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发表于 2003-8-28 16:05
Patient Care® Archive
August 2003
Patient Care® Archive
August 2003
Hereditary hemochromatosis-early diagnosis can lead to cure
RAYMOND T. CHUNG, MD, Medical Director, Liver Transplant Program, and
Director, Hepatology Service, Massachusetts General Hospital; and Assistant
Professor of Medicine, Harvard Medical School, Boston, Mass.
NORTON J. GREENBERGER, MD, Clinical Professor of Medicine, Harvard Medical
School; and Senior Physician, Brigham and Women's Hospital, Boston, Mass.
Screening for iron overload can help diagnose hemochromatosis before
symptoms develop. Prompt identification and appropriate treatment with
therapeutic phlebotomy can prevent the morbidity and mortality associated
with this genetic disorder.
Jump to: Choose article section...Overview of the disorderPrevention and
diagnosisCurative treatmentPerspectives on genetic screening
The most important fact about hereditary hemochromatosis (HH) is that the
manifestations and complications of this common inherited disorder of iron
metabolism are fully preventable if the disease is recognized early enough
and adequately treated. Unfortunately, by the time a patient presents with
symptoms or is referred for care to a liver specialist, the disease
phenotype may be well-established. Untreated HH can lead to significant
morbidity and mortality, and the resulting complications often cannot be
reversed.
HH represents a natural target for a public health campaign focused on
disease recognition and screening, since early diagnosis could prevent the
development of virtually all cases of this disorder. Furthermore, disease
screening and early recognition of HH present an ideal opportunity for
primary care practitioners to intervene in a disease that affects as much as
0.5% of the population and has debilitating and life-threatening
consequences. As the most common classically inherited disease in the United
States, HH is more prevalent than cystic fibrosis, sickle cell anemia,
phenylketonuria, alpha1-antitrypsin deficiency, and Tay-Sachs disease.1
Overview of the disorder
HH, the most common genetic disorder affecting Caucasians, is particularly
prominent in persons of Northern European descent, with 1 of 300 such
persons being homozygous for the HH gene mutation. The gene frequency may be
as high as 10% in some populations, which translates to a disease frequency
of 1 in 200 to 400 cases.
HH is a disorder of iron metabolism, in which patients absorb 2 to 3 times
as much dietary iron as unaffected persons. Over time, this excess iron may
accumulate in various organs, including the liver, pancreas, and heart,
causing tissue damage and dysfunction. About 90% of patients who will
develop the HH phenotype begin exhibiting symptoms between ages 40 and 60.
The most common form of HH is due to a single point mutation in the HFE
gene, resulting in abnormal functioning of the HFE gene product. This
protein normally functions like a brake, preventing unchecked absorption of
iron. Tight regulation of HFE and related genes maintains normal absorption
at about 10% of dietary iron. The HFE protein forms a heterodimer with
beta2-microglobulin, which is expressed on duodenal crypt cells. The
mechanism by which this combination regulates intestinal iron transport is
not yet well-defined. Iron gradually accumulates, causing serum iron levels
to rise, but it may take decades for iron stores to reach levels at which
signs and symptoms of iron overload begin to appear. Men are likely to
develop HH earlier than women because of the protective effect of iron loss
associated with menstruation.
The main genetic defect linked to phenotypic HH is the C282Y mutation.
Patients homozygous for this mutation usually, but not always, develop signs
and symptoms of iron overload by midlife. It is not clear why HH exhibits
variable expression-why some individuals homozygous for the C282Y mutation
do not develop the disease phenotype. While about 0.3% of the US population
is homozygous for the C282Y mutation, the proportion of people who carry 1
copy of the HH gene represents another 6% to 7% of the population.
This single genetic defect can cause multisystemic disease. Iron overload
affects multiple organs:
. The liver, resulting in cirrhosis and complications such as liver failure
and liver cancer
. The pancreas, impairing insulin production and causing diabetes
. The heart, with the potential for cardiac arrhythmias and congestive heart
failure (CHF)
. The pituitary gland, with iron deposition leading to testicular atrophy
and impotence
. The skin, stimulating melanin deposition that causes increased
pigmentation, or "bronzing"
. Systemic effects such as chronic fatigue, joint disease, loss of libido,
and amenorrhea.
The second mutation linked to HH is H63D, whose significance is less clear.
H63D is a more common mutation than C282Y in the general population, and
although its link to HH is less well-defined, it should be included in
genetic screening for HH. Individuals that have 1 copy of the C282Y mutation
and do not carry the H63D mutation are not at increased risk for HH.
Heterozygotes for both the C282Y and H63D mutations face an increased risk
of HH, but the risk is not nearly as great as for C282Y homozygotes.
Prevention and diagnosis
Prevention of HH can be as simple as an inexpensive serum iron panel to
check for iron overload before symptoms develop. Treatment would then be
straightforward with therapeutic phlebotomy to lower serum iron stores to
normal levels. Manifestations of HH are preventable-and "cure" is
possible-without the need to eliminate the underlying genetic disorder.
Most patients who are identified as having HH have no symptoms on diagnosis
and are found because of increased serum iron levels on routine screening.
Alternatively, identification may follow HH screening precipitated by
diagnosis of the disease in a relative. In the classical presentation of HH
with symptoms, a patient will typically have cirrhosis without an obvious
cause and without diabetes. Nonspecific symptoms of iron overload that
should lead to screening for HH include chronic fatigue, arthralgias,
new-onset diabetes, CHF, cardiac arrhythmias that develop at an unusually
young age, loss of libido, amenorrhea, or erectile dysfunction.
Other disorders that should be considered in the differential diagnosis of
iron overload/hemochromatosis include genetic mutations other than C282Y
that may occur in specific ethnic groups, diseases associated with
ineffective erythropoiesis, such as thalassemias (although patients with
these conditions will likely have obvious anemia), drug insult to the liver,
Wilson's disease, alpha1-antitrypsin deficiency, nonalcoholic fatty liver
disease, primary sclerosing cholangitis, and a variety of conditions that
can cause moderate increases in serum iron levels, including alcoholic liver
disease, chronic hepatitis, arthritis, lupus, and other chronic inflammatory
disorders.
In patients with HH, the physical examination may reveal
. Hepatomegaly
. Arthritis, typically affecting the fingers
. Hyperpigmentation of the skin
. Testicular atrophy
. Signs of CHF or arrhythmias (infrequently).
RAYMOND T. CHUNG, MD, Medical Director, Liver Transplant Program, and
Director, Hepatology Service, Massachusetts General Hospital; and Assistant
Professor of Medicine, Harvard Medical School, Boston, Mass.
NORTON J. GREENBERGER, MD, Clinical Professor of Medicine, Harvard Medical
School; and Senior Physician, Brigham and Women's Hospital, Boston, Mass.
Screening for iron overload can help diagnose hemochromatosis before
symptoms develop. Prompt identification and appropriate treatment with
therapeutic phlebotomy can prevent the morbidity and mortality associated
with this genetic disorder.
Jump to: Choose article section...Overview of the disorderPrevention and
diagnosisCurative treatmentPerspectives on genetic screening
The most important fact about hereditary hemochromatosis (HH) is that the
manifestations and complications of this common inherited disorder of iron
metabolism are fully preventable if the disease is recognized early enough
and adequately treated. Unfortunately, by the time a patient presents with
symptoms or is referred for care to a liver specialist, the disease
phenotype may be well-established. Untreated HH can lead to significant
morbidity and mortality, and the resulting complications often cannot be
reversed.
HH represents a natural target for a public health campaign focused on
disease recognition and screening, since early diagnosis could prevent the
development of virtually all cases of this disorder. Furthermore, disease
screening and early recognition of HH present an ideal opportunity for
primary care practitioners to intervene in a disease that affects as much as
0.5% of the population and has debilitating and life-threatening
consequences. As the most common classically inherited disease in the United
States, HH is more prevalent than cystic fibrosis, sickle cell anemia,
phenylketonuria, alpha1-antitrypsin deficiency, and Tay-Sachs disease.1
Overview of the disorder
HH, the most common genetic disorder affecting Caucasians, is particularly
prominent in persons of Northern European descent, with 1 of 300 such
persons being homozygous for the HH gene mutation. The gene frequency may be
as high as 10% in some populations, which translates to a disease frequency
of 1 in 200 to 400 cases.
