Iron overloading can contribute
to the development of disease in different ways because humans have no
physiological pathway for the excretion of iron. 4g of iron is found in an
average male adult. Each ml of packed erythrocytes contains about 1 mg i.e
about more than 2g of iron is in the form of haemoglobin, 1g of iron is found
in different body tissues predominantly liver and the rest of is present in
iron containing proteins and myoglobin. The primary mechanism of regulation of
concentration of iron in body depends on the absorption of iron. The
pathological conditions due to iron overload in different vital organs such as
heart arise due to increased iron absorption from the intestine which is the
primary site for the regulation of iron haemostasis. The hormone that regulates
the level of iron in body is a 25 amino acid peptide, hepcidin. Hepcidin
inhibits the absorption of dietary iron and also regulates the release of iron
from storage in hepatocytes. Hepcidin deficiency in body plays an important
role in iron overload . Iron overload mostly occurs due to
genetic abnormalities like hereditary haemochromatosis. Excessive iron in the
body can be result of blood transfusions especially transfusions in thalassemia
overload Cardiomyopathy- General considerations
of the most critical complications associated with excessive iron in human body
is cardiomyopathy. Cardiomyopathy weakens the force of cardiac muscle
contractions thereby reducing the efficiency of blood circulation. Iron
overload cardiomyopathy is a restrictive cardiomyopathy associated with
diastolic dysfunction and is considered secondary to the deposition of iron in
cardiac muscles . Excessive iron in tissues interferes with the
ability of transferrin and ferritin protein to prevent the accumulation of free
iron. In heart, iron overloading causes production of free radicals, superoxide
and hydrogen peroxide, largely obtained from abnormal mitochondrial DNA .
The myocardial damage is largely associated with the production of reactive
oxygen species, initiated by the large amounts of iron .
Excessive iron causes oxidative damage to the myocardial cells, membranes and
mitochondrial respiratory chain enzyme . Large amounts of iron bound to lipofuscin
increase the sensitivity of lipofuscin loaded lysosomes to oxidative stress.
Excessive accumulation of lipofuscin in myocardial cells causes defective
lysosomal function. These defective lysosomes interferes with the normal
autophagy and results in intracellular accumulation of aged and malfunctioning
mitochondria, defective proteins and other waste products. These waste products
have destructive effect on the performance and survival of cardiomyocytes.
Lysosomal destabilization causes aging of myocardium and variety of cardiac
pathologies . Iron overload enhances the release of arachidonic
acid and incorporation of arachidonic acid into phosphatidylcholine, as well as
cyclooxygenase-2 induction and eicosanoid production, in neonatal rat
ventricular myocytes. The effects of arachidonic acid and metabolites on
cardiomyocyte rhythmicity suggest a connection between these signals and
electromechanical alterations in iron-overload– induced cardiomyopathy.
Increased release of arachidonic acid may contribute to progression of
hypertrophy to heart failure in iron overload– induced cardiomyopathy .
The patients with iron overload are
usually asymptomatic in the early stages of disease. Because of the varied
etiologies, symptoms may vary in different patients. Excessive iron overload in
heart can result into irreversible heart failure if not detected earlier, so
early identification of disease is very important. Initially a patient may
experience shortness of breath because of exertion. This is usually due to left
ventricular dysfunction resulting from restrictive pathophysiology. In cases of
cardiac iron overload, iron first gets deposited in the epicardium and then
progresses to endocardium and finally myocardium of the ventricle. The systolic
function of the heart remains well preserved in the initial stages of the
disease. In the later stages when iron deposition occurs in atrial tissue, AV
blocks and spraventricular arrhythmias may occur. Deposition of iron in the
conduction system gives arise to nodal disease causing bradyarrythmias,
therefore increasing the requirement for pacemaker placement. Left ventricular
dilation and atrial fibrillation leads to the myocardial damage and this
increases the risk of sudden cardiac death in iron overloaded patients .
the last decade, cardiac magnetic resonance imaging has evolved as the most
validated technique for the assessment of myocardial iron load and risk of
cardiomyopathy in iron overload. In pathological states where excessive iron is
present in the myocardial tissue, acts as a paramagnetic agent, producing
changes in magnetic resonance signal intensity and susceptibility. Particularly
it reduces magnetic resonance imaging relaxation times and leads to a reduction
in the apparent myocardial T2* value .
