Future doctors Redden and Ibrahim discuss with Dr. Arreaza the different causes of fatigue, including physical and mental illnesses. Dr. Arreaza describes the steps to evaluate fatigue. Some common misconceptions are explained, such as vitamin D deficiency and “chronic Lyme disease”.
Written by Michael Ibrahim, MSIV, and Jordan Redden, MSIV, Ross University School of Medicine. Edits and comments by Hector Arreaza, MD
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Dr. Arreaza: Today is a great day to talk about fatigue. It is one of the most common and most complex complaints we see in primary care. It involves physical, mental, and emotional health. So today, we’re walking through a case, breaking down causes, red flags, and how to work it up without ordering the entire lab catalog.
Michael:
Case: This is a 34-year-old female who comes in saying, "I’ve been feeling drained for the past 3 months." She says she’s been sleeping 8 hours a night but still wakes up tired. No recent illnesses, no weight loss, fever, or night sweats. She denies depression or anxiety but does report a lot of work stress and taking care of her two little ones at home. She drinks 2 cups of coffee a day, doesn’t drink alcohol, and doesn’t use drugs. No medications, just a multivitamin. Regular menstrual cycles—but she’s noticed they’ve been heavier recently.
Jordan:
Fatigue is a persistent sense of exhaustion that isn’t relieved by rest. It’s different from sleepiness or muscle weakness.
Classification based on timeline:
• Acute fatigue: less than 1 month
• Subacute: 1 to 6 months
• Chronic: more than 6 months
This patient’s case is subacute—going on 3 months now.
Dr. Arreaza:
And we can think about fatigue in types:
• Physical fatigue: like muscle tiredness after activity
• Mental fatigue: trouble concentrating or thinking clearly (physical + mental when you are a medical student or resident)
• Pathological fatigue: which isn’t proportional to effort and doesn’t get better with rest
And of course, there’s chronic fatigue syndrome, also called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is a diagnosis of exclusion after 6 months of disabling fatigue with other symptoms.
Michael:
The differential is massive. So, we can also group it by systems.
Jordan:
Let’s run through the big ones.
Endocrine / Metabolic Causes
• Hypothyroidism: A classic cause of fatigue. Often associated with cold intolerance, weight gain, dry skin, and constipation. May be subtle and underdiagnosed, especially in women.
• Diabetes Mellitus: Both hyperglycemia and hypoglycemia can cause fatigue. Look for polyuria, polydipsia, weight loss, or blurry vision in undiagnosed diabetes.
• Adrenal Insufficiency: Think of this when fatigue is paired with hypotension, weight loss, salt craving, or hyperpigmentation. Can be primary (Addison's) or secondary (e.g., due to long-term steroid use).
Michael:
Hematologic Causes
• Anemia (especially iron deficiency): Very common, especially in menstruating women. Look for fatigue with pallor, shortness of breath on exertion, and sometimes pica (craving non-food items).
• Vitamin B12 or Folate Deficiency: B12 deficiency may present with fatigue plus neurologic symptoms like numbness, tingling, or gait issues. Folate deficiency tends to present with megaloblastic anemia and fatigue.
• Anemia of Chronic Disease: Seen in patients with chronic inflammatory conditions like RA, infections, or CKD. Typically mild, normocytic, and improves when the underlying disease is treated.
Michael:
Psychiatric Causes
• Depression: A major driver of fatigue, often underreported. May include anhedonia, sleep disturbance, appetite changes, or guilt. Sometimes presents with only somatic complaints.
• Anxiety Disorders: Mental fatigue, poor sleep quality, and hypervigilance can leave patients feeling constantly drained.
• Burnout Syndrome: Especially common in caregivers, healthcare workers, and educators. Emotional exhaustion, depersonalization, and reduced personal accomplishment are key features.
Jordan:
Infectious Causes
• Epstein-Barr Virus (EBV):
Mononucleosis is a well-known cause of fatigue, sometimes lasting weeks. May also have sore throat, lymphadenopathy, and splenomegaly.
• HIV:
Consider it in high-risk individuals. Fatigue can be an early sign, along with weight loss, recurrent infections, or night sweats.
• Hepatitis (B or C):
Can present with chronic fatigue, especially if liver enzymes are elevated. Screen at-risk individuals.
• Post-viral Syndromes / Long COVID:
Fatigue that lingers for weeks or months after viral infection. Often, it includes brain fog, muscle aches, and post-exertional malaise.
Important: Chronic Lyme disease is a controversial term without a consistent clinical definition and is often used to describe patients with persistent, nonspecific symptoms not supported by objective evidence of Lyme infection. Leading medical organizations reject the term and instead recognize "post-treatment Lyme disease syndrome" (PTLDS) for persistent symptoms following confirmed, treated Lyme disease, emphasizing that prolonged antibiotic therapy is not effective. Research shows no benefit—and potential harm—from extended antibiotic use, and patients with unexplained chronic symptoms should be thoroughly evaluated for other possible diagnoses.
