t live without enough of it Can t live with too much of it Camp Sunshine July 15 th 2015 Adapted from DBA Day Iron Overload by Dr Lawrence Wolfe Oxygen solubility Plasma 23 mlL ID: 322808
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Slide1
Iron: Can’t live without enough of it Can’t live with too much of it
Camp Sunshine, July 15th 2015
Adapted from DBA Day Iron Overload
by Dr. Lawrence WolfeSlide2
Oxygen solubility
Plasma
2.3 ml/L
Whole Blood
200 ml/L
Hemoglobin and Myoglobin Reduce oxygen
’
s reactivity
O
2
X
H
2
O
OxX
Oxygen Transport Proteins – Hemoglobin/Myoglobin
Protected environment provided by Mb and HbSlide3
The Heme Prosthetic Group
The heme iron has two oxidation states: Fe
2+
, ferrous; Fe
3+
, ferric
Ferrous iron can form up to 6 bonds
Ferric iron doesn’t bind oxygen
O2
Fe2+
H
2O
Fe
3+
protected environment of globin chains
pathogenic variants
protoporphyrin IX
When bound to proteins both oxygen and iron are in protected states and bad things don’t happenSlide4
Compartment
Iron Content (mg)
Total Body Iron (%)
hemoglobin iron
1500(W)-2000(M)
67
storage iron (ferritin, hemosiderin)
1000
27myoglobin iron
1303.5
other tissue iron (cytochromes, etc.)
8
0.2
transport iron (transferrin)3
0.08
labile pool80
2.2
Iron Metabolism – Distribution in the Human Body
Iron is an essential, but also potentially highly toxic nutrient. Its uptake, transport, and storage in the body are highly regulated
Iron Distribution in Humans
Fe
2+
+ H
2
O
2
Fe
3+
+ OH
-
+ OH
proteins
nucleic acids
lipids
Fenton Reaction
mutation
macrophage
bone marrow
reactive oxygen species (ROS)
chain reaction more ROS production
excess
AKA:
n
ontransferrin
bound iron (NTBI)Slide5
ferrihydrite
Fe
3+
OH/PO
4
Adapted from Casiday and Frey, Washington University St. Louis
Fe
3+
Fe
2+
Iron Storage - Ferritin
Ferritin enters serum by an unknown mechanism under normal conditions (values proportional to cellular content) and is used as a non-invasive measure of iron stores. Measurements of serum ferritin can be used in the diagnosis of disorders of iron metabolism or tissue damage. Normal values: men 12-300 ng/ml; women 10-150 ng/ml.
Ferritin can also be released to serum by damage to cells of the liver, spleen, or bone marrow and other pathogenic states
L subunits (iron binding)
H subunits (ferrioxidase activity)
(hemosiderin)Slide6
Iron Transport - Transferrin
Fe
2+
Fe
2+
Fe
3+
ceruloplasmin
+
transferrin
Fe
3+
-transferrin-Fe
3+
transferrin receptor
internalization
33%
67%
enterocytes liver macrophages
t
ransferrin saturationSlide7
Iron Uptake from Diet
ingested iron
Fe
3+
Fe
2+
R
DMT1
Fe
2+
ferriportin
ferritin
not absorbed
Fe
2+
Fe
3+
transferrin
enterocyte
daily requirement
men 10 mg/1mg
menstruating women 20mg/
2mg
vitamin C, ethanol
poor
bioavailablity
GUT
CIRCULATION
macrophages play an important role in regulating circulating iron using transporters similar or identical to those found on enterocytes
DMT1
circulating iron
ferriportin
circulating iron
ceruloplasmin
macrophages/ferriportin
macrophages/DMT1
Replace iron lost by sloughing of intestinal and skin cells and by bleedingSlide8
ingested iron
Fe
3+
Fe
2+
R
DMT1
Fe
2+
ferriportin
ferritin
internalization, degradation
not absorbed
hepcidin
HFE
TfR2
HJV
Fe
2+
enterocyte
loss with cellular slough
circulatory system
Regulation of Iron AbsorptionSlide9
ingested iron
Fe
3+
Fe
2+
R
DMT1
Fe
2+
ferriportin
ferritin
internalization, degradation
not absorbed
hepcidin
HFE
TfR2
HJV
Fe
2+
enterocyte
loss with cellular slough
