Anemia: Diagnostic Approach and Common Causes

A practical framework for anemia — classification by MCV and reticulocyte count, and the workup and management of iron deficiency, anemia of chronic disease, anemia of renal disease, B12/folate deficiency, and hemolytic anemia

Key Points

• Anemia is a reduction in hemoglobin/hematocrit below the age- and sex-specific reference range; it is a manifestation of an underlying disorder, not a diagnosis in itself — always identify the cause.
• Two orthogonal frameworks drive the workup: mean corpuscular volume (MCV) classifies anemia as microcytic, normocytic, or macrocytic; the reticulocyte count separates hypoproliferative (low retic) from hemolysis/blood-loss (high retic) states.
• Iron deficiency is the most common cause worldwide — confirm with ferritin (low) and iron studies (low iron, high TIBC, low transferrin saturation), and always search for the source of blood loss, especially GI malignancy in older adults.
• Anemia of chronic disease (anemia of inflammation) is hepcidin-mediated iron sequestration; ferritin is normal-to-high, distinguishing it from true iron deficiency — though the two frequently coexist.
• Anemia of renal disease results from erythropoietin deficiency; treat with iron repletion and erythropoiesis-stimulating agents or HIF-PH inhibitors, targeting hemoglobin ~10–11 g/dL (over-correction increases cardiovascular and thrombotic risk).
• A high reticulocyte count with elevated LDH and indirect bilirubin and a low haptoglobin points to hemolysis — the direct antiglobulin (Coombs) test then separates immune from non-immune causes.

A Framework for Anemia

Anemia is defined as a hemoglobin concentration below the reference range for age and sex (commonly 100 fL):** B12 or folate deficiency (megaloblastic), alcohol, liver disease, hypothyroidism, myelodysplastic syndrome, reticulocytosis, certain drugs. **2. By marrow response (reticulocyte count):** The reticulocyte count (ideally the reticulocyte production index) tells you whether the marrow is responding appropriately. - **Low/inappropriately normal reticulocytes (hypoproliferative):** production problem — iron/B12/folate deficiency, anemia of chronic disease, renal disease, marrow failure.…

Iron Deficiency Anemia

Iron deficiency is the most common cause of anemia worldwide. It is classically **microcytic and hypochromic** with a low reticulocyte response and an elevated red cell distribution width (RDW). **Causes:** - **Blood loss (most important in adults):** gastrointestinal (peptic ulcer, colonic/gastric malignancy, angiodysplasia, NSAID use), menstrual/gynecologic, and less commonly urinary or from repeated phlebotomy. - **Malabsorption:** celiac disease, atrophic gastritis, prior gastric/bariatric surgery, and *Helicobacter pylori* infection. - **Increased demand / inadequate intake:**…

Anemia of Chronic Disease (Anemia of Inflammation)

Anemia of chronic disease (ACD), better termed **anemia of inflammation**, is the most common anemia in hospitalized and chronically ill patients. It accompanies chronic infection, autoimmune and inflammatory disease, and malignancy. **Pathophysiology:** Inflammatory cytokines (especially IL-6) drive hepatic production of **hepcidin**, the master iron-regulatory hormone. Hepcidin degrades ferroportin, trapping iron in macrophages and enterocytes — so iron is present in the body but unavailable for erythropoiesis ("functional iron deficiency"). Inflammation also blunts erythropoietin response…

Anemia of Renal Disease

Chronic kidney disease (CKD) causes anemia primarily through **erythropoietin (EPO) deficiency** — the peritubular cells of the kidney are the main source of EPO, and as functioning renal mass declines, EPO production falls. Uremia also shortens red cell survival and impairs iron utilization, and iron deficiency is common (from blood loss, dialysis, and reduced absorption). **Features:** Typically a **normocytic, normochromic, hypoproliferative** anemia whose severity tracks with the degree of renal impairment (usually apparent once eGFR falls below ~30–45 mL/min/1.73m², earlier in…

B12 and Folate Deficiency (Megaloblastic Anemia)

Vitamin B12 (cobalamin) and folate are both required for DNA synthesis; deficiency of either causes **megaloblastic anemia** — a **macrocytic (MCV often >110 fL)** anemia with characteristic marrow and smear findings. **Smear and labs:** Macro-ovalocytes and **hypersegmented neutrophils** are hallmark findings. Because the defect impairs all dividing cells, ineffective erythropoiesis produces intramedullary hemolysis — a **markedly elevated LDH and elevated indirect bilirubin with a low reticulocyte count** (a useful clue). Pancytopenia can occur in severe cases. **Vitamin B12 deficiency:**…

Hemolytic Anemia

Hemolytic anemias result from **premature red cell destruction** outpacing marrow production. The unifying laboratory picture is a **high reticulocyte count** (appropriate marrow response) with markers of red cell breakdown: **elevated LDH, elevated indirect (unconjugated) bilirubin, and a low haptoglobin.** The peripheral smear is often diagnostic. **The pivotal branch point is the direct antiglobulin (Coombs) test:** **Immune hemolytic anemia (DAT-positive):** - **Warm autoimmune hemolytic anemia (IgG, active at 37°C):** the most common form — idiopathic or secondary to lymphoproliferative…

Other Causes and When to Refer

Beyond the common causes above, several other mechanisms should be considered when the anemia does not fit a straightforward pattern: - **Acute blood loss:** hemoglobin may initially appear normal before equilibration; look for tachycardia, hypotension, and an occult source (GI, retroperitoneal, trauma, procedural). - **Bone marrow failure and infiltration:** aplastic anemia (covered separately), myelodysplastic syndromes (macrocytic anemia with dysplasia and cytopenias — suspect in older adults with unexplained macrocytosis), and marrow replacement by malignancy or fibrosis…