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Hereditary
Hemochromatosis
Virginie SCOTET, PhD
Claude FÉREC, MD, PhD
Laboratoire de Génétique Moléculaire,
INSERM EMI 01-15 , Brest, FRANCE
Hereditary hemochromatosis

Definition
–
Common inherited disorders of iron
metabolism
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One can distinguished six forms of
HH, associated with  genes and 
patterns of inheritance (genetic
heterogeneity)
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A main form linked to the HFE gene
Five rare forms
Hereditary hemochromatosis
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The  genes implicated in HH
Type of HH
Gene
Inheritance
N° OMIM
HH of type I
HFE
Autosomal recessive
235200
HH of type IIA Unidentified Autosomal recessive
602390
Autosomal recessive
602390
Autosomal recessive
604250
Autosomal dominant
606069
Autosomal dominant
134770
HH of type IIB
HAMP
HH of type III
HH of type IV
HH of type V
TfR2
SLC11A3
H-Ferritine
Hereditary hemochromatosis of type I

Definition
–
The main form of HH is linked to the
HFE gene and is called HH of type I
–
It occurs predominantly in populations
of North-western European descent,
with a prevalence of 3-8 in 1000
–
It is characterised by excessive iron
absorption, leading progressively to the
destruction of different organs tissues
Hereditary hemochromatosis of type I

Natural history: 3 phases
–
Phase of latency
–
Biochemical expression ( age of 20)
Increase of iron parameter levels (serum iron,
transferrin saturation, serum ferritin)
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Clinical expression ( age of 40-50)
Clinical picture associating fatigue, arthritis,
hepatomegaly, skin pigmentation and diabetes
Evolution towards cirrhosis and carcinoma
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Hereditary hemochromatosis of type I
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Treatment
–
HH is one of the sole genetic diseases
benefiting from a simple and efficient
treatment when implemented early
–
Treatment relies on regular phlebotomies
–
Without its early implementation, this
disease has a poor prognosis and can
progress toward irreversible damage
Hereditary hemochromatosis of type I

Discovery of the HFE gene in 1996
–
A main mutation: C282Y (80-95% of cases)
– Two susceptibility factors: H63D, S65C
– About 15 private mutations
P.I105T
P.R6S
ATG
5 ’UTR
P.G93R
S65C
P.H63D
P.
P.Q283P
P.A176V
P. E168Q
P.
C282Y
P.C282S
P.E168X
P.R330M
TGA
3 ’UTR
IVS3 + 1 G>T
IVS5 + 1 G>A
P.V68delinsG P.P160delinsP
P.K254delinsK
P.R74X
P.W169X
P.L50_L57delinsC
3 ’UTR
Hereditary hemochromatosis of type I

Complex pathology
–
The penetrance of the different genotypes
is incomplete
Biochemical expression
Clinical expression


–
The phenotypic expression of HH can also
be influenced by environmental factors
Hereditary hemochromatosis of type I

Role of environmental factors
–
Aggravating factors
Factors that increase iron stores
Diet with a high iron content
Excessive alcohol consumption
Protective factors
Factors that reduce iron stores
Regular blood donation
Chronic bleeding
Factors modulating iron absorption
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Aim of the study

To analyse the influence of excessive
alcohol consumption on the disease
expression in patients homozygous
for the main mutation (C282Y)
Population and methods

Study design
–

Retrospective study of C282Y-homozygous
patients treated in a blood centre of western Brittany (France) where HH is frequent
Clinical questionnaire
–
Completed at the first visit to the centre
– Registered items: socio-demographic data,
genotype, biochemical and clinical signs,
treatment, daily alcohol consumption
Population and methods

Statistical analysis
–
Description of biochemical and clinical
characteristics of HH patients according
to their alcohol consumption
Excessive:  60 grams per day
Moderate:  60 grams per day


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Study of the effect of alcohol intake on
the disease expression using a linear
regression analysis
Results

Population description
–
–
378 patients
Gender
Males: 60.3%
Females: 39.7%
Age at onset
Males: 46.5 y. (14.2)
Females: 48.8 y. (12.1)
Main circumstances of diagnosis
Basis of clinical features: 57.4%
Family testing: 30.7%
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Results
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Excessive alcohol consumption
–
8.7% of patients (n=33/378)
13.6% of males
(n=31/228)
1.3% of females
(n=2/150)
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Effect of alcohol on HH expression
–
Iron parameters and liver enzymes are
significantly higher in patients having
excessive alcohol consumption (Table 1)
–
Clinical signs are more frequent, notably
skin pigmentation (OR=3.4 - p<0.001) (Fig. 1)
Table 1: Biochemical parameters
according to alcohol consumption
Variables
Alcohol consumption
> 60 g/day  60 g/day
p-value
Number
33
345
M:31 - F:2
M:197 - F:148
Gender
Ferritin (µg/L) 1,745.2(1792.1) 968.7 (1129.3) <0.0001
Iron (µmol/L)
39.9(6.3)
36.0 (7.4)
0.0040
Saturation (%) 87.1(9.3)
80.1(13.7) 0.0071
ALT (IU/L)
66.3(48.1)
41.1(28.3) 0.0003
AST (IU/L)
56.2(47.8)
34.9 (18.4) 0.0002
Fig. 1: Clinical signs
according to alcohol consumption
100
Frequency
80
Alcohol consumption
> 60 g/day
< 60 g/day
60
40
20
0
Fatigue
Skin
Arthritis Hepat- Metabolic
omegaly disorders
pigmentation
Discussion

Main results
–
This study provides precise quantitative
data about the impact of alcohol intake
on the expression of HH
–
Excessive alcohol intake combined with
a genetic factor increases HH severity
and thus the risk of cirrhosis and cancer
–
This is expressed by higher iron parameters and more frequent clinical signs
Discussion

Implications for public health
–
Preventive strategies
– Patients homozygous for the C282Y
mutation should have very moderate
alcohol consumption

Example of multifactorial disease
–
The phenotypic expression of HH is the
result of interactions between genetic
and environmental factors