Hereditary Hemochromatosis

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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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 G>T IVS5 + 1 G>A P.L50_L57delinsC P.P160delinsP P.V68delinsG P.K254delinsK P.R74X P.W169X

8. 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

9. 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

10. Aim of the study • To analyse the influence of excessive alcohol consumption on the disease expression in patients homozygous for the main mutation (C282Y)

11. 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

12. 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

13. 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%

14. 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)

15. Table 1: Biochemical parameters according to alcohol consumption Alcohol consumption Variables p -value > < 60 g/day 60 g/day Number 33 345 Gender M:31 - F:2 M:197 - F:148 Ferritin (µg/L) 1,745.2 (1792.1) 968.7 <0.0001 (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

16. Fig. 1: Clinical signs according to alcohol consumption Frequency 100 Alcohol consumption > 60 g/day 80 < 60 g/day 60 40 20 0 Fatigue Skin Metabolic Arthritis Hepat-omegaly pigmentation disorders

17. 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

18. 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