Running the Ironman Brad Lewis SFGH

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Running the IronmanBrad LewisSFGH

• Blood alone moves the wheels of history.
• Benito Mussolini
• Blood will tell, but often it tells too much.
• Don Marquis

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An Approach to Anemia
Anemia
?

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An Approach to Anemia
Anemia
?
Smear LDH Bilirubin Iron Studies B12 Coombs
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Evaluating HemolysisThe Bucket with The Hole
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Evaluating HemolysisThe Bucket with The Hole
Retic
Hemoglobin Level
Loss or Hemolysis
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Reticulocytes
Retic 1/mm Retic 20
Corr Retic Retic x hgb/nl hgb
Retic 1/mm Retic 30
RPI corrected retic. count/Maturation time
(Maturation time 1 for Hct45, 1.5 for 35, 2
for 25, and 2.5 for 15.)
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An Approach to Anemia
Anemia
Retic Hi
Retic Low
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An Approach to Anemia
Anemia
Retic Hi
Retic Low
MCV Hi
MCV Nl
MCV Lo
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An Approach to Anemia
Anemia
Retic Hi
Retic Low
Destruction
Loss
MCV Hi
MCV Nl
MCV Lo
Intrinsic Extrinsic Splenic Mechanical Recovery
Tissue On Floor Occult
Iron (Lead) Thal Frags
Chronic Disease Renal Mixed Mild/Treated Early Tra
nsfused Endocrine Intrinsic BM Dilution
B12 Folate Liver ETOH Thyroid Toxic MDS
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Anemia
Retic Hi
Retic Low
Destruction
Loss
MCV Hi
MCV Nl
MCV Lo

Iron (Lead) Thalassemia Fragmentation Sideroblasti
c Anemia acquired congenital
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Diagnostic TestsLow Retic Microcytic

• Iron/TIBC vs. Ferritin
• Hemoglobin Electropheresis
• GENETIC SCREENING OF FAMILY
• The Normal Electropheresis
• Smear?
• Value of MCV and RDW
• Lead?

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23 yo Chinese Woman 13 wks Pregnant Hgb 11, MCV
72

• What Tests?

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23 yo Chinese Woman 13 wks Pregnant Hgb 11, MCV
72

• What Tests?
• Iron Studies first
• may mask beta-Thal by decreasing Hgb A2
• What if Hemoglobin Electropheresis is normal?
• If iron nl, then not beta-thal
• BUT alpha-thal carrier state has normal HPLC

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Diagnostic TestsLow Retic Microcytic

• Iron/TIBC vs. Ferritin
• Hemoglobin Electropheresis
• GENETIC SCREENING OF FAMILY
• The Normal Electropheresis
• Smear?
• Value of MCV and RDW
• Lead?

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Body Iron Distribution and Storage
Andrews NC. N Engl J Med. 199934119861995.
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Iron Metabolism
Spleen
Liver
RBC
Plasma Fe-Tf
Bone Marrow
Duodenum
Tomas Ganz ASH 2006
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Iron Metabolism
20 mg/d
Spleen
RBC
Plasma Fe-Tf
Bone Marrow
Duodenum
Tomas Ganz ASH 2006
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Iron Metabolism
Spleen
RBC
Plasma Fe-Tf
Bone Marrow
Duodenum
Tomas Ganz ASH 2006
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Hepcidin

• Small molecule which blocks iron movement
• Evolutionary conservation
• Problems with assays
• Regulation
• Increased by dietary iron lt1day
• Congenital absencegtgtjuvenile hemochromatosis
• Decreased by anemia, hypoxia

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Hepcidin Regulation
Adequate Iron Intake
Increased
Inflammation IL-6
Hypoxia
Hepcidin
Anemia?
Decreased
RBC turnover
Hemochromatosis
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Hepcidin and Inflammation

• Suppressed in hours by IL-6 (?others)
• Not in IL-6 deficient mice
• Plasma Iron turnover q3hrs
• 30 drop in 1 hour if recycling blocked
• Anemia of Acute Disease
• ??Role in host defense

Bone Marrow
Tomas Ganz ASH 2006
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Infectious Risk of Iron Overload

• Bacterial
• Hepcidin, lactoferrin, transferrin bacteriostatic
  in vitro
• Listeria, Yersenia, Aeromonus
• Cunninghamella bertholletiae
• Fungal
• Increased growth in vitro
• Case reports of increased Mucor in MDS pts
• ? Increased risk with chelation with streptomyces
  pilosis

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Hepcidin and Iron Transport
Low Hepcidin
High Hepcidin
Iron
Iron
DMT1
ferritin
ferritin
lysosome
Fpn
Enterocytes Macrophages
Fpn
Hepcidin
Iron release into Plasma
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Iron Metabolism
Iron Signal
Spleen
Hepcidin
RBC
Plasma Fe-Tf
Hepcidin
Bone Marrow
Duodenum
Erythropoiesis Signal
Tomas Ganz ASH 2006
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Iron Metabolism
Iron Signal
Spleen
Hepcidin
RBC
Plasma Fe-Tf
Hepcidin
Bone Marrow
Duodenum
Erythropoiesis Signal
Tomas Ganz ASH 2006
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Evaluating IronStores vs. Response

• Ferritin
• Sensitive/specific
• Except increased in inflammation, liver disease,
  malignancy
• Fe/TIBC (Transferrin) and Saturation
• Decreased in inflammation, malignancy
• THEREFORE
• Iron Trial
• Serum (soluble) Transferrin Receptor
• Mediates iron transfer into cell
• Increased in Fe-def, rapid cell production
• CHR-Retic Hemoglobin Concentration?
• Follow-up GI Eval
• 10 -15 with malignancy
• ?Only if ferritin lt100?

