Virginie SCOTET, PhDClaude FÉREC, MD, PhD

Laboratoire de Génétique Moléculaire, INSERM EMI 01-15 , Brest, FRANCE

Hereditary Hemochromatosis

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

Hereditary hemochromatosis

The genes implicated in HH

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

Type of HH Gene Inheritance N° OMIM

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)

– Clinical expression ( age of 40-50) Clinical picture associating fatigue, arthritis, hepatomegaly,

skin pigmentation and diabetes Evolution towards cirrhosis and carcinoma

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

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

ATG TGA5 ’UTR 3 ’UTR 3 ’UTR

IVS3 + 1 G>T IVS5 + 1 G>A

P.R6S P.G93R P.A176VP.I105T

P. E168Q P.P.C282YC282YP.Q283P

P.R330MP.S65CS65C

P.V68delinsGP.L50_L57delinsC

P.P160delinsPP.K254delinsK

P.H63DH63D P.C282S

P.R74X P.W169X

P.E168X

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

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 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

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

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%

Results

Excessive alcohol consumption– 8.7% of patients (n=33/378)

13.6% of males (n=31/228) 1.3% of females (n=2/150)

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 (OR=3.4 - p<0.001) (Fig. 1)

Table 1: Biochemical parameters according to alcohol consumption

Variables Alcohol consumption

p-value

NumberGender

Ferritin (µg/L) 1,745.2(1792.1) 968.7(1129.3) <0.0001Iron (µmol/L) 39.9(6.3) 36.0 (7.4) 0.0040Saturation (%) 87.1(9.3) 80.1(13.7) 0.0071ALT (IU/L) 66.3(48.1) 41.1(28.3) 0.0003AST (IU/L) 56.2(47.8) 34.9 (18.4) 0.0002

M:31 - F:2 M:197 - F:148

60 g/day 60 g/day

33 345

Fig. 1: Clinical signs according to alcohol consumption

0

20

40

60

80

100

Fatigue Skinpigmentation

Arthritis Hepat-omegaly

Metabolicdisorders

> 60 g/day< 60 g/day

Alcohol consumptionFrequencyFrequency

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

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