Anemia profile
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Anemia - Complete Profile
Definition
Anemia is defined as a reduction in blood hemoglobin concentration (or hematocrit) below the normal range for a given age, sex, and physiologic state. Practically, this means Hb < 13.5 g/dL in adult males and < 12 g/dL in adult females.
Classification
1. By MCV (Morphologic / Wintrobe Classification)
| Type | MCV | Key Causes |
|---|---|---|
| Microcytic | < 80 fL | Iron deficiency, Thalassemia, Anemia of chronic disease (ACD), Sideroblastic anemia |
| Normocytic | 80-100 fL | Aplastic anemia, Renal disease, Endocrinopathies, Myeloma, Marrow invasion, Pure red cell aplasia |
| Macrocytic | > 100 fL | Oval macrocytes: B12 deficiency, Folate deficiency, Chemotherapy, Myelodysplasia; Round macrocytes: Alcohol, Liver disease, Hypothyroidism, Reticulocytosis, Dysproteinemia |
2. By Mechanism (Pathophysiologic Classification)
| Mechanism | Examples |
|---|---|
| Blood loss | Acute trauma; chronic GI/gynecological bleeding |
| Hemolysis (increased destruction) | Hereditary spherocytosis, G6PD deficiency, Sickle cell, Thalassemia, AIHA, PNH, TTP/HUS |
| Decreased production | Iron/B12/folate deficiency, aplastic anemia, ACD, EPO deficiency, marrow infiltration |
3. By Reticulocyte Count (Functional)
- Hyperproliferative (reticulocytes ↑): Hemolysis or blood loss - the marrow is responding normally
- Hypoproliferative (reticulocytes ↓ or normal): Defective production - marrow failure, nutritional deficiency, or chronic disease
Major Anemia Types - Detailed
A. Iron Deficiency Anemia (IDA)
Most common anemia worldwide.
Causes:
- Dietary lack (infants, vegans, elderly, impoverished)
- Impaired absorption (sprue, gastrectomy, celiac)
- Increased requirement (pregnancy, infancy, adolescence)
- Chronic blood loss - most common cause in developed countries (GI lesions, gynecologic bleeding)
Iron deficiency in adult males or postmenopausal females must be attributed to GI blood loss until proven otherwise - to prematurely ascribe another cause risks missing a GI cancer.
Iron Metabolism:
- Normal daily requirement: ~1 mg absorbed; dietary intake 10-20 mg/day (only 10-15% absorbed)
- Heme iron (from meat) is ~20% absorbable vs 1-2% for non-heme iron
- Storage iron: Ferritin (main storage, correlates with body stores) and Hemosiderin (aggregated ferritin, Prussian blue positive)
- Absorption enhanced by: ascorbic acid, citric acid, amino acids
- Absorption inhibited by: tannins (tea), carbonates, oxalates, phosphates
Stages of Iron Deficiency:
- Pre-latent: Iron stores deplete; serum ferritin falls; no anemia yet
- Latent: Serum iron falls, TIBC rises, transferrin saturation falls below 15%; no anemia
- Overt IDA: Hemoglobin falls; microcytic hypochromic anemia appears
Lab Findings in IDA:
| Parameter | Finding |
|---|---|
| Hb / Hct | Decreased |
| MCV | Low (microcytic) |
| MCH / MCHC | Low (hypochromic) |
| Serum iron | ↓ |
| TIBC (Transferrin) | ↑ |
| Transferrin saturation | < 15% |
| Serum ferritin | ↓ (< 12 µg/L) |
| Serum hepcidin | ↓ (reduced iron inhibits hepcidin synthesis) |
| Reticulocytes | Low initially, rise after treatment |
Peripheral Blood Smear - IDA:
Hypochromic microcytic RBCs - the zone of central pallor is greatly enlarged. "Pencil cells" (elongated poikilocytes) are characteristic. Fully hemoglobinized cells visible from a recent transfusion.
Clinical Features:
- General anemia symptoms: fatigue, pallor, dyspnea on exertion
- Koilonychia (spoon nails), alopecia
- Atrophic glossitis, angular cheilitis
- Pica (craving for clay, ice [pagophagia], flour)
- Plummer-Vinson syndrome (triad): microcytic anemia + esophageal web + atrophic glossitis
- Central nervous system: pica, restless leg syndrome
Treatment: Oral iron supplementation - reticulocytosis appears in 5-7 days, Hb normalizes in 6-8 weeks; continued for 3+ months to replete stores.
