The
effect of iron overload on some organs, such as the skin, are
trivial, while hemosiderotic harm to others, such as the liver, can
be fatal. Few notable symptoms precede advanced injury. Abdominal
discomfort, lethargy, and fatigue are common but nonspecific
complaints. Dyspnea with exertion and peripheral edema indicate
significant cardiac compromise and reflect advanced iron loading.
As
the major site of iron storage, the liver is a conspicuous victim of
excess iron depositon. Mild to moderate hepatomegaly develops
early, followed by shrinkage produced by fibrosis and
cirrhosis. Hepatic tenderness occurs occasionally.
Hematoxylin
and eosin staining reveals a brownish pigment in the hepatocytes
which Perl's Prussian blue staining unmasks as iron. Large amounts
of iron are also deposited in Kupfer cells of patients with
transfusional iron overload. Electron microscopy reveals substantial
hemosiderin aggregates in addition to large quantities of
ferritin.
As
with many other conditions that injure the liver, hepatic damage
secondary to excessive iron deposition produces fibrosis. With long
standing hemochromatosis, micronodular cirrhosis can also develop.
Hemosiderotic liver damage produces very little inflammation.
Consequently, significant hepatic iron deposition and even fibrosis
can occur with very little increase in the serum transaminase
levels. Disturbances in liver synthetic function indicate advanced
disease.
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Congestive
cardiomyopathy is the most common defect that occurs with iron
overload, but other problems have been described including
pericarditis, restrictive cardiomyopathy, and angina without
coronary artery disease. A strong correlation exists between the
cumulative number of blood transfusions and functional cardiac
derangements in children with thalassemia.
The
physical examination is surprisingly benign even in patients with
heavy cardiac iron deposition. Once evidence of cardiac failure
appears, however, heart function rapidly deteriorates, often without
response to medical intervention. Biventricular failure produces
pulmonary congestion, peripheral edema, and hepatic engorgement.
Vigorous iron extrication has reversed this potentially lethal
complication on occasion.
Iron
deposition in the Bundle of His and the Purkinje system produces
conduction defects. Sudden death is common in these patients,
presumably due to arythmias. At one time, patients treated
with the chelator desferrioxamine for transfusional iron overload
received supplements of ascorbic acid in the range of 15 to 30 mg/kg
per day to promote iron mobilization. Reports of sudden death
prompted cessation of this practice. At lower doses (2 to 4 mg/kg),
ascorbic acid is a safe adjunct to chelation therapy in patients
with transfusional iron overload.
Cardiac
dysfunction can occur with very little tissue iron deposition.
The total quantity of iron is less important than the unbound, or
"toxic" iron subset. The concentration of unbound iron in tissues is
extremely small, and virtually impossible to measure. This "toxic"
iron is precisely the component bound and neutralized by iron
chelators (in the case of desferrioxamine, the association constant
is about 1032). Therefore, cardiac damage is best
prevented in patients with transfusional iron overload by
maintaining a constant low level of chelator in the circulation (and
consequently in the tissues, where the protection is rendered.)
Chick cardiac myocytes in culture contract spontaneously. Iron salts
added to the culture medium poison the cells and abrogate this
function. Desferrioxamine chelates extracellular, and importantly
intracellular iron, and restores myocyte contractility.
Echocardiography
in children and radionuclide ventriculography in adults are the most
useful non-invasive diagnostic techniques. The echocardiographic
abnormalities correlate roughly with the number of transfusions.
Exercise radionuclide ventriculograms are particularly sensitive in
the detection of cardiac dysfunction in patients with iron overload.
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Dysfunction
of the endocrine pancreas is common in patients with iron overload.
Some people develop overt diabetes mellitus requiring insulin
therapy. The disturbances in carbohydrate metabolism are often more
subtle, however. An oral glucose tolerance test often unmasks
abnormal insulin production. Vigorous exorcism of the excess iron
occasionally reverses the islet cell dysfunction. Exocrine
pancreatic function, in contrast, is usually well-preserved.
