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Influences of HFE mutations on iron indices in healthy blood donors
164
Poster Sessions
9-21 INCIDENCE OF DRUG-INDUCED HEPATOBILIARY INJURIES: AFRENCH POPULATION-BASED STUDY
[5941 HUMAN HEPATIC STELLATE CELLS (HSC) PROMOTE SCATTERING AND INVASION OF COLON CANCER CELLS
Main Lemoine 1, Catherine Sgro2, Francois Clinard3, Kader Ouazir t , Henri Chanay I , Christian Mlard 1, Christian Guilleminet 1, Claude Lenoir 1, Patrick Hillon I . 1Centre Hospitalier De Nevers, Nevers;
Cristina Rigamonti, Antonio Mazzocca, Silvia Cappadona, Vinicio Carloni, Massimo Pinzani. Dipartimento di Medicina Interna,
2Centre Hospitalier Universitaire - Service Pharmacovigilance, Dijon; 3Centre D'Epidemiologie De Population, Facult~ De Mddecine, Dijon Cedex, France The aim of this population-based study was to assess the incidence and seriousness of drug-induced hepatic adverse effects (ADRs) that remain unknown in the general population. M1 new cases of symptomatic druginduced hepatic injuries were collected by 139 trained physicians (GPs and specialists) between November 1997 and November 2000 in an area containing 81301 inhabitants who could hardly go elsewhere for medical care. Over three years, 59 cases of hepatic ADRs were collected, 88% of them in outpatients. Global crude annual incidence rate was 24.2 -4- 3.1 per 100 000 inhabitants; corresponding standardized annual global rate was 15.5 + 2.2. There was no difference between urban and rural areas. In male, specific incidence rates remained stable with age; in female, they were 2 fold higher after 50 year old than before this age. Diagnosis was carded out by GPs in half of cases. The outcome was recovery for 56 patients and death for 3. The main drugs implicated were psychotrops, antibiotics and hypolipidaemic drugs. Our results suggest that the number of hepatic ADRs in the French population would be 30 times greater than that notified by spontaneous reporting to French regulatory authorities. In conclusion, this study shows that incidence and seriousness of drug induced hepatitis are largely underestimate in a general population. These results may be useful for further evaluation of drug-induced bepatotoxicity.
~ 9 - ~ INFLUENCES OF HFE MUTATIONS ON IRON INDICES IN HEALTHY BLOOD DONORS Raffaella Mafiani 1, Alessandra Salvionil, Viviana Mauri 1, Laura Fossati 1, Cristina Arosio 2, Alessia Riva 1, Anna Vergani 1, Valentina Baldini 3, Paolo Cerntti 4, Alberto Piperno 1. i Clinica Medica,
Universitfi Milano Bicocca Ospedale San Gerardo Monza; 21stituto Auxologico Italiano Ospedale San Luca Milano ; 3Servizio Immunotrasfusionale Laboratorio di Ematologia Ospedale San Gerardo Monza; 4Unita Operativa Autonoma di Medicina Trasfusionale Ospedale San Biagio Domodossola, Italy Background: Hereditary hemochromatosis is common in Italian populations of Northern descent. Screening donors for hemochromatosis will identify subjects with the disease and those with raised iron indices. Aim: To evaluate whether blood donors carrying one or more HFE mutations have a lower risk to develop iron deficiency we measured iron indices, frequency of blood donations and HFE genotypes in healthy blood donors originating from Northern Italy. Materials and methods. 606 healthy blood donors from the Blood Bank of San Gerardo Hospital in Monza (group A) and 319 from Domodossola (group B) were enrolled. Average number of donations per months and hemoglobin levels were estimated in all blood donors; serum iron and ferritin were considered as indices of iron status in group A and in group B, respectively. C282Y, H63D and $65C were analysed in all the individuals, whereas W 169X and E 168X nonsense mutations in group A and group B, respectively. Results: The number of donations per months and levels of hemoglobin at last donation were not significantly different in blood donors divided according to HFE genotypes in each group, considered separately. In group A, serum iron at last donation, significantly increased from HFE wild type to H63D heterozygotes, to C282Y heterozygotes, and to C282Y/H63D compound heterozygotes. Serum ferritin was not significantly different according to HFE genotypes in the group studied. Conclusion: Blood donors, heterozygotes for HFE mutations have similar amounts of iron stores as those with the wild type genotype, but have a lower risk of developing iron deficient erythropoiesis.
