Running the Ironman

Brad LewisSFGH

Blood alone moves the wheels of history.Benito Mussolini

Blood will tell, but often it tells too much.Don Marquis

AnemiaAn Approach to Anemia

?

AnemiaAn Approach to Anemia

SmearLDH

BilirubinIron Studies

B12Coombs

?

Evaluating HemolysisThe Bucket with The Hole

Evaluating HemolysisThe Bucket with The Hole

Retic

Hemoglobin Level

Loss or Hemolysis

Reticulocytes

Retic #=1/mmRetic %= 20%

Retic # = 1/mmRetic % = 30%

Corr Retic = Retic x hgb/nl hgb

RPI = corrected retic. count/Maturation time (Maturation time = 1 for Hct=45%, 1.5 for 35%, 2 for 25%, and

2.5 for 15%.)

Retic Hi Retic Low

AnemiaAn Approach to Anemia

Retic Hi Retic Low

Anemia

MCV HiMCV NlMCV Lo

An Approach to Anemia

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

IntrinsicExtrinsicSplenicMechanicalRecovery

TissueOn FloorOccult

Iron(Lead)ThalFrags

B12FolateLiverETOHThyroidToxicMDS

Chronic DiseaseRenalMixedMild/TreatedEarlyTransfusedEndocrineIntrinsic BMDilution

An Approach to Anemia

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

Iron(Lead)ThalassemiaFragmentationSideroblastic Anemia

acquiredcongenital

Diagnostic TestsLow Retic Microcytic

Iron/TIBC vs. FerritinHemoglobin Electropheresis

• GENETIC SCREENING OF FAMILY• The “Normal” Electropheresis

Smear?Value of MCV and RDWLead?

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

• What Tests?

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

Diagnostic TestsLow Retic Microcytic

• Iron/TIBC vs. Ferritin• Hemoglobin Electropheresis

• GENETIC SCREENING OF FAMILY• The “Normal” Electropheresis

• Smear?• Value of MCV and RDW• Lead?

Andrews NC. N Engl J Med. 1999;341:1986–1995.

Body Iron Distribution and Storage

Dietary iron

Utilization UtilizationDuodenum

(average, 1-2 mgper day)

Muscle(myoglobin;

300 mg)

Liver(1000 mg)

Bone marrow(300 mg)Circulating

erythrocytes(hemoglobin;

1800 mg)

Reticuloendothelialmacrophages

(600 mg)

Sloughed mucosal cellsDesquamation/menstruation

Other blood loss(average, 1-2 mg per day)

Storageiron

Plasma

Iron loss

transferrin(3 mg)

Iron Metabolism

PlasmaFe-Tf

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

Liver

Iron Metabolism

PlasmaFe-Tf

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

20 mg/d

Iron Metabolism

PlasmaFe-Tf

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

Hepcidin

• Small molecule which blocks iron movement

• Evolutionary conservation• Problems with assays

• Regulation• Increased by dietary iron <1day• Congenital absence>>juvenile hemochromatosis• Decreased by anemia, hypoxia

Hepcidin Regulation

Hepcidin

Adequate Iron Intake

InflammationIL-6

RBC turnover

Hypoxia

Hemochromatosis

Increased

Decreased

Anemia?

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

PlasmaFe-Tf

3 mg

RBC

Spleen 20 mg/d

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

Hepcidin and Iron Transport

Fpn

Fpn

Low Hepcidin High HepcidinIron Iron

ferritinferritin

Hepcidin

Iron release into Plasma

lysosome

EnterocytesMacrophages

DMT1

Iron Metabolism

PlasmaFe-Tf

HepcidinHepcidin

Hepcidin

Iron Signal

Erythropoiesis Signal

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

Hep

cidin

Iron Metabolism

PlasmaFe-Tf

HepcidinHepcidin

Hepcidin

Iron Signal

Erythropoiesis Signal

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

Hep

cidin

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 <100?

Colon CA in Iron Deficiency

Am J Gastroenterol. 2007;102(1):82-88.

Evaluating Iron in Inflammation

Bone Marrow Iron Stores?? Saturation (Fe/Transferrin) <8-10% Iron Trial

?IV repletion, check 1 month % Hypochromic RBC’s

Nl. <2.5%, Fe-deficient >10% 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

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

Iron Overload

NTBI circulates in the plasma

LiverLiver

Insoluble iron complexes are

deposited in body tissues

PancreasPancreas EndocrineEndocrine

Serum transferrin iron binding capacity exceeded

Iron overload

CardiacCardiac ReproductiveReproductive

NTBI = non-transferrin bound ironAdapted from: Olivieri NF, et al. Blood. 1997;89:739-761; Olivieri NF. N Engl J Med. 1999;341:99-109.

Excess iron promotes free radical formation

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. 2001;115:239–252.2. Feder JN, et al. Nat Genet. 1996;13:399–408.

Diseases With High Risk of Iron Overload

• Diseases requiring frequent or repeatedtransfusions• -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

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. 2001;115:239–252.2. Kushner JP, et al. Hematology. 2001;47–61.

Iron Metabolism

PlasmaFe-Tf

HepcidinHepcidin

Hepcidin

Iron Signal

Erythropoiesis Signal

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

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

Hemochromatosis Diagnosis

• Consider in :

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

Hemochromatosis Diagnosis

• Fe/TIBC >60%• 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

Hemochromatosis Management

• Ferritin >1000 associated with sx• Fe/TIBC saturation >75%

• Unstable/labile iron with increased risk of oxidant damage• Urgent phlebotomy

• IF sx or end organ damage• Weekly to <1000 ferritin as tolerated• Target ferritin <50

• ? Role of deferasirox (Exjade)• Rarely in hemochromatosis• intolerance