clinical grading for patients at risk of iron overload cardiomyopathy is based
on cardiac T2* values. These patients are divided into three categories.
zone= T2* >20 ms
patients are at low risk for the imminent development of congestive heart
zone= T2* between 10 and 20 ms
these patients cardiac deposition has probably occurred are at intermediate
risk of cardiac decompensation.
zone= T2* <10 ms
patients are at high-risk of cardiac decompensation and need immediate
attention and chelation therapy
and experimental evidences support the hypothesis that lowering iron levels in
the body can decrease the risk of cardiovascular abnormalities. In order to
remove excess iron from the body, iron chelation therapy must be given in order
to reduce the chances of mortality induced by iron overload cardiomyopathy. The
most commonly and widely used drug is deferroxamine . In a
randomized controlled trial it was observed that deferiprone improved right
ventricular volume in a much better way when used as monotherapy as compared to
deferoxxamine . Deferitrin,
hydroxybenzylethylenediamine-diacetic acid, desferrithiocin, pyridoxal
isonicotinoyl hydrazone, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone,
and L1NA-II (a deferiprone derivative) are among the newer chelating agents
that are under active investigation. A drug with satisfactory oral
bioavailability and good long-term efficacy and safety would be extremely
useful, and a quest for such an agent is ongoing . L type voltage
gated calcium channel blockers (i.e amlodipine and verapamil) at therapeutic
levels attenuated oxidative stress and myocardial iron accumulation. These
drugs also prevent hypotension and also preserve heart structure and function.
L type voltage gated calcium channel blockers provide protective function to
the heart and reduce the iron overload in cardiomyopathy . The
diet plays an important role in decreasing the coronary events. It was observed
that when milk whey protein was given to experimental murine model with iron
supplementation, the mice receiving milk whey protein with iron had higher
cardiac levels of glutathione peroxidase and glutathion than the mice treated
with iron only and reduced levels of cytotoxic aldehydes . Heart
transplantation can be done in order to increase the survival rate and improve
the quality of life. It can be done in combination with aggressive other
suitable therapies to reduce the iron overload. Caines et al. published a
review in 2005 of 16 severe iron overload cardiomyopathic patients who received
heart transplant from 1967-2003 with age ranging from 14-63 years. Three
patients died in the first year due to development of infectious complications.
Within thirty days mortality rate was 12%. 10 year survival rate was 41% with
Kaplan-Meirer analysis, with, 1, 3 and 5 year survival rates of 81% .
The conditions largely associated
with iron overload cardiomyopathy are genetic in nature. These include
hereditary haemochromatosis and beta thalassemeia major.
Haemochromatosis and Cardiomyopathy
Hereditary haemochromatosis is an
autosomal recessive disorder related to excessive iron in organs and results
into organ damage. This disease was first described in 18th century
because of the three major clinical indications of this disease i.e. cirrhosis,
hyperpigmentation of the skin and diabetes, however only less than 15% patients
present with this clinical triad. This disease is most exclusively found in populations
of Northern Europe . All these symptoms are related to increased
and inappropriate absorption of iron. Excessive iron causes organ damage that
leads to diabetes, cirrhosis and cardiomyopathies, hypogonadism and arthritis.
Hereditary haemochromatosis is characterized by excessive absorption of iron
from the diet taken and an increased recycling of iron by macrophages despite
adequate available iron stores . In 19th century it
became clear that the disease is hereditary in nature and occurs due to a
defect in gene residing on short arm of chromosome 6. The HFE gene was finally
identified in 1996 . Four types of inherited iron overload have been
Type 1 is the most common form of
hereditary haemochromatosis and is associated with mutations in the HFE gene on
chromosome 6. The patients with type 1 usually have an autosomal recessive
Type 2 (juvenile hemochromatosis) is an
autosomal recessive disorder. Mutations in this type are identified in the HJV
gene (subtype A) on chromosome 1 and the HAMP gene (subtype B) on chromosome
Type 3 patients also have an autosomal
recessive inheritance with mutations on chromosome 3 in the TfR2 gene.