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Colon CA in Iron Deficiency
Am J Gastroenterol. 2007102(1)82-88.
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Evaluating Iron in Inflammation

• Bone Marrow Iron Stores??
• Saturation (Fe/Transferrin) lt8-10
• Iron Trial
• ?IV repletion, check 1 month
• Hypochromic RBCs
• Nl. lt2.5, Fe-deficient gt10 correlates with Fe
  response
• Reticulocyte Hgb Concentration?
• Sensitive, specific for diagnosis in dialysis pts
• Responds to iron in 48 hours
• Serum (soluble) Transferrin Receptor
• Increased in Fe deficiency or increased RBC
  turnover

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Treatment of Iron Deficiency

• Oral always preferred
• ?low dose equally effective (325 mg FeSO4)
• ?role for Vitamin C
• When to use IV iron
• Recent decreased risk of anaphylaxis
• Poor compliance
• Side-effects, etc
• Poor Absorption
• Jejeunal/duodenal disease
• Sprue
• Chronic Disease
• Anemia of Malignancy

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Iron Overload
Iron overload
Serum transferrin iron binding capacity exceeded
NTBI circulates in the plasma
Insoluble iron complexes are deposited in body
tissues
Excess iron promotes free radical formation
Liver
Pancreas
Endocrine
Cardiac
Reproductive
NTBI non-transferrin bound iron Adapted from
Olivieri NF, et al. Blood. 199789739-761
Olivieri NF. N Engl J Med. 199934199-109.
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Basic Causes of Iron Overload

• Acquired iron overload1
• Transfusional
• Ineffective erythropoiesis
• Toxic ingestion (very rare in adults)
• Hereditary
• HFE hemochromatosis
• Homozygous C282Y mutation in HFE gene2
• Defective regulatory receptor in intestine
  results in increased absorption of iron
• Other genetic mutations

1. Porter JB. Br J Haematol. 2001115239252. 2.
Feder JN, et al. Nat Genet. 199613399408.
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Diseases With High Risk of Iron Overload

• Diseases requiring frequent or repeatedtransfusio
  ns
• ?-Thalassemia (major and intermedia)
• Sickle cell anemia
• Myelodysplastic syndromes (MDS)
• Aplastic anemia
• Rare chronic anemias
• Blackfan-Diamond anemia (red cell aplasia)
• Fanconi anemia (hypoplastic anemia)
• Others

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Iron Loading From Blood Transfusions

• 1 unit of blood contains 200 mg of iron1
• Chronic transfusion-dependent patients have an
  iron excess of 0.4 to 0.5 mg/kg/day2
• There is no physiologic mechanism to remove
  excess iron
• Therefore, iron accumulates with repeated blood
  transfusions
• Signs of iron overload can be seen anywhere
  between 10 and 20 transfusions1
• Iron overload can result in iron-related
  dysfunction of key organs1,2

1. Porter JB. Br J Haematol. 2001115239252. 2.
Kushner JP, et al. Hematology. 20014761.
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Iron Metabolism
Iron Signal
Spleen
Hepcidin
Hepcidin
RBC
Hepcidin
Plasma Fe-Tf
Bone Marrow
Duodenum
Erythropoiesis Signal
Tomas Ganz ASH 2006
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Hereditary Hemochromatosis

• Autosomal recessive
• HFE gene in 90 (hepcidin deficiency)
• Rare Transferrin Receptor 2 defect
• Variable penetrance, caucasions only
• Severe Disease
• Hemojuvelin
• HAMP (hepcidin)
• Autosomal dominant
• Rare, ferroportin defect
• Severe, early onset, Hepatocytes only
• Other rare defects
• DMT1(microcytosis), atransferrenemia,
  ceruloplasmin

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Hemochromatosis Diagnosis

• Consider in
• Chronic fatigue
• Arthropathy
• Impotence
• Hyperpigmentation
• Cirrhosis
• DM
• Cardiomyopathy
• Screening elevated Fe sat or Ferritin

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Hemochromatosis Diagnosis

• Fe/TIBC gt60
• Decreased in early, family-hx diagnosis
• Decreased with inflammation
• HFE testing (C282Y)
• Compound hetero C282Y/H63D
• Rarely a problem, unless ETOH
• Ferritin to quantify iron overload
• IF confusing, consider MRI

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Hemochromatosis Management

• Ferritin gt1000 associated with sx
• Fe/TIBC saturation gt75
• Unstable/labile iron with increased risk of
  oxidant damage
• Urgent phlebotomy
• IF sx or end organ damage
• Weekly to lt1000 ferritin as tolerated
• Target ferritin lt50
• ? Role of deferasirox (Exjade)
• Rarely in hemochromatosis
• intolerance

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