B. Megaloblastic Anemia (B12 / Folate Deficiency)
Pathogenesis: Impaired DNA synthesis (thymidine synthesis requires B12 and folate as cofactors) → nuclear maturation delay while cytoplasmic maturation continues → nuclear-cytoplasmic asynchrony → ineffective hematopoiesis + pancytopenia.
Causes of Megaloblastic Anemia:
| B12 Deficiency | Folate Deficiency | Other |
|---|---|---|
| Inadequate diet (strict vegetarians) | Inadequate diet, alcoholism, infancy | Methotrexate, hydroxyurea |
| Pernicious anemia (autoimmune - anti-IF antibodies) | Malabsorption (celiac, sprue) | 5-FU, other chemotherapy |
| Gastrectomy | Anticonvulsants, oral contraceptives | Myelodysplasia |
| Ileal resection / Crohn's disease | Increased requirements (pregnancy, hemolysis, cancer) | |
| Bacterial overgrowth / Fish tapeworm | Hemodialysis (increased loss) |
Lab Findings:
| Parameter | Finding |
|---|---|
| MCV | ↑ (macrocytic, often > 110 fL) |
| Peripheral smear | Macro-ovalocytes, hypersegmented neutrophils (≥5 lobes) |
| WBC / Platelets | ↓ (pancytopenia from ineffective hematopoiesis) |
| LDH | ↑↑ (from ineffective hematopoiesis / intramedullary cell death) |
| Indirect bilirubin | ↑ (mild hemolysis) |
| Reticulocytes | Low (despite hypercellular marrow) |
| Serum B12 | ↓ in B12 deficiency |
| Serum folate / RBC folate | ↓ in folate deficiency |
| Methylmalonic acid (MMA) | ↑ in B12 deficiency only (not in folate deficiency) |
| Homocysteine | ↑ in both B12 and folate deficiency |
Key Peripheral Smear Finding - Megaloblastic Anemia:
Hypersegmented neutrophil (≥5 nuclear lobes) - a hallmark of megaloblastic anemia. Macro-ovalocytes are also seen in the background.
B12 vs Folate Deficiency - Key Distinctions:
| Feature | B12 Deficiency | Folate Deficiency |
|---|---|---|
| Neurological signs | Yes - subacute combined degeneration (posterior + lateral columns) | No neurological signs |
| MMA | ↑ | Normal |
| Homocysteine | ↑ | ↑ |
| Onset | Slow (years - large hepatic stores) | Faster (weeks to months - small stores) |
Pernicious Anemia (PA):
- Autoimmune atrophic gastritis → loss of parietal cells → intrinsic factor (IF) deficiency → B12 malabsorption
- Antibodies: Anti-parietal cell antibodies (~90%); Anti-intrinsic factor antibodies (more specific, ~60%)
- Associated with other autoimmune diseases (thyroiditis, Addison's, vitiligo)
- Treatment: IM/SC hydroxocobalamin or cyanocobalamin (bypasses gut absorption defect)
C. Anemia of Chronic Disease (ACD) / Anemia of Inflammation
Pathogenesis: Inflammation → IL-6 → ↑ hepatic hepcidin → hepcidin blocks ferroportin on macrophages → iron sequestered in storage pool → iron-starved erythroid precursors (functional iron deficiency despite adequate total body iron).
Associated Conditions:
- Chronic infections (osteomyelitis, TB, bacterial endocarditis, lung abscess)
- Chronic immune disorders (rheumatoid arthritis, IBD, SLE)
- Neoplasms (Hodgkin lymphoma, lung and breast carcinomas)
Lab Findings:
| Parameter | ACD | IDA |
|---|---|---|
| Serum iron | ↓ | ↓ |
| TIBC | ↓ (or normal) | ↑ |
| Serum ferritin | ↑ (or normal) | ↓ |
| Storage iron (Prussian blue) | ↑ in marrow macrophages | Absent |
| Hepcidin | ↑ | ↓ |
| Morphology | Normocytic normochromic (may be mildly microcytic) | Microcytic hypochromic |
Treatment: Treat underlying disease; erythropoietin-stimulating agents in cancer patients.
