What are the differential diagnoses for a patient presenting with fatigue and pallor?

Differential Diagnoses for Fatigue and Pallor

The primary differential diagnoses for a patient presenting with fatigue and pallor include iron deficiency anemia, anemia of chronic disease, vitamin B12/folate deficiency, hemolytic anemia, hypothyroidism, depression, and malignancy-related causes. 1, 2, 3

Hematologic Causes (Most Common)

Iron Deficiency Anemia

• Most common cause of microcytic anemia worldwide, characterized by low serum ferritin (<30 ng/mL), low serum iron, elevated transferrin, and decreased transferrin saturation 1, 4, 5
• Primary etiologies include chronic blood loss (gastrointestinal bleeding, menstrual periods), inadequate dietary intake, or malabsorption 4, 5
• Presents with fatigue, pallor, and may include hair loss and restless legs syndrome 4

Anemia of Chronic Disease/Inflammation

• Second most common anemia type globally, presenting with normocytic or mildly microcytic anemia 6, 7
• Distinguished by low serum iron, low transferrin, but elevated or normal ferritin (>100 ng/mL), reflecting iron sequestration rather than true deficiency 1, 7, 5
• Associated with chronic inflammatory conditions, autoimmune diseases, malignancy, chronic kidney disease, and inflammatory bowel disease 1, 7
• Hepcidin excess prevents iron absorption and recycling, causing functional iron deficiency despite adequate stores 7, 5

Vitamin B12 or Folate Deficiency

• Causes macrocytic anemia (MCV >100 fL) with fatigue and pallor 1, 6
• May present with neurologic symptoms (B12 deficiency specifically) and elevated methylmalonic acid and homocysteine 8
• Can coexist with iron deficiency, creating a mixed picture 8

Hemolytic Anemia

• Characterized by elevated LDH, elevated indirect bilirubin, low/undetectable haptoglobin, and elevated reticulocyte count 6, 8
• Causes include autoimmune hemolytic anemia, hereditary spherocytosis, enzyme deficiencies, and paroxysmal nocturnal hemoglobinuria 6

Endocrine and Metabolic Causes

Hypothyroidism

• One of the first and most important causes to investigate in patients with fatigue and pallor 2, 3
• Frequently presents with nonspecific symptoms including fatigue, weight gain, cold intolerance, and constipation 2, 3

Other Endocrine Disorders

• Adrenal insufficiency, hypogonadism, and hypopituitarism should be considered, particularly in patients with additional risk factors 2
• Vitamin D deficiency and magnesium deficiency correlate with muscle fatigue 2

Psychological and Sleep-Related Causes

Depression

• Affects 18.5% of patients presenting with tiredness, significantly more frequent than in those without fatigue 3
• Fatigue and depression commonly coexist in chronic disease states, including inflammatory bowel disease and malignancy 1
• Depression is an independent condition from fatigue with different temporal patterns 1

Sleep Disorders

• Affect 30-75% of patients with fatigue, ranging from insomnia to hypersomnia 1, 3
• Sleep apnea may develop secondary to treatment effects (surgery, hormonal changes, body composition alterations) 1
• Poor sleep hygiene (irregular sleep schedule, caffeine/alcohol use, poor sleep environment) contributes significantly 1

Malignancy-Related Causes

Cancer and Chemotherapy-Induced Anemia

• Results from bone marrow suppression, nutritional deficiencies, chronic inflammation, or hemolysis 1
• Cancer-related fatigue is defined as persistent, disproportionate tiredness not relieved by rest that interferes with normal functioning 1
• Approximately 50% of cancer patients report fatigue at diagnosis, with prevalence of 40-72% during treatment 1

Inflammatory and Autoimmune Conditions

Inflammatory Bowel Disease

• Fatigue prevalence of 40-72% in IBD patients, with 30-50% experiencing fatigue even in remission 1
• Multifactorial causes include poor oral intake, malabsorption, chronic blood loss, and chronic inflammation 1
• Iron deficiency (with or without anemia) and vitamin B12 deficiency are common treatable causes 1

Rheumatologic Disorders

• Polymyalgia rheumatica-like syndrome presents with severe proximal myalgia, fatigue, and highly elevated inflammatory markers but normal creatine kinase 2
• Inflammatory arthritis may present with joint symptoms, positive rheumatoid factor, or anti-CCP antibodies 2

Medication and Substance-Related Causes

• Systematic review of all medications and supplements is essential, as sedating medications commonly contribute to fatigue 1, 3
• Statin-induced myopathy presents with myalgia and normal-to-mildly elevated creatine kinase 2
• Polypharmacy, particularly with neuropsychiatric drugs, increases fatigue risk 1

Cardiac Causes

• Cardiac dysfunction should be assessed, particularly in patients with cardiovascular risk factors or history of cardiotoxic treatments 3
• Heart failure presents with orthopnea (highly specific), dyspnea, and edema 9

Critical Diagnostic Pitfalls to Avoid

• Laboratory results affect management in only 5% of fatigue cases, but core testing remains essential to exclude treatable causes 3
• Overlooking psychological causes (depression, anxiety) leads to inadequate treatment 3
• Missing coexisting conditions: anemia of chronic disease can evolve to include true iron deficiency (ACD+ID), requiring different management 7, 5
• Ignoring medication side effects perpetuates the problem 3
• Failing to assess sleep disorders results in incomplete management 3