Anemia and Iron Flashcards
Describe the normal lifespan of a red cell.
Proerythroblast to mature blood cell = 8 days
o 5 days in division
o 3 days in reticulocyte maturation
o 1 day maturation in peripheral blood
• About 1% circulating RBCs are reticulocytes
• Normal absolute rectiulocytes = 50,000/μl
o Lifespan = 120 days
o Destroyed by macrophages in spleen and liver
o Normally balanced: production = destruction
• With acute hemorrhage: see more reticulocytes in blood
o “Shift cells” = immature reticulocytes with higher RNA content; larger and bluer
Define anemia and describe its clinical consequences, and describe the ways in which the body compensates for anemia.
Anemia:
o Decreased red cell mass below normal for age and gender
o Usually decreased hematocrit, hemoglobin, RBC count
Causes:
• Hypoproliferative = decreased cell production
• Ineffective erythropoiesis = impaired production
• Increased destruction (hemolysis) or losses (bleeding)
• Hemodilution (increased plasma volume with normal red cell mass)
o Decreased plasma volume (in acute blood loss or dehydration) can mask anemia
Clinical consequences
o Slow decline in Hct to 30% = no symptoms in normal sedentary patients
o When < 30% = weakness, fatigue, SOB, confusion, pallor (conjunctiva, palms)
o < 25% = poorly tolerated (especially in elderly)
• May need transfusions
Severity of symptoms determined by:
• Rate of development (slower the onset, fewer the symptoms)
• Cardiac and lung function
• Age
• Level of physical activity
• Hgb oxygen dissociation curve (2,3 DPG promotes oxygen delivery to tissues)
Compensation
o Increased HR
o Increased left ventricular stroke volume
o Increased 2,3-DPG → right shifted O2 dissociation curve = unload more O2 to tissues
Be able to use the reticulocyte count to assess red cell production and help determine the cause of anemia.
o Measures effective marrow production (release of newly made red cells from marrow)
Reported in 2 ways:
1) Percentage of circulating cells
2) Absolute number of reticulocytes/μl blood
• Normally ~50,000/μl (red count x % reticulocytes = 5,000,000/μl x 1%)
Increased when released from marrow
o Anemia → Erythropoietin → early release of reticulocytes
• Doubles reticulocyte counts
o Exceptions: inflammation and renal disease (no Epo)
Normal bone marrow:
o Able to double its RBC production when anemic
o So along with early reticulocyte release → quadruples reticulocytes (= 200,000)
Interpretations:
o If over 200,000 in anemic patient → anemia is not due to inadequate RBC production
o If over 300,000 in anemic patient → chronic peripheral hemolysis
o If less than 100,000 in anemic patient → inadequate RBC production (Takes about 1 week for reticulocyte production to reach steady state after anemia onset)
o If over 100,000 in normal Hct patient → hemolysis or ongoing blood loss
• Shortened RBC lifespan
Be able to use the G:E ratio to assess red cell production and help determine the cause of anemia.
o Ratio of Granulocytic precursors to nucleated RBCs in aspirate of bone marrow
o Normally = 3:1
o Used to assess erythroid activity when marrow granulocyte production is normal
• Represents total red cell production (including defective cells that don’t make it into blood)
Be able to use the MCV to assess red cell production and help determine the cause of anemia.
MCV (10^-15 L) = Hematocrit (L/ L of blood)/erythrocyte count (RBC/L blood)
• Or: [Hct/RBC count] x 10
o Useful in primary morphologic classification of anemia:
Macrocytic: • MCV >100 fl • Defective DNA synthesis or reticulocytosis Microcytic: • MCV <80 fl • Decreased hemoglobin production Normocytic: • MCV 80-100 fl
Other useful morphologic findings: Poikilocytosis: variation in RBC shape Anisocytosis: variation in RBC size • RDW: quantitative expression of variability in RBC size • High RDW = anisocytosis
Describe normal iron intake and absorption
10-15 mg/day in diet
o 5-10% absorbed
o Increased absorption in iron deficiency, pregnancy, erythroid hyperplasia, hypoxia
o Heme iron best absorbed (Meat, poultry, fish)
Fe2+ better absorbed than Fe3+
• Enhanced absorption: ascorbic acid
• Inhibit absorption: carbonates (sodas), tannate (tea and coffee), oxalate (spinach, rhubarb), phosphates, egg yolk phosphorylation
Absorbed in duodenum
o Oxidized to Fe3+
o Bound to transferrin in blood
o Iron transferred to cells → reduced to Fe2+ → inserted into heme or stored
Stored in Ferritin
• Hemosiderin = denatured ferritin
• Small amount (nanograms) of ferritin in blood = correlates with body iron stores
No ability to regulate excretion
Most iron = stored in RBCs:
Describe normal iron metabolism
Liver makes hepcidin
• Interacts with ferroportin = inhibits iron release from villus enterocytes and macrophages
• High plasma iron or inflammation → increased hepcidin → increased serum ferritin (more iron stored) & decreased iron and TIBC (less iron transported)
• Low iron levels → decreased hepcidin → stimulates iron absorption and release into blood
HFE gene = modulates hepcidin production
• Mutations → decreased hepcidin release → iron overload (hereditary hemochromatosis)
Normally = balance
1-2 mg/day lost via desquamation and GI blood loss
In early childhood = negative balance
• Higher requirements due to rapidly expanding RBC mass and muscle
Menstruation, pregnancy, lactation = negative balance
• Pregnancy = depletes iron stores, so likely to cause a deficiency
Positive balance (eventual iron overload) = inherited disorders or from repeated blood transfusions
Ferrokinetics:
o Erythropoiesis = requires 20 mg iron/day
o Most is recycled from old RBCs
o 1-2 mg new iron absorbed from gut
o 1-2 mg iron lost via enterocyte sloughing
o Excess iron stored in liver
Diagnose iron deficiency and distinguish it from other causes of microcytic anemia.
