FATIGUE

Persistent subjective lack of energy impairing function — requires systematic evaluation to exclude serious pathology

SYMPTOMS / ASSOCIATED SX

  • Duration, timing (AM vs. PM), relationship to activity (worse with exertion vs. rest)

  • Constitutional: weight loss, fever, night sweats (malignancy, infection)

  • Dyspnea on exertion, orthopnea (HF, anemia)

  • Cognitive slowing, depression, anhedonia, sleep disturbance (mood disorder, hypothyroidism)

  • Polyuria/polydipsia/weight loss (DM); myalgias/proximal weakness (inflammatory, drug-induced)

DENIES

  • Hemoptysis, hematochezia, lymphadenopathy (occult malignancy)

  • B symptoms: fever, night sweats, unintentional weight loss (lymphoma, TB)

  • Exertional chest pain/dyspnea at rest (cardiac)

SOCIAL HISTORY

  • Alcohol, substance use, sleep patterns, shift work, psychosocial stressors

  • Occupational exposures; dietary history; caregiver burden

MAIN ETIOLOGY

  • Psychiatric (most common in primary care ~40–50%): depression, anxiety, somatization

  • Medical: anemia, hypothyroidism, uncontrolled DM, CKD, CHF, COPD, OSA, malignancy, chronic infection (HIV, Hep, TB)

  • Medications: beta-blockers, sedatives, statins, antidepressants

  • Post-viral: post-COVID syndrome, EBV, Lyme disease

  • ME/CFS: post-exertional malaise ≥6 months; exclusion diagnosis

MOST COMMON DDX

  • Anemia (CBC, reticulocyte count, iron studies, B12/folate)

  • Hypothyroidism (TSH; weight gain, cold intolerance, slow DTRs)

  • Depression (PHQ-9 ≥10; anhedonia, sleep disturbance)

  • OSA (Epworth Sleepiness Scale ≥10; polysomnography)

  • Uncontrolled DM (HbA1c)

  • Adrenal insufficiency (AM cortisol <3; ACTH stim; hypoNa + hyperK + hyperpigmentation)

DATA

  • CBC with diff; BMP; TSH; LFTs; iron studies (ferritin, TIBC, serum iron); B12, folate

  • ESR, CRP; ANA, RF if rheumatologic; AM cortisol; ACTH stim if Addison's suspected

  • HIV, Hep B/C, Lyme if risk factors; HbA1c

  • CXR; ECG; PHQ-9, GAD-7; Epworth Sleepiness Scale

HOME MEDS

  • Beta-blockers — may cause fatigue; consider dose reduction if non-essential

  • Statins — fatigue + myalgia; check CK

  • Sedating agents (antihistamines, benzodiazepines, TCAs) — reduce if possible

PLAN

  • Treat identified cause:

    • Iron deficiency: ferrous sulfate 325 mg PO BID–TID; or IV iron (ferric carboxymaltose 750 mg) if intolerant/malabsorption

    • Hypothyroidism: levothyroxine 1.6 mcg/kg/day PO (25–50 mcg/day in elderly/cardiac); titrate TSH q6–8 weeks

    • B12 deficiency: cyanocobalamin 1000 mcg IM daily ×7 → weekly ×4 → monthly; or PO 1000–2000 mcg daily

    • Adrenal insufficiency: hydrocortisone 20 mg AM + 10 mg PM; fludrocortisone 0.1 mg daily (primary AI)

    • Depression: sertraline 50 mg PO daily; or mirtazapine 7.5–15 mg qhs if appetite/sleep benefit needed

    • OSA: CPAP referral

  • ME/CFS: pacing (energy management); cognitive behavioral therapy; avoid over-exertion (post-exertional malaise)

  • CHF-related: optimize diuresis, ACE inhibitor/ARB, beta-blocker titration

  • PT/OT if significant functional decline

  • DISCHARGE:

    • Initiate treatment for identified cause before discharge

    • Sleep study referral if OSA suspected

    • PCP follow-up 2–4 weeks; re-evaluate unexplained fatigue at 3 months

RED FLAGS

  • Fatigue + B symptoms → malignancy/lymphoma workup urgently

  • Fatigue + exertional dyspnea + orthopnea → decompensated CHF or significant anemia

  • Fatigue + Hgb <7 with symptoms → transfusion consideration

  • Adrenal crisis: fatigue + hypotension + hypoNa + hyperK → hydrocortisone 100 mg IV bolus NOW

  • Myxedema coma: severe hypothyroidism + AMS → ICU; levothyroxine IV; hydrocortisone; warming

SENIOR IM RESIDENT PEARLS

  • Most common identifiable causes: anemia, hypothyroidism, depression, uncontrolled DM, CKD, CHF, OSA

  • Ferritin <30 ng/mL = iron deficiency even with normal CBC; functional iron deficiency: ferritin 30–100 with transferrin saturation <20%

  • IV iron (ferric carboxymaltose) equivalent or superior to PO in CKD and IBD — fewer GI side effects

  • Common mistake: checking TSH once — hypothyroidism takes 6–12 weeks of treatment before fatigue resolves; titrate TSH to 1–2.5

  • PHQ-9 ≥10: sensitivity 88%, specificity 88% for major depression — screen every fatigued patient

  • Common mistake: diagnosing ME/CFS before ruling out all medical causes — requires ≥6 months post-full-workup