- Email: [email protected]
Inherited trombophilic disorders in patients with portal vein thrombosis
Genetics, genetic disease, gene therapy
[ PIC10105 ]
[ P/C10/07 ]
HEPATIC PATHOLOGY IN C282Y/I-I63D COMPOUND HETEROZYGOTES M. Schtniger-Hekele, E Wrba 1, E. Penner, Ch. Miiller, E Ferenci Univ. Klinik ftir Inhere Medizin IV, University of Vienna, Austria. 1Klinisches Institut far klinische Pathologic, University of Vienna, Austria.
INHERITED TROMBOPHILIC DISORDERS IN PATIENTS WITH PORTAL VEIN THROMBOSIS L. Amitrano, M.A. Guardascione, V. Brancaccio l, M. Margaglione2, RR.J. Ames3, G. D'Andrea 2, L. Iannaccone l, A. Balzano Gastroenterology Unit, A. Cardarelli Hospital, Naples, Italy. 1Coagulation Unit, A. Cardarelli Hospital, Naples, Italy. 2Aterosclerosis and Thrombosis Unit, I.R.C.S. Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy. 3Department of Haematology, Guy's & St. Thomas' Hospital Trust, London, UK. Portal vein thrombosis (PVT) is a rare disease. Its pathogenesis is often multifactorial and may have different causes in cirrhotic (CC) and non cirrhotic CNC) patients. AIM:we investigated the presence and the role of inbedted thrombophilic disorders of coagulation in a group of CC and NC patients with PVT. METHODS: the prevalence of lupus anticoagulant, anticardiolipin antibodies (ACA), protein C deficiency, protein S deficiency, antithrombin Ill deficiency, factor V Leiden (FVL) mutation, G20210A mutation of prothromhin (PTHR A 2021o ) and TT677 mutation of methylenetetrahydrofolate reductase (MTI-IFR C. 6~...> T) were evaluated in 23 CC and 14 NC patients with PVT and compared with a population of 431 healthy controls (HC) of the same geographical area. RESULTS: no CC or NC patients had lupus anticoagulant or tested ~ositive for ACA. Patients HC (431) c c (23) NC 04) 1 (7.1%) Protein C 0 Protein S 1 (7.1°/'o) AT III 0 FVL 3 (13%) 22 (5.1%) PTHR A 2o21o 8 (34.8%) * 20 (4.7%) MTI-]FR C 677 _> T 10 (43.5%) * 3 (21.4%) 78 (18.1%) P < 0.001 CONCLUSIONS : inherited thrombophilic coagulation disorders seem to have a role in the pathogenesis of portal vein thrombosis in cirrhotic but not in non cirrotic patients.
Backoround: While hepatic pathology of homozygotic carriers of the mutation for hemochromatosis is well defined, the impact of the compound heterozygotic carrier state is unknown. Aims: To evaluate the range of hepatic pathology in compound heterozygotic patients for hemochromatosis-associated mutations C282Y/H63D of the HFE gene. Patients: In our institution within 3 years 31 patients with compound heterozygosity for C282Y/H63D were detected by molecular biology techniques. Liver biopsies were available from 14 patients. Methods: The extent of light microscopic changes of liver architecture was studied on H.E. stains. In addition, the extent and the distribution of iron deposition was studied by histochemistry (prussian blue stain) and hepatic iron was quantitatied by atom absorption spectroscopy. In addition, serum ferritin concentration and transferrin saturation was measured. Results: 10 (71%) of 14 patients reveal some type of hepatic pathology. We found only one patient with portal tract and Iobular inflammation, but fibrosis in 10 patients; In 9 of them no accompanying inflammatory reaction was noted. Stainable iron was detected in 9 (64%) patients and was found in 5 patients in 25-75% and in 4 patients in more than 75% of hepatocytes. Iron was seen in Rappaport zone 1 and 2 in all 9 patients with stainable iron and in 5 patients also in Rappaport zone 3. Mean hepatic iron was 2150 (range: 494-6813) pg/g dry weight, the mean hepatic iron index was 0.72 (range: 0.21-1.88). In 3 of 14 patients (21%) serum iron saturation was greater than 45% and serum ferritin concentration was above the upper limit of normal in 9 patients. 3 patients suffered from liver cirrhosis, two of them had also hepatocallular carcinoma, one patient had chronic hepatitis C; all other patients were clinically asymptomatic. Conclusion: Compound heterozygosity for C282Y/H63D mutations of the HFE gene is associated with significant histologic changes in the liver. Thus, liver biopsy should be performed in those patients.
I P/C10/06 I
[ P/C10/08 ]
RESTRICTING HFE GENOTYPING TO PATIENTS WITH A TRANSFERRIN SATURATION >60% IS A COST EFFECTIVE SCREENING STRATEGY IN LIVER CLINIC PATIENTS S. Moodie, L. Ang, G.E. Levin, J. Stenner, V. Murdav, J.D. Maxwell St. George's Hospital and Medical School, London SW17 ORE, UK. Testing for the Cys/tyr (C282Y) genotype that is homozygous in approximately 90°/0 of patients with hereditary haemochromatosis may provide a suitable screening test. Aims: to determine the most cost effective strategy for screening patients with liver disease for genetic haemochromatosis based on serum iron markers and ethnic origin. Method~: 326 patients with significant liver disease from an ethnically mixed London population were tested for FIFE genotype. Non-fasting serum ferritin if) and transfarrin saturation (TFS) were measured in most patients. Ethnic origin was determined from family history. Genomic DNA was prepared from EDTA blood, amplified by PCR, and C282Y mutations detected by restriction fragment length analysis. Results: C282Y mutations were only found in patients of Northern European origin (including Celts), of which 140 were heterozygotes and 3.5% were homozygotes. Assuming a £5 cost for each iron marker, and £40 for genotyping, we calculated the cost per patient screened and sensitivity for detecting C282Y homozygotes Jsing the following testing sWat, Ferritin TFS Genotypins~ Sensitivity Cost All patients All patients All patients 100% £50 £18.60 If F>200mcg/l 86% All patients None £13.81 If F>200mc~/l 86% N. European None If F>200mcg/l 71% £5.82 None Celtic £9.73 IfTFS >60% 86% All patients None If TFS >60% 86% £7.75 N.European None If "ITS >600/0 £3.29 57% None Celtic Conclusions: In our study population the most cost-effective and sensitive screening strategy to detect genetic haemochromatosis was to only measure transferrin saturations in patients of Northern European origin, and to perform genotyping when the TFS is > 60%.
THE DISTRIBUTION OF HAEMOCHROMATOSIS GENE MUTATIONS WITHIN A MULTIRACIAL SOUTH LONDON POPULATION S. Moodie, L. Ang, J. Stenner, A. Fisher, V. Murda¥, J.D. Maxwell St. George's Hospital and Medical School, London SW17 ORE, UK. Recently two genotypes have been associated with around 90% of phenotypic haemochromatosis, homozygosity for Cys/Tyr (C262Y), and compound heterozygotes with His/Asp (H63D). Several population studies have shown that genetic haemochromatosis is predominately a disorder of people of European ancestry, and that the highest prevalence may be in people of Celtic origin. Aims: To determine the relationship between ethnic origin and FIFE gene mutations in an ethnically mixed population of South London. Mgth0~l~: Ethnic origin was determined from family and social history in a prospective study of 326 patients with liver disease referred to a medical clinic. Those with a parent or grandparent from Scotland, Ireland, Wales or Cornwall were classed as Celtic. Genomic DNA was prepared from EDTA blood, amplