Download IRON OVERLOAD

IRON OVERLOAD
Prepared by:
Najla AbdulAziz Al-Sweel
Supervised by:
Dr.Sadia Ajumand
Iron Homeostasis:
Iron absorption is regulated by three
mechanisms:
1-dietary regulator
2-stores regulator
3-erythropoietic regulator
Definition of iron overload:
A polyetiologic condition characterized by
a moderate or severe increase in body
iron levels that has or will have negative
effects on health.
Classification:
1-Primary iron overload
A) Hereditary hemochromchromatosis:
B) Aceruloplasminaemia
C) Congenital atransferrinaemia
D) Neonatal hemochromatosis
2-Secondary iron overload
A) Dietary iron overload
B) Parenteral iron overload
C) Iron loading anaemias
D) Long term haemodialysis
E)Chronic liver disease:
F) Porphyria cutanea tarda
G) Post-portacaval shunting
H)Dysmetabolic iron overload syndrome
3-Miscellaneous
Iron overload in sub-Sahara Africa
PRIMARY IRON OVERLOAD
Hereditary Hemochromatosis (HH) Type 1
Haemochromatosis is a hereditary disease characterized by
improper processing by the body of dietary iron which causes iron to
accumulate in a number of body tissues, eventually causing organ
dysfunction. It is the main iron overload disorder.
Epidemiology:
Worldwide frequency of the C282Y and H63D mutations was found
to be 1.9% and 8.1%, respectively.
HH is the most commonly inherited disorder in white patients,
especially in Caucasians of northern European descent.
Symptoms of HH occur more frequently in males than in females,
with a male-to-female ratio of 3:1.
Symptoms of HH develop in persons older than 40 years.
Genetics of HH Type 1:
The HFE gene resides on
chromosome 6, is located at
band 6p22 and encodes a
protein containing 343 amino
acids. This HFE protein spans
the cell membrane.
Its external portion includes a
nonfunctional peptide-binding
domain, it has an alpha3 loop,
the site where HFE associates
with an accessory protein
called beta2-microglobulin.
This interaction is necessary
for normal presentation on the
cell surface.
The role of HFE in the regulation of
cellular iron uptake:
Mutations in the HFE gene are
responsible for 90% of HH Type 1 cases.
These mutations include:
1. C282Y (major mutation):
This missense mutation, caused by a guanine to adenine
transition at nucleotide 845 (TGC TAC), results in the
substitution of cysteine (C) by tyrosine (Y) at amino acid
position 282 in the HFE protein product.
2. H63D (minor mutation):
This missense mutation caused by a guanine to cytosine
transition at the187th nucleotide, results in the
substitution of histidine (H) by aspartate (D) at amino
acid position 63 in the HFE protein.
*Other mutations have been described in HFE but most are
very low frequency.
The effect of major and minor HFE mutations
on cellular iron uptake:
Factors which influence the phenotypic
expression of HH Type 1:
Environmental factors which affect iron stores
Factors which affect iron absorption
Inheritance of HH Type 1:
The pattern of inheritance in families of HH is
described as autosomal recessive, meaning that
a child must inherit two mutated copies of the
gene, one from each parent, in order to develop
HH.
Pathophysiology:
The causative defect--the one permitting excessive iron
absorption--is most likely to be within the intestinal lining.
The sensor pathway inside the enterocyte is disrupted
due to the genetic errors.
Persons affected with HH absorb 3 to 4 mg/day of iron.
Thus the iron stores of the body increase. As they
increase the iron which is initially stored as ferritin starts
to get stored as a breakdown product of ferritin called
haemosiderin which is toxic to tissue.
As ferrous iron accumulates in the parenchymal tissues,
the intracellular iron-binding sites are overwhelmed.
Labile iron can promote damage of cellular organelles by
radical formation which results in lipid peroxidation,
cellular injury, and fibrosis.
Consequences
1. Damage to the liver:
2. Damage to the heart:
3. Damage to the endocrine
system:
4. Damage to the skeletomuscular
system:
5. Effects on skin:
6. Compromise of the immune
system:
Withholding iron from potential pathogens
is a strategy used in host defense.
Very high transferrin saturations
compromise the bacteriostatic properties
of transferrin.
The natural history of HH
includes three phases:
A phase of latency.
A phase of biochemical
expression, asymptomatic,
which appears around the
age of 20.
A phase of clinical
expression, symptomatic,
which appears later during
adulthood.
Signs and Symptoms:
Hemochromatosis is
notoriously protean.
Diagnosis:
1. Transferrin saturation test:
Normal TS values range from 16% to 45%, if the TS test result
is >45% it is considered elevated and is suggestive of HH.
2. Serum ferritin test:
Normal SF levels are <200ng/ml in premenopausal females
and <300ng/ml in males, SF levels >200ng/ml in
premenopausal females or >300ng/ml in males or
postmenopausal females is considered elevated.
3. Confirming the HH diagnosis:
A. Quantitative phlebotomy
B. Molecular genetic testing
C. Liver biopsy
A hemochromatosis diagnosis identifies a patient who needs
treatment and a family potentially at risk. Family-based
detection is an efficient way to identify those who have an
increased risk of developing hemochromatosis, and an
important disease prevention opportunity.
Treatment and Management:
Periodic phlebotomy is a simple, inexpensive, safe, and
effective treatment.
Therapeutic phlebotomy includes an induction phase to
induce iron depletion and a maintenance phase to
prevent excess iron reaccumulation.
Prognosis:
The degree of iron overload at the time of
diagnosis, as well as organ dysfunction, have
prognostic implications.
The causes of death in untreated patients
include cardiac failure (30%), liver failure or
portal hypertension (25%), and hepatocellular
carcinoma (30%).
When HH is found early and properly managed,
long-term prognosis, including life expectancy,
should not differ from that of persons without the
disorder.
Current Research in
Hemochromatosis is
Concentrated in Four Areas:
Genetics
Pathogenesis
Epidemiology
Screening and testing
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