Hereditary hemochromatosis-early diagnosis

OCD

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).

OCD

Hereditary hemochromatosis-early diagnosis can lead to cure - (2 OF 2)

Factors that can exacerbate HH include hepatitis, heavy alcohol abuse, and
obesity. The most serious consequences of undiagnosed and untreated HH are
cirrhosis that can progress to end-stage liver disease and liver failure,
hepatocellular carcinoma, CHF, and diabetes. An association may also exist
between hemochromatosis and the development of nonhepatocellular
malignancies.2 Based on the observation that excess iron accumulation in the
brain is commonly found in individuals with Alzheimer's disease (AD), and
considering evidence that the HFE protein is expressed in blood vessels and
some cells in the brain, some authors have proposed that hemochromatosis may
be a risk factor for AD.3

The diagnosis of HH is based on abnormal serum iron measurements and is
confirmed by genetic testing. Identification of the genetic defect
responsible for HH has enabled DNA analysis to replace liver biopsy as the
definitive diagnostic test. Liver biopsy is still recommended, however, in
patients with liver enlargement, abnormal liver function tests, or a serum
ferritin level that is greater than 1000 ng/mL to determine whether
cirrhosis and advanced-stage liver disease are present. Patients with acute
or fulminant hepatitis, in which large amounts of iron are stored in the
liver and released into the blood, may have increased serum iron and
ferritin levels that fall in the range suggestive of HH. However, signs of
acute liver injury, such as greatly elevated aminotransferase levels and,
commonly, a history of alcohol abuse, will point toward a diagnosis of
hepatitis. Serum ferritin and transferrin saturation levels will also be
elevated in 18% to 35% of patients with chronic hepatitis.4

Laboratory testing to rule out a diagnosis of HH should include liver
function tests to look for elevated aminotransferase levels and a
blood-glucose measurement to identify undiagnosed diabetes. Fasting serum
iron tests should include serum ferritin and transferrin saturation.
Elevated nonfasting ferritin and transferrin saturation measurements should
be repeated following a 12-hour fast. Serum ferritin greater than 1000
ng/mL, in the absence of any other type of acute liver disease, is virtually
diagnostic of HH. A serum ferritin level greater than 300 ng/mL in men and
200 ng/mL in premenopausal women is above the normal reference range and
suggestive of HH.

Serum transferrin saturation represents the ratio of the serum iron
concentration to the total iron-binding capacity. Transferrin saturation
greater than 50% in men and premenopausal women and greater than 60% in
postmenopausal women is above the reference range and highly suggestive of
HH. Liver biopsy in a patient with HH typically reveals increased hepatic
iron stores. Levels above 80 mmol/g/d of dry weight liver tissue are
abnormal. A hepatic iron index-the hepatic iron per dry weight divided by
the patient's age-of greater than 1.9 is above normal and highly suggestive
of HH.

Curative treatment
Periodic phlebotomy that reduces serum iron levels to within the normal
range provides a lifelong cure for iron overload and HH. In the absence of
complications preceding the diagnosis of HH, appropriate treatment will
prevent the development of clinical manifestations and the consequences of
the underlying genetic mutation and resulting disorder of iron metabolism.
The average life expectancy after diagnosis of HH increases
dramatically-from 1 to 6 years to 11 to 21 years-following initiation of
therapeutic phlebotomy.5

Therapeutic phlebotomy may alleviate some clinical manifestations of HH that
occur before symptoms of the disease or cirrhosis develop.5 It typically
results in resolution of some clinical symptoms, such as weakness,
hepatomegaly, cardiomyopathy, and hyperpigmentation, and substantial
improvement in quality of life.1 Treatment to reduce iron stores will
generally not reverse existing complications of iron overload, including
endocrine abnormalities such as diabetes and structural abnormalities such
as liver fibrosis. Furthermore, phlebotomy does not diminish the increased
risk of hepatocellular carcinoma once cirrhosis develops.

Iron overload seems to impair endothelial function, as shown by reduced
endothelium-dependent dilation of the brachial artery and increased
intima-media thickness of the carotid artery in men with HH who are
homozygous for the C282Y mutation and not undergoing phlebotomy therapy.6
This suggests an association between iron overload and early structural
atherosclerotic changes. In contrast, among male HH patients undergoing
phlebotomy, the intima-media thickness of the carotid artery does not differ
significantly from that of persons without HH. In addition, phlebotomy in
previously untreated patients leads to improvement in endothelium-dependent
dilation of the brachial artery. Thus, iron depletion therapy appears to
normalize endothelial function and may reduce the increased risk of
cardiovascular events associated with HH.

