Anemia: Basic Approach • History and physical • Reticulocyte count • Blood smear
Reticulocyte count • Needs to be corrected for hct • Absolute: % retic x rbc count • Corrected: retic% x (hct/45) • Retic index: correct retic/f
Reticulocyte count • Corrected for hematocrit • (Pt/40)*retic – >2%: blood loss or hemolysis – 0.5-2 marrow not responding – <0.5: marrow broken
• Absolute retic count
When to Do a Bone Marrow? • • • • • • •
Circulating immature cells Pancytopenia Very low reticulocyte count (<0.01%) Nucleated red cells Evidence of marrow infiltration Staging of malignancies Unexplained anemias
Iron Absorption • Food iron ferric (Fe+++) form • Stomach acid convert ferrous (Fe++) form • Absorbed jejunum • Mobilferrin transport through cell
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Iron Absorption
Fe Fe
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Tf Fe
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RBC
Res Storage
Developing RBC
Transferrin
Losses
Po Intake
2 Key Proteins • Transferrin: – Transports up to 2 Fe molecules through blood
• Ferritin: – Long-term storage of Fe
Iron Stores Other Proteins (14%) Transferrin (0.4%)
Storage (24%) Hemoglobin (62%)
Fe and IRE • Cellular iron controls production of transferrin receptor and ferritin • High Fe: – High ferritin and low transferrin receptor
• Low Fe: – Low ferritin and high transferrin receptor
Groups That Develop Fe Deficiency • • • • •
Infants 20-50% Kids 5% Adolescents 5% Menstruating women 20% Pregnancy 50%
Other Effects of Fe Deficiency • Pica • Exercise intolerance – Iron supplementation improved performance in deficient but not anemia athletes
• Central nervous system effects – Improved test scores with iron supplementation
Prevalence of Iron Deficiency • Women 25-30% • Men 1% • Elderly 30% • Pregnant women 60%
Etiology of Iron Deficiency • Kids: use for tissue growth • Women: menstruation • Others: blood loss • In patient with ferritin < 50 serous pathology seen in over half (cancer in 10%)
Differential Diagnosis of Microcytosis • Anything that impairs hemoglobin production • Iron: iron deficiency and anemia of chronic disease • Globin: thalassemia • Heme: sideroblastic anemias
Microcytosis Iron
Protoporphyrin Sideroblastic
Iron Deficiency ACD
Heme + Globin Thalassemia Hemoglobin
ACD: definition • ?? • Classic: anemia seen with cancer, infection or severe inflammation • However, physiology of ACD seen with many illness and in patients who are otherwise healthy
ACD: Definition • Anemia characterized by: – Iron sequestration – Relative lack of EPO response – Not due to any other cause
ACD: diseases • Much broader range of diagnosis than traditional infection, inflammation, or cancer • 70% seen with severe CHF • COPD • Diabetes • No other disease • ACD is a common response to stress
ACD: Laboratory Findings • • • • •
Hct can be as low as 20% Often microcytic but > 70fl Very low serum irons Low serum TIBC High ferritin (>100 ng/dl)
What Causes ACD? • • • •
Shortened RBC half-life Inflammatory cytokines Lack of EPO Iron sequestration
Shortened RBC Half-life • RBC survival studies suggested increase RBC destruction • ?Importance
Inflammatory Cytokines • Cytokines such as IL-1 and TNF suppress erythropoiesis • Infusions of inflammatory cytokines lead to anemia • Suppression of red cell procurers • Suppression of EPO production • Anti-TNF antibodies correct anemia
Lack Of EPO • Consistent finding is lack of appropriate EPO response to anemia • EPO levels are only slightly raised despite severe anemia • Can be aggravated by medicines and other conditions
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Iron Sequestration • • • • •
Decreased iron absorption Low serum irons Low serum TIBC Very high ferritins Lack of iron in rbc precursors
Iron Sequestration: Why? • Free iron is toxic to tissues • Microorganism need iron and can avidity absorb it – In ACD serum iron drops to 10-15m – Microorganism need 10-6m
• Increased infections seen with excess iron
Why ACD? • Decrease in iron • Decrease activity level • Decrease rbc due to increase viscosity from acute phase reactants
ACD: Therapy • Treat primary cause • EPO – 40,000 units/wk – Improves QOL
• Need iron! – “Functional iron deficiency“ – PO iron – IV iron replacement for ESRD
Diagnosis of Iron Deficiency Anemia • MCV • Serum iron • TIBC • Iron saturation • Ferritin • Bone marrow tests
Testing for Iron Deficiency • • • • • •
“Classic” tests only helpful in few patients Tests affected by concurrent illness and age Fe: VARIES WILDLY MCV: lacks sensitivity and specificity RDW: totally and completely worthless Saturation: low in both ACD and iron deficiency
MCV • Decreased due to lack of rbc iron • Can be decreased in anemia of chronic disease • MCV < 70 seen only in iron deficiency and thalassemia • Can be normal in iron deficiency
RDW • Absolutely worthless test! • Of absolutely no predictive value for Fe deficiency, anemia of chronic disease, thalassemia, etc…… • Should never be use!!!!!!!
