Transcript Hereditary Haemachromatosis

Hereditary Haemachromatosis
Dr Eileen C Kelleher
Haematologist
[email protected]
October 1st 2016
Haemachromatosis
• Inherited disorder resulting from an inborn
error of metabolism, which leads to
progressive iron overload, of the parenchymal
cells of the liver, pancreas and heart
• In its fully developed stage, organ structure
and function are impaired
Haemachromatosis
• excessive intestinal absorption of dietary iron
• pathological increase in total body iron stores
• humans have no means to excrete excess iron
– ( except menstuation and pregnancies)
• excess iron accumulates in tissues and organs
disrupting their normal function
• most susceptible organs include the liver, adrenal
glands, heart, skin, gonads, joints and pancreas
‘Haemochromatosis Gene’, or HFE
• ‘Haemochromatosis Gene’, or HFE, revealed by Feder
and colleagues in 1996
• Pathogenesis had been unravelled !
• since emerged, this was just one piece of a complex
puzzle
• that is still being assembled
• individuals screened for pathogenic mutations
• not all those with mutations came to harm or
developed HH
• the disease has incomplete penetrance
The HFE gene
• C282Y substitution of cysteine for tyrosine the commonest
– 98% of Irish HH genoptype
• H63D aspartate for histidine substitution
• Homozygosity for the C282Y mutation
• confers the greatest risk of developing HH
• ‘Compound heterozygotes’ with shared C282Y and H63D
mutations
• May develop disease
• H63D homozygotes
• Rarely develop clinical disease
• To be diagnosed with HH, an individual requires both
• HFE genotype
• objective clinical manifestations of iron overload (phenotype)
‘Haemochromatosis Gene’, or HFE
Prevalence
• Commonest genetic disorder in Caucasions
• Particularly of northern European and Celtic decent
– Homozygous 1 in100 to 1 in 200
– Carrier 1in 8 to 1 in 10
• Ireland
– 93% of HH patients are C282Y
– estimate a prevalence of C282Y homozygosis 1 in 83
persons
– indicating that over 25,000 Irish adults are at risk for
developing HH
– Carrier frequency 1 in 5 to 1 in 10
HFE penetrance- phenotype
• Despite this high prevalence
– approximately 30 % of males and 20 % of females
who are C282Y homozygous will actually develop
clinically-significant complications related to iron
overload
• Irish studies indicate that these figures could
be higher in a homogeneous Irish population.
Phenotype
• Age
• Sex
• Blood loss
– Pathological and physiological
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Blood donations
Dietary iron
Alcohol
Hepatitis B & C
Obesity
Dietay supplements
– Iron and Vitamin C
Signs and Symtoms
• Organs commonly affected
– liver, heart , endocrine glands (pituitary, pancreas)
• may present with the following clinical
syndromes
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Cirrhosis of the liver
Diabetes
Cadiomyopathy
Arthritis
Gonadal failure
Pigmentation of the skin
Joint pain and bone pain
Investigations
• Serum Ferritin
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> 300 mg/l for men and post menopausal female
> 200 mg/l for pre menopausal female
Iron over load
But not exclude HH genotype
• Transferrin saturation and Ferritin (Fasting)
– both elevated good positive predictive of HFE
– Normal Ferritin is good predict
• HFE genotyping
Investigations
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U&E
Liver profile
Blood sugar and Hb A1c
Lipds
ECG
CxR
U/S liver, Liver biopsy or MRI liver if abn LFTs,
alpha feto protein
Management
• Dietary and oral supplements advice
• Venesections
• Alcolol intake
Management
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Venesections
When evidence of iron overload
Rather than waiting for symtoms
400-500mls per occasion
– Some much less
• Until ferritin 50 -100 ng/ml
• Every 1-2 weeks
• Usual maintenance 3-4 per year
Venesections
• Takes approxmately 30 minutes on the chair
• Ensure drink 500 ml fluid within 1 hour before
hand
• Rest for 30-60 minutes after venesection
• No strenous work for following 24 hours
• Depends on the age and co morbidities of the
patient
• Consent
Venesections
• Bon Secour Hospital
• Phlebtomy Department
• Una Howard and team
Venesection
• IBTS
– Patient is stable on 3-4 venesections per year
– Meets the criteria for voluntary blood donations
– No complications of the HH
Screening
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Family members
Serum Ferritin +/- Transferrin Saturation
Iron overload present
Genotyping
Conclusion
• Inherited disorder of Iron overload
• Commonest genetic disease among
Caucasions, especially Celtic, particularly
Ireland
• Patients are predominantly men
• Early detection and treatment prevents organ
damage and normal life expectancy
• Amenable to diagnosis, treatment