Download Opportunistic screening for haemochromatosis

Haemochrom-AH/NH
06/04/2006
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Innovations in Practice
Opportunistic screening
for haemochromatosis
Tomás Ó Ceallaigh outlines why and how his practice adopted a policy of
screening patients for haemochromatosis and says GPs should be aware
of iron overload in patients
MY INTEREST IN HAEMOCHROMATOSIS BEGAN when I noticed
a significant number of patients in my practice presenting
with both high serum ferritin and transferrin levels.
Haemochromatosis, a term coined in 1889 by Von Recklinghausen,1 is derived from the Greek, meaning haima blood, chroma – colour, osis – condition. It is a common
genetic autosomal recessive condition causing excessive
iron absorption, resulting in damage to the liver, heart, pancreas and other organs. It is usually diagnosed between
40-60 years of age. It was first described by Trousseau in
1865,2 who noted an association between cirrhosis, diabetes and skin pigmentation.
Less than 15% of patients with haemochromatosis will
present with this classical triad. Iron accumulates initially
in the transferrin pool, demonstrated by a rise in the transferrin saturation which is a measure of the iron transport
level. Subsequently, there is a rise in iron transport stores,
particularly in the liver parenchyma, accompanied by a progressive rise in serum ferritin. There is often a delay of 10
years between the onset of symptoms and its diagnosis. The
most common symptoms include fatigue and abdominal
pain.
Genetics
There are five types of haemochromatosis. The
haemochromatosis gene (HFE) was first identified by Feder3
in 1996, following the original work by Simon et al4 noting
a link between the haemochromatosis locus and the major
histocompatibility complex. It is located on the short arm of
chromosome 6. The mutation occurred approximately 2000
years ago. This is absent in non-Caucasian populations or
found in very low frequency. The H63D is an older mutation.
• Type 1, the most common, is an autosomal recessive condition caused by a mutation in HFE which was the first
haemochromatosis gene identified and primarily found in
northern Europeans. A single mutation in HFE results in
the substituting of a tyrosine residue in place of a cystine
at position 282 (C 282Y). A second mutation in the HFE
gene H63D can cause the disease if found also with a
single C282Y mutation, ie. compound heterozygous.
• Type 2 is a rare autosomal recessive gene condition
• Type 3 is autosomal recessive gene condition described
initially in Southern Italy
• Type 4 is an autosomal dominant gene
• Type 5 H Ferritin – auto dominant condition.
Studies to date have shown not all patients homozygous
for haemochromatosis will develop haemochromatosis or
develop elevated ferritin levels, ie. phenotypic expression.
The penetrance of the C282Y mutations was initially
assumed to be highly penetrant; however, one study by
Beutler5 in 2002 suggested a penetrance of less than one
per cent. In a longitudinal study carried out by Olynyle6 in
1999 only 50% of C282Y homozygotes had clinical features
of haemochromatosis and a quarter had serum ferritin that
remained within the normal range for four years. The penetrance of compound heterozygous C282Y/H63D is low in
both males and females. H63D genotype is of low penetrance. The expression of a phenotype is dependent on many
factors with an interaction between genetic and epigenetic
factors, age, sex, diet and alcohol.
Ireland has the highest frequency of the Y allele at 14.2%.
Its distribution declines in north to south and west to east
directions in Europe, ie. declining from Celtic areas. The
prevalence in Ireland of homozygous is 1: 86, of compound
heterozygous is 1:6 and heterozygous C282Y is 1:5.
Screening
Patients with diabetes mellitus, early onset impotence,
atypical cardiac failure, and arthritis should be screened for
haemochromatosis. Family members of patients diagnosed
with iron overload should also be screened. Cascade screening has been proposed by Krawzcak.7 This would identify
40% of individuals at risk by screening first, second and
third degree relatives of patients with iron overload who are
over 30 years of age. Krawzcak7 suggests that this would be
50 times more efficient than population screening. An
overnight fasting transferrin saturation (TS) is considered to
be the best initial screening tool; it is calculated as 100
multiplied by the serum iron concentration, divided by the
total iron-binding capacity.
Serum may be elevated in acute or chronic viral hepatitis
or alcoholic liver disease. A transferrin saturation (TS) of
> 45% has a sensitivity and specificity of 94% and a positive predictive valve of 6% for haemochromatosis. If a
patient has a TS greater than 45% the TS levels should be
checked again after three to six months.
