What is the appropriate workup and management for anemia in a general adult population, including those with chronic kidney disease or suspected gastrointestinal blood loss?

Workup of Anemia in Adults

Initial Hemoglobin Thresholds for Diagnosis and Evaluation

Anemia should be diagnosed and a comprehensive workup initiated when hemoglobin falls below 13.5 g/dL in adult males or below 12.0 g/dL in adult females. 1

• In patients with chronic kidney disease (CKD), initiate workup at hemoglobin <12 g/dL in adult males and postmenopausal females, or <11 g/dL in premenopausal females 1
• These thresholds represent approximately 80% of normal mean hemoglobin levels and identify patients most likely to have pathological processes requiring intervention 1

Essential Initial Laboratory Tests

Order a complete blood count with red cell indices (MCV, MCH, MCHC), reticulocyte count, serum ferritin, transferrin saturation, and comprehensive metabolic panel as the foundation of anemia workup. 1, 2

Iron Studies Interpretation

• Serum ferritin is the single most useful test for iron deficiency 1
• Absolute iron deficiency: ferritin <100 μg/L in non-dialysis patients or <200 μg/L in hemodialysis patients, with transferrin saturation ≤20% 3
• Functional iron deficiency: transferrin saturation <20% despite ferritin >100 μg/L, indicating inadequate iron availability despite adequate stores 3, 4
• Critical pitfall: In inflammatory states, ferritin >100 μg/L with transferrin saturation <20% still indicates functional iron deficiency requiring treatment 2

Additional Essential Tests

• Reticulocyte count: Low or inappropriately normal values suggest deficiencies preventing erythropoiesis or bone marrow disease; elevated values indicate hemolysis or acute blood loss 2
• Vitamin B12 and folate levels: Mandatory to exclude macrocytic causes that may be masked in combined deficiency states 2, 4
• Serum creatinine and estimated GFR: CKD causes anemia through reduced erythropoietin production and is present in 6.76% of the population 5
• Haptoglobin and lactate dehydrogenase (LDH): To identify hemolysis 2
• Urinalysis: To exclude renal blood loss 6, 2

Pattern-Based Diagnostic Approach

Microcytic Anemia (MCV <80 fL)

• Iron deficiency is the most common cause; confirm with ferritin and transferrin saturation 1
• If iron studies are normal, order hemoglobin electrophoresis to exclude thalassemia 7
• Normal Hgb A2 level (2.2-3.3%) excludes beta-thalassemia trait, which shows Hgb A2 >3.3% 7
• Consider anemia of chronic disease when microcytosis occurs with normal iron studies and normal hemoglobin electrophoresis 7

Normocytic Anemia (MCV 80-100 fL)

• 80.5% of patients with hemoglobin ≤11 g/dL have normocytic anemia 5
• Check transferrin saturation even with "normal" ferritin, as 58.8% of normocytic anemia patients with Hb ≤11 g/dL have ferritin <100 μg/L 5
• Evaluate for anemia of chronic disease, CKD, or combined deficiency states 4, 5
• Combined deficiency states can mask typical MCV changes—simultaneous iron and B12/folate deficiency may present as normocytic 2

Macrocytic Anemia (MCV >100 fL)

• Measure vitamin B12 and folate levels 2, 4
• Consider medication review for drugs affecting folate metabolism 2

Gastrointestinal Investigation Protocol

In men and postmenopausal women with newly diagnosed iron deficiency anemia without obvious explanation, perform urgent bidirectional endoscopy (gastroscopy and colonoscopy) as first-line investigations. 1, 6

• Approximately one-third of men and postmenopausal women with IDA have underlying GI pathology, most commonly malignancy 1
• Screen for celiac disease serologically (tissue transglutaminase or endomysial antibody), as it is found in 3-5% of IDA cases 2
• If anemia persists or recurs despite treatment with negative bidirectional endoscopy, proceed to wireless capsule endoscopy for small bowel evaluation (diagnostic yield 50-73%) 2

Chronic Kidney Disease-Specific Considerations

All CKD patients should be screened for anemia during initial evaluation, with hemoglobin testing at least annually regardless of CKD stage or cause. 1

• Anemia develops early in CKD and worsens with progressive renal insufficiency; prevalence increases from 8.7% in stage 2 to 52.4% in stage 5 1
• Mean hemoglobin decreases consistently when GFR falls below 60 mL/min/1.73 m² (stage 3 CKD) 1
• In hemodialysis patients, obtain blood samples predialysis to document and monitor anemia 1
• Iron supplementation is recommended for all CKD patients with anemia; intravenous iron is preferred for dialysis patients (stage 5D), while either IV or oral iron is appropriate for non-dialysis CKD stages 3-5 3

Medication Review

Review all medications that may contribute to anemia or GI blood loss before considering advanced therapies. 2, 5

• 73% of CKD patients with anemia have been prescribed NSAIDs, 61% aspirin, 14.1% warfarin, and 12.4% clopidogrel 5
• 53.1% are on both aspirin and NSAIDs, significantly increasing bleeding risk 5
• Consider azathioprine and other immunosuppressants causing bone marrow suppression 2

Frequency of Monitoring

• Hemoglobin should be measured at least annually in all CKD patients 1
• Check hemoglobin response at 4 weeks after starting iron replacement 6
• Continue iron for 3 months after hemoglobin normalizes to replenish stores 6

Critical Pitfalls to Avoid

• Never accept normal ferritin at face value in inflammatory states—ferritin >100 μg/L with transferrin saturation <20% still indicates functional iron deficiency 2
• Never assume negative endoscopy rules out GI blood loss—persistent or recurrent anemia requires capsule endoscopy 2
• Never overlook combined deficiency states—normocytic anemia can result from simultaneous iron and B12/folate deficiency 2
• Never perform empiric iron trials in men over 40 or postmenopausal women without GI investigation—this delays diagnosis of underlying malignancy 8
• The coexistence of iron deficiency anemia and hypercalcemia strongly suggests GI malignancy until proven otherwise 6