Subject: hemochromatosis/heart
CLINICOPATHOLOGIC CONFERENCE: CASE STUDY OF CARDIOMYOPATHY
[ Findings: ]
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Discussion:
Based on the increased transferrin saturation, mixed
restrictive-dilated cardiomyopathy, diabetes mellitus, and
hypothyroidism, the most likely diagnosis is hemochromatosis, an
excessive accumulation of iron in the body. The iron accumulates as
ferritin and hemosiderin and causes direct toxicity to tissues. The
damage may be mediated by either lipid peroxidation via iron-catalyzed
free radical reactions, iron stimulation of collagen formation, or
direct intercalations of iron with DNA.
Typically, the patient presents with a combination of five
findings -- liver cirrhosis, cardiomyopathy with arrhythmias,
endocrine dysfunction, arthropathy, and skin pigmentation. Damage to
the liver leads to micronodular pattern of cirrhosis. Although SGOT
and SGPT are within normal limits, the liver damage could be
responsible for the ascites and the abnormal TIBC of the patient.
Also, myocytes of the heart are directly damaged by deposits within
the fiber, which leads to dilated cardiomyopathy and arrhythmias.
Furthermore, both the acinar cells and the islets cells of the
pancreas can be affected, which causes diabetes mellitus. Deposits can
occur in the hypothalamus, pituitary, and thyroid gland. Damage to any
of these organs can lead to hypothyroidism. The normal TSH with low
thyroxine levels indicates that the hypothalamus or pituitary are more
likely to be affected. Damage to the hypothalamus or pituitary usually
presents with hypogonadism, but we are not given this information.
Diagnosis of hemochromatosis is made by measuring TIBC (low, 162
(g/dl) transferrin saturation (high, 92%) and serum ferritin levels
(not available for our patient). The diagnosis is confirmed by liver
or heart biopsy, and treatment of hemochromatosis is phlebotomy and
iron chelation.
Hemochromatosis may be either hereditary or secondary. Secondary
hemochromatosis can be caused by such diseases as (-thalassemia,
sickle cell anemia, or sideroblastic anemia. The iron overload can
occur because of either repeated blood transfusions for the anemia or
increased iron absorption in response to insufficient erythropoiesis.
Diagnosis of these anemias can be achieved by detailed history,
peripheral blood stain, and bone marrow examination to look for
characteristic abnormal red blood cells and erythroid hyperplasia.
Hereditary hemochromatosis is an autosomal recessive inborn error of
the "ferristat," causing a malregulation in intestinal iron
absorption. The prevalence of homozygosity among Caucasians is
0.2-0.45%. There is very strong evidence that the genetic defect is
tightly linked to the Human Leukocyte Antigen (HLA)-A locus on the
short arm of Chromosome 6, although the normal gene function or the
mechanism by which dysfunction leads to hemochromatosis is unknown.
Furthermore, currently there is no animal model for extensive
molecular studies. Recent research utilizes yeast artificial
chromosomes (YACs) to sequence by brute force the DNA next to HLA-A
(Ajioka and Kushner, personal communication, 1995), and the use of
linkage disequilibriums to narrow down the stretch of DNA to be
sequenced (Yaouanq, 1994).
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pccheng@merle.acns.nwu.edu
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Subject: High Iron & Your Heart
Comments: Hemochromatosis is a disorder of iron metabolism characterized by
excessive deposition of
the metal in parenchymal tissues (heart, liver, pancreas, gonads). In
general, iron overload can occur as
a familiar or idiopathic disorder, a disorder related to ineffective
erythropoiesis, a result of excessive
transfusional therapy in the setting of refractory anemias, a secondary
manifestation of chronic liver
disease due to alcohol abuse, or due to chronic elevated oral intake. The
clinical presentation is usually
directly related to the degree of deposition in each affected organ system.
Although excess iron tends to
concentrate in the liver and pancreas, approximately one third of patients
with untreated
hemochromatosis will die of congestive heart failure. The pattern of heart
failure can simulate either a
restrictive or congestive cardiomyopathy. The restrictive presentation
represents the earliest
manifestation of cardiac hemochromatosis with progressive iron deposition
leading to a dilated form of
cardiomyopathy. Interestingly, the degree of fibrosis may be minimal and with
phlebotomy LV function
may be restored. Diagnosis of iron overload can be made by high serum iron
and ferritin levels as well as
total transferrin saturation. In symptomatic subjects biopsy of an affected
organ is necessary to confirm
the diagnosis. If congestive heart failure is the presenting symptom,
endomyocardial biopsy is warranted
as it is as safe as liver biopsy in obtaining a tissue diagnosis.
