Transcript Iron: Can*t live without enough of it Can*t live with too much of it

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 Wolfe
Oxygen Transport Proteins – Hemoglobin/Myoglobin
Oxygen solubility
Plasma
2.3 ml/L
Whole Blood
200 ml/L
Hemoglobin and Myoglobin
Reduce oxygen’s reactivity
O2
Protected
environment
provided by
Mb and Hb
H2O
X
OxX
The Heme Prosthetic Group
The heme iron has two
oxidation states: Fe2+,
ferrous; Fe3+, ferric
Ferrous iron can
form up to 6 bonds
Ferric iron doesn’t bind oxygen
protoporphyrin IX
O2
Fe2+
H2O
Fe3+
protected
environment of
globin chains
pathogenic
variants
When bound to proteins both oxygen and iron are in
protected states and bad things don’t happen
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
Compartment
Iron Content (mg)
Total Body Iron
(%)
hemoglobin iron
1500(W)-2000(M)
67
storage iron (ferritin, hemosiderin)
1000
27
myoglobin iron
130
3.5
other tissue iron (cytochromes, etc.)
8
0.2
transport iron (transferrin)
3
0.08
labile pool
80
2.2
AKA: nontransferrin reactive oxygen
species (ROS)
bound iron (NTBI)
Fe2+ + H2O2
Fe3+ + OH- + OH
Fenton Reaction
macrophage
bone marrow
excess
proteins
nucleic acids
lipids
mutation
chain reaction more ROS production
Iron Storage - Ferritin
L subunits (iron binding)
H subunits (ferrioxidase
activity)
Fe3+
OH/PO4
Fe3+
Fe2+
ferrihydrite
(hemosiderin)
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
Adapted from Casiday and Frey,
Washington University St. Louis
Iron Transport - Transferrin
enterocytes
liver
macrophages
transferrin saturation
Fe2+
Fe2+
ceruloplasmin
Fe3+
+
33%
Fe3+-transferrin-Fe3+
transferrin
67%
transferrin
receptor
internalization
Iron Uptake from Diet
Replace iron lost by sloughing of intestinal and
skin cells and by bleeding
poor bioavailablity
ingested iron
macrophages/
ferriportin
not absorbed
vitamin C, ethanol
daily requirement
Fe3+
men 10 mg/1mg
menstruating women
20mg/2mg
Fe2+
GUT
R DMT1
enterocyte
ferritin
Fe2+
ferriportin
macrophages play an important
role in regulating circulating iron
using transporters similar or
identical to those found on
enterocytes
DMT1
Fe3+
transferrin
macrophages/
DMT1
2+
Fe
ceruloplasmin
circulating iron
ferriportin circulating iron
CIRCULATION
Regulation of Iron Absorption
ingested iron
not absorbed
Fe3+
Fe2+
loss with
cellular slough
R DMT1
enterocyte
circulatory system
ferritin
Fe2+
internalization,
degradation
ferriportin
hepcidin
Fe2+
HFE HJV TfR2
Regulation of Iron Absorption
ingested iron
not absorbed
Fe3+
Fe2+
loss with
cellular slough
R DMT1
enterocyte
circulatory system
ferritin
Fe2+
internalization,
degradation
ferriportin
hepcidin
Fe2+
HFE HJV TfR2
Iron Overload: Hereditary Hemochromatosis
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
juvenile
HJV
Rare
↓↓
++++
Symptoms start after first
decade: abdominal pain,
hypogonadism, heart
failure, diabetes mellitus
juvenile
HAMP
very 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
Transfusion therapy results in
iron overload
• 1 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/year
– 0.4 mg iron/kg body wt/day
• In addition, up to 4 mg/day may
be absorbed from the gut
– Up to 1.5 g iron/year
200–250 mg iron:
Whole blood: 0.47 mg iron/mL
‘Pure’ red cells: 1.16 mg iron/mL
Porter JB. Br J Haematol 2001;115:239–252
• Overload can occur after 10–20
transfusions
Iron overload is an inevitable
consequence of multiple blood
transfusions
Normal distribution and turnover
of body iron
Erythron
2g
20–30 mg/day
20–30 mg/day
Parenchyma
0.3 g
Liver 1 g
Transferrin
2–3
mg/day
20–30
mg/day
1–2
mg/day
Gut
Iron balance is achieved in the normal state
Hershko C et al. Ann NY Acad Sci 1998;850:191–201
Reticuloendothelial
macrophages
0.6 g
Imbalance of distribution and turnover
of body iron with transfusion therapy
Erythron
Transfusions
20–40
mg/day
NTBI
Parenchyma
Transferrin
Reticuloendothelial
macrophages
Gut
Iron balance is disturbed by blood transfusion because the body cannot
remove the excess iron
NTBI, non-transferrin-bound iron
Hershko C et al. Ann NY Acad Sci 1998;850:191–201
Iron overload leads to formation
of NTBI
Transferrin saturation due to:
• Frequent blood transfusions, or
• Ineffective erythropoiesis leading to
increased iron absorption
Normal: no NTBI
produced
Subsequent formation
of NTBI in plasma
Pituitary
Parathyroid
Thyroid
Iron overload
Heart
Transferrin saturation
100%
30%
Uncontrolled iron loading
of organs
Fe
Fe
Liver
Pancreas
Fe
Gonads
Fe
Fe
Fe
Fe
Uncontrolled uptake of labile iron
leads to cell and organ damage
Non-transferrin
iron
Storage
iron
Uncontrolled uptake
Transferrin iron
Controlled uptake
Labile
Iron
Free-radical generation
Organelle damage
Porter JB. Am J Hematol 2007;82:1136–1139
Functional
iron
Iron overload negatively affects
organ function
Labile iron
Free radical generation
Lipid peroxidation
Organelle damage
TGF-β1
Lysosomal fragility
Collagen synthesis
Enzyme leakage
Cell death
Fibrosis
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
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
Cardiac failure
Liver cirrhosis/
fibrosis/cancer
Insoluble iron complexes are deposited
tissues and
end-organ toxicity occurs
Diabetes
mellitus
Infertility
in body
Endocrine
disturbances→
growth failure