There are two alternatives in relation to screening. The
first approach is to perform a repeat fasting transferrin and
serum ferritin. If the ferritin is normal, annual follow-up of
the TS and ferritin would be appropriate to monitor for signs
of iron overload. A second approach would be to genetically
screen all patients who have an elevated fasting TS and a
normal ferritin. If the ferritin level is greater than 200µg/l in
pre-menopausal women, greater than 300µg/l in postFORUM April 2006 55
Haemochrom-AH/NH
06/04/2006
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Innovations
Hereditary haemochromatosis (hh)
Carrier mother
Genetic combinations:
Carrier father
H
h
H
h
(HH)
Non-carrier
Chance (25%)
(Hh)
Carrier
Chance (50%)
(Hh)
Carrier
Chance (50%)
(hh)
Affected*
Chance (25%)
*The possibility of being affected with hereditary haemochromatosis is 25% in children of parents who carry the mutant HFE gene
Symptoms and signs of
haemochromatosis
Symptoms
Signs
• Fatigue
• Skin pigmentation
• Abdominal pain
• Cardiomyopathy
• Loss of libido
• Hepatomegaly
• Arthralgia
• Palpitations
• Impotence
• Depression
• Weight loss
menopausal women or men, the likelihood of haemochromatosis must be strongly suspected. Serum ALT and serum
AST must also be measured in patients diagnosed with
hereditary haemochromatosis. End organ damage should be
assessed.
Therapy
Dietary advice
A patient should avoid breakfast cereals as these are fortified with iron, avoid iron supplements and avoid vitamin
C, which increases iron absorption. Patients should minimise alcohol consumption and abstain if there is underlying
liver disease. Regular tea consumption will reduce iron
accumulation. Patients should moderate red meat and offal
consumption and avoid raw shellfish or handling it as there
is a risk of vibrio vulnificus.
Phlebotomy
This is usually initiated when the serum ferritin levels are
> 200µg/l in women or 300µg/l in men. Normally, 450500ml is removed weekly until the serum ferritin level is
between 20-50µg/l. Once these levels have been reached,
ie. iron depletion state, phlebotomy is performed every three
to four months to maintain desired levels of iron.
Symptoms of fatigue, cardiomyopathy and skin pigmentation improve significantly after venesection; however,
impotence rarely improves. Haemoglobin should be measured prior to each phlebotomy. After 10 venesections,
serum ferritin should be measured. A liver biopsy is recommended if the ferritin is greater than 1000µg, or the patient
has an elevated AST or hepatomegaly. It was used formerly
prior to the advent of genetic testing to diagnose haemochromatosis. It used to establish cirrhosis, which is unlikely to
develop if the patient has a normal AST, no hepatomegaly,
and a ferritin less 1000µg. The exclusion of cirrhosis is
important as there is a 200 times greater risk of hepatocellular neoplasia and patients may need six monthly
ultrasound and alpha fetoprotein levels.
56 FORUM April 2006
The practice audit
Our practice in Strokestown, Co Roscommon, is predominantly a rural single-handed practice. We have a practice
staff complement of four including one GP, a sessional
female GP, practice nurse and secretary.
One patient had been previously identified with
haemochromatosis who was undergoing venesection prior to
adapting this policy. The practice adopted a policy of performing an iron screen test in all patients presenting with
symptoms of fatigue, abdominal pain, arthralgia, impotence
and depression.
It was also included in the patient’s annual check up. If
the transferrin was greater than 50%, the test was repeated
including a serum ferritin. If at this stage it was elevated we
performed the genetic test and patients were informed of
the implications on their life insurance.
Results
In all, 62 genetic tests were carried out and 240 iron
screens were carried out. The results were as follows:
• Homozygous C282Y
11
(Seven patients undergoing venesection)
• Heterozygous C282Y
5
• Homozygous H63D
2
• Compound C282 Y/H63D
4
• Heterozygous H63D
4
When a diagnosis of haemochromatosis was made
patients were advised that family members are at risk and
in particular first-degree relatives. A leaflet was given to the
patient, including useful addresses such as the Irish
Haemochromatosis Association and the Haemochromatosis
Society of Australia (see below).
One should be aware of iron overload for patients with
vague symptoms. As hereditary haemochromatosis is very
prevalent in Ireland (as my figures illustrate), opportunistic
screening is to be encouraged. It fulfills many of the criteria for screening as it is highly prevalent in a selected
population. There is a presymptomatic phase and a reliable
and safe diagnostic test, and a relatively inexpensive treatment is available. However, the genetic test is expensive and
if the penetrance is low a large number would need to be
screened to prevent one case of severe tissue damage. A
genetic self-test is available at a costs of e80.
Tomás Ó Ceallaigh is in practice in Béal Átha na mBuillí,
Co Roscomáin
Useful addresses
1. Irish Haemochromatosis Association, The Carmichael Centre, North
Brunswick Street, Dublin 7 Tel: (01) 873 5911
2. The Haemochromatosis Society Australia Inc.ABN:79827 140 617,PO
Box 154, Coopers Plains Qld 4108, Australia. Phone/Fax 334 58051
3. Haemochromatosis – An iron overload disorder.
www.ghsoc.org/pages/print.html
Full references on request