IRON METABOLISM AND

MANAGEMENT OF IRON
OVERLOAD
DR. M.D. MAINA
MB.chB, Mmed(Int Medicine),
MSc(Haem) London

INTRODUCTION
defined as an excess of storage iron
of more than 5 g, is confined to the
hereditary forms of
haemochromatosis, and the ironloading.

Hereditary
haemochromatosis

classified according to the genetic defect causing iron overload.

Northern European origin,most patients
with HH are homozygous for the HFE pCys282TyrC
mutation(pC282Y). non-HFE HH, are very rare .
All the other types, often indicated as non-HFE HH, are very rare.
Types 1, 2 and 3 HH are autosomal recessive, and share common
features due to hepcidin deficiency, including high transferrin
saturation and hepatocyte iron accumulation.
Type 4 HH, inherited as a dominant condition, is a heterogeneous
disease with variable clinical phenotype A/B. Digenic inheritance
has been rarely described in patients who are heterozygous for
HFE pC282Y and have a mutation in the one of the other genes.

HFE haemochromatosis

HFE gene is northern European origin.

MHC class I-like ,gene located at 6p21.
Association of HH with HLA-A3.
Homozygosity for a GA substitution at nucleotide
845 of the HFE gene results in a cysteine to
tyrosine substitution at amino acid282
(pC282Y).Present in 90 % of HH patients.
A second variant (187CG) results in a histidine to
aspartic acid substitution at amino acid 63
(pHis63Asp or pH63D).
pC282Y homozygous genotype was higher in white
(1 in 227, 0.44%).

 Homozygous genotype 90% in northern

Europe and about 60% in southern
Europe.
The pH63D mutation is found throughout
the world with amean allele frequency of
15%. Asmall proportion of HH patients are
compound heterozygotes for the pC282Y
and pH63D mutations.

 In pC282Y homozygotes, there is a gradual

accumulation of iron, leading to tissue damage,
which may present as cirrhosisof the liver,
diabetes, hypogonadism, cardiomyopathy,
arthritis and a slate-grey skin (melanin)
pigmentation.
Cardiac involvement in the early stages is
characterized by diastolic dysfunction and
arrhythmias, in the later stages by DCM.
HCC may develop up to 25% of established cases
with cirrhosis. Alcohol is a definite risk for
cirrhosis in homozygous pC282Y.
Full phenotypic expression of the disorder is
dependent on other factors, including dietary
iron intake, blood donations or blood loss, and
other genetic factors modifying the genotype.

 Subjects homozygous for HFE pC282Y compared with

control subjects with normal HFE genotype have shown
the same frequencies of haemochromatosis symptoms
and complications such as lethargy, arthralgia and
diabetes,with either raised serum transaminases or
fibrosis/cirrhosis. Homozygosity for pC282Y is ass with
more HCC & cirrhotic and hepatoma than in others.
relative risk for HCCin cirrhotic patients with HH is
approximately 20, with an annual incidence of 34%.
serum -fetoprotein monitorning is needed.
High ferritin 1000 g/L is a risk factor for liver fibrosis
with a prevalence of 2045%. A serum ferritin level
>1000 g/L has 100% sensitivity and 70% specificity
for diagnosing of cirrhosis.(MRI) and Fibroscan
evaluation and complete cardiac and endocrinological
evaluation.
ferritin cut-off might be lower in the presence of
cofactors for liver disease such as alcohol.

 50% of homozygous women have raised transferrin

saturation,and progression through iron accumulation
and tissue damage is usually, but not always, slower.
Most men who are homozygous for pC282Y have a
raised transferrin saturation before the age of 30
years; a proportion will have an elevated serum ferritin
concentration, but only a minority will eventually
develop fibrosis and cirrhosis of the liver.
5% of pC282Y undiagnosed of HH.