HH is a disorder of iron metabolism, in which patients absorb 2 to 3 times
as much dietary iron as unaffected persons. Over time, this excess iron may
accumulate in various organs, including the liver, pancreas, and heart,
causing tissue damage and dysfunction. About 90% of patients who will
develop the HH phenotype begin exhibiting symptoms between ages 40 and 60.
The most common form of HH is due to a single point mutation in the HFE
gene, resulting in abnormal functioning of the HFE gene product. This
protein normally functions like a brake, preventing unchecked absorption of
iron. Tight regulation of HFE and related genes maintains normal absorption
at about 10% of dietary iron. The HFE protein forms a heterodimer with
beta2-microglobulin, which is expressed on duodenal crypt cells. The
mechanism by which this combination regulates intestinal iron transport is
not yet well-defined. Iron gradually accumulates, causing serum iron levels
to rise, but it may take decades for iron stores to reach levels at which
signs and symptoms of iron overload begin to appear. Men are likely to
develop HH earlier than women because of the protective effect of iron loss
associated with menstruation.
The main genetic defect linked to phenotypic HH is the C282Y mutation.
Patients homozygous for this mutation usually, but not always, develop signs
and symptoms of iron overload by midlife. It is not clear why HH exhibits
variable expression-why some individuals homozygous for the C282Y mutation
do not develop the disease phenotype. While about 0.3% of the US population
is homozygous for the C282Y mutation, the proportion of people who carry 1
copy of the HH gene represents another 6% to 7% of the population.
This single genetic defect can cause multisystemic disease. Iron overload
affects multiple organs:
. The liver, resulting in cirrhosis and complications such as liver failure
and liver cancer
. The pancreas, impairing insulin production and causing diabetes
. The heart, with the potential for cardiac arrhythmias and congestive heart
failure (CHF)
. The pituitary gland, with iron deposition leading to testicular atrophy
and impotence
. The skin, stimulating melanin deposition that causes increased
pigmentation, or "bronzing"
. Systemic effects such as chronic fatigue, joint disease, loss of libido,
and amenorrhea.
The second mutation linked to HH is H63D, whose significance is less clear.
H63D is a more common mutation than C282Y in the general population, and
although its link to HH is less well-defined, it should be included in
genetic screening for HH. Individuals that have 1 copy of the C282Y mutation
and do not carry the H63D mutation are not at increased risk for HH.
Heterozygotes for both the C282Y and H63D mutations face an increased risk
of HH, but the risk is not nearly as great as for C282Y homozygotes.
Prevention and diagnosis
Prevention of HH can be as simple as an inexpensive serum iron panel to
check for iron overload before symptoms develop. Treatment would then be
straightforward with therapeutic phlebotomy to lower serum iron stores to
normal levels. Manifestations of HH are preventable-and "cure" is
possible-without the need to eliminate the underlying genetic disorder.
Most patients who are identified as having HH have no symptoms on diagnosis
and are found because of increased serum iron levels on routine screening.
Alternatively, identification may follow HH screening precipitated by
diagnosis of the disease in a relative. In the classical presentation of HH
with symptoms, a patient will typically have cirrhosis without an obvious
cause and without diabetes. Nonspecific symptoms of iron overload that
should lead to screening for HH include chronic fatigue, arthralgias,
new-onset diabetes, CHF, cardiac arrhythmias that develop at an unusually
young age, loss of libido, amenorrhea, or erectile dysfunction.
Other disorders that should be considered in the differential diagnosis of
iron overload/hemochromatosis include genetic mutations other than C282Y
that may occur in specific ethnic groups, diseases associated with
ineffective erythropoiesis, such as thalassemias (although patients with
these conditions will likely have obvious anemia), drug insult to the liver,
Wilson's disease, alpha1-antitrypsin deficiency, nonalcoholic fatty liver
disease, primary sclerosing cholangitis, and a variety of conditions that
can cause moderate increases in serum iron levels, including alcoholic liver
disease, chronic hepatitis, arthritis, lupus, and other chronic inflammatory
disorders.
In patients with HH, the physical examination may reveal
. Hepatomegaly
. Arthritis, typically affecting the fingers
. Hyperpigmentation of the skin
. Testicular atrophy
. Signs of CHF or arrhythmias (infrequently).
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