University of Florence, Florence, Italy Colon cancer metastasis in the liver develop in 40-50% of patients after removal of the primary tumor. During cancerogenesis the stromal component may influence malignant behaviour of neoplastic epithelial cells, through the secretion of soluble factors. Organ preference for metastatic colonization is influenced by dynamic molecular cross-talk between the cancer cells and the target host tissue, particularly mesenchymal elements. We evaluated whether activated human HSC play a role in influencing the proliferative and invasive phenotype of a human colon carcinoma cell line (clone A). Proliferation assay was performed by challenging clone A cells with HSC conditioned medium (HSC-CM). Clone A migration and invasion were assessed by using a modyfied Boyden chamber tecnique. Incubation with HSC-CM did not increase colon cancer cell proliferation, but, interestingly, induced changes in cell morphology, such as filopodia formation, and scattering. These features were associated by reorganization of cytoskeletal actin, as evaluated by immunofluorescence assay. Scattering induced by HSC-CM was comparable to that observed after cell stimulation with hepatocyte growth factor/scatter factor (HGF/SC). As expected, HGF/SF effect on clone A was blocked by using anti-c Met antibody. Conversely, HSC-CM mediated scatter effect was not inhibited by anti-c Met antibody. It is therefore conceivable that factor(s) other than HGF/SF could be involved in this effect. Furthermore, HSC-CM enhanced colon carcinoma cell motility and invasion. These findings indicate that liver microenviroument may favor the invasive behaviour of colon carcinoma cells, by inducing cytoskeletal remodeling and scattering.
~-5-1 WHAT THE PATIENTS KNOW ABOUT HEPATITIS C INFECTION AND HOW HCV INFECTION AFFECTS THEIR LIFE-STYLE? Giulia Tositti l, Paolo Fabris ] , Annarosa Floreard 2, Alessandro Grasso 3, Sidarta Canton2, Elena Pignattafi 1, Clara Stecca 1, Mafia Teresa Giordani 1, Fausto De Lalla 1. 1Dept. of Infectious Diseases, San
Bortolo Hospital, Vicenza; 2Dept. of Surgical and Gastroentemlogical Sciences, University of Padua; 3Dept. of Internal Medicine Savona, Italy Aims: To evaluate the grade of knowledge on HCV infection in a consecmive series of HCV-posive patients, and to assess how HCV positivity affects their life-style before and after the first consultation in 3 centres from Northern Italy. Methods: An anonymous self-administered multiple-choice questionnaire was administered to 177 HCV-positive (Group A) attending the out-patient clinic for the first time, and to 92 pts (Group B) at the second or third visit. The areas explored by the questionnaire were: source of infection, psychological sphere, sexual behaviour, diet, alcohol intake and therapy. Results: The two groups were comparable in term of sex, age, and social level. At the first visit, 47% of subjects knew the source of infection. The sources of information were: general practitioner 45%, magazines 23%, friends 20%, others 22%. HCV positivity worsened psychological status in 36.4% of cases, and modified sexual behaviour, diet, alcohol intake in 20%, 40%, and 15.3%, respectively; The grade of knowledge on HCV infection improved after the first visit, particularly concerning transmission and behaviour, but their psychological status remained unchanged (Group A 36.4% vs Group B 35%). Fifty-percent of patients thought that a specific treatment is necessary and this rate didn't change after the first consultation. Overall, the need of more information on HCV infection significantly improved thereafter (Group A 92% vs Group B, 71%, p < 0.05). Conclusions: An education program should be addressed to the general practitioners. At the mean time, our data support the idea that counselling should be improved by the specialists.