Clinical and laboratory

diagnosis
clinical presentations
and their lack of specificity for HH
mean that a high degree of clinical suspicion is needed.
Fatigue, abdominal pain(hepatomegaly or HCC), diabetes
mellitus, signs and symptoms of gonadal failure and
arthritis (2nd and 3rd metacarpophalangeal joints )may be
present for several years before the diagnosis is made.
Erosive arthropathy of hip and knee joints occurs in 10%.
Grey skin pigmentation results from excess melanin
deposition.
transferrin saturation: 45% in most men & 50%
women.
ferritin concentration rises, and values in excess of 200
g/L (women) and 300 g/L (men) suggest iron overload.

Mutated HFE Genes =

Hemochromatosis?
No, because of
Incomplete penetrance:
Even though some individuals have the
susceptible genotype they may never manifest
symptoms of the disease due to:
Environmental factors: blood donation
Genetic factors: other modifying genes

Low penetrance for C282Y homozygotes

Biochemical penetrance(about 70%), of HH
is high, the clinical penetrance is low (about
25%) among men and (1%) among women.

 Serum ferritin reflect iron turnover in

phagocytic cells ,not liver parenchyma.
Patients with infection, inflammation or
malignancy or in those undergoing surgery,
transferrin saturation , ferritin concentration.
Testing adult first-degree relatives screening
identify homozygous patients of no symptoms.
annually should be checked transferrin
saturation and serum ferritin.
No need to do population screening for
pC282Y , since there is low homozygote
developing iron overload.

Symptoms Traditional
Concept
Classic Triad:
Cirrhosis
(hepatic damage)
Diabetes (type II)
(pancreatic damage)
Bronzing of skin
(hyperpigmentation)

Traditional triad means diagnosed too late!

Damage may be only partially reversible
Goal is to detect the disease BEFORE organ damage occurs
clinical presentations and their lack of specificity for HH mean
that a high degree of clinical suspicion is needed. Fatigue,
abdominal pain(hepatomegaly or HCC), diabetes mellitus,
signs and symptoms of gonadal failure and arthritis (2 nd and 3rd
metacarpophalangeal joints ) may be present for several years
before the diagnosis is made.
Erosive arthropathy of hip and knee joints occurs in 10%.
Grey skin pigmentation results from excess melanin deposition.

Non-Specific Symptoms and

Signs
Liver: hepatomegaly, elevated liver enzymes
Cardiac: myocardial infarction,
cardiomyopathy
Endocrine: impotence/amenorrhea, diabetes
Musculoskeletal: arthritis/arthralgia
Fatigue: unexplained, severe and chronic

Generally not evident until 40-60 years of age

Some patients may present earlier

Associations with other

conditions
including inherited sideroblastic anaemia,

-thalassaemia trait or other haemolytic

anaemias.
HH more worse in patient with liver
disease( HCV, alcohol and NAFLD.
Porphyria cutanea tarda,which may be
associated with iron overload, an
important trigger of disease
manifestations.

 Liver iron concentration :dried fragment of liver biopsy.

The normal ranges are 0.171.8 mg/g dry weight. 3.0
mg/g dry weight indicate iron overload.
Iron quantitation in liver, heart and other organs is
performed by non-invasive methods, mainly MRI
techniques.
ferritin concentration >1000 g/L & high liver enzymes
should be assessed hepatocyte iron accumulation with
typical periportal predominance. Fibroscan is noninvase better than biopsy.

Consider Hemochromatosis!
In asymptomatic patients with:
Unexplained elevation of liver enzymes
or asymptomatic hepatomegaly
Abnormal serum iron markers on routine
blood work
Lethargy/fatigue
First degree relatives of a confirmed HH
case.
DM with hepatomegaly.

Diagnostic testing for HH

Transferrin saturation:
> 45% indicates significant Fe accumulation

Serum ferritin - levels indicating significant iron

accumulation:
>200 mcg/L pre-menopausal women
>300 mcg/L post-menopausal women
>300 mcg/L for men

Liver biopsy if ferritin >1000 to assess damage

Consider genetic testing DNA testing for common
mutations (C282Y, H63D)

Genetic Testing for HH

Should be offered to those

patients with:

Appropriate clinical presentation

Elevated transferrin saturation and ferritin
Liver biopsy suggestive of iron overload
First degree relative of a known case
* Must be offered to an affected family
member or index case FIRST
A known mutation should be identified before
offering DNA testing to other family members

 storage iron in normal adults has been

shown to be about 750 mg in men and
250 mg in women.

