Hereditary Hemochromatosis

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Hereditary Hemochromatosis
Virginie SCOTET, PhD Claude FÉREC, MD,
PhD Laboratoire de Génétique Moléculaire, INSERM
EMI 01-15 , Brest, FRANCE
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Hereditary hemochromatosis

• Definition
• Common inherited disorders of iron metabolism
• One can distinguished six forms of HH, associated
  with ? genes and ? patterns of inheritance
  (genetic heterogeneity)
• A main form linked to the HFE gene
• Five rare forms

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Hereditary hemochromatosis

• 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
HH of type IIB
HAMP
Autosomal recessive
602390
HH of type III
TfR2
Autosomal recessive
604250
HH of type IV
SLC11A3
Autosomal dominant
606069
HH of type V
H-Ferritine
Autosomal dominant
134770
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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

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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)
• 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

• 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

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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.Q283P
P.A176V
P.G93R
P.R330M
P.R6S
P.C282Y
P. E168Q
P.S65C
ATG
P.C282S
TGA
P.H63D
3 UTR
5 UTR
3 UTR
P.E168X
IVS3 1 GgtT
IVS5 1 GgtA
P.L50_L57delinsC
P.V68delinsG
P.P160delinsP
P.K254delinsK
P.R74X
P.W169X
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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

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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)

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Population and methods

• Study design
• Retrospective study of C282Y-homozygous patients
  treated in a blood centre of wes-tern 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

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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
• Study of the effect of alcohol intake on the
  disease expression using a linear regression
  analysis

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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

• Excessive alcohol consumption
• 8.7 of patients (n33/378)
• 13.6 of males (n31/228)
• 1.3 of females (n2/150)
• 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 (OR3.4 - plt0.001) (Fig. 1)

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Table 1 Biochemical parameters according to
alcohol consumption
Alcohol consumption
Variables
p
-value
gt
lt
60 g/day
60 g/day
Number
33
345
Gender
M31 - F2
M197 - F148
Ferritin (µg/L)
1,745.2
(1792.1)
968.7
lt0.0001
(1129.3)
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
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Fig. 1 Clinical signs according to alcohol
consumption
Frequency
100
Alcohol consumption
gt 60 g/day
80
lt 60 g/day
60
40
20
0
Fatigue
Skin
Arthritis
Metabolic
Hepat-omegaly
pigmentation
disorders
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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 para-meters and
  more frequent clinical signs

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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