Fatigue is generally defined as a subjective feeling of tiredness, exhaustion, or lack of energy. According to research, nearly 20-30% of people experience chronic fatigue at some point in their lives.

People struggling with fatigue may find it difficult to wake up in the morning, concentrate at work, or enjoy activities they once loved. It is frustrating because even after rest, the sensation of tiredness may persist.

By understanding the mechanisms at play, individuals can take steps to manage fatigue, improve energy levels, and enhance their quality of life.

Mechanism

Fatigue is not just a simple result of a lack of sleep or physical exertion. Multiple physiological systems interact to cause the sensation of tiredness. Key systems that play a role include:

The Central Nervous System (CNS)

The CNS, which includes the brain and spinal cord, plays a central role in fatigue. When we engage in activities, whether mental or physical, the brain consumes energy in the form of glucose. If glucose levels drop or if the brain is overstimulated for long periods, feelings of tiredness can arise.

Moreover, neurotransmitters such as serotonin, dopamine, and norepinephrine regulate mood, motivation, and energy.

Imbalances in these chemicals can contribute to both mental and physical fatigue. For instance, low levels of dopamine, the “feel-good” neurotransmitter, are often associated with lethargy and a lack of motivation.

Energy Production in Cells: The Mitochondria

Every cell in the body relies on energy, primarily produced in the mitochondria through a process called oxidative phosphorylation.

This energy, stored in the form of ATP (adenosine triphosphate), fuels bodily functions. When the mitochondria are not functioning correctly—due to illness, aging, or oxidative stress—cells produce less energy, leading to fatigue.

This is why people with mitochondrial disorders or chronic conditions like fibromyalgia often experience chronic fatigue.

The Role of Hormones

Hormones, particularly those from the thyroid gland and adrenal glands, play a significant role in regulating energy.

Thyroid hormones control metabolism, and if the thyroid gland is underactive (hypothyroidism), people often feel sluggish and tired.

Adrenal hormones, such as cortisol, are released during stress to provide a burst of energy. Fatigue can be caused by both high and low cortisol levels.

Low cortisol (adrenal insufficiency or Addison’s disease) impairs energy production and stress responses, causing severe fatigue and weakness.

High cortisol (Cushing’s syndrome) disrupts normal metabolism, leading to tiredness and muscle weakness.

Immune System

Chronic inflammation is another key contributor to fatigue. When the immune system is activated, whether due to infection, autoimmune disease, or chronic illness, it releases cytokines—small proteins that mediate inflammation.

Cytokines can affect brain function, leading to fatigue. This is often seen in people with conditions like rheumatoid arthritis, lupus, or chronic fatigue syndrome (CFS).

Causes

Lack of Sleep

One of the most obvious causes of fatigue is inadequate sleep. The body needs 7-9 hours of quality sleep to restore energy, repair tissues, and regulate hormones.

Sleep deprivation disrupts the natural circadian rhythm, leading to daytime drowsiness and impaired cognitive function.

Nutritional Deficiencies

A diet lacking in essential nutrients, such as iron, vitamin D, or B12, can cause fatigue. Iron deficiency, for example, leads to anemia, a condition where the body cannot produce enough red blood cells to carry oxygen. This results in weakness and lethargy.

Similarly, vitamin D deficiency can affect bone health and energy levels, while B12 is critical for proper brain and nerve function.

Stress and Mental Health

Chronic stress is a leading cause of fatigue. Prolonged exposure to stressors triggers the body’s “fight or flight” response, which uses up energy and can lead to burnout.

Mental health disorders, such as depression and anxiety, also play a role. People with depression often experience both physical and emotional fatigue, making it hard to carry out even basic tasks.

Chronic Illnesses

Certain chronic illnesses can cause fatigue. Conditions like diabetes, heart disease, and cancer affect how the body produces and uses energy.

Similarly, cancer patients often deal with “cancer-related fatigue,” which is thought to result from both the disease and its treatments.

How To Approach

Proper evaluation involves a systematic approach, starting with a thorough history, followed by physical examination, and finally, targeted investigations.

History

Onset and Duration: Ask about when the fatigue started. Is it acute (days to weeks) or chronic (more than 6 months)?

Acute fatigue might be related to an infection or sudden lifestyle change, while chronic can point to conditions like depression, chronic illness, or sleep disorders.

Pattern: Is the fatigue constant or does it fluctuate throughout the day? Does it worsen after physical or mental exertion (post-exertional malaise, common in chronic fatigue syndrome)?