Poster Sessions
9-21 INCIDENCE OF DRUG-INDUCED HEPATOBILIARY INJURIES: AFRENCH POPULATION-BASED STUDY
[5941 HUMAN HEPATIC STELLATE CELLS (HSC) PROMOTE SCATTERING AND INVASION OF COLON CANCER CELLS
Main Lemoine 1, Catherine Sgro2, Francois Clinard3, Kader Ouazir t , Henri Chanay I , Christian Mlard 1, Christian Guilleminet 1, Claude Lenoir 1, Patrick Hillon I . 1Centre Hospitalier De Nevers, Nevers;
Cristina Rigamonti, Antonio Mazzocca, Silvia Cappadona, Vinicio Carloni, Massimo Pinzani. Dipartimento di Medicina Interna,
2Centre Hospitalier Universitaire - Service Pharmacovigilance, Dijon; 3Centre D'Epidemiologie De Population, Facult~ De Mddecine, Dijon Cedex, France The aim of this population-based study was to assess the incidence and seriousness of drug-induced hepatic adverse effects (ADRs) that remain unknown in the general population. M1 new cases of symptomatic druginduced hepatic injuries were collected by 139 trained physicians (GPs and specialists) between November 1997 and November 2000 in an area containing 81301 inhabitants who could hardly go elsewhere for medical care. Over three years, 59 cases of hepatic ADRs were collected, 88% of them in outpatients. Global crude annual incidence rate was 24.2 -4- 3.1 per 100 000 inhabitants; corresponding standardized annual global rate was 15.5 + 2.2. There was no difference between urban and rural areas. In male, specific incidence rates remained stable with age; in female, they were 2 fold higher after 50 year old than before this age. Diagnosis was carded out by GPs in half of cases. The outcome was recovery for 56 patients and death for 3. The main drugs implicated were psychotrops, antibiotics and hypolipidaemic drugs. Our results suggest that the number of hepatic ADRs in the French population would be 30 times greater than that notified by spontaneous reporting to French regulatory authorities. In conclusion, this study shows that incidence and seriousness of drug induced hepatitis are largely underestimate in a general population. These results may be useful for further evaluation of drug-induced bepatotoxicity.
~ 9 - ~ INFLUENCES OF HFE MUTATIONS ON IRON INDICES IN HEALTHY BLOOD DONORS Raffaella Mafiani 1, Alessandra Salvionil, Viviana Mauri 1, Laura Fossati 1, Cristina Arosio 2, Alessia Riva 1, Anna Vergani 1, Valentina Baldini 3, Paolo Cerntti 4, Alberto Piperno 1. i Clinica Medica,
Universitfi Milano Bicocca Ospedale San Gerardo Monza; 21stituto Auxologico Italiano Ospedale San Luca Milano ; 3Servizio Immunotrasfusionale Laboratorio di Ematologia Ospedale San Gerardo Monza; 4Unita Operativa Autonoma di Medicina Trasfusionale Ospedale San Biagio Domodossola, Italy Background: Hereditary hemochromatosis is common in Italian populations of Northern descent. Screening donors for hemochromatosis will identify subjects with the disease and those with raised iron indices. Aim: To evaluate whether blood donors carrying one or more HFE mutations have a lower risk to develop iron deficiency we measured iron indices, frequency of blood donations and HFE genotypes in healthy blood donors originating from Northern Italy. Materials and methods. 606 healthy blood donors from the Blood Bank of San Gerardo Hospital in Monza (group A) and 319 from Domodossola (group B) were enrolled. Average number of donations per months and hemoglobin levels were estimated in all blood donors; serum iron and ferritin were considered as indices of iron status in group A and in group B, respectively. C282Y, H63D and $65C were analysed in all the individuals, whereas W 169X and E 168X nonsense mutations in group A and group B, respectively. Results: The number of donations per months and levels of hemoglobin at last donation were not significantly different in blood donors divided according to HFE genotypes in each group, considered separately. In group A, serum iron at last donation, significantly increased from HFE wild type to H63D heterozygotes, to C282Y heterozygotes, and to C282Y/H63D compound heterozygotes. Serum ferritin was not significantly different according to HFE genotypes in the group studied. Conclusion: Blood donors, heterozygotes for HFE mutations have similar amounts of iron stores as those with the wild type genotype, but have a lower risk of developing iron deficient erythropoiesis.
