Anemia is a common clinical problem in medicine. A physiologic approach (outlined in Chap. 51) provides the most efficient path to diagnosis and management. Anemias arise either because red blood cell (RBC) production is inadequate or because RBC lifespan (normally 120 days) is shortened through loss from the circulation or destruction.
These are the most common anemias. Usually the RBC morphology is normal and the reticulocyte index (RI) is low. Marrow damage, early iron deficiency, and decreased erythropoietin production or action may produce anemia of this type.
Marrow damage may be caused by infiltration of the marrow with tumor or fibrosis that crowds out normal erythroid precursors or by the absence of erythroid precursors (aplastic anemia) as a consequence of exposure to drugs, radiation, chemicals, viruses (e.g., hepatitis), autoimmune mechanisms, or genetic factors, either hereditary (e.g., Fanconi’s anemia) or acquired (e.g., paroxysmal nocturnal hemoglobinuria). Most cases of aplasia are idiopathic. The tumor or fibrosis that infiltrates the marrow may originate in the marrow (as in leukemia or myelofibrosis) or be secondary to processes originating outside the marrow (as in metastatic cancer or myelophthisis).
Early iron-deficiency anemia (or iron-deficient erythropoiesis) is associated with a decrease in serum ferritin levels (<15 μg/L), moderately elevated total iron-binding capacity (TIBC) (>380 μg/dL), serum iron (SI) level <50 μg/dL, and an iron saturation of <30% but >10% (Fig. 68-1). RBC morphology is generally normal until iron deficiency is severe (see below).
FIGURE 68-1 Measurements of marrow iron stores, serum ferritin, and total iron-binding capacity (TIBC) are sensitive to early iron-store depletion. Iron-deficient erythropoiesis is recognized from additional abnormalities in the serum iron (SI), percent transferrin saturation, the pattern of marrow sideroblasts, and the red cell protoporphyrin level. Pts with iron-deficiency anemia demonstrate all the same abnormalities plus hypochromic microcytic anemia. (From RS Hillman, CA Finch: Red Cell Manual, 7th. ed, Philadelphia, Davis, 1996, with permission.)
Decreased stimulation of erythropoiesis can be a consequence of inadequate erythropoietin production [e.g., renal disease destroying the renal tubular cells that produce it or hypometabolic states (endocrine deficiency or protein starvation) in which insufficient erythropoietin is produced] or of inadequate erythropoietin action. The anemia of chronic disease is a common entity. It is multifactorial in pathogenesis: inhibition of erythropoietin production, inhibition of iron reutilization (which blocks the response to erythropoietin), and inhibition of erythroid colony proliferation by inflammatory cytokines (e.g., tumor necrosis factor, interferon γ). Hepcidin, a small iron-binding molecule produced by the liver during an acute-phase inflammatory response, may bind iron and prevent its reutilization in hemoglobin synthesis. The laboratory tests shown in Table 68-1 may assist in the differential diagnosis of hypoproliferative anemias. Measurement of hepcidin in the urine is not yet practical or widely available.
TABLE 68-1 DIAGNOSIS OF HYPOPROLIFERATIVE ANEMIAS
These result from either defective hemoglobin synthesis, leading to cytoplasmic maturation defects and small relatively empty red cells, or abnormally slow DNA replication, leading to nuclear maturation defects and large full red cells. Defects in hemoglobin synthesis usually result from insufficient iron supply (iron deficiency) or decreased globin production (thalassemia) or are idiopathic (sideroblastic anemia). Defects in DNA synthesis are usually due to nutritional problems (vitamin B12 and folate deficiency), toxic (methotrexate or other cancer chemotherapeutic agent) exposure, or intrinsic marrow maturation defects (refractory anemia, myelodysplasia).
Laboratory tests useful in the differential diagnosis of the microcytic anemias are shown in Table 68-2. Mean corpuscular volume (MCV) is generally 60–80 fL. Increased lactate dehydrogenase (LDH) and indirect bilirubin levels suggest an increase in RBC destruction and favor a cause other than iron deficiency. Iron status is best assessed by measuring SI, TIBC, and ferritin levels. Macrocytic MCVs are >94 fL. Folate status is best assessed by measuring red blood cell folate levels. Vitamin B12 status is best assessed by measuring serum B12, homocysteine, and methylmalonic acid levels. Homocysteine and methylmalonic acid levels are elevated in the setting of B12 deficiency.
TABLE 68-2 DIAGNOSIS OF MICROCYTIC ANEMIA
ANEMIA DUE TO RBC DESTRUCTION OR ACUTE BLOOD LOSS
Trauma, GI hemorrhage (may be occult) are common causes; less common are genitourinary sources (menorrhagia, gross hematuria), internal bleeding such as intraperitoneal from spleen or organ rupture, retroperitoneal, iliopsoas hemorrhage (e.g., in hip fractures). Acute bleeding is associated with manifestations of hypovolemia, reticulocytosis, macrocytosis; chronic bleeding is associated with iron deficiency, hypochromia, microcytosis.
Causes are listed in Table 68-3.
TABLE 68-3 CLASSIFICATION OF HEMOLYTIC ANEMIASa
1. Intracellular RBC abnormalities—most are inherited enzyme defects [glucose-6-phosphate dehydrogenase (G6PD) deficiency > pyruvate kinase deficiency], hemoglobinopathies, sickle cell anemia and variants, thalassemia, unstable hemoglobin variants.
