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Mrs. M is a 42-year-old woman who has had fatigue for the past 6 months.

Image not available.What is the differential diagnosis of fatigue? How would you frame the differential?

Before considering the differential diagnosis, it is important to understand what the patient means by fatigue, which is conventionally defined as a sensation of exhaustion after usual activities, or a feeling of insufficient energy to begin usual activities. Most people consider the terms fatigue, tiredness, and lack of energy synonymous. However, patients sometimes use these terms when they are actually experiencing other symptoms, especially excessive sleepiness, weakness, or dyspnea on exertion.

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Image not available.Always ask patients what they mean when they report fatigue. Always ask directly about weakness, excessive sleepiness, and dyspnea.

Acute fatigue is common in conjunction with a variety of acute illnesses, ranging from uncomplicated viral infections to exacerbations of heart failure (HF). Fatigue is also a prominent symptom in some chronic diseases, such as multiple sclerosis and cancer. This chapter will not discuss fatigue in such patients but will focus on evaluating the symptom of fatigue lasting weeks to months in patients without already diagnosed conditions known to cause fatigue.


The differential diagnosis of fatigue is extremely broad and best organized with an organ/system approach.


  1. Psychiatric

    1. Depression

    1. Anxiety

    1. Somatization disorder

    1. Substance abuse

  2. Sleep disorders

    1. Insomnia

    1. Obstructive sleep apnea

    1. Periodic leg movements

    1. Narcolepsy

  3. Endocrine

    1. Thyroid disease

    1. Diabetes

    1. Hypoadrenalism

  4. Medications (Table 16–1)

  5. Hematologic or oncologic

    1. Anemia

    1. Cancer

  6. Renal: renal failure

  7. GI: liver disease

  8. Cardiovascular: chronic heart disease

  9. Pulmonary: chronic lung disease

  10. Neuromuscular: myositis, multiple sclerosis

  11. Infectious: chronic infections

  12. Rheumatologic: autoimmune diseases

  13. Fatigue of unknown etiology

    1. Chronic fatigue syndrome

    1. Idiopathic chronic fatigue: fatigue for which no medical, psychiatric, or sleep pattern explanation can be found.


Figure 16-1 outlines the evaluation of fatigue in an algorithm.

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Table 16–1. Medications That Affect Sleep.
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Image not available.The most common causes of fatigue are psychiatric disorders, sleep disorders, and medication side effects.
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Mrs. M reports that she is tired all the time, beginning first thing in the morning and lasting all day. ...

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