Transcript Myelodysplastic Syndromes - Professional Practice Group

Running the Ironman
Brad Lewis
SFGH
Blood alone moves the wheels of history.
Benito Mussolini
Blood will tell, but often it tells too much.
Don Marquis
An Approach to Anemia
Anemia
?
An Approach to Anemia
Anemia
?
Smear
LDH
Bilirubin
Iron Studies
B12
Coombs
Evaluating Hemolysis
The Bucket with The Hole
Evaluating Hemolysis
The Bucket with The Hole
Retic
Hemoglobin Level
Loss or Hemolysis
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 Hct=45%, 1.5 for 35%, 2 for 25%, and
2.5 for 15%.)
An Approach to Anemia
Anemia
Retic Hi
Retic Low
An Approach to Anemia
Anemia
Retic Hi
Retic Low
MCV Lo
MCV Nl
MCV Hi
An Approach to Anemia
Anemia
Retic Hi
Loss
Retic Low
Destruction MCV Lo
Tissue Intrinsic
On Floor Extrinsic
Occult Splenic
Mechanical
Recovery
Iron
(Lead)
Thal
Frags
MCV Nl
Chronic Disease
Renal
Mixed
Mild/Treated
Early
Transfused
Endocrine
Intrinsic BM
Dilution
MCV Hi
B12
Folate
Liver
ETOH
Thyroid
Toxic
MDS
Anemia
Retic Hi
Loss
Retic Low
Destruction MCV Lo
MCV Nl
Iron
(Lead)
Thalassemia
Fragmentation
Sideroblastic Anemia
acquired
congenital
MCV Hi
Diagnostic Tests
Low Retic Microcytic
Iron/TIBC vs. Ferritin
Hemoglobin Electropheresis
• GENETIC SCREENING OF FAMILY
• The “Normal” Electropheresis
Smear?
Value of MCV and RDW
Lead?
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 Tests
Low Retic Microcytic
• Iron/TIBC vs. Ferritin
• Hemoglobin Electropheresis
• GENETIC SCREENING OF FAMILY
• The “Normal” Electropheresis
• Smear?
• Value of MCV and RDW
• Lead?
Body Iron Distribution
and Storage
Utilization
Dietary iron
Duodenum
(average, 1-2 mg
per day)
Utilization
Plasma
transferrin
(3 mg)
Muscle
(myoglobin;
300 mg)
Circulating
erythrocytes
(hemoglobin;
1800 mg)
Storage
iron
Liver
(1000 mg)
Sloughed mucosal cells
Desquamation/menstruation
Other blood loss
(average, 1-2 mg per day)
Iron loss
Andrews NC. N Engl J Med. 1999;341:1986–1995.
Bone
marrow
(300 mg)
Reticuloendothelial
macrophages
(600 mg)
Iron Metabolism
Spleen
Liver
RBC
Plasma
Fe-Tf
Duodenum
Bone Marrow
Tomas Ganz ASH 2006
Iron Metabolism
Spleen
20 mg/d
RBC
Plasma
Fe-Tf
Duodenum
Bone Marrow
Tomas Ganz ASH 2006
Iron Metabolism
Spleen
RBC
Plasma
Fe-Tf
Duodenum
Bone Marrow
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
Adequate
Iron Intake
Inflammation
Hypoxia
IL-6
Hepcidin
Anemia?
RBC turnover
Hemochromatosis
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
Spleen
20 mg/d
RBC
Plasma
Fe-Tf
3 mg
Bone Marrow
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
Low Hepcidin
Iron
High Hepcidin
Iron
DMT1
ferritin
ferritin
Fpn
Fpn
Enterocytes
Macrophages
Iron release into Plasma
lysosome
Hepcidin
Iron Metabolism
Iron Signal
Spleen
RBC
Plasma
Fe-Tf
Duodenum
Bone Marrow
Erythropoiesis Signal
Tomas Ganz ASH 2006
Iron Metabolism
Iron Signal
Spleen
RBC
Plasma
Fe-Tf
Duodenum
Bone Marrow
Erythropoiesis Signal
Tomas Ganz ASH 2006
Evaluating Iron
Stores 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
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Bone Marrow Iron Stores??
Saturation (Fe/Transferrin) <8-10%
Iron Trial
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?IV repletion, check 1 month
% Hypochromic RBC’s
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Reticulocyte Hgb Concentration?
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Nl. <2.5%, Fe-deficient >10% correlates with Fe response
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
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Jejeunal/duodenal disease
Sprue
“Chronic Disease”
Anemia of Malignancy
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
Cardiac
Liver
Pancreas
Reproductive
Endocrine
NTBI = non-transferrin bound iron
Adapted from: Olivieri NF, et al. Blood. 1997;89:739-761; Olivieri NF. N Engl J Med. 1999;341:99-109.
Basic Causes of Iron Overload
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Acquired iron overload1
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Transfusional
Ineffective erythropoiesis
Toxic ingestion (very rare in adults)
Hereditary
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HFE hemochromatosis
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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 repeated
transfusions
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-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
Iron Signal
Spleen
RBC
Plasma
Fe-Tf
Duodenum
Bone Marrow
Erythropoiesis Signal
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 :
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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