Therapy is directed at reducing the total iron burden. With weekly
phlebotomy, 200-250mg of iron can
be mobilized. Desferoxamine infusions are less effective and costly. Without
therapy, death is usually due
to cardiac complications in younger patients and progressive liver
decompensation or hepatoma in older
patients.
Subject: heart/iron overload/case presentation
Case Presentation
The Heart In Iron Overload
by Michael J. Ptacin MD, FACC, Associate Professor of Medicine
A fifty-four-year-old white male was referred to cardiology
clinic for evaluation of the new onset of congestive heart failure.
He was completely asymptomatic until two months prior to
presentation. Gradually, he developed dyspnea at 100 feet of level
walking, two pillow orthopnea, paroxysmal nocturnal dyspnea and
progressive ankle edema. He did not relate symptoms compatible with
a myocardial infarct or angina pectoris. He described rapid heart
action which did not result in loss of consciousness. He denied
smoking, diabetes mellitus, hypertension or lipid disorders. The
review of systems was striking for a forty pound weight loss,
polyuria, polydipsia and polyphagia.
Physical exam revealed a cachectic white male in mild
respiratory distress. He was slightly hypotensive. The skin was
cool, clammy and had a slate gray appearance. The CVP was grossly
elevated. The carotid exam was consistent with a low volume pulse.
Rales were present throughout the chest. A loud third sound was
heard over a laterally displaced, diffuse apical beat. The liver was
enlarged and unusually firm. Massive peripheral edema was present.
EKG: Sinus rhythm, left bundle branch block. CXR: moderate
cardiomegaly with four chamber enlargement, early interstitial
edema. Chemistries: glucose (625), mild elevations in the Total
Bilirubin, SGOT and Alkaline Phosphatase, and a normal hemogram. The
patient was admitted to the cardiology service.
[INLINE] [INLINE] With the presence of biventricular heart failure,
firm hepatomegaly, new onset diabetes mellitus and cutaneous
hyper-pigmentation a presumptive diagnosis of a hemochromatosis was
made.
A serum ferritin drawn on admission was 12, 130 (nl
Figure E - A photomicrograph of a Prussian blue stain of the myocardium
showing severe deposition of iron.
Comments: Hemochromatosis is a disorder of iron metabolism
characterized by excessive deposition of the metal in parenchymal
tissues (heart, liver, pancreas, gonads). In general, iron overload
can occur as a familiar or idiopathic disorder, a disorder related
to ineffective erythropoiesis, a result of excessive transfusional
therapy in the setting of refractory anemias, a secondary
manifestation of chronic liver disease due to alcohol abuse, or due
to chronic elevated ora (HOME) l intake. The clinical presentation is
usually directly related to the degree of deposition in each
affected organ system. Although excess iron tends to concentrate in
the liver and pancreas, approximately one third of patients with
untreated hemochromatosis will die of congestive heart failure. The
pattern of heart failure can simulate either a restrictive or
congestive cardiomyopathy. The restrictive presentation represents
the earliest manifestation of cardiac hemochromatosis with
progressive iron deposition leading to a dilated form of
cardiomyopathy. Interestingly, the degree of fibrosis may be minimal
and with phlebotomy LV function may be restored. Diagnosis of iron
overload can be made by high serum iron and ferritin levels as well
as total transferrin saturation. In symptomatic subjects biopsy of
an affected organ is necessary to confirm the diagnosis. If
congestive heart failure is the presenting symptom, endomyocardial
biopsy is warranted as it is as safe as liver biopsy in obtaining a
tissue diagnosis.
Therapy is directed at reducing the total iron burden. With
weekly phlebotomy, 200-250mg of iron can be mobilized. Desferoxamine
infusions are less effective and costly. Without therapy, death is
usually due to cardiac complications in younger patients and
progressive liver decompensation or hepatoma in older patients.
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Subject: cardiomyopathy/iron/chelation
Br Heart J 1995 May;73(5):486-7
Reversal of haemochromatotic cardiomyopathy in beta thalassaemia by chelation
therapy.