Associated Symptoms: Explore other symptoms such as:

Weight changes (involuntary weight loss could indicate cancer or hyperthyroidism, while weight gain could be linked to hypothyroidism)

Fever, night sweats, or infection signs (suggesting infection or autoimmune disease)

Mood changes (depression or anxiety)

Pain, especially in the joints or muscles (conditions like fibromyalgia or rheumatoid arthritis)

Lifestyle Factors: Discuss sleep habits, diet, physical activity, and any recent life stressors or changes. Poor sleep hygiene, malnutrition, or chronic stress are common contributors to fatigue.

Medication History: Some medications, such as sedatives, anti-hypertensives, or antidepressants, can contribute to fatigue. Ask if there have been any recent medication changes.

Physical Examination

General Appearance: Look for signs of weight loss, pallor (anemia), jaundice (liver disease), or edema (heart or kidney dysfunction).

Vital Signs: Check for abnormalities such as:

Blood pressure: Hypotension or orthostatic hypotension may indicate adrenal insufficiency or dehydration.

Heart rate: Tachycardia can be seen in hyperthyroidism or infections.

Respiratory rate: Dyspnea with fatigue might suggest heart failure or chronic lung disease.

Thyroid Examination: Evaluate for an enlarged thyroid (goiter), nodules, or tenderness, as these may suggest thyroid disease.

Neurological Examination: Assess muscle strength, reflexes, and coordination. Neurological signs such as muscle weakness, tremors, or diminished reflexes may indicate conditions like multiple sclerosis or peripheral neuropathy.

Musculoskeletal Examination: Check for tenderness, joint swelling, or muscle pain, which could indicate rheumatoid arthritis, fibromyalgia, or a connective tissue disorder.

Cardiovascular and Pulmonary Examination: Listen for heart murmurs or abnormal lung sounds that may suggest heart failure or chronic lung disease.

Investigations

After gathering information from the history and physical examination, targeted investigations can help in diagnosing the cause. Some key tests include:

Complete Blood Count (CBC): This is a standard test to check for anemia (low red blood cells), infection (elevated white blood cells), or other blood disorders.

Thyroid Function Tests: Fatigue can be a symptom of both hypothyroidism and hyperthyroidism. TSH (thyroid-stimulating hormone) and free T4 levels help assess thyroid function.

Blood Glucose Levels: Testing for diabetes, especially if there is a history of excessive thirst, frequent urination, or weight loss.

Liver and Kidney Function Tests: Chronic liver or kidney disease can cause fatigue. Abnormal liver enzymes or elevated creatinine/BUN levels can provide clues.

Electrolytes and Calcium Levels: Electrolyte imbalances (like sodium, potassium, calcium) can contribute to fatigue and weakness, especially in cases of adrenal insufficiency or dehydration.

Inflammatory Markers: Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels can indicate inflammation or infection, as seen in autoimmune diseases or chronic infections.

Iron Studies and Vitamin B12/Folate Levels: Iron deficiency anemia and deficiencies in vitamin B12 or folate are common causes of fatigue, especially in those with poor diets or absorption issues.

Sleep Studies: If sleep apnea or another sleep disorder is suspected, a polysomnography (sleep study) may be conducted to assess sleep quality and breathing patterns.

Adrenal Function Tests: If adrenal insufficiency is suspected (low cortisol levels), an ACTH stimulation test may be necessary.

Management

Once the cause of fatigue is identified, treatment can begin. Below are some approaches to managing and preventing fatigue:

Improving Sleep Hygiene

Adopting good sleep habits is crucial for combating fatigue. This includes establishing a regular sleep schedule, creating a relaxing bedtime routine, and minimizing exposure to screens before bed.

Additionally, addressing sleep disorders, such as insomnia or sleep apnea, through lifestyle changes or medical interventions is important.

Balanced Nutrition and Hydration

Eating a balanced diet that includes a variety of fruits, vegetables, whole grains, and lean proteins can prevent nutritional deficiencies that contribute to fatigue. Staying hydrated is also essential, as even mild dehydration can cause tiredness.

Stress Management

Managing stress through techniques like meditation, yoga, or deep breathing exercises can help reduce the mental and physical toll that stress takes on the body.

In some cases, professional therapy or counseling may be necessary to address chronic stress or mental health issues.

Physical Activity

While it may seem counterintuitive, regular physical activity can boost energy levels. Exercise increases the production of endorphins, which improve mood and energy.

It also helps improve cardiovascular health, ensuring better oxygen delivery to the body’s tissues.

Treating Underlying Conditions

In cases where fatigue is due to an underlying health condition, such as anemia, hypothyroidism, or depression, treating the root cause is essential.

This may involve medication, dietary supplements, or other medical interventions.

Conclusion

Fatigue is a symptom with a broad range of potential causes, requiring a thorough and methodical approach to diagnosis.

By carefully evaluating the patient’s history, conducting a detailed physical examination, and performing targeted investigations.

If you’re experiencing persistent fatigue, it’s important to consult a healthcare provider to determine the best course of action.