved in synthesizing neurotransmitters including serotonin, dopamine, and norepinephrine — all of which affect energy, mood, motivation, and mental clarity.
• Homocysteine metabolism: B12 is needed to convert homocysteine to methionine. Deficiency causes homocysteine accumulation, which is associated with fatigue and cardiovascular risk.

Characteristics of B12 deficiency fatigue:

• Profound, persistent exhaustion that doesn’t improve with rest
• Weakness, especially in arms and legs
• Fatigue accompanied by mental “fog” — difficulty thinking clearly
• Feeling physically and mentally drained simultaneously
• Fatigue that develops gradually over months to years
• Exercise intolerance and breathlessness

Other symptoms of B12 deficiency:

• Numbness or tingling in hands and feet (paresthesias) — often the neurological symptom noticed first
• Balance problems and difficulty walking (ataxia)
• Memory problems, confusion, and difficulty concentrating
• Mood changes — depression, irritability, personality changes
• Pale or jaundiced (yellowish) skin
• Sore, red, swollen tongue (glossitis)
• Mouth ulcers
• Vision problems
• Shortness of breath, especially with exertion
• Heart palpitations
• Loss of appetite and weight loss

The neurological symptoms of B12 deficiency can become permanent if not treated promptly, making early detection critically important. Some people develop neurological symptoms before anemia appears.

Who is at risk for B12 deficiency:

• Vegans and strict vegetarians (B12 is found almost exclusively in animal products)
• Adults over 50 (reduced absorption due to decreased stomach acid)
• People with pernicious anemia (autoimmune condition affecting B12 absorption)
• People with GI conditions (Crohn’s disease, celiac disease, bacterial overgrowth)
• People who’ve had gastric surgery (bypass, sleeve gastrectomy)
• Long-term users of metformin (diabetes medication)
• Long-term users of proton pump inhibitors or H2 blockers

What to test:

Vitamin B12 measures circulating B12 levels. However, serum B12 can sometimes appear normal while functional deficiency exists.

Methylmalonic acid (MMA) is a more sensitive marker — it rises when B12 is functionally deficient, even if serum B12 looks normal.

Homocysteine also rises in B12 deficiency (though it’s less specific, as folate deficiency also raises it).

Complete blood count may show macrocytic anemia (large red blood cells) — but this is a late finding.

Vitamin D Deficiency: The Sunshine and Energy Connection

Vitamin D deficiency has reached epidemic proportions — studies suggest 40-75% of adults have insufficient levels, with rates even higher in northern latitudes, among older adults, and in those with darker skin. Fatigue and muscle weakness are among the most common symptoms, though often unrecognized because they develop so gradually that people don’t connect them to a vitamin deficiency.

How vitamin D affects energy:

• Mitochondrial function: Vitamin D receptors are present in mitochondria and influence energy production at the cellular level. Studies show vitamin D affects the expression of genes involved in oxidative phosphorylation — the primary pathway for ATP (energy) production.
• Muscle function: Vitamin D is essential for muscle strength, performance, and coordination. Deficiency causes muscle weakness (particularly in proximal muscles — thighs and upper arms) and fatigue with physical activity. This is why vitamin D deficiency is associated with falls in older adults.
• Immune modulation: Chronic vitamin D deficiency affects immune function, potentially contributing to low-grade inflammation that causes fatigue. Vitamin D also affects autoimmune disease risk.
• Mood regulation: Vitamin D influences serotonin production in the brain. Low levels are consistently associated with depression, which manifests as fatigue, low motivation, and reduced energy.
• Sleep quality: Emerging research suggests vitamin D affects sleep quality, with deficiency associated with poorer sleep and daytime fatigue.