circulatory system
Regulation of Iron AbsorptionSlide10
gene
frequency
hepcidin
severity
clinical findings
classic
HFE
Heterozygous frequency: 1/10 North Americans
↓++
symptoms start after 4th decade: chronic fatigue, hepatic fibrosis and cirrhosis, cardiomyopathy, diabetes mellitus, infertility, joint pain
juvenileHJV
Rare
↓↓
++++
Symptoms start after first decade: abdominal pain, hypogonadism, heart failure, diabetes mellitusjuvenile
HAMPvery rare
↓↓
++++
Symptoms similar to
HJV
-related HH
TfR2
very rare
↓
+++
Symptoms similar to
HFE
-related HH
SLC40A1
(ferriportin)
rare
↓
+
Symptoms similar to
HFE
-related HH
Iron Overload: Hereditary HemochromatosisSlide11
Transfusion therapy results in iron overload1 blood unit contains 200 mg iron
A 60 kg patient with thalassemia receiving 45 units of blood annually has transfusional iron intake of 9 g iron/year0.4 mg iron/kg body wt/dayIn addition, up to 4 mg/day may be absorbed from the gut
Up to 1.5 g iron/year
Overload can occur after 10–20 transfusions
200
–250 mg iron:Whole blood: 0.47 mg iron/mL ‘Pure’ red cells: 1.16 mg iron/mLPorter JB. Br J Haematol 2001;115:239–252Iron overload is an inevitable consequence of multiple blood transfusionsSlide12
Erythron2 g
Hershko C
et al
.
Ann NY Acad Sci
1998;850:191–201
Normal distribution and turnover
of body iron
Iron balance is achieved in the normal state
2–3 mg/dayParenchyma0.3 gLiver 1 g
20
–30 mg/dayReticuloendothelialmacrophages0.6 g
1
–2 mg/day
20–30 mg/day
Gut
20
–
30 mg/day
TransferrinSlide13
Parenchyma
Reticuloendothelial
macrophages
Gut
NTBI
Erythron
TransferrinTransfusions
20–40 mg/dayTransferrin
Reticuloendothelial
macrophages
Parenchyma
NTBI, non-transferrin-bound iron
Hershko C et al. Ann NY Acad Sci
1998;850:191–201Imbalance of distribution and turnover of body iron with transfusion therapyIron balance is disturbed by blood transfusion because the body cannot remove the excess iron Slide14
Iron overload leads to formation of NTBI
Uncontrolled iron loading of organs
Subsequent formation of NTBI in plasma
Fe
Fe
Fe
Fe
Fe
Fe
Fe
100%
30%
Normal: no NTBI produced
Iron overload
Transferrin saturation due to:
Frequent blood transfusions, or
Ineffective erythropoiesis leading to increased iron absorption
Transferrin saturation
Pituitary
Parathyroid
Thyroid
Heart
Liver
Pancreas
GonadsSlide15
Transferrin iron
Controlled uptake
Non-transferrin
iron
Uncontrolled uptake
Organelle damage
Free-radical generation
Functional
iron
Labile
Iron
Storage
iron
Uncontrolled uptake of labile iron
leads to cell and organ damage
Porter JB.
Am J Hematol
2007;82:1136
–113
9 Slide16
Labile ironCell death
Fibrosis
Organelle damage
TGF-
β
1
Free radical generation
Lipid peroxidation
Lysosomal fragility
Enzyme leakage
Collagen synthesis
TGF, transforming growth factor
Cohen AR and Porter JB. In Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, Steinberg MH
et al.
(Eds); 2001:979–1027
Iron overload negatively affects organ functionSlide17
Liver cirrhosis/ fibrosis/cancer
Diabetes mellitus
Endocrine disturbances
→ g
rowth failure
Cardiac failure
Infertility
Excess iron is deposited in multiple organs, resulting in organ damage
Iron overload
Capacity of serum transferrin to bind iron is exceeded
NTBI circulates in the plasma; some forms of NTBI (eg LPI) load tissues with excess iron
Excess iron promotes the generation of free hydroxyl radicals, propagators of oxygen
-
related tissue damage
Insoluble iron complexes are deposited in body tissues and end-organ toxicity occurs