Iron Overload (cont.)
What are the symptoms and signs of hemochromatosis?
Patients with early hemochromatosis have no symptoms and
are unaware of their condition. The disease may then be discovered when elevated
iron blood levels are noted by routine blood testing. In men, symptoms may not
appear until 40-50 years of age. Iron deposits in the skin cause darkening of
the skin. Since females lose iron through menstrual blood loss, they develop organ damage from
iron accumulation 15 to 20 years later than men on average.
Iron deposits in the pituitary gland and
testicles cause shrinkage of the testicles and impotence. Iron deposits in the
pancreas cause a
decrease in insulin production resulting in diabetes mellitus (please read the
Diabetes
Mellitus article). Iron deposits in the heart muscle can cause heart failure as
well as abnormal heart rhythms. Iron accumulation in the liver causes scarring
of the liver (cirrhosis) and an increased risk of developing liver cancer. For
further information on the consequences of cirrhosis, please read the
Cirrhosis
article.
How is hemochromatosis diagnosed?
Most patients with hemochromatosis are diagnosed early
and have no symptoms. Their hemochromatosis is discovered when elevated levels
of iron in the blood are found as part of routine blood testing; or when blood
iron levels are measured as in screening studies in family members of patients
with hereditary hemochromatosis. Some patients are diagnosed as having
hemochromatosis when their doctors perform blood iron levels as part of the
evaluation for abnormal elevations in blood levels of liver enzymes AST and ALT.
Blood iron tests
There are several blood tests that reflect the amount of iron in the body;
ferritin level, iron level, total iron binding capacity (TIBC), and transferrin
saturation.
Ferritin is a blood protein whose levels correlate with
the amount of iron stored in the body. Blood ferritin levels usually are low in
patients with iron deficiency anemia, and are high in patients with
hemochromatosis and other conditions that cause an increase in body iron levels.
Since ferritin also can be elevated in certain infections such as viral
hepatitis and other
inflammatory conditions in the body, an elevated ferritin level alone is not
sufficient to accurately diagnose hemochromatosis.
Serum iron, TIBC, and transferrin saturation are often performed together.
Serum iron is the measure of the amount of iron in serum (the liquid portion of
the blood). TIBC is a measure of the total amount of iron that can be carried in
serum by transferrin, a protein that carries iron in serum from one part of the
body to another. Transferrin saturation is a number calculated by dividing serum
iron by TIBC—it is a number that reflects what percentage of the transferrin
that is being used to transport iron. In healthy individuals the transferrin
saturation is between 20 and 50 percent. In patients with iron deficiency anemia, the
serum iron and transferrin saturation are abnormally low; and in patients with
hereditary hemochromatosis the serum iron and transferrin saturation are
abnormally high.
Since serum iron can be elevated by eating and can fluctuate during the day,
serum iron measurements should be done fasting, usually in the morning before
breakfast.
Liver biopsy
The most accurate test for diagnosing hemochromatosis is
measurement of the iron content of liver tissue obtained by a biopsy. A liver biopsy
involves the removal of a sample of liver tissue for analysis and is
usually performed with a needle under local anesthesia. After numbing the skin
and the underlying tissues, the doctor inserts the needle into the liver through
the right lower rib cage, sometimes under ultrasound guidance. The tissue
obtained by the needle is studied under a microscope for signs of active liver disease, fibrosis and
cirrhosis (permanent scarring), and iron content (usually significantly elevated
in hemochromatosis).
The liver biopsy also has prognostic value because it determines whether the
patient already has irreversible advanced cirrhosis. Patients with
hemochromatosis but an otherwise normal liver biopsy have longevity similar to
other healthy adults if adequately treated, while patients with cirrhosis as a
result of hemochromatosis have significantly reduced longevity. Furthermore, the
risks of cirrhotic patients developing
liver cancer (hepatocellular carcinoma)
are substantially higher than normal subjects even with adequate treatment of
the iron overload with phlebotomy (see below).
Genetic Tests
The gene for hereditary hemochromatosis was identified in 1996. The gene is
referred to as the HFE gene. Hereditary hemochromatosis is associated in most
patients with two mutations of the HFE gene; C282Y and H63D.
A C282Y homozygote is a person who has inherited one mutated C282Y gene from
each parent. A C282Y homozygote is considered at risk of developing iron
overload. In fact, C282Y homozygotes account for 95% of all hereditary
hemochromatosis. Conversely, not every C282Y homozygote develops iron overload.
Studies have shown that an estimated 50% of C282Y homozygotes may not develop
iron overload or its complications.
A C282Y/H63D compound heterozygote is a person who has inherited one mutated
C282Y gene from one parent and a second mutated H63D gene from the other parent.
Most compound heterozygotes have normal iron levels though some can develop mild
to moderate iron overload.
A C282Y heterozygote is a person who has inherited one mutated C282Y gene
from one parent but a second normal HFE gene from the other parent. Children
born of two C282Y heterozygotes have a 25% chance of being a C282Y homozygote
and, therefore, will be at risk of developing hemochromatosis. A C282Y
heterozygote does not develop iron overload.
An algorithm for diagnosing hereditary hemochromatosis is as follows:
- Adults suspected of having hereditary hemochromatosis (for example, adult,
first-degree relatives of a patient with hereditary hemochromatosis) are
subjected to measurements of fasting serum iron, TIBC, transferrin saturation
and ferritin.
- Patients with elevated serum iron, ferritin, and transferrin saturation of
greater than 45% are subjected to
genetic testing
- Patients with transferrin saturation greater than 45%
who are C282Y homozygotes have hemochromatosis and, therefore, should be treated
with therapeutic phlebotomy (see below).
Who should undergo liver biopsy?
Not all patients with hemochromatosis need to undergo liver biopsy. The
purpose of liver biopsy is to identify those patients with cirrhosis and to
exclude other possible liver diseases. (Patients with hemochromatosis and
cirrhosis are at increased risk of complications, especially liver cancer.)
Young patients (<40 years of age) who are C282Y
homozygotes with normal liver blood levels and serum ferritin levels <1000
ng/ml have a very low risk of having cirrhosis of the liver. Therefore, these
patients can be treated with therapeutic phlebotomy without a liver biopsy.
Their prognosis is excellent with
adequate treatment.
Older patients (>40 years of age) who have serum ferritin levels >1000 ng/ml,
and have abnormally elevated liver blood levels may already have developed
cirrhosis. Doctors may recommend liver biopsies in these patients provided that
it is safe for them to undergo liver biopsy.
Next: How is hemochromatosis treated? »
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