Type 4 is an autosomal
dominant condition with heterozygous mutations on chromosome 2 in the
ferroportin 1 gene .
In most cases of hereditary
haemochromatosis it was seen that gene responsible for the expression of
hepcidin becomes defective and results into the production of defective
hepcidin. This defective hepcidin is unable to regulate the absorption and
release of iron . Pereira A.C., et
al. in 2001 studied the distribution of haemochromatosis related mutations in
319 patients with heart failure due to cardiomyopathy of different etiologies.
It was observed that patients with ischemic cardiomyopathy were heterozygotes
for the C282Y mutations. The D63 mutation was not found to be related to the
ischemic cardiomyopathy . Mitochondrial DNA damage is
catalyzed by chronic iron overload and is associated with decreased expression
of mitochondrial DNA that encodes mRNA and proteins in patients with
haemochromatosis. This causes loss of mitochondrial respiratory capacity and
leads directly to cardiac dysfunction. Mitochondrial DNA is more sensitive to
oxidative damage as compared to the nuclear DNA. In haemochromatic patients
sudden heart failure and death occurs due to rapid deterioration of systolic
function and one possibility of this could be mitochondrial failure arising
from damage to mitochondrial DNA . Oxidative
damage is mediated by iron overload in the heart. The removal of superoxide
radicals produced during oxidative damage is catalysed by manganese
mitochondrial superoxide dismutase (MnSOD) in hereditary haemochromatosis
patient. Valenti L. in 2004 observed that mice in which MnSOD gene has been
knocked out develop fatal cardiomyopathy and this might be due to critical high
mitochondrial concentration and oxygen tension in heart. In patients with
hereditary haemochromatosis the presence of 16Val allele was associated with
increased risk of cardiomyopathy. Patients with Val allele had higher dominance
of cardiomyopathy than diabetes, cirrhosis or hypogonadism, independent of age,
sex and alcohol misuse. The A16V mitochondrial superoxide dismutase polymorphism
affects the risk of cardiomyopathy in hereditary haemochromatosis and is found
to be associated with hereditary haemochromatosis . In 2003 it
was observed that if HFE gene is knocked out in mice, their hearts were found
more susceptible to ischemia-reperfusion injury. This occurs due to increased
myocardial infarct size, increased post ischemic ventricular dysfunction and
cardiomyocyte apoptosis when compared with wild-type control hearts. The degree
of injury increased in the heartls of the mice fed high-iron diet. The hearts
of the HFE knockout mice showed increased content of reactive oxygen species
and increased iron deposition in cardiomyocytes. Increased formation of
malondialdehyde also increased the formation of reactive oxygen species and reduced
antioxidant enzymes including glutathione peroxidase, catalase and superoxide
Intense transepithelial uptake of
iron in patients with hereditary haemochromatosis leads to iron accumulation in
body that results in pancreatitis, hepatocellular carcinoma, cirrhosis and
cardiomyopathy. Two types of mutations are considered to be modulators of
first type of mutation causes substitution of tyrosine for cysteine at 282
amino acid position of protein product (cys282tyr C282Y).
second type of mutation involves the substitution of aspartic acid for
histidine at position 63 (his63asp, H63D).
hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, or C282Y/wild-type are risk
factors for ischemic heart disease and myocardial infarction. These types of
mutations are common in white population of North Europe,
in whom 12% are heterozygous for C282Y and 24% are heterozygous for H63D [25-26].
Allen K.J, et al. assessed HFE mutations in 31,192 persons in Northern
Europe between the ages of 40 and 69. The proportion of C282Y
homozygotes who had documented iron overload related disease were 28.4% men and
1.2% women. So iron overload disease in C282Y homozygotes is more prevalent in
men than women .