Politi A, Sticca M, Galli M
Department of Cardiology, S Anna Hospital, Como, Italy.
Haemochromatotic cardiomyopathy is the main cause of morbidity and
mortality in patients with beta thalassaemia major. Once congestive
heart failure develops most patients die in a few months. Congestive
heart failure was reversed and echocardiographic findings were
restored to normal in a 24 year old woman with beta thalassaemia who
resumed treatment with chelation therapy (desferrioxamine).
PMID: 7786668, UI: 95306234
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Subject: Iron and heart disease
High Iron Levels May Increase Risk of Heart Attack
Library: MED
Keywords: HIGH BLOOD PRESSURE RESEARCH HIGH IRON
Description: High levels of iron in the body can damage arteries, speeding
the development of atherosclerosis and sharply increasing the risk of heart
attack, according to a study reported at the 54th Annual Fall Conference of
the American Heart Association's Council for High Blood Pressure Research.
10/25/2000
FOR RELEASE:
1:30 p.m. ET, Wednesday
October 25, 2000
CONTACT:
Maggie Francis (214) 706-1397
Carole Bullock (214) 706-1279
Caroleb@heart.org
Abstract P130
American Heart Association meeting report: High iron levels may speed
atherosclerosis and increase risk of heart attack
WASHINGTON, Oct. 25 -- High levels of iron in the body can damage arteries,
speeding the development of atherosclerosis and sharply increasing the risk
of heart attack, according to a study reported today at the 54th Annual Fall
Conference of the American Heart Association's Council for High Blood
Pressure Research.
The researchers found that iron can damage the endothelium -- the inner
lining of the blood vessels. The endothelium keeps blood flowing to the heart
and brain by expanding and contracting arteries. High cholesterol levels,
diabetes or high blood pressure can damage the endothelium so that it doesn't
function well.
"A number of studies have demonstrated that elevated iron stores in the body
are closely related to both heart attacks and atherosclerosis of the carotid
arteries, the main arteries leading to the brain, which can cause strokes,"
says Hidehiro Matsuoka, M.D., Ph.D., chief of the Kurume Medical School's
Division of Hypertension, who directed the research. The Japanese study is
the first, however, to show that iron loading has adverse effects on the
endothelium and that reducing iron concentrations in the blood improves
endothelial function.
"Our study shows that we should recognize iron as a risk factor for
atherosclerosis and understand the need to control our body iron levels to
prevent cardiovascular disease," Matsuoka explains.
The researchers believe that iron is somehow interfering with the action of a
chemical released by the endothelium, called nitric oxide, which plays a
central role in the anti-atherosclerotic effects of the endothelium. Nitric
oxide causes the blood vessels to relax in order to accommodate increased
blood supply pumped by the heart during physical exercise, exertion or other
activity.
One phase of the study focused on a cohort of 10 healthy volunteers, who were
injected with high doses of iron. High-resolution ultrasound was used to
examine the function of their artery walls. A second phase tracked the
effects of lowering blood levels of iron with a chemical called deferoxamine
in 10 cigarette smokers, all of whom were free of apparent cardiovascular
disease.
The researchers found that iron loading in healthy volunteers increased
levels of the chemical malondialdehyde, a marker of oxidation, and impaired
endothelial function. However, iron removal in smokers significantly
decreased levels of the chemical and restored normal endothelial function.
Too much iron can be particularly dangerous for smokers due to the effects of
oxidation, which occurs when there are high levels of reactive oxygen
molecules, or "free-radicals," in the blood. Free radicals are associated
with the oxidation of the "bad" low-density lipoprotein (LDL) cholesterol,
allowing it to enter and damage the artery walls.
"We wanted to examine the effect of iron removal in smokers because, among
coronary risk factors, smoking is one of the strongest causes of oxidation,"
says Matsuoka. "Collectively, iron impairs endothelial function via oxidative
stress on the blood vessels," he emphasizes.
"Many scientists attribute the significantly low risk of cardiovascular
disease among pre-menopausal women to the protective effects of estrogen,"
says Matsuoka. "But the hypothesis has been raised that the iron depletion
associated with menstruation also protects against heart disease."
Matsuoka points out that this hypothesis is supported by two large studies
showing that people who donate blood also have a lower risk of heart attacks
and strokes. These findings have led to several prospective studies to
determine if there is any merit to this phenomenon.