Characteristics of vitamin D deficiency fatigue:

• General tiredness and lack of energy that’s hard to describe — a vague, persistent unwellness
• Muscle weakness, especially in thighs and upper arms — difficulty rising from a chair, climbing stairs
• Fatigue with physical exertion that seems disproportionate
• Feeling worse in winter months when sun exposure is limited (though deficiency can occur year-round)
• Slow recovery from physical activity
• Fatigue accompanied by musculoskeletal aches

Other symptoms of vitamin D deficiency:

• Bone pain, especially in lower back, hips, pelvis, and legs
• Muscle aches, cramps, and general musculoskeletal discomfort
• Frequent infections — colds, flu, respiratory infections, slow recovery from illness
• Slow wound healing
• Depression, low mood, or seasonal affective patterns
• Hair loss (though multiple factors affect hair)
• Poor sleep quality
• Impaired cognitive function

Who is at risk for vitamin D deficiency:

• People who spend most time indoors — office workers, those who are homebound
• Those living in northern latitudes with limited strong sunlight (above 37° latitude, which includes most of the US)
• People with darker skin — melanin reduces vitamin D synthesis in the skin by up to 90%
• Older adults — skin synthesizes vitamin D less efficiently with age, and older adults often spend less time outdoors
• People who cover most of their skin for cultural or religious reasons or consistently use high-SPF sunscreen
• Those with obesity — vitamin D is sequestered in fat tissue, reducing bioavailability
• People with malabsorption conditions — celiac disease, Crohn’s disease, gastric bypass surgery
• Those taking certain medications — some anticonvulsants, glucocorticoids, and cholesterol medications affect vitamin D metabolism

What to test:

25-hydroxyvitamin D (25(OH)D) is the standard test for vitamin D status. This measures the storage form of vitamin D and reflects overall status over the past 2-3 weeks. It’s the test you want — not 1,25-dihydroxyvitamin D, which is the active form but doesn’t reflect stores.

While reference ranges vary between laboratories, many experts consider the lower end of standard ranges to be insufficient for optimal health. Many people report improvement in fatigue when vitamin D levels are optimized, even when starting values were technically within the “normal” range.

Blood Sugar Dysregulation: The Energy Roller Coaster

Fatigue is one of the most common symptoms of blood sugar problems — both high blood sugar (as in diabetes or prediabetes) and the ups and downs of reactive hypoglycemia. If your energy crashes at predictable times, especially after meals or in the afternoon, blood sugar may be the issue.

How blood sugar affects energy:

Glucose is your body’s primary fuel, especially for the brain. Stable blood sugar means stable energy. But when blood sugar regulation is impaired:

• High blood sugar: In diabetes or prediabetes, cells become resistant to insulin and can’t efficiently take up glucose for energy. Despite high blood sugar, cells are essentially starving — glucose is in the blood but can’t get into cells where it’s needed.
• Blood sugar swings: When blood sugar spikes (after eating refined carbohydrates) then crashes (as insulin overshoots), energy follows the same pattern — a brief boost followed by exhaustion, brain fog, and cravings.
• Reactive hypoglycemia: In some people, insulin response is exaggerated, causing blood sugar to drop too low several hours after eating, resulting in fatigue, shakiness, and difficulty concentrating.

Characteristics of blood sugar-related fatigue:

• Energy crashes at predictable times, especially mid-morning or mid-afternoon
• Fatigue after meals, especially carbohydrate-heavy meals
• Feeling better immediately after eating, then crashing
• Needing to eat frequently to maintain energy
• Fatigue accompanied by irritability, difficulty concentrating, or shakiness
• Energy that depends heavily on what and when you eat
• Craving sweets or carbohydrates when tired

Other symptoms of blood sugar problems:

• Increased thirst
• Frequent urination
• Blurred vision
• Slow wound healing
• Frequent infections
• Unexplained weight changes
• Numbness or tingling in hands and feet (if progressed to diabetes)
• Skin tags and dark patches of skin (acanthosis nigricans)

The insulin resistance connection:

Insulin resistance — where cells don’t respond properly to insulin — is a major cause of fatigue. Even before blood sugar rises to prediabetic or diabetic levels, insulin resistance impairs cellular energy production. High circulating insulin also promotes inflammation, which contributes to fatigue.

What to test:

Fasting glucose measures blood sugar after an overnight fast. Elevated fasting glucose indicates diabetes or prediabetes.

HbA1c reflects average blood sugar over 2-3 months. It’s useful for detecting prediabetes and diabetes, and for monitoring blood sugar control.

Fasting insulin is crucial but often overlooked. Elevated fasting insulin indicates insulin resistance — which causes fatigue — even when glucose is still normal. This is the earliest detectable stage of metabolic dysfunction.

