Definition: hemoglobin <13.5 or hematocrit < 41 in men, or 12 and 36 in women. MCV < 80 fL, smear with hypochromic appearance reflecting decreased hemoglobin content.

Differential Diagnosis

Typically due to reduced iron availability, reduced heme synthesis, or reduced globin production. A helpful mnemonic is TAILS: Thalassemia, Anemia of chronic disease, Iron deficiency, Lead poisoning, Sideroblastic anemia.

Evaluation

The first step is obtaining iron studies and peripheral blood smear to differentiate between iron deficiency anemia (most common) and anemia of chronic disease or other causes.

• Iron deficiency anemia:
  • Blood smear: anisopoikilocytosis (↑RDW), hypochromia and microcytosis, often thrombocytosis.
  • Iron studies: characteristically low serum ferritin level (<30 µg/L), which is the most specific lab abnormality. Additionally, serum iron levels are low and transferrin levels are high, resulting in reduced transferrin saturation (iron level divided by transferrin level). With systemic inflammation, ferritin levels increase although a level less than 100 µg/L with a transferrin saturation <20% should raise suspicion for concomitant iron deficiency.
  • Consider further investigation based on clinical concern for underlying etiology:
    • Chronic blood loss: GI (both upper [PUD] and lower [CRC]), GU losses (uterine bleeding, hematuria, intravascular hemolysis [PNH]), chronic infestation (hookworm), regular blood donations.
    • Decreased intestinal absorption: IBD, post-gastrectomy, duodenal bypass, bariatric surgery, celiac disease, H. pylori, PPI/H2 blockers, autoimmune atrophic gastritis.
    • Increased iron demand: pregnancy, treatment with erythropoiesis-stimulating agents.
    • Poor iron intake: vegetarians, malnutrition.
    • Other: CKD, CHF, acute blood loss anemia of major surgery.
• Anemia of chronic inflammation/disease:
  • May manifest as either a microcytic or normocytic anemia, but MCV is rarely <70.
  • Blood smear: may show hypochromic/microcytic cells, but these are not required to make the diagnosis.
  • Iron studies: characteristically low serum iron and transferrin, with normal or elevated ferritin levels. 
  • Pathophysiology: 1) inflammatory cytokines suppress renal erythropoietin production; and 2) hepcidin, an acute phase reactant that modulates both iron absorption and metabolism, is increased, leading to decreased serum iron and transferrin despite normal ferritin levels.
    • Thus, this form of anemia may be due to chronic inflammatory states, including cancer, infection, or autoimmune processes, resulting in inefficient utilization of iron by erythrocyte precursors in the bone marrow.
• Thalassemia:
  • Blood smear: anisocytosis, poikilocytosis, microcytosis, hypochromia, target cells, and basophilic stippling.
  • Iron studies: typically normal iron studies, low MCV, and increased RBC count. Of note, a microcytic anemia with MCV <60 is highly suspicious for an underlying thalassemia.
  • Reticulocytes are commonly slightly elevated.
  • Additional work-up: the most useful element is a history of life-long anemia that has been unresponsive to iron therapy and/or a strong family history of anemia. Hemoglobin electrophoresis will show elevated HbA2 and HbF in beta-thalassemia. Alpha-thalassemia can only be definitively diagnosed by molecular diagnostic techniques. Note that patients should be iron replete before ordering hemoglobin electrophoresis in order to avoid inaccurate results. At UCSF, electrophoresis is ordered by writing for “hemoglobinopathy evaluation” or “alpha/beta thalassemia mutations.”
• Sideroblastic anemia:
  • Blood smear: microcytosis, anisocytosis.
  • Iron studies: typically show increased serum transferrin saturation with reduced transferrin levels, as well as elevated serum ferritin.
  • Bone marrow biopsy: erythroid precursors with increased mitochondrial iron deposition in a ring around the nucleus, a.k.a. ringed sideroblasts.
  • Etiology:
    • Can be either congenital or acquired. 
    • Acquired causes include lead or zinc poisoning, drugs (e.g. isoniazid), ethanol, as well as Vitamin B6 (pyridoxine) or copper deficiency, and myelodysplastic syndromes.
• Lead poisoning (plumbism):
  • Blood smear: classically shows coarse basophilic stippling. Often microcytic and hypochromic; can be normocytic and normochromic.
  • Obtain a serum lead, iron, ferritin and transferrin levels. A concomitant iron deficiency is often present. Iron studies may reflect either sideroblastic anemia or iron deficiency.  
  • Most adult cases come from workplace exposures. May also be in paint in houses built before 1970s, improperly glazed ceramics, herbal remedies, and moonshine.
  • Symptoms include abdominal pain, headache, irritability, arthralgias (saturnine gout), and fatigue.

Management

• Iron deficiency anemia:
  • Treatment should initially be directed at correcting the underlying cause – low threshold for EGD/colonoscopy and prompt evaluation of abnormal vaginal bleeding in post-menopausal patients.
  • To replete iron stores, start with PO iron (ferrous sulfate). Traditionally administered in high and divided doses, however, studies have shown that alternate day low-dose (60mg) repletion increased efficacy and reduced gastrointestinal side effects.
  • Indications for IV repletion: oral iron intolerance due to persistent GI side effects, defective iron absorption as seen by oral iron refractoriness (after 4 weeks of therapy), severe anemia (Hgb 7-8 g/dL), CKD, HFrEF. Iron sucrose 200mg QD for 5 doses for total 1000mg repletion. Active infection is a contraindication. Minor to moderate infusion reactions include nausea, pruritus, flushing, myalgia/arthralgia. More serious reactions include dyspnea, hypotension, and rarely anaphylaxis.
• Anemia of inflammation/chronic disease: treatment should be directed at the underlying cause of the anemia.
• Lead poisoning:
  • Prevention of further exposure is key.
  • Chelation therapy with oral succimer is recommended for symptomatic patients or asymptomatic patients with blood levels >80 µg/dL. Patients with encephalopathy can be treated with IV calcium EDTA.

Key Points

• Key diagnostic elements are the clinical history, reticulocyte count, peripheral blood smear and iron studies. 
• Transfusion may obscure some of the analysis, so be sure to obtain these studies for analysis prior to transfusion.

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Kosnett MJ. Chapter 91. Lead. In: Olson KR. eds. Poisoning & Drug Overdose, 6e. New York, NY: McGraw-Hill; 2012.

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