The differential diagnosis for chronic fatigue is extensive: thyroid dysfunction (both hypothyroidism and, less commonly, hyperthyroidism), anemia (iron deficiency, B12 deficiency, folate deficiency, chronic disease anemia), diabetes, obstructive sleep apnea, chronic kidney disease, liver disease, heart failure, and malignancy. Autoimmune conditions — lupus, rheumatoid arthritis, inflammatory bowel disease — frequently present with fatigue as a dominant complaint.
A basic fatigue workup should include: complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid stimulating hormone (TSH), iron studies (serum iron, ferritin, TIBC), B12 and folate, HbA1c or fasting glucose, urinalysis, and CRP or ESR if inflammatory conditions are suspected. In appropriate clinical contexts, add: cortisol (adrenal insufficiency), testosterone (hypogonadism), celiac serology (tissue transglutaminase IgA), and HIV testing.
Iron deficiency deserves particular attention. Iron deficiency without anemia is extremely common — particularly in premenopausal women — and can cause significant fatigue before hemoglobin falls below normal thresholds. Ferritin is the most sensitive marker. A ferritin below 30 ng/mL may be clinically significant even with a normal hemoglobin. Many patients are told their 'blood work is normal' when ferritin was never ordered.
When the workup is negative — and it often is — the clinical focus appropriately shifts to sleep, mood, and functional contributors. But 'nothing is wrong' should never be the endpoint without a thorough investigation. Chronic fatigue syndrome (now termed SEAD — Systemic Exertion Intolerance Disease) is a real, disabling condition that requires specific clinical criteria and a specialized approach.