Serum Iron • Decreased in any stressful situation • Marked variation in levels
Total Iron Binding Capacity • Surrogate for transferrin • Increased in iron deficiency • Decreased in inflammation • Specific (diagnostic) but not sensitive
Iron Saturation • Iron/TIBC • <16% seen in both iron deficiency and anemia of chronic disease • Does not add to information provided by TIBC
Serum Ferritin • Serum ferritin proportional to iron stores • Needs iron to be produced • Acute phase reactant only in presence of iron • Most accurate non-invasive test of iron stores
Ferritin • Needs iron to be synthesized • Rises with age • Value needs to be interpreted for age and situation
Iron Deficiency • Serum ferritin is best non-invasive test of iron status – > 100 ng/dl rules out iron deficiency – Lower limit changes with age and condition • Patient over 65 with ferritin < 50 all iron deficient – Iron deficiency predictor of colon cancer
Bone Marrow • Direct measure of iron stores • “Gold standard” • Invasive and expensive
Trial of Oral Iron • Effected by inflammation and compliance • Useful in young women
Summary • RDW, FEP, serum iron, saturation: worthless • TIBC: specific but not sensitive • Ferritin: best non-invasive test • Bone marrow: gold standard
Tests of Iron Deficiency Test IDA sFe MCVD/N TIBC Sat D Ferr sTfr I
ACDboth D D D D/N D/N I D D/N D D D I D D I
History of Iron Replacement • Nails driven in apples • Blaud pills 1832 – 325 mg ferrous sulfate
• 1890’s role of iron disputed – No effect with 60 mg ferrous sulfate
Therapy • Iron supplements – GI upset – Compliance – Take with vitamin C – Start with 1/day • Diet – Increase heme sources – Decrease fiber and tea • Intravenous iron
Response to Oral Iron • Increased retic 7-10 days • Increased hct 2-3 weeks • Normalized 2 months
Failure to Respond to Iron • • • • • •
Blood loss Wrong diagnosis Other heme disease Noncompliance Defective absorption Concurrent B12 or folate deficiency
Lack of Absorption • Iron absorption poorly understood • Reasons for poor absorption – Lack of stomach acid – Lack of stomach – ? Genetic defects
When to Use IV Iron • • • •
Unable to tolerate oral iron Unable to be replaced with oral iron Risk of anaphylaxis 1% with older preparation Iron sorbitol and iron sucrose now used and are much safer
Cost Form Pills Steak IV iron
Iron Content 66mg/tab 1mg/oz 50mg/ml
Cost ($/G) 1 350 450
Side Effects GI upset weight gain, anaphylaxis
! Iron deficiency in adults is due to iron loss until proven otherwise!!!
Iron Deficiency: GI Evaluation • Most patients with identifiable source of GI blood loss • Very high number with tumors • Most common cause of missed cancer diagnosis • Who not to evaluate?
Lesions Identified in Patients With Iron Deficiency • Esophageal: 12% • Stomach: 25% – Cancer: 3%
• Ulcer: 6% • Large intestine: 22% – Cancer: 9%
• Nothing: 35%