Phlebotomy is safe and effective and can protect a patient against decreased
life expectancy and organ damage, especially cardiac and liver dysfunction.
Treatment should begin when serum ferritin levels rise above 300 ng/mL in
men and postmenopausal women and 200 ng/mL in premenopausal women. In the
setting of severe iron overload, phlebotomy should continue at least weekly
until the serum ferritin level drops below 50 ng/mL, nearly a state of iron
deficiency, and the hemoglobin level is less than 13 g/dL. Most patients
will then require follow-up phlebotomy every 3 to 4 months-perhaps less
frequently for women-to maintain normal iron levels.

Removal of each unit of blood disposes of 200 to 250 mg of iron. The serum
ferritin level serves as a measure of how much blood to remove. For every
nanogram per milliliter in elevation of serum ferritin, 8 mg of iron
accumulates in the liver. For example, a serum ferritin level of 1000 ng/mL
corresponds to about 8 g of iron in the liver and means that a total of 32
units of blood should be withdrawn during the initial weekly treatment
phase. Dietary considerations in patients with HH include limiting
consumption of red meat and avoiding vitamin C supplements, both of which
can contribute to increased serum iron levels.

Perspectives on genetic screening
Following diagnosis of HH in an index patient, all immediate family members
are identified as being at increased risk. Siblings and children should
undergo genetic screening for the C282Y and H63D mutations. Testing of
adolescents should begin at age 16, since iron overload can occur by age 18
to 20 in individuals homozygous for the C282Y mutation or heterozygous for
the C282Y/H63D mutations.

Although population-based genetic screening can identify individuals at
increased risk of developing HH, not all C282Y homozygotes will develop the
disease, and predictive factors are lacking. Furthermore, identification of
genetic carriers could result in medical profiling and other consequences
regarding access to health care insurance. An additional argument against
widespread genetic screening is the less costly and widely available option
of disease screening via serum iron levels, which can detect existing
disease before clinical complications develop.



PRODUCED BY VICKI GLASER


REFERENCES

1. Press RD. Hereditary hemochromatosis: impact of molecular and iron-based
testing on the diagnosis, treatment, and prevention of a common, chronic
disease. Arch Pathol Lab Med. 1999;123:1053-1059.

2. Geier D, Hebert B, Potti A. Risk of primary non-hepatocellular
malignancies in hereditary hemochromatosis. Anticancer Res. 2002;22(6B):
3797-3799.

3. Connor JR, Milward EA, Moalem S, et al. Is hemochromatosis a risk factor
for Alzheimer's disease? J Alzheimers Dis. 2001;3:471-477.

4. Tung BY, Emond MJ, Bronner MP, et al. Hepatits C, iron status, and
disease severity: relationship with HFE mutations. Gastroenterology.
2003;124:318-326.

5. Cogswell ME, McDonnell SM, Khoury MJ, et al. Iron overload, public
health, and genetics: evaluating the evidence for hemochromatosis screening.
Ann Intern Med. 1998;129:971-979.

6. Gaenzer H, Marschang P, Sturm W, et al. Association between increased
iron stores and impaired endothelial function in patients with hereditary
hemochromatosis. J Am Coll Cardiol. 2002;40:2189-2194.

SUGGESTED READING

Asberg A, Tretli S, Hveem K, et al. Benefit of population-based screening
for phenotypic hemochromatosis in young men. Scand J Gastroenterol.
2002;37:1212-1219.

Burke W, Thomson E, Khoury MJ, et al. Consensus statement: hereditary
hemochromatosis: gene discovery and its implications for population-based
screening. JAMA. 1998;280:172-178.

Mainous AG III, Gill JM, Pearson WS. Should we screen for hemochromatosis?
An examination of evidence of downstream effects on morbidity and mortality.
Arch Intern Med. 2002;162:1769-1774.

McDonnell SM, Pradyumna DP, Felitti V, et al. Screening for hemochromatosis
in primary care settings. Ann Intern Med. 1998;129: 962-970.

McLaren CE, Barton JC, Adams PC. Hemochromatosis and Iron Overload Screening
(HEIRS) study design for an evaluation of 100,000 primary care-based adults.
Am J Med Sci. 2003;325:53-62.

Witte DL, Crosby WH, Edwards CQ, et al. Practice guideline development task
force of the College of American Pathologists: hereditary hemochromatosis.
Clin Chim Acta. 1996;245:139-200.



Hereditary hemochromatosis--early diagnosis can lead to cure. Patient Care
August 2003;37:54-59.


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