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HAEMACHROMATOSIS
A guide for clinical practice in the era of genetic testing
Second Edition
Contents
•
Digestive Health Foundation
•
Definition
•
Prevalence
•
Inheritance
•
Clinical Manifestations
•
Diagnosis
•
Treatment
•
Prognosis
•
Key Points
•
References
•
Acknowledgements
•
Application Statement
DIGESTIVE HEALTH FOUNDATION
The Digestive Health Foundation (DHF) is an educational body committed to promoting
better health for all Australians by promoting education and community health programs
related to the digestive system.
The DHF is the educational arm of the Gastroenterological Society of Australia (GESA),
the professional body representing the Specialty of gastrointestinal and liver disease in
Australia
Since its establishment in 1990 the DHF has been involved in the development of
programs to improve community awareness and the understanding of digestive
diseases.
Research and education into gastrointestinal disease are essential to contain the effects
of these disorders on all Australians.
To obtain hard copies of any of the Guidelines or Consumer Leaflets please print off the
Order Form, fill in your request and send the Order Form with payment to:
GESA
145 Macquarie Street
SYDNEY NSW 2000
Telephone: 0292565454
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Email:
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Website:
http://www.gesa.org.au
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
2
DEFINITION
Haemochromatosis is a common inherited disorder in which excessive iron absorption
leads to greatly increased body iron stores with deposition of iron in parenchymal cells
of the liver, heart, pancreas and other organs. This disorder is also termed genetic,
hereditary, primary or idiopathic haemochromatosis. Disorders other than
haemochromatosis which give rise to iron overload are classified under the broad
heading of secondary iron overload syndromes (usually iron-loading anaemias such as
thalassaemia major).
PREVALENCE
Recent studies in Australia, the United Kingdom and Europe show that the prevalence of
homozygous haemochromatosis is 3.6 per 1000 individuals (1). The prevalence of
clinical disease is much less than this. The frequency of heterozygous subjects (carriers)
has been estimated to be about 12%.
INHERITANCE
The strong HLA association of hereditary haemochromatosis led to the recent discovery
and cloning of the haemochromatosis gene (HFE gene). The majority of familial cases
are due to a cystine to tyrosine mutation at the 282 position (the C282Y mutation).
Homozygosity for C282Y is present in 60-90% of patients with haemochromatosis. Up to
10% of cases will have one gene with the C282Y mutation, and a second histidine to
aspartate mutation at position 63 (H63D mutation) – this is called compound
heterozygosity. Some patients may have no mutation – non-HFE related hereditary
haemochromatosis. This has been described mostly in Mediterranean countries.
Most C282Y heterozygotes (one mutation only) express minor or no abnormalities of
non-metabolism but a few develop progressive iron-overload and overt disease.
The male: female ratio for Homozygosity is 1:1, although the male: female ratio for
clinical disease is about 5:1, due primarily to physiological blood and iron loss in women
(menstruation and pregnancy).
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
3
CLINICAL MANIFESTATIONS
In the majority of patients with overt haemochromatosis the first symptoms develop
between the ages of 30 and 60 years. Menstruation and pregnancy account for the
delayed presentation of the disorder in women.
The most common symptoms are:
1. lethargy and weakness
2. arthralgia
3. loss of libido
4. upper abdominal discomfort
Physical examination may be normal, but if present, the most common physical signs
are:
1.
2.
3.
4.
hepatomegaly
grey skin pigmentation
testicular atrophy
joint swelling and tenderness
Diabetes mellitus usually is present only in patients with advanced disease. Liver
function tests are frequently normal, but may be abnormal in symptomatic patients. With
many patients now detected in the course of family screening, up to 50% will have no
symptoms or signs suggestive of the disorder (3).
Many patients will have no symptoms or signs suggestive of the disorder.
The complications of untreated haemochromatosis include the following:
• liver disease with fibrosis or cirrhosis
• arthritis
• gonadal failure
• diabetes mellitus
• cardiac failure and arrhythmias
• hepatocellular carcinoma in about 30% of patients with cirrhosis
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
4
DIAGNOSIS
Haemochromatosis should be suspected in:
(1)
patients with liver disease of unknown cause, including patients with suspected
alcoholic liver disease;
(2)
family members of haemochromatosis patients. Such subjects are
frequently asymptomatic with no clinical signs;
(3)
other increased risk groups such as patients with diabetes mellitus, typical
arthritis, cardiomyopathy, or chronic fatigue.
The approach to testing for haemochromatosis may be summarised as follows (4, 5):
1.
All first degree relatives (siblings, offspring and parents) and second degree
relatives (cousins, aunts and uncles) of the index case should be tested, however the
risk is greatest in siblings of the index case or siblings of other affected family members.
These relatives should be tested by screening for the C282Y mutation, as well as
transferrin saturation and ferritin. Those found to be homozygous are at high risk of iron
overload whilst those found to be heterozygous are at low risk. Those found to be normal
do not develop iron overload. HLA typing is not necessary.
People found to be homozygous for the C282Y mutation but with normal ferritin
and transferrin saturation should have their iron studies checked again every 2-5 years.
All first degree relatives and second degree relatives
of the index case should be tested for haemochromatosis
by testing for the genetic mutation
2.
It has been recommended that testing for haemochromatosis within families
commence at age 10 years. However, screening of young children of a patient
with haemochromatosis can be foregone if the spouse is tested and does not have the
C282Y mutation.
3.
In people with no family history, the transferrin saturation (ratio of serum iron and
iron binding capacity) and serum ferritin concentration are the most useful
screening tests, although the transferrin saturation is more sensitive in detecting
early iron overload. Rarely, both tests may be normal. These tests should be
done in the morning after an overnight fast. In general, transferrin saturation is
abnormal when it is greater than 45% and serum ferritin when it is greater than
250 ug/l in pre-menopausal women and 300 ug/l in men and post-menopausal
women. If the transferrin saturation or serum ferritin is increased on more than one
occasion, haemochromatosis should be suspected - even if there are no clinical
symptoms or abnormal liver function tests. In this situation, the HFE gene test should
then be ordered.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
5
The transferrin saturation and serum ferritin concentration
are the most useful initial tests for haemochromatosis
in people with no family history
4.
Certain increased risk groups should also be tested for haemochromatosis:
patients with liver disease, diabetes, typical arthritis, cardiomyopathy or testicular
failure. Serum iron and ferritin studies may be difficult to interpret in these
conditions because of non-specific increases in the serum levels. Testing for the
HFE gene mutation may be very helpful.
5.
Although haemochromatosis is common, there is no evidence at this stage that
screening of the general population is cost-effective.
6.
Liver biopsy has long been the gold standard in the diagnosis of
haemochromatosis. Not only does it allow histological staining of iron and
measurement of hepatic iron concentration, it remains the only reliable way to
determine the presence of cirrhosis. However, since the discovery of the HFE
gene, the diagnosis can be made confidently on blood testing alone,
Furthermore, a recent study suggests that one can confidently exclude the
presence of severe fibrosis or cirrhosis in patients homozygous for the classical
C282Y mutation, if the serum ferritin is less than 1000, the AST level is normal
and there is no hepatomegaly.
Haemochromatosis can usually be confidently diagnosed
without liver biopsy. However, biopsy is recommended if
blood tests suggest presence of cirrhosis
7.
Secondary iron overload should be excluded by examination of the blood film,
particularly for evidence of thalassaemia, hereditary spherocytosis and other iron
loading anaemias. Excessive alcohol consumption may cause a mild increase in
liver iron ("alcoholic siderosis"). The serum ferritin concentration is often nonspecifically increased in the presence of excessive alcohol consumption and, if
so, the level usually returns to normal when alcohol is ceased.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
6
TREATMENT
The treatment of haemochromatosis consists of life-long venesection therapy, which
depletes the body of iron by removal of iron in haemoglobin (500ml of blood contains
approximately 250mg of iron). An initial course of one or two venesections per week,
each of 500ml, is performed until the excess iron stores are removed (see below). Once
this is achieved, which may take 1-2 years to unload 10-20g of excess body iron,
patients usually require one venesection every 3-4 months to keep iron stores at low
normal levels without rendering the patient iron-deficient. It is rare for patients not to
tolerate venesection therapy, but this may occur in patients with severe cardiac disease,
anaemia or hypoproteinemia. These patients may be given chelation therapy
(desferrioxamine) for removal of iron but this is costly and in practice is rarely needed.
The treatment of haemochromatosis consists of life-long venesection therapy
Venesection therapy is performed using a standard blood collection bag. Immediately
prior to venesection, the patient should rest for 15 minutes and drink 500ml of water.
Firm pressure is applied to the venipuncture site for 5 minutes following removal of the
needle, and the patient should rest for 15 minutes following the procedure. Fainting may
sometimes occur when the patient stands. The patient may feel tired during the 24 hours
following venesection and strenuous exercise should be avoided.
To monitor the first phase of venesection treatment, the haemoglobin concentration is
measured approximately second weekly and the serum ferritin each month. The
endpoint of this initial course of treatment is signalled by a sustained fall in the
haemoglobin concentration (to under 11.0g/dl) or a serum ferritin concentration in the
low normal range (20-50 ug/l). There is no need to make the patient iron-deficient. The
patient then enters the maintenance phase of treatment with measurement of the serum
ferritin concentration approximately 6-monthly, maintaining it below 100 ug/l. A liver
biopsy is repeated only if there was initial uncertainty with respect to the presence or
absence of cirrhosis. Cirrhosis rarely, if ever, regresses to normal despite venesection
therapy, nor does it develop if the patient is non-cirrhotic at diagnosis and is adequately
treated.
There is no value in a low iron diet in the management of haemochromatosis, however,
it is reasonable for patients to choose to reduce red meat intake if they wish to do so
(eg. To approximately 90-120 g/day), as this may reduce the frequency of venesections.