Medical Management

The goal - detect patients before symptoms of iron

overload.
Phlebotomy weekly.
Check ferritin every ~10 phlebotomies
Stop frequent phlebotomy when ferritin 25-50mcg/L
Maintenance phlebotomy every 3-4 months
Dietary recommendations: No limiting except alcohol
avoiding raw shellfish for possible infection with Vibrio
vulnificus, which is a particular risk in iron-loaded patients
removal of excess iron by regular phlebotomy greatly
reduces the morbidity and mortality from cardiac and
hepatic failure.
In some patients, diabetes mellitus, hypogonadism and
arthralgia improve, but cirrhosis and destructive arthritis
are irreversible.

 Early cardiac disease may respond to phlebotomy,

while severe cardiomyopathy requires iron chelation.
Iron chelation:subcutaneous desferrioxamine (DFO):
may have a role in the short term management of
patients with life-threatening cardiac failure.hepcidin
production.

Iron compartments in normal

adults (Weight 70kg, Height
177cm)
Compartment
Iron content (mg)
Total body iron (%)
Serum haemoglobin

2000

67

Storage Iron (ferritin,

haemosiderin)

1000

27

Myoglobin Iron

130

3.5

Labile pool

80

2.2

Other tissue Iron

0.2

Transport Iron

0.08

Storage Compartment
Iron is stored in either ferritin (water soluble) or
haemosiderin (water insoluble.)
Serum ferritin concentration usually correlates
roughly with total body Iron stores.
Serum ferritin levels are important in the
diagnosis of Iron metabolism disorders i.e. Iron
deficiency and Iron overload.
Haemosiderin is found predominantly in
macrophages.
Under pathological conditions it may accumulate
in large quantities in almost every tissue in the
body.

Labile Iron Pool

Iron leaves the plasma and enters
the interstitial and intracellular fluid
compartments before it is
incorporated into heme or storage
compounds.
Labile pool Iron is considered
equivalent to chelatable Iron pool.

Iron Metabolism
Iron haemostasis in humans is maintained by strict
regulation according to body needs.
Approximately 1mg (10% of total dietary Iron) is
absorbed daily predominantly from the duodenum.
Fe3+ is reduced to Fe2+ that is transported into the
cell by divalent metal transporter (DMT-1) located
in the apical brush border.
The Iron is then transported across the basolateral
membrane by ferroportin with the aid of
ferroxidase hephaestin.
In circulation Fe2+ is bound to transferrin and is
transported to the liver and bone marrow.
In the liver transferrin receptors 1 and 2 mediate
the endocytosis of Iron which is then stored as
ferritin and released by a ferroportin mediated
mechanism when body needs increase.

 The presence of ferroportin on the cell

membrane is regulated by hepcidin.
Hepcidin is a 25-amino acid peptide
produced in the liver.
It acts by binding ferroportin transporter
triggering its degradation.
This reduces Iron absorption in the gut.
Low hepcidin levels increase Iron
absorption by increasing ferroportin
levels.