2. G6PD deficiency—leads to episodes of hemolysis precipitated by ingestion of drugs that induce oxidant stress on RBCs. These include antimalarials (chloroquine), sulfonamides, analgesics (phenacetin), and other miscellaneous drugs (Table 68-4).
TABLE 68-4 DRUGS THAT CARRY RISK OF CLINICAL HEMOLYSIS IN PERSONS WITH G6PD DEFICIENCY
3. Sickle cell anemia—characterized by a single-amino-acid change in β globin (valine for glutamic acid in the 6th residue) that produces a molecule of decreased solubility, especially in the absence of O2. Although anemia and chronic hemolysis are present, the major disease manifestations relate to vasoocclusion from misshapen sickled RBCs. Infarcts in lung, bone, spleen, retina, brain, and other organs lead to symptoms and dysfunction (Fig. 68-2).
FIGURE 68-2 Pathophysiology of sickle cell crisis.
4. Membrane abnormalities (rare)—spur cell anemia (cirrhosis, anorexia nervosa), paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis (increased RBC osmotic fragility, spherocytes), hereditary elliptocytosis (causes mild hemolytic anemia).
5. Immunohemolytic anemia (positive Coombs’ test, spherocytes). Two types: (a) warm antibody (usually IgG)—idiopathic, lymphoma, chronic lymphocytic leukemia, systemic lupus erythematosus, drugs (e.g., methyldopa, penicillins, quinine, quinidine, isoniazid, sulfonamides); and (b) cold antibody—cold agglutinin disease (IgM) due to Mycoplasma infection, infectious mononucleosis, lymphoma, idiopathic; paroxysmal cold hemoglobinuria (IgG) due to syphilis, viral infections.
6. Mechanical trauma (macro- and microangiopathic hemolytic anemias; schistocytes)—prosthetic heart valves, vasculitis, malignant hypertension, eclampsia, renal graft rejection, giant hemangioma, scleroderma, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, disseminated intravascular coagulation, march hemoglobinuria (e.g., marathon runners, bongo drummers).
7. Direct toxic effect—infections (e.g., malaria, Clostridium perfringens toxin, toxoplasmosis).
8. Hypersplenism (pancytopenia may be present).
Elevated reticulocyte index, polychromasia and nucleated RBCs on smear; also spherocytes, elliptocytes, schistocytes, or target, spur, or sickle cells may be present depending on disorder; elevated unconjugated serum bili-rubin and LDH, elevated plasma hemoglobin, low or absent haptoglobin; urine hemosiderin present in intravascular but not extravascular hemolysis, Coombs’ test (immunohemolytic anemias), osmotic fragility test (hereditary spherocytosis), hemoglobin electrophoresis (sickle cell anemia, thalassemia), G6PD assay (best performed after resolution of hemolytic episode to prevent false-negative result).
GENERAL APPROACHES The acuteness and severity of the anemia determine whether transfusion therapy with packed RBCs is indicated. Rapid occurrence of severe anemia (e.g., after acute GI hemorrhage resulting in Hct <25%, following volume repletion) or development of angina or other symptoms is an indication for transfusion. Hct should increase 3–4% [Hb by 10 g/L (1 g/dL)] with each unit of packed RBCs, assuming no ongoing losses. Chronic anemia (e.g., vitamin B12 deficiency), even when severe, may not require transfusion therapy if the pt is compensated and specific therapy (e.g., vitamin B12) is instituted.
1. Iron deficiency: find and treat cause of blood loss, oral iron (e.g., FeSO4 300 mg tid).
2. Folate deficiency: common in malnourished, alcoholics; less common now than before folate food supplementation; folic acid 1 mg PO qd (5 mg qd for pts with malabsorption).
3. Vitamin B12 deficiency: can be managed either with parenteral vitamin B12 100 μg IM qd for 7 d, then 100–1000 μg IM per month or with 2 mg oral crystalline vitamin B12 per day. An inhaled formulation is also available.
4. Anemia of chronic disease: treat underlying disease; in uremia use recombinant human erythropoietin, 50–150 U/kg three times a week; role of erythropoietin in other forms of anemia of chronic disease is less clear; response more likely if serum erythropoietin levels are low. Target Hb 9–10 g/dL.
5. Sickle cell anemia: hydroxyurea 10–30 mg/kg per day PO increases level of HbF and prevents sickling, treat infections early, supplemental folic acid; painful crises treated with oxygen, analgesics (opioids), hydration, and hypertransfusion; consider allogeneic bone marrow transplantation in pts with increasing frequency of crises.
6. Thalassemia: transfusion to maintain Hb >90 g/L (>9 g/dL), folic acid, prevention of Fe overload with deferoxamine (parenteral) or deferasirox (oral) chelation; consider splenectomy and allogeneic bone marrow transplantation.
7. Aplastic anemia: antithymocyte globulin and cyclosporine leads to improvement in 70%, bone marrow transplantation in young pts with a matched donor.
8. Autoimmune hemolysis: glucocorticoids, sometimes immunosuppressive agents, danazol, plasmapheresis, rituximab.
9. G6PD deficiency: avoid agents known to precipitate hemolysis.
For a more detailed discussion, see Adamson JW, Chap. 103; Benz EJ, Chap. 104; Hoffbrand AV, Chap. 105; Luzzato L, Chap. 106; Young NS, Chap. 107; pp. 844–897, in HPIM-18.