The first step in the diagnosis
of hereditary haemochromatosis is screening the transferrin saturation. If the
fasting transferrin saturation in a patient is =45%, then serum ferritin levels
should be tested. If the ferritin level is =200 µg/L in premenopausal women or
=300 µg/L in postmenopausal women or in men then the possibility of hereditary
haemochromatosis must strongly be considered. The next step in evaluation is
genotyping. If a patient has elevated transferrin saturation and ferritin
levels then genotyping must be recommended. If the patient is found to be
homozygous for the C282Y mutation, presence of hereditary haemochromatsis is
definite, and therapy should be initiated. In
patients with hereditary haemochromatosis the life expectancy is reduced
due to myocardial damage leading to cardiac complications and sudden cardiac
death, but a case of sudden cardiac death in a young man was reported and it was
seen that none of the known hereditary haemochromatosis mutations were present.
This case suggests that genetic screening alone is not sufficient to identify
the persons at risk of developing hereditary haemochromatosis.
This is because the genotypes (i.e., C282Y/H63D, C282Y/wild, or H63D/H63D)
which are less clearly associated with clinical hereditary haemochromatosis and
excessive iron indices diagnosis is more difficult to establish. In these types
of patients further evaluation with liver biopsy might be necessary .
If diagnosis after liver biopsy remains in doubt, a trial of phlebotomy could
be considered. It is generally clinically agreed that iron overload is present
if 16-500 ml (equivalent to 4 g of iron) phlebotomies can be done without inducing
iron deficiency .
The treatment for hereditary
haemochromatosis from medieval times is phlebotomy i.e performing of periodic
bleeding. Initially about 500-1000 ml of blood containing about 400-500 mg of
iron are removed weekly until serum ferritin levels are reduced below 50 ng/ml
and transferrin concentration is reduced to a value below 30% (requiring 2 to 3
years). Maintainance therapy during life with less aggressive bleeding is
necessary to keep the transferrin saturation value below 50% and the serum
ferritin levels less than 100 ng/ml. The quality of patients’ lives is greatly
affected because the rate of iron reloading is highly variable and the
transferrin saturation remains elevated in many treated patients and does not
normalize unless the patients become iron deficient. Gene therapy could alter
specific targets to greatly reduce the accumulation of iron in haemochromatosis
patients. The targets that have been studied so far include
1. reduction of the
basolateral ferroportin transporter levels in enterocytes
2. reduction of the
apical DMT-1 transporter levels in enterocytes
of the wild type HFE protein in enterocytes
of the iron uptake inhibitory protein hepcidin generated by hepatocytes. 
The word “thalassemia” comes from
a Greek word “thalassa” meaning sea. The disease is highly prevalent in the
areas bordering the sea like Middle East, North India, Southeast Asia and Mediterranean Basin. Thalassemia is the most common
genetic disorder that causes decreased globin, protein composition of
haemoglobin. Two clinical forms of thalassemia have been identified,
ß-thalassemia major and thalassemia intermedia. Beta thalassemia major (TM) is
the severe form of genetic disorder arising either from homozygous or compound
heterozygous defects. TM requires repetitive blood transfusions because of
severe anemia that arises from the defective erythropoises. Repetitive
transfusions increase iron content in body .
Two thirds of deaths in
ß-thalassemic patients occur due to heart failure. The pathogenesis of cardiac
failure in ß-thalassemia is complex and is thought to be linked to the viral
infections and immunogenetic factors . Iron overload
cardiomyopathy however doesn’t occur in the initial stages of disease and the
patient is usually asymptomatic, but is considered as the most serious
complication. Iron overload cardiomyopathy usually begins when 20g or more iron
gets accumulated and no iron chelation therapy is given. Restrictive
cardiomyopathy usually occurs first, followed by dilated cardiomyopathy .
Diastolic dysfunction occurs prior to the systolic dysfunction and heart
failure. Left side heart failure is more common than right side failure. In a
group of 52 patients with thalassemia major, the mean age of the patients
diagnosed with heart failure was 25±5 years. These 52 patients were given
repetitive blood transfusions, regular iron chelation therapy and conventional
heart failure therapy and it was seen that 5 year survival rate was 48% .
In a cohort study of 202 well treated patients with thalassemia major the
prevalence of cardiac failure was 2.5% with a mean age of 27±6 years. Of these
2.5%, 5% had a history of acute pericarditis . In patients with
thalassemia major without heart failure the HLA-DRB1*1401 allele was found more
frequently, whereas the HLA-DQA1*0501 allele was found more frequent in
patients with heart failure. This suggests that the HLA-DQA1*0501 allele might
be related to an increased risk for heart failure, whereas the HLA-DRB1*1401
allele might be protective against heart failure .