Iron overload - Causes

Increased Absorption
Hereditary haemochromatosis. It results from mutation of HFE
gene is associated allel HLA-A3 and HLA-B8.This leads in decreace
In hepcidin levels and increases iron absorption.
Infective erythropoesis i.e. thallassemia intermedia, sideroblastic anaemia
Chronic liver disease
Increased Iron Intake
African siderosis (dietary and genetic)
Repeated red cell transfusion
Transfusional siderosis i.e. Aplastic anaemia, sickle cell disease, sideroblastic
anaemia, red cell aplasia, myelodysplasia, primary myelofibrosis and
thallassemia major
SICKLE CELL DISEASE

Sporadic blood transfusion

primary prevention of stroke in patients with abnormal transcranial

Doppler

velocities

prevention recurrence of stroke

short term transfusion programs in pregnancy

Mechanism of organ damage in

Iron overload
Saturation of transferrin by excess circulating
Iron results in increased non-transferrin bound
Iron (NTBI) and labile plasma iron (LPI.)
NTBI and LPI tend to enter tissues more
readily and form reactive oxygen species
(ROS.)
Excessive Iron deposits in hepatic
parenchyma, endocrine organs and cardiac
myocytes all leading to end organ damage by
ROS-mediated lipid peroxidation.

Mechanism of end organ

damage in Iron overload

Assessment of Iron overload

Serum ferritin
Serum ferritin correlates roughly with
total body Iron stores, and can be used
in assessing Iron overload.
It is however increased in inflammatory
conditions.
Serum ferritin is not an accurate
indicator of hepatic Iron concentration
(HIC.)

Liver biopsy
This is the gold standard. It gives an accurate
estimation of Iron overload.
Normal HIC is 0.4 - 2.2mg per gram of liver
dry weight.
HIC of more than 15mg/g liver dry weight is
consistently associated with liver fibrosis.
NB: Liver biopsy is an invasive procedure, has
risks of complication (<1%), associated with
sampling errors and lacks reproducibility.

T2*MRI
It is a well validated predictor of HIC and
cardiac complications from Iron overload.
Increasing Iron content in the liver and
the heart reduces relaxation times as
measured by T2*.
Cardiac values < 20ms correlate with:
a decline in left ventricular ejection values
an increase in cardiac arrhythmias
a need for cardiac medication

Therapy of transfusional Iron

overload
Pharmacological therapy
Chelation therapy to prevent or treat Iron overload in
recurrent transfusion
Chelation works by targeting unbound Iron, including
NTBI and LPI that causes tissue injury.
Indication of chelation therapy
Elevated HIC > 7mg/g liver dry weight has been used
as a guide to start therapy.
Serum ferritin > 1000ng/ml is used as a guide for
patients with thallassemia.
Transfusional overload: 20-30 unit packed cells should
have chelation therapy initiated.
. Serum ferritin > 1000mg or 20 units packed cells
transfused is indication
of chelation therapy .

Chelation Agent
Desferrioxamine (DFO)
It was introduced in the 1970s.
It is administered subcutaneously by infusion of
30-50ng/kg over 8-12 hours every night for 5-7
days a week.
With good compliance the drug can prevent or
reverse cardiac dysfunction and improves survival.
Adverse effects
Reversible sensorineural deafness
Retinal damage
Growth retardation
NB: Compliance is poor

Deferiprone
Orally active Iron chelator that causes
predominantly urinary Iron excretion.
It is given at 75mg/kg in three doses daily.
It is used alone or in combination with
desferrioxamine.
Deferiprone is more effective than
desferrioxamine at removing cardiac Iron.
Compliance is better.
Side effects
Athropathy, neutropenia, G.I. Disturbance
and Zinc deficiency.

Deferasirox (Exjade/ Asunra)

Newest oral chelating
Given at 20-40mg/kg
The dosing recommendation is pediatric
> 2years is the same as for adults
The tablet is dispersed by stirring in a
glass of water or apple juice (100-200ml)
until a fine suspension is obtained
It is taken on an empty stomach 30
minutes before meals

Contraindications
1. Patients with creatinine clearance <
40ml/min
2. High risk myelodysplastic syndrome
(MDS)
3. Non-haematological malignancies who
are not expected to benefit from
chelation therapy due to rapid
progression of their disease.
4. Hypersensitivity to deferasirox.

Conclusion
Life expectancy has increased
dramatically for thallassemia major
and other transfusion-dependent
patients with chelation therapy.
In many cases cardiac and liver
damage caused by iron overload can
be reversed and endocrine status
may be improved.