11811 - Hereditary Hemochromatosis Virginie SCOTET PhD Claude FREC MD PhD Laboratoire de Gntique Molculaire INSERM EMI 01-15 Brest FRANCE

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Unformatted text preview: Hereditary Hemochromatosis Virginie SCOTET, PhD Claude FREC, MD, PhD Laboratoire de Gntique Molculaire, INSERM EMI 01-15 , Brest, FRANCE Hereditary hemochromatosis x Definition Common inherited disorders of iron metabolism One can distinguished six forms of HH, associated with genes and patterns of inheritance (genetic heterogeneity) s s A main form linked to the HFE gene Five rare forms Hereditary hemochromatosis x The genes implicated in HH Gene HFE HAMP TfR2 SLC11A3 H-Ferritine Type of HH HH of type I HH of type IIB HH of type III HH of type IV HH of type V Inheritance Autosomal recessive N OMIM 235200 602390 602390 604250 606069 134770 HH of type IIA Unidentified Autosomal recessive Autosomal recessive Autosomal recessive Autosomal dominant Autosomal dominant Hereditary hemochromatosis of type I x 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 x Natural history: 3 phases Phase of latency Biochemical expression ( age of 20) Increase of iron parameter levels (serum iron, transferrin saturation, serum ferritin) s Clinical expression ( age of 40-50) Clinical picture associating fatigue, arthritis, hepatomegaly, skin pigmentation and diabetes Evolution towards cirrhosis and carcinoma s s Hereditary hemochromatosis of type I x 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 x 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 5 'UTR P P. R6S S65C P.H63D P. I105T P.G93R P. A176V P. E168Q P. P. P. Q283P P. C282Y P. R330M TGA 3 'UTR 3 'UTR C282S IVS5 + 1 G>A .L50_L57delinsC P.E168X IVS3 + 1 G>T P.V68delinsG P.P160delinsP P.K254delinsK P.R74X P.W169X Hereditary hemochromatosis of type I x Complex pathology The penetrance of the different genotypes is incomplete Biochemical expression Clinical expression s s The phenotypic expression of HH can also be influenced by environmental factors Hereditary hemochromatosis of type I x Role of environmental factors Aggravating factors Factors that increase iron stores s 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 s s s s s Aim of the study x To analyse the influence of excessive alcohol consumption on the disease expression in patients homozygous for the main mutation (C282Y) Population and methods x Study design Retrospective study of C282Y-homozygous patients treated in a blood centre of western Brittany (France) where HH is frequent x 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 x Statistical analysis Description of biochemical and clinical characteristics of HH patients according to their alcohol consumption Excessive: 60 grams per day s s Moderate: < 60 grams per day Study of the effect of alcohol intake on the disease expression using a linear regression analysis Results x 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% s s s s s s Results x Excessive alcohol consumption 8.7% of patients (n=33/378) 13.6% of males (n=31/228) 1.3% of females (n=2/150) s s x 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 Alcohol consumption > 60 g/day < g/day 60 Variables p-value Number 33 345 M:31 - F:2 M:197 - F:148 Gender Ferritin (g/L) 1,745.2(1792.1) 968.7 (1129.3) <0.0001 Iron (mol/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 80 60 40 20 0 Frequency Alcohol consumption > 60 g/day < 60 g/day Fatigue Skin Arthritis Hepat- Metabolic omegaly disorders pigmentation Discussion x 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 x Implications for public health Preventive strategies Patients homozygous for the C282Y mutation should have very moderate alcohol consumption x Example of multifactorial disease The phenotypic expression of HH is the result of interactions between genetic and environmental factors ...
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This note was uploaded on 02/23/2012 for the course PHARM 290 taught by Professor Staff during the Fall '10 term at Rutgers.

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11811 - Hereditary Hemochromatosis Virginie SCOTET PhD Claude FREC MD PhD Laboratoire de Gntique Molculaire INSERM EMI 01-15 Brest FRANCE

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