University of Florence, Florence, Italy Colon cancer metastasis in the liver develop in 40-50% of patients after removal of the primary tumor. During cancerogenesis the stromal component may influence malignant behaviour of neoplastic epithelial cells, through the secretion of soluble factors. Organ preference for metastatic colonization is influenced by dynamic molecular cross-talk between the cancer cells and the target host tissue, particularly mesenchymal elements. We evaluated whether activated human HSC play a role in influencing the proliferative and invasive phenotype of a human colon carcinoma cell line (clone A). Proliferation assay was performed by challenging clone A cells with HSC conditioned medium (HSC-CM). Clone A migration and invasion were assessed by using a modyfied Boyden chamber tecnique. Incubation with HSC-CM did not increase colon cancer cell proliferation, but, interestingly, induced changes in cell morphology, such as filopodia formation, and scattering. These features were associated by reorganization of cytoskeletal actin, as evaluated by immunofluorescence assay. Scattering induced by HSC-CM was comparable to that observed after cell stimulation with hepatocyte growth factor/scatter factor (HGF/SC). As expected, HGF/SF effect on clone A was blocked by using anti-c Met antibody. Conversely, HSC-CM mediated scatter effect was not inhibited by anti-c Met antibody. It is therefore conceivable that factor(s) other than HGF/SF could be involved in this effect. Furthermore, HSC-CM enhanced colon carcinoma cell motility and invasion. These findings indicate that liver microenviroument may favor the invasive behaviour of colon carcinoma cells, by inducing cytoskeletal remodeling and scattering.
~-5-1 WHAT THE PATIENTS KNOW ABOUT HEPATITIS C INFECTION AND HOW HCV INFECTION AFFECTS THEIR LIFE-STYLE? Giulia Tositti l, Paolo Fabris ] , Annarosa Floreard 2, Alessandro Grasso 3, Sidarta Canton2, Elena Pignattafi 1, Clara Stecca 1, Mafia Teresa Giordani 1, Fausto De Lalla 1. 1Dept. of Infectious Diseases, San
Bortolo Hospital, Vicenza; 2Dept. of Surgical and Gastroentemlogical Sciences, University of Padua; 3Dept. of Internal Medicine Savona, Italy Aims: To evaluate the grade of knowledge on HCV infection in a consecmive series of HCV-posive patients, and to assess how HCV positivity affects their life-style before and after the first consultation in 3 centres from Northern Italy. Methods: An anonymous self-administered multiple-choice questionnaire was administered to 177 HCV-positive (Group A) attending the out-patient clinic for the first time, and to 92 pts (Group B) at the second or third visit. The areas explored by the questionnaire were: source of infection, psychological sphere, sexual behaviour, diet, alcohol intake and therapy. Results: The two groups were comparable in term of sex, age, and social level. At the first visit, 47% of subjects knew the source of infection. The sources of information were: general practitioner 45%, magazines 23%, friends 20%, others 22%. HCV positivity worsened psychological status in 36.4% of cases, and modified sexual behaviour, diet, alcohol intake in 20%, 40%, and 15.3%, respectively; The grade of knowledge on HCV infection improved after the first visit, particularly concerning transmission and behaviour, but their psychological status remained unchanged (Group A 36.4% vs Group B 35%). Fifty-percent of patients thought that a specific treatment is necessary and this rate didn't change after the first consultation. Overall, the need of more information on HCV infection significantly improved thereafter (Group A 92% vs Group B, 71%, p < 0.05). Conclusions: An education program should be addressed to the general practitioners. At the mean time, our data support the idea that counselling should be improved by the specialists.