Pituitary
dysfunction produces a plethora of endocrine disturbances. Reduced
gonadotropin levels are common. When coupled with primary reductions
in gonadal synthesis of sex steroids, this phenomenon delays sexual
maturation in some children with transfusional iron overload.
Secondary infertility is common. Although Addison's syndrome is
uncommon with iron overload, production of ACTH is occasionally
deficient. A metapyrone stimulation test shows delayed or diminished
pituitary secretion of ACTH.
Thyroid
function is usually well-preserved in patients with iron overload.
In contrast, parathyroid activity is frequently compromised.
Functional hypoparathyroidism can be demonstrated in many patients
by inducting hypocalcemia with an intravenous bolus of
ethelyenediamine tetraacetic acid (EDTA) while monitoring the
production of parathyroid hormone.
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Miscellaneous Abnormalities with Iron
Overload
Hyperpigmentation
is a nonspecific skin response to a variety of insults including
excessive exposure to ultraviolet light (tanning), thermal injury,
and drug eruptions. Cutaneous iron deposition damages the skin and
enhances melanin production by melanocytes. Ultraviolet light
exposure and iron are often synergistic in the induction of skin
pigmentation, so that many patients tan very readily. Fair-skinned
people who routinely tan poorly often never develop
hyperpigmentation despite very large body iron burdens, highlighting
the genetic contribution to skin pigmentation. In contrast, patients
with moderate baseline pigmentation (for example, people of
Mediterranean descent) frequently develop a striking almond-colored
hue. With particularly heavy iron overload, visible iron deposits
sometimes appear in the skin as a grayish discoloration.
Arthropathy,
a common feature with hereditary hemochromatosis, is rare in
patients with secondary iron overload. The large joints, such as the
hips are affected most commonly. Decades of iron deposition in
articular cartilage in hereditary hemochromatosis is the presumed
cause of this condition. Chondrocalcinosis is a late but
characteristic feature of the arthropathy seen in hereditary
hemochromatosis. Other troubling musculoskeletal problems include
severe, recurrent cramps and disabling myalgias. Muscle biopsy shows
iron deposits in the myocytes, but the pathophysiologic connection
to the pain and cramps is unclear.
Bone
disease, manifested as osteoporosis, is a significant problem in
patients with thalassemia. Bone marrow expansion often thins the
bone cortex, making these patients very susceptible to fractures.
The etiology of the bony disorder in patients with thalassemia is
unclear. One possible contributor is the desferrioxamine used to
prevent iron overload. The chelator has a very high specificity for
iron. It may, however, chelate a small amount of the calcium that is
necessary for the production of new bone. Over the years, a very low
rate of mineral scavenging from bone by desferrioxime could
contribute to osteoporosis.
Pulmonary
hypertension is a problem that has been widely recognized only
recently in patients with iron overload. A number of reports have
involved patients with thalassemia major or thalassemia intermedia
with iron overload. No report exists of similar problems in people
with iron overload from other causes, such as hereditary
hemochromatosis. The combination of iron overload in the pulmonary
tissues and high blood flow through the pulmonary vascular bed may
be at fault. More work is needed to clarify these issues.
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Withholding
iron from potential pathogens is one strategy used in host defense.
Transferrin's extremely high affinity for iron, coupled with the
fact that two-thirds of the iron binding sites of the protein
normally are unoccupied, essentially eliminates free iron from
plasma and extracellular tissues. Both transferrin and the
structurally related protein, lactoferrin, are bacteriostatic in
vitro for many bacteria.
The
very high transferrin saturations attained in patients with iron
overload compromise the bacteriostatic properties of the protein.
Iron sequestration is not a frontline defense against microbes.
Therefore, iron overload does not produce the susceptibility to
infection seen with defects in more central systems (e.g., chronic
granulomatous disease.) Nonetheless, a number of infections, often
with unusual organisms, have been reported in patients with iron
overload :
of Hemochromatosis