The combination of fasting glucose and fasting insulin allows calculation of HOMA-IR, a measure of insulin resistance.

Chronic Inflammation: The Hidden Energy Drain

Inflammation is your body’s response to injury, infection, or irritation. Acute inflammation is helpful — it’s part of healing. But chronic, low-grade inflammation is different. It’s a persistent immune activation that drains energy and contributes to fatigue.

How inflammation causes fatigue:

• Cytokine effects: Inflammatory molecules (cytokines like IL-1, IL-6, and TNF-alpha) directly affect the brain, inducing fatigue, malaise, and “sickness behavior” — the same tired, achy feeling you have when fighting an infection.
• Metabolic effects: Chronic inflammation impairs insulin sensitivity, disrupts thyroid function, and affects mitochondrial energy production.
• Iron sequestration: Inflammation causes the body to hide iron from potential pathogens, reducing iron available for hemoglobin and energy production (anemia of chronic disease).
• Sleep disruption: Inflammatory cytokines affect sleep architecture, reducing sleep quality even when sleep duration seems adequate.

Sources of chronic inflammation:

• Autoimmune conditions (rheumatoid arthritis, lupus, inflammatory bowel disease, Hashimoto’s)
• Chronic infections
• Obesity (fat tissue produces inflammatory signals)
• Gut dysbiosis and intestinal permeability
• Poor diet (high in processed foods, sugar, refined carbohydrates)
• Chronic stress
• Poor sleep
• Environmental toxins

What to test:

hs-CRP (high-sensitivity C-reactive protein) is a general marker of inflammation. Elevated hs-CRP indicates systemic inflammation from some source.

ESR (erythrocyte sedimentation rate) is another general inflammation marker, though less specific than hs-CRP.

Ferritin — while primarily an iron marker, ferritin rises with inflammation. Very high ferritin with normal or low iron suggests inflammation rather than iron overload.

If inflammation is detected, further testing may be needed to identify the source.

Sleep Disorders: When Sleep Doesn’t Restore

Sometimes the cause of fatigue is literally sleep — or rather, sleep that isn’t doing its job. Sleep disorders like sleep apnea cause profound fatigue even when people think they’re sleeping enough.

Sleep apnea:

Obstructive sleep apnea is remarkably common, affecting an estimated 20-30% of adults, yet the majority are undiagnosed. In sleep apnea, the airway repeatedly collapses during sleep, causing brief awakenings (often unremembered) that prevent deep, restorative sleep.

Signs of sleep apnea:

• Loud snoring
• Witnessed pauses in breathing during sleep
• Waking gasping or choking
• Morning headaches
• Excessive daytime sleepiness despite adequate sleep time
• Difficulty concentrating
• Irritability
• Waking with dry mouth or sore throat

Risk factors include obesity, large neck circumference, male sex (though women are affected too, especially after menopause), and certain facial structures.

Other sleep disorders:

• Insomnia: Difficulty falling asleep, staying asleep, or waking too early
• Restless legs syndrome: Uncomfortable sensations in legs that create an urge to move, disrupting sleep
• Periodic limb movement disorder: Repetitive leg movements during sleep
• Circadian rhythm disorders: Mismatch between internal clock and required sleep schedule

What to test:

Sleep disorders are typically diagnosed with sleep studies rather than blood tests. However, blood tests can identify conditions that contribute to or mimic sleep disorders:

• Ferritin — low ferritin is associated with restless legs syndrome
• TSH — thyroid dysfunction affects sleep
• Glucose and HbA1c — diabetes can cause sleep-disrupting symptoms

If sleep apnea is suspected based on symptoms, a formal sleep study (polysomnography) is the diagnostic test.

Hormonal Causes of Fatigue

Adrenal function and cortisol:

Cortisol, produced by the adrenal glands, follows a daily rhythm — high in the morning to help you wake up and mobilize energy, declining through the day, lowest at night. Disruptions to this pattern affect energy.

True adrenal insufficiency (Addison’s disease) is rare but serious, causing profound fatigue along with weight loss, low blood pressure, and darkening of the skin. More common are patterns of cortisol dysregulation from chronic stress, which can cause fatigue without meeting criteria for disease.