Michael:
Cardiopulmonary Causes
• Congestive Heart Failure (CHF): Fatigue from poor perfusion and low cardiac output. Often comes with dyspnea on exertion, edema, and orthopnea.
• Chronic Obstructive Pulmonary Disease (COPD): Look for a smoking history, chronic cough, and fatigue from hypoxia or the work of breathing.
• Obstructive Sleep Apnea (OSA): Daytime fatigue despite adequate hours of sleep. Patients may snore, gasp, or report morning headaches. High suspicion in obese or hypertensive patients.
Jordan:
Autoimmune / Inflammatory Causes
• Systemic Lupus Erythematosus (SLE): Fatigue is often an early symptom. May also see rash, arthritis, photosensitivity, or renal involvement.
• Rheumatoid Arthritis (RA): Fatigue from systemic inflammation. Morning stiffness, joint pain, and elevated inflammatory markers point to RA.
• Fibromyalgia: A chronic pain syndrome with widespread tenderness, fatigue, nonrestorative sleep, and sometimes cognitive complaints ("fibro fog").
Cancer / Malignancy
• Leukemia, lymphoma, or solid tumors: Fatigue can be the first symptom, often accompanied by weight loss, night sweats, or unexplained fevers. Consider when no other cause is evident.
Michael:
Medications:
Common culprits include:
◦ Beta-blockers: Can slow heart rate too much.
◦ Antihistamines: Sedating H1 blockers like diphenhydramine.
◦ Sedatives or sleep aids: Can cause grogginess and daytime sedation.
• Substance Withdrawal: Fatigue can be seen in withdrawal from alcohol, opioids, or stimulants. Caffeine withdrawal, though mild, can also contribute.
Dr. Arreaza:
Whenever we evaluate fatigue, we need to keep an eye out for red flags. These should raise suspicion for something more serious:
• Unintentional weight loss
• Night sweats
• Persistent fever
• Neurologic symptoms
• Lymphadenopathy
• Jaundice
• Palpitations or chest pain
This patient doesn’t have these—but that doesn’t mean we stop here.
Dr. Arreaza:
Those are a lot of causes, we can evaluate fatigue following 7 steps:
So, students, do we send the whole lab panel?
Michael:
Not necessarily. Labs should be guided by history and physical. But here’s a good initial panel:
• CBC: To check for anemia or infection
• TSH: Screen for hypothyroidism
• CMP: Look at electrolytes, kidney, and liver function
• Ferritin and iron studies
• B12, folate
• ESR/CRP for inflammation (not specific)
• HbA1c if diabetes is on the radar
Jordan:
And if needed, consider:
• HIV, EBV, hepatitis panel
• ANA, RF
• Cortisol or ACTH stimulation test
Imaging? Now that’s rare—unless there are specific signs. Like chest X-ray for possible cancer or TB, or sleep study if you suspect OSA.
Dr. Arreaza:
Unaddressed fatigue isn’t just inconvenient. It can impact on quality of life, affect job performance, lead to mood disorders, delay diagnosis of serious illness, increase risk of accidents—especially driving. So, don’t ignore your patients with fatigue!
Jordan:
And some people—like women, caregivers, or shift workers—are especially at risk.
Michael:
The cornerstone of treatment is addressing the underlying cause.
Jordan:
If it’s iron-deficiency anemia—treat it. If it’s depression—get mental health involved. But there’s also:
Lifestyle Support: Better sleep hygiene, light physical activity, mindfulness or CBT for stress, balanced nutrition—especially iron and protein, limit caffeine and alcohol
Dr. Arreaza:
Sometimes medications help—but rarely.
And for chronic fatigue syndrome, the current best strategies are graded exercise therapy and CBT, along with managing specific symptoms.
Beta-alanine has potential to modestly improve muscular endurance and reduce fatigue in
older adults, but more high-quality research is needed.
SSRI: fluoxetine and sertraline.
Iron supplements: Even without anemia, but low ferritin [Anecdote about low ferritin patient]
Jordan:
This case reminds us to take fatigue seriously. In her case, it may be multifactorial—work stress, caregiving burden, and possibly iron-deficiency anemia. So, how would we wrap up this conversation, Michael?
Michael:
We don’t need to order everything under the sun. A focused history and exam, targeted labs, and being alert to red flags can guide us.
Jordan:
And don’t forget the basics—sleep, stress, and nutrition. These are just as powerful as any prescription.
Dr. Arreaza:
We hope today’s episode on fatigue has given you a clear framework and some practical tips. If you enjoyed this episode, share it and subscribe for more evidence-based medicine!
Jordan:
Take care—and get some rest~
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