Microcytic Anemia Disorders

Anemia

• Def:
  • Reduction in circulating RBC mass due to blood loss, destruction, or impaired production
  • Hb < 13.5 g/dl in males
  • Hb < 12.5 g/dl in females
• Presentation:
  • Low RBCs reduces oxygen-carrying capacity:
    • -fatigue, weakness, dyspnea
    • -pale skin and conjunctive (even blue)
    • -headache, dizziness, lightheadedness
    • -angina (esp. if already have CVD)
• Micro: MCV , 80 fl/rbc
  
• Normo: MCV = 80 – 100
  
• Macro: MCV > 100

Microcytic Anemia

• Types (4):
  • Iron deficiency (IDA)
    
  • Anemia of Chronic Disease
    
  • Sideroblastic anemia
    
  • Thalassemia

Sideroblastic anemia (ringed sideroblasts)

• Def:
  • Microcytic anemia due to decreased production of heme molecules as a result of defective protoporphyrin
• Path:
  • Heme molecule production is completed in mitochondria of erythroblasts – if protoporphyrin is deficient the iron is trapped in the mitochondria, resulting in an iron-ringed SIDEROBLAST
  • The iron is never incorporated into the RBC and the cell is small
• Causes:
  • Congenital:
    • A genetic defect in ALA synthase
      
  • Acquired: 
    • Chronic alcoholism
      
    • Vitamin B6 deficiency
      
    • Lead poisoning
• Diagnosis:
  • MCV <80
    
  • Increased ferritin
    
  • Decreased TIBC
    
  • Increased serum iron

Anemia of Chronic Disease

• Def:
  • Defect in Iron Utilization
• Associated with:
  • chronic infection, neoplasm, and chronic inflammatory disease
    
  • -RE cells fail to release iron to developing RBCs – results in intramarrow destruction

Lead poisoning (basophilic stippling)

• Presentation:
  • Adult Presentation:
    
    • Headache
      
    • Peripheral neuropathy
      
    • Renal PCT damage (Fanconi Syndrome)
  • Child Presentation:
    
    • Abdominal colic & constipation
      
    • Encephalopathy
      
    • Growth retardation
• Lab:
  • -microcytic anemia
    
  • -decreased MCV &MCHC
    
  • -RPI <2, ineffective erythropoiesis
    
  • -RDW increased
    
  • -WBCs and platelets normal

Iron Deficiency

• Causes:
  • Lack of any of the normal hemoglobin components (heme or globin) – this reduces the iron carrying capacity of the RBC (cells will also be smaller and paler due to reduced Hb)
    
  • Dietary lack – rare. Maybe children, breastfeeding
    
  • Blood loss – GI, urine, menses, pregnancy, IV hemolysis, hookworm
    
  • Malabsorption – celiac (lose duodenal villi), gastrectomy (lose gastric acid for Fe3 to Fe2 conversion), gastric bypass (bypass duodenal absorption)
• Iron absorption and shedding:
  • We ingest iron in non-heme bound form (about 10 mg per day) of this we absorb only 1 mg
  • Gastric acid/Vit C convert Fe3+ (more in plants) to Fe2+ (more in animals) in the gut, which makes it more easily absorbed.
  • The iron is then absorbed into duodenal enterocytes and enters the blood via the ferroportin channel (KEY REGULATORY STEP – hepcidin inhibits)
  • Once in the blood, transferring binds iron to transport it to tissues
  • Liver hemochromatosis (HFE) proteins sense the level of iron delivery to signal the hepatocyte to produce hepcidin, which inhibits ferroportin to prevent further iron absorption.
  • It also helps keep stored iron in the macrophages and liver as ferritin, rather than allowing it to circulate.
• Labs for measuring iron status:
  • -microcytic anemia
    
  • -decreased MCV &MCHC
    
  • -RPI <2, ineffective erythropoiesis
    
  • -RDW increased
    
  • -WBCs and platelets normal
  • Note:
    • Serum iron – how much free iron is in the blood
      
    • Total iron-binding capacity (TIBC) – how many transferrin molecules are in the blood
      