Morning cortisol can screen for adrenal insufficiency (very low cortisol) or excess (very high). For more subtle dysregulation, salivary cortisol testing at multiple times throughout the day may be informative.

Sex hormones:

In men, low testosterone commonly causes fatigue along with decreased libido, reduced muscle mass, depressed mood, and difficulty concentrating. Testosterone declines gradually with age, but some men experience more significant drops.

In women, fatigue can relate to:

• Perimenopause and menopause: Fluctuating and declining estrogen and progesterone affect energy, sleep quality, and mood
• Postpartum period: Hormonal shifts, sleep deprivation, and the demands of caring for a newborn
• PCOS: Hormonal imbalances and associated insulin resistance can cause fatigue

Relevant tests include testosterone (in men), estradiol, progesterone, FSH, and LH depending on symptoms and context.

Other Conditions That Cause Fatigue

Chronic infections:

Ongoing infections can cause persistent fatigue as the body devotes resources to fighting them. Examples include Epstein-Barr virus (which can cause prolonged fatigue even after acute infection), hepatitis, Lyme disease, and chronic sinus infections.

Heart conditions:

When the heart can’t pump efficiently, oxygen delivery to tissues suffers, causing fatigue — often the earliest symptom of heart problems. This is particularly relevant in heart failure, where fatigue may precede more obvious symptoms like shortness of breath and swelling.

BNP can screen for heart failure. Hemoglobin ensures anemia isn’t mimicking heart-related symptoms.

Kidney disease:

The kidneys produce erythropoietin, a hormone that stimulates red blood cell production. Kidney dysfunction reduces erythropoietin, causing anemia and fatigue. Kidney disease also causes buildup of toxins that affect energy.

Creatinine and eGFR assess kidney function.

Liver disease:

The liver processes toxins, stores energy, and produces proteins. Liver dysfunction impairs these functions, causing fatigue along with other symptoms.

ALT, AST, albumin, and bilirubin assess liver function.

Depression and mental health:

Fatigue is a core symptom of depression — sometimes the most prominent one. Depression-related fatigue often includes difficulty getting out of bed, lack of motivation, mental exhaustion, and fatigue that doesn’t respond to rest.

While depression is primarily a clinical diagnosis, blood tests can rule out medical conditions that mimic or contribute to depression (thyroid dysfunction, B12 deficiency, anemia).

The Testing Strategy for Fatigue

Given the many possible causes of fatigue, comprehensive testing is valuable. Here’s a logical approach:

First-line tests for persistent fatigue:

Thyroid panel:

• TSH
• Free T4
• Free T3
• TPO antibodies

Iron status:

• Ferritin
• Iron
• TIBC

Complete blood count:

• Hemoglobin
• Hematocrit
• MCV (identifies type of anemia)

Vitamins:

• Vitamin B12
• Vitamin D
• Folate

Metabolic markers:

• Fasting glucose
• HbA1c
• Fasting insulin

Inflammation:

• hs-CRP

Organ function:

• Creatinine / eGFR (kidneys)
• ALT (liver)

Additional tests based on symptoms:

• If hormonal symptoms are present: cortisol, testosterone, estradiol, FSH, LH
• If heart symptoms are present: BNP
• If neurological symptoms accompany fatigue: MMA (methylmalonic acid) for functional B12 status
• If autoimmune symptoms are present: ANA and other autoimmune markers

What to Do With the Results

If thyroid dysfunction is found:

Hypothyroidism is treated with thyroid hormone replacement (levothyroxine). Once levels normalize, energy typically improves significantly — though it may take several weeks to feel the full effect.

If iron deficiency is found:

Iron supplementation can replenish stores, though it takes time — typically 3-6 months to fully restore ferritin. Identifying the cause of iron loss (heavy periods, GI bleeding, poor absorption) is also important.

If B12 deficiency is found:

B12 supplementation — oral or injections depending on severity and cause — can restore levels. Neurological symptoms may take longer to resolve than fatigue.

If vitamin D deficiency is found:

Vitamin D supplementation can improve levels, with energy often improving as levels normalize. Maintenance supplementation is typically needed, especially for those with limited sun exposure.