D. Hemolytic Anemias
Two major categories of hemolysis:
Extravascular Hemolysis (Spleen/macrophage mediated)
- RBCs destroyed by splenic macrophages
- Findings: Splenomegaly, jaundice (↑ unconjugated bilirubin), pigment gallstones (chronic)
- Iron is efficiently recycled - NO iron deficiency
Intravascular Hemolysis (RBCs lyse within vessels)
- RBCs burst in circulation
- Findings: Hemoglobinemia, hemoglobinuria (pink/red urine), hemosiderinuria, ↓ haptoglobin, ↓ iron stores (iron lost in urine)
- Haptoglobin is ↓ in BOTH types
General hemolytic anemia findings:
- ↑ Reticulocytes (regenerative response)
- ↑ LDH, ↑ indirect bilirubin
- ↓ Haptoglobin
- Marrow erythroid hyperplasia
- Possible extramedullary hematopoiesis (liver, spleen, lymph nodes) in severe cases
Common subtypes:
| Anemia | Defect | Key Feature |
|---|---|---|
| Hereditary spherocytosis | Spectrin/ankyrin mutations → membrane defect | Spherocytes, osmotic fragility ↑, splenomegaly |
| G6PD deficiency | Hexose monophosphate shunt enzyme defect | Heinz bodies, bite cells; triggered by oxidant stress (primaquine, fava beans, infections) |
| Sickle cell disease | HbS (Glu→Val substitution) | Sickle cells, vaso-occlusive crises, autosplenectomy, HbS on electrophoresis |
| Thalassemia | Deficient α or β globin synthesis | Target cells, microcytosis; thalassemia major requires transfusions |
| Autoimmune hemolytic anemia | Warm (IgG) or Cold (IgM) antibodies against RBCs | Positive direct Coombs (DAT) test |
| TTP / HUS | Microangiopathic; thrombotic occlusion fragments RBCs | Schistocytes (helmet cells), thrombocytopenia |
| PNH | Acquired mutation (PIG-A) - loss of GPI-anchored proteins (CD55, CD59) | Complement-mediated hemolysis; thrombosis; flow cytometry diagnostic |
E. Aplastic Anemia
Definition: Chronic primary hematopoietic failure → pancytopenia (anemia + neutropenia + thrombocytopenia) from bone marrow hypoplasia.
Mechanism: Mostly autoimmune - T cells attack stem cells. Also: stem cell intrinsic defects.
Causes:
| Acquired | Inherited |
|---|---|
| Idiopathic (~70%) | Fanconi anemia (DNA repair defect; autosomal recessive) |
| Drugs: chloramphenicol, benzene, alkylating agents, gold salts, phenylbutazone | Telomerase defects (dyskeratosis congenita) |
| Viral infections (hepatitis B/C, CMV, EBV, parvovirus B19) | |
| Whole-body irradiation |
Lab: Pancytopenia + hypocellular bone marrow biopsy (marrow replaced by fat cells) + absent/reduced reticulocytes.
Treatment: Bone marrow transplant (young patients with matched donor) or immunosuppression (anti-thymocyte globulin + cyclosporine + eltrombopag).
Summary Comparison Table
| Feature | IDA | ACD | Megaloblastic | Hemolytic | Aplastic |
|---|---|---|---|---|---|
| MCV | ↓ | N or ↓ | ↑ | N or ↑ | N |
| Serum iron | ↓ | ↓ | N | N | N |
| TIBC | ↑ | ↓/N | N | N | N |
| Ferritin | ↓ | ↑/N | N | N | N |
| Reticulocytes | ↓ | ↓ | ↓ | ↑ | ↓ |
| Haptoglobin | N | N | N | ↓ | N |
| LDH | N | N | ↑↑ | ↑ | N |
| Bilirubin (indirect) | N | N | ↑ | ↑ | N |
| B12/Folate | N | N | ↓ | N | N |
| Bone marrow | Erythroid hyperplasia | Erythroid hyperplasia | Megaloblasts; hypercellular | Erythroid hyperplasia | Hypocellular (fat cells) |
Key Clinical Pearls
- Ferritin is an acute-phase reactant - it may be normal or elevated in ACD even with concurrent iron deficiency. Serum transferrin receptor (sTfR) or sTfR/log ferritin ratio helps distinguish IDA from ACD.
- Methylmalonic acid distinguishes B12 from folate deficiency - MMA is elevated only in B12 deficiency; homocysteine is elevated in both.
- Hypersegmented neutrophils (≥5 lobes, or any 6-lobed neutrophil) are the earliest and most sensitive sign of megaloblastic change.
- In hemolytic anemia, a low haptoglobin is the most sensitive single test; schistocytes on smear indicate microangiopathic process.
- Reticulocyte production index (RPI) < 2 = hypoproliferative (production problem); > 3 = hyperproliferative (loss/destruction problem).
- IDA in an adult male or postmenopausal female = GI bleeding until proven otherwise - always investigate for colorectal cancer.
Sources: Robbins, Cotran & Kumar - Pathologic Basis of Disease (9780443264528); Harrison's Principles of Internal Medicine 22E (9781265977061); Robbins & Kumar Basic Pathology (9780323790185)
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