    • % transferrin saturation – how many transferrin molecules are bound by iron
      
    • Serum ferritin – how much iron is stored
• Stages of iron deficiency:
  • 1. Reduction in serum iron (lower serum iron, increased TIBC, decreased % transferrin saturation)
    
  • 2. Depletion of stored iron (decreased serum ferritin)
    
  • 3. Mild anemia and mild microcytosis
    
  • 4. Increasing microcytic hypochromic anemia with wide shape and size variability of RBCs as deficiency worsens
• Management:
  • Iron sulfate – 325 mg daily or every other day
    
  • Gastric acid and Vit C to increase absorption
    
  • Other oral supplements: ferrous gluconate, ferrous fumarate
    
  • In pts where oral absorption is ineffective or intolerable – can give IV iron bound to sucrose which is more efficient

Thalassemia

• Def:
  • Microcytic anemia due to decreased production of globin chains (alpha or beta depending on which chain is deficient)
  • Lack of globins results in decreased Hb and causes the anemia
  • Also increases the amount of the “normal” globin chain, which then has nothing to bind to and precipitates, binding to and damaging the RBC membrane
  • These damaged cells are removed by the reticuloendothelial system (spleen – extravascular hemolysis)
  • Also with less heme to bind iron, toxic-free iron accumulates in the RBCs and causes death within the BM (intravascular hemolysis)
  • Usually inherited mutations/deletions that are actually beneficial against malaria.
• Presentation:
  •  

Alpha Thalassemia

• Def:
  • Most common hemoglobinopathy, seen in 30% of West Africans and 5-15% of SE Asians (because protects against malaria)
  • Alpha globin gene normally is duplicated, with 4 total copies – disease spectrum depends on how many of the 4 genes are dysfunctional
• Types:
  • 1 deletion – asymptomatic
  • 2 trans deletions (opposite chromosomes) – asymptomatic but microcytic (not anemic though). Seein both black and asian populations
  • 2 cis deletions – asymptomatic but microcytic (not anemic), with a risk of severe thalassemia in offspring if other parent has one or two deletions (ONLY IN ASIA)
  • 3 deletions – Hemoglobin H disease – unbound beta chains form HbH tetramers that damage the RBCs with hypochromia, microcytosis, moderately severe hemolytic anemia, growth retardation, and iron overload
  • 4 deletions – fatal in utero – hydrops fetalis
• Blood smear:
  • Microcytosis, hypochromia, and target cells (precipitation of protein with destruction) despite normal iron studies
    
  • Need molecular studies to identify the haplotype of gene deletion

Hydrops fetalis

• Def:
  • When the fetus has all 4 alpha chains of hemoglobin deleted (as a result of two cis-deleted parents mating)
    
  • A fetus cannot form any alpha chains and instead form gamma tetramers (Hb Barts) that destroy RBCs and is fatal in utero

Beta Thalassemia

Beta Thalassemia Major

• Def:
  • Homozygous for B gene deletions (B0/B0) on Ch 11
  • More severe form with severe anemia a few months after birth
  • HbF (a2y2) is temporarily protective as fetal Hb does not use B chains, but later on alpha chains form tetramers and result in reduced RBC production and severe extravascular hemolysis in the spleen
  • This leads to iron overload (which we can try to treat with chelation, BM transplants, and now splicing of mutation)
  • Lack of B chains means there is pretty much no HbA, so there is a compensatory rise in HbA2 and HbF
  • Often preset with skeletal and facial deformities due to increased RBC production (marrow expansion as it tries to make up the blood)
• Blood smear:
  • Similar to alpha – target cells and severe hypochromia
    
  • also see Howell-jolly bodies and some nucleated RBCs due to extramedullary hematopoiesis

Beta thalassemia minor

• Def:
  • B thalassemia minor – only one of the B genes is abnormal (heterozygous – B+/B0)
    
  • More mild form with asymptomatic microcytic hypochromic cells and target cells on a smear (like the alpha)
    
  • Often see increased RBC count
    
  • A compensatory increase of HbF and HbA2 to allow unbound alpha chains to bind free delta and fetal be chains