Tests to determine iron status: Serum iron • Ion being transported in blood • Normally ~100 μg/dl • Bound to transferrin
Total iron binding capacity (TIBC)
• Total amount of transferrin in blood
• Normally ~300 μg/dl
Serum ferritin
• Iron storage protein in tissues
• Small amount present in blood = correlates to body iron stores
Causes of iron deficiency
Chronic blood loss
• Exceptions: rapid growth, malabsorption
Young women = usually due to menstrual blood loss and/or pregnancy
Must rule out GI blood loss: • Esophageal disease • Hiatal hernia • Ulcer • Inflammatory bowel disease • Angiodysplasia • Hemorrhoids • Cancer
Signs/symptoms of iron deficiency
o Decreased work capacity, exercise tolerance, productivity
o Cheilosis (fissures at angles of mouth)
o Atrophy of lingual epithelium
o Brittle fingernails and toenails (spoon nail shape)
o Abnormal brain metabolism → delayed sensory development, motor function, language skills
o Pica
Treatment of iron deficiency
Oral ferrous salts
• Can get GI side effects
• Slow-release forms better tolerated but not as well absorbed
Oral iron-polysaccharide complex
IV iron dextran or iron sucrose
• If oral iron not absorbed or not tolerated
• Slight risk of anaphylaxis
Should see increased hemoglobin within 2-3 weeks
Describe the pathophysiology and clinical consequences of iron overload.
Causes:
Hereditary hemochromatosis
• Autosomal recessive disease
• From HFE gene mutation = Disrupts signaling that normally increases hepcidin levels due to high iron
• Genotype common but low penetrance
• Treat = phlebotomy (prevents problems and can reverse early tissue damage)
Other inherited disorders
• Mutations in other genes regulating iron metabolism
• More common in Africans and African-Americans
Chronic ineffective erythropoiesis
• Thalassemia
Repeated transfusion
• Toxicity after about 100 units
Diagnosis
o Increased serum iron
o High transferrin saturation (>90% in hemochromatosis)
o Very high serum ferritin (>1000)
o Increased liver and marrow iron (liver iron amount = best indicator of severity)
o DNA test available for hereditary hemochromatosis
Clinical consequences: o Cirrhosis, hepatocellular carcinoma o Cardiomyopathy, heart failure o Endocrine failure • Especially diabetes • Gonadal failure with impotence o Arthropathy (arthritis in multiple joints) o Bronze skin color
Describe the pathophysiology of anemia of inflammation and the anemia associated with renal failure.
Anemia of inflammation
o In hospitalized patients = most common cause of anemia
o Hct rarely < 25 unless additional factors present
o Causes: infection, autoimmune disorders, cancer
Mechanisms:
• Inflammation (IL-6) → increased hepcidin expression → Impaired release of stored iron from macrophages
• Lower EPO production
• Inflammatory cytokines = direct inhibition of red cell precursors
• Shortened red cell survival
Benefit: decreased iron available to bacteria, etc.
Lab findings:
• Normocytic or mild microcytosis
• Not many shift cells
• Low serum iron, normal or low TIBC, normal or high serum ferritin
• Relatively low EPO level for degree of anemia
Anemia associated with renal failure
o May be compounded by blood loss during dialysis, inflammation, decreased RBC lifespan
o Reversible with EPO injections
Other low EPO anemias: o Endocrine disorders • Hypothyroidism, hypopituitarism o Protein-calorie malnutrition o Right-shifted hemoglobin O2 dissociation curve (tissues getting O2 even though anemic)