"I don't think it's a good idea for people to take in more iron than is
normally contained in a healthful diet," Matsuoka says, "but compared to the
heavy intravenous doses of iron used in our study, oral iron supplements are
relatively safe. Taken orally, excessive iron will be excreted, but long-term
overload that increases the body's iron stores is strongly associated with
cardiovascular events such as heart attack, chest pain or stroke."
Co-authors of the study include Kei Fukami, Shuji Iida, Akira Satoh, Seiya
Okuda, and Tsutomu Imaizumi.
###
NR00-1199 (HBP2000-Matsuoka)
Subject: iron/diet and myocardial infarction in the elderly
Dietary Iron Intake and Risk of Myocardial Infarction in the Rotterdam
Study.
Kerstin Klipstein-Grobusch, Diederick E. Grobbee, Johanna H. den
Breeijen, Heiner Boeing, Albert Hofman, and Jacqueline C. M. Witteman
Department of Epidemiology and Biostatistics, Erasmus University
Medical School, Rotterdam, the Netherlands
Am J Epidemiol 1999;149:421-28
Free iron has been implicated in lipid peroxidation and ischemic
myocardial damage, and it has been suggested that iron is an
independent risk factor for myocardial infarction. The authors
investigated whether dietary iron is associated with an increased
risk of fatal and nonfatal myocardial infarction in the Rotterdam
Study, a community-based prospective cohort study of 7,983 elderly
subjects in Rotterdam, the Netherlands. The study sample consisted of
4,802 participants who at baseline had no known history of myocardial
infarction and for whom dietary data were available. From 1990 to
1996, 124 subjects had a myocardial infarction. No association was
observed between total iron intake and risk of myocardial infarction
after adjustment for age and sex (relative risk for the highest vs.
the lowest tertile of intake = 0.89, 95 percent confidence interval
(CI)0.55--1.45, p for trend = 0.640). Heme iron intake was positively
associated with risk of myocardial infarction (relative risk for the
highest vs. the lowest tertile of intake = 1.83, 95 percent CI
1.16--2.91, p for trend = 0.008) after adjustment for age and sex, and
this association persisted after multivariate adjustment (relative
risk = 1.86, 95 percent CI 1.14--3.09, p for trend = 0.010). A
distinction between fatal and nonfatal cases of myocardial infarction
indicated that the association of heme iron with myocardial infarction
was more pronounced in fatal cases. The results suggest that a high
dietary heme iron intake is related to an increased risk of myocardial
infarction and that it may specifically affect the rate of fatality
from myocardial infarction.
Subject: stroke/iron
Iron levels linked to stroke damage
April 25, 2000
Reuters
NEW YORK, Apr 24 (Reuters Health) - People with high levels of
iron in their bodies may be at higher risk for severe damage to the
brain after a stroke, according to study results released Monday.
People at high risk of having a stroke who have high iron
levels might benefit from cutting back on iron in the diet, according
to the study's lead author, Dr. Antoni Davalos.
An ischemic stroke -- the most common type of stroke -- is
caused by a disruption in blood flow to the brain, often due to a
blocked artery in the neck or head.
Some research has linked iron levels to the severity of stroke
damage, so Davalos, of the Hospital Universitari Doctor Josep Trueta
in Girona, Spain, and colleagues measured levels of ferritin (which
indicates the total amount of iron in the body) in the spinal fluid
and blood of 100 stroke patients. The investigators divided the
patients into two groups -- those whose condition remained stable or
began to improve after the stroke, and those whose condition
progressively worsened.
Compared with people whose condition stabilized or improved,
those with progressive damage had significantly higher levels of
ferritin, the authors report in the April 25th issue of Neurology, the
journal of the American Academy of Neurology.
Davalos and colleagues suspect that increased iron levels lead
to greater brain damage by increasing the formation of molecules
called free radicals, which can damage cells. In addition, high levels
of iron can promote the release of glutamate, a brain chemical
involved in the death of brain cells. In the study, glutamate levels
were highest in people with progressing stroke.
"Our findings support future therapeutic studies of agents
which inhibit iron's toxic effects on brain cells immediately after
stroke," Davalos said in a statement. Studies should also be conducted
to see whether lowering iron levels in people at risk for stroke who
have high ferritin levels might help prevent stroke, he noted.
SOURCE: Neurology 2000;54:1568-1574.
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