Transcript HEREDITARY HAEMOCHROMATOSIS

HEREDITARY
HAEMOCHROMATOSIS
What Is It?
• An inherited disease characterised by excess
iron deposition in various organs
• Leads to eventual fibrosis and functional
organ failure
Prevalence and Aetiology
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Transmitted by an autosomal recessive gene
Caucasian heterozygote ~ 1/10
Caucasian homozygote ~ 1/400 (ie1/20 x 1/20)
Most common form has been shown to be
due to a missense mutation in the HFE gene
on the short arm of chromosome 6
Mechanism of Damage
• Still somewhat unclear but…
• There is failure of expression of HFE on the
basolateral surface of the crypt cell  the
duodenal crypts are unable to incorporate iron
from plasma transferrin and are therefore rendered
iron deficient  increased expression of DMT-1
protein  increased intestinal iron absorption in
relation to body iron stores
Mechanism of Damage
• Inappropriate iron uptake by the mucosal
cells exceeds the capacity of transferrin;
excess iron is then taken up by the liver and
other tissues
• Excessive iron deposition in the tissues can
cause serious damage to organs, particularly
the heart, liver and endocrine organs
Pathogenesis
• In symptomatic people the total iron body content
is 20-40g compared with 3-4g in a normal person.
• Particularly increased in the liver and pancreas
(50-100x normal)
• In established disease the liver shows extensive
iron deposition and fibrosis. Early in the disease,
the iron is deposited in the periportal hepatocytes
but later it is distributed widely throughout all
zones. Cirrhosis is a late feature.
Clinical Features
• Depends on a number of factors – including sex,
diet, presence of associated hepatotoxins
(especially alcohol) and genotype
• Overt clinical manifestations occur more
frequently in men
• Most affected individuals present in the 5th decade
• Symptoms include weakness/fatigue, arthritis,
palpitations, abdo pain and those of diabetes
• Classical triad: bronze skin pigmentation (due to
excess melanin deposition), hepatomegaly and
diabetes mellitus
Clinical Features
• Hypogonadism secondary to pituitary dysfunction
is the most common endocrine feature
• Cardiac manifestations, particularly heart failure
and arrythmias are common, particularly in young
patients
• Calcium pyrophosphate is deposited
asymmetrically in both large and small joints
(chondrocalcinosis) arthopathy
Complications
• 30% of people with cirrhosis will go on to develop
HCC
• Diagnosis in the pre-cirrhotic stage  normal life
expectancy
• Diagnosis once cirrhosis has developed 
shortened life expectancy and a high risk of liver
cancer, even when iron depletion has been
achieved
• Various complications of other manifestations eg
of diabetes
Investigations
• Homozygotes:
Serum iron elevated
TIBC reduced
Complete or almost complete transferrin
saturation - serum iron/ TIBC x 100. A value
greater than 55% (men) or 50% (women) suggests
iron accumulation
Serum ferritin elevated (usually >500μg/L)
Liver biochemistry is often normal, even with
established cirrhosis
Investigations
• Heterozygotes:
May have normal biochemistry or may have
modest increases in serum iron transferrin
saturation or serum ferritin (usually >400μg/L)
• Liver biopsy may define the extent of tissue
damage, assess tissue iron and the hepatic iron
concentration can be measured - >180μmol/g dry
weight of liver indicates liver haemochromatosis
Investigations
• MRI shows dramatic reduction in the signal
intensity of the liver and pancreas
(paramagnetic effect of ferritin and
haemosiderin). In secondary iron overload
involving the reticuloendothelial cells
(haemosiderosis) the pancreas is spared –
allows distinction between these two
conditions. Can do quantitative MRI for
liver iron.
Treatment and Management
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Venesection
prolongs life
may reverse tissue damage
may initially need weekly (250-500ml) then only
3-4 per year to prevent re-accumulation of iron
- each 500 mL of blood taken removes ~250 mg of
iron (Hb). Synthesis of new Hb removes iron from
the stores, which are then gradually depleted
- monitor serum iron, ferritin and MCV – only fall
when available iron is depleted
Treatment and Management
• In the rare patient who cannot tolerate venesection
(because of severe cardiac disease or anaemia)
iron chelation therapy via desferrioxamine
infusion has been successful in removing iron
• Manifestations usually improve or disappear,
except for diabetes (insulin requirements may
diminish), testicular atrophy and
chondrocalcinosis
Screening
• In all cases of hereditary haemochromatosis, all
first-degree family members must be screened to
detect early and asymptomatic disease
• Serum ferritin is an excellent test for this but
genetic markers are also available.
• In the general population, the serum iron and
transferrin are the best and cheapest tests available
Genetic Screening
1) Confirmation of the diagnosis in cases of
suspected iron overload. The genetic test will
reduce costs and accelerate the diagnostic
process so that effective treatment can be started
earlier
2) Investigation of the families of patients with
haemochromatosis if the proband is homozygous
for HFE C282Y or is a compound heterozygote
Level of Screening?
• Genetic screening at a population level cannot be
justified at present because it is not yet possible to
provide those at risk with a reliable estimate of the
likelihood of developing clinical
haemochromatosis
• If heterozygotes for both C282Y and H63D are
included, about 2% of the population would need
to be offered regular testing to detect iron overload
as well as counselling and family studies.
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