The diagnosis of
iron overload in thalassemic patients has until recently been carried out by
using ferritin levels and liver iron concentrations as surrogate markers and
echocardiography. Generally it was observed that the patients have developed
cardiomyopathy by the time changes are seen in echocardiography. However
determining certain parameters in echocardiography such as Total diameter index
can predict cardiac iron overload. This method is highly specific for
determining cardiac iron overload but has low sensitivity. Most recent study
reveals the significance of cardiac magnetic resonance imaging technique in
assessing the cardiac iron overload and identifying thalassemia patients at the
risk of developing cardiac disease . Cardiac magnetic resonance
imaging also helps in tailoring the therapies for removal excess iron. The iron
uptake mechanisms were studied in cultured thalassemic cardiomyoctes model. T
type calcium channels pathway was found responsible for the uptake of iron in
cultured thalassemic cardiomyocytes so T type calcium channel blockers could
also prevent iron uptake in cultured thalassemic cardiomyocytes. L-type calcium
channel blockers however could not prevent the uptake of iron in ß-thalassemia patient .
beta thalassemic patients iron chelation therapy is very important in saving
lives because prior to the introduction of chelating therapy most patients did
not reach to the second decade of life, mainly owing to heart diseases.
Desferroxamine, deferiprone and deferasirox are iron chelators currently
available. Desferroxamine is now not very much preferred due to poor
compliance. Deferasirox is a new iron chelator orally bioavailable. Deferasirox
protects the cells from non transferrin bound serum iron and plasma iron.
Plasma iron is mainly responsible for generating reactive oxygen species which
is responsible for damaging cells. The oral iron chelators have better
compliance because of oral use. These three chelators when used properly will
improve the prevention and treatment of iron overload and improve the quality
of life of patients receiving transfusions . Deferiprone (>80
mg/kg/day) is found to be effective in the removal of cardiac iron, in the
reversal of iron overload related cardiomyopathy, in the maintenance of normal
iron stores and the overall long-term survival of thalassemia patients .
A 15-year-old male with beta-thalassemia major developed dilated cardiomyopathy
secondary to iron overload. This patient was treated with deferoxamine but the
therapy was unsuccessful, presumably due to poor compliance. Deferasirox was
then given for 15 months and it was observed that left ventricular
end-diastolic dimension normalized, and ejection fraction improved to 58%.
Treatment with deferasirox resulted in a reversal of iron-induced
cardiomyopathy in thalassemic patients . In 2006, first human
gene therapy trial was done in France
for sickle cell disease and thalassemia. The first patient treated failed for
technical reasons because he required back up of his own thalassemic bone
marrow. In 2007, an 18 year old patient was transplanted and has been recently
reported to be free of transfusions after 40 months of post-transplant follow
up . It is hoped that introduction of healthy hematopoietic stem
cells in severe congenital anemia lacking appropriate ß-hemoglobin production,
such as in ß-thalassemia, may reverse
the primary pathophysiology in the disease and reduce the need for transfusions. Stem cell transpalntation requires chemotherapy and
radiation techniques to make it successful if perfectly matched donors are not
available. Presently, clinical trials are underway to test low-intensity
radiation along with immunosuppressant drugs without chemotherapy to accomplish
successful stem cell transplantation with a half-matched donor in order to
broaden its use .
Iron overload is a serious
complication of hereditary haemochromatosis and ß-thalassemia. Early diagnosis
can make this complication less serious and easily treatable and this can be
accomplished with cardiac imaging of iron quantity in cardiomyocytes. The
mechanisms of iron homeostasis and the uptake of iron by cardiomyocytes are
emerging and elucidated to some extent to understand the underlying
possibilities in order to adopt the best possible treatment. Newer chelating
agents are being introduced to increase the compliance of patients. Heart
transplant, gene therapy and stem cells techniques must further are
investigated to increase the survival rate and more sophisticated methods be
developed to improve the quality of life of patients.
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