If blood sugar problems are found:

For insulin resistance and prediabetes, lifestyle modifications (diet, exercise, weight loss) are highly effective. Stabilizing blood sugar through dietary changes often produces noticeable energy improvements within weeks.

If chronic inflammation is found:

Identifying and addressing the source of inflammation is key. This might involve treating an underlying condition, dietary changes (anti-inflammatory diet), improving gut health, or addressing chronic stress.

If sleep apnea is suspected:

A sleep study can confirm the diagnosis. Treatment (typically CPAP therapy or dental devices) often dramatically improves energy and daytime functioning.

When Tests Are Normal

Sometimes comprehensive testing returns normal results, yet fatigue persists. This can be frustrating, but it’s actually useful information — it means the fatigue isn’t from the conditions those tests detect.

Normal results don’t mean the fatigue isn’t real — it absolutely is. They mean the cause isn’t one of the common conditions detected by standard blood tests. This narrows down the possibilities and guides the next steps.

Possibilities to consider when standard tests are normal:

• Sleep quality issues: Even without sleep apnea, poor sleep quality from various causes can cause significant fatigue. Sleep may be fragmented, not deep enough, or disrupted by factors like alcohol, screen time, or an inconsistent schedule.
• Chronic fatigue syndrome (ME/CFS): A condition characterized by profound fatigue not explained by underlying medical conditions, worsened by physical or mental exertion (post-exertional malaise), and not improved by rest
• Lifestyle factors: Overcommitment, chronic stress, inadequate recovery time, poor diet, dehydration, sedentary lifestyle (paradoxically, too little activity causes fatigue)
• Mental health: Depression, anxiety, burnout, chronic stress — these can cause profound fatigue and may not be obvious
• Medication side effects: Many medications cause fatigue as a side effect, including blood pressure medications, antihistamines, antidepressants, and others
• Post-viral fatigue: Prolonged fatigue following viral infections, which has gained recognition in the context of long COVID
• Values at suboptimal levels: Results may be “normal” by reference range standards but not optimal for you individually — this is where tracking trends over time helps
• Conditions not detected by standard blood tests: Some conditions causing fatigue require specialized testing or evaluation beyond standard blood work

If comprehensive blood testing is normal, consider sleep evaluation, mental health assessment, medication review, and honest examination of lifestyle factors. Sometimes the cause is multifactorial — several minor issues combining to cause significant fatigue.

The Bottom Line

Fatigue that doesn’t improve with rest isn’t something you should just accept or push through. It’s often a signal that something in your body needs attention — whether that’s a thyroid producing insufficient hormones, iron stores that have been depleted, blood sugar that’s dysregulated, or one of many other identifiable causes.

The frustrating nature of fatigue — its vagueness, its many possible causes — is also what makes comprehensive testing so valuable. Blood tests can identify or rule out numerous conditions in a single evaluation, transforming “I’m always tired” into specific, actionable information.

You deserve to feel energized. If you don’t, finding out why is the first step toward getting your energy back.

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Key Takeaways

• Persistent fatigue is a symptom, not a diagnosis — it has many possible causes that require different solutions
• Thyroid dysfunction is one of the most common causes — and one of the most commonly missed. TSH, Free T4, Free T3, and TPO antibodies provide a complete picture.
• Iron deficiency causes fatigue before anemia develops — ferritin should be tested, not just hemoglobin
• B12 deficiency is common in vegetarians, older adults, and those with absorption issues — and can cause neurological symptoms alongside fatigue
• Vitamin D deficiency affects up to 75% of adults — and causes fatigue, muscle weakness, and mood changes
• Blood sugar dysregulation causes energy crashes — fasting insulin can detect insulin resistance years before glucose becomes abnormal
• Chronic inflammation drains energy — hs-CRP can identify systemic inflammation that needs investigation
• Sleep apnea is common and underdiagnosed — if you snore and wake unrefreshed, consider evaluation
• Comprehensive blood testing can identify many causes — thyroid panel, iron studies, vitamins, metabolic markers, and inflammation testing cover the most common culprits
• Normal results don’t mean the fatigue isn’t real — but they do help narrow down possibilities and guide next steps