Pancytopenia 6s6j6o

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

Fe

Fe

Iron Absorption

Fe Fe

Fe Fe

Fe

Fe

Fe Fe Fe

Fe

Fe

Fe

Tf Fe

Fe

Fe

Fe

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

1000

100

10

1 15

20

25

30

35

40

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%