Vitamin C (ascorbic acid) supplements should be avoided, since vitamin C can increase
iron absorption and iron toxicity. As with any liver disease, alcohol consumption should
be kept to a minimum (less than 20 g/day) but abstention is not required.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
7
PROGNOSIS
The prognosis of haemochromatosis has been significantly improved by venesection
therapy. Overall cumulative survival is 76% at 10 years and 49% at 20 years (7). Noncirrhotic patients diagnosed and treated early have a normal life expectancy compared
to age and sex-matched controls, provided they continue treatment. Life expectancy is
reduced in those who present with cirrhosis or diabetes mellitus. Patients with cirrhosis
have a risk of death due to primary liver cancer even when complete iron depletion is
achieved. Almost all cases of primary liver cancer in haemochromatosis occur in
patients with established cirrhosis, especially males. Thus, cirrhotic patients, should be
checked every six months with hepatic ultrasound and serum alpha-fetoprotein levels.
Non-cirrhotic patients diagnosed and treated early have
a normal life expectancy
Skin pigmentation usually decreases with venesection. The response of hypogonadism
to venesection is variable. Insulin-dependent diabetes mellitus is usually not reversed by
venesection, although the requirement for insulin may be reduced in some patients.
Arthropathy usually responds poorly to venesection treatment. In fact, arthropathy may
antedate the onset of liver disease or may occur for the first time after venesection
therapy. Venesection therapy usually leads to some improvement in cardiac symptoms,
cardiomegaly, and haemo dynamic abnormalities.
KEY POINTS
1.
Haemochromatosis is a common genetic disease in Australia (the most common
genetic disease in people of Northern European descent).
2.
Many homozygous patients with early stage disease are asymptomatic.
3.
Haemochromatosis should be suspected in patients with a family history of the
disease, or in patients with liver disease, diabetes, arthritis, skin pigmentation,
impotence or cardiomyopathy.
4.
Early diagnosis and treatment of the disease prevents organ damage and results
in normal life expectancy.
5.
The best initial tests for detection of haemochromatosis are the serum transferrin
saturation and serum ferritin concentration.
6.
The diagnosis can be confirmed by detecting Homozygosity for the HFE gene.
7.
Family members of an affected individual should be screened by testing for the
HFE gene, as well as transferrin saturation and ferritin.
8.
Liver biopsy is required to establish or exclude the presence of cirrhosis when
blood tests are suggestive of this.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
8
REFERENCES
1.
Leggett BA, Halliday JW, Brown NN, Bryant S and Powell LW. Prevalence of
haemochromatosis amongst asymptomatic Australians. Br J Haematol 1990; 74:
525-30.
2.
Simon M, Bourel M, Geuetet B, Fauchet R. Idiopathic haemochromatosis:
demonstration of recessive transmission and early detection by family HLA
typing. N Engl J Med 1977; 297: 1017-21.
3.
Valberg LS, Lloyd DA, Ghent CN. Clinical and biochemical expression of the
genetic abnormality in idiopathic haemochromatosis. Gastroenterology 1980; 79:
884-92.
4.
Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in
early haemochromatosis and determination of the critical iron level associated
with fibrosis. Hepatology 1986; 6: 24-29.
5.
Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ and
Strohmeyer G. Survival and causes of death in cirrhotic and noncirrhotic patients
with primary haemochromatosis. N Engl J Med 1985; 313: 1256-62.
6.
Feder JN, Gnirke A, Thomas W, Tsuchibashi Z, Ruddy DA et al. A novel MHC
class-I like gene is mutated in patients with hereditary haemochromatosis. Nat
Genet 1996; 13:399-408.
7.
Guyander D, Jacquelinet C, Moirand R, Turlin B, Mendler MH et al. Non-invasive
prediction of fibrosis in C282Y homozygous haemochromatosis.
Gastroenterology1998; 115:929-36.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
9
ACKNOWLEDGEMENTS
First Edition:
Dr Mark Bassett (Co-ordinator)
Professor Lawrie Powell
Dr John Olynyk
Dr Katrina Watson
Professor Richard Smallwood
Professor June Halliday
Professor William Reed
Second Edition Revision:
Professor Lawrie Powell
Dr Tom Yapp
Ms Cosette Monk, RN
Dr Katrina Watson
The document has also been endorsed by the Australian Liver Association.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
10
Application Statement
This document has been prepared by the Digestive Health Foundation of the
Gastroenterological Society of Australia and every care has been taken in its
development. The document is intended to be used as a guide only and not as
authoritative statement of every conceivable step or circumstance which may or could
relate to the management of Haemochromatosis.
Practitioners should use this document as an aid in relation to the early diagnosis of
Haemochromatosis and not as a complete or authoritative statement.
The Gastroenterological Society of Australia, and other compilers of this document shall
not be liable to users of this material nor to any other person, firm, company or other
body for any loss, direct, indirect or consequential, on whatsoever account for any
omission or by any other person, company or body relying or acting upon or purporting
to rely or act upon any matter contained therein or arising thereout of.
Haemochromatosis –
A guide for clinical practice in the era of genetic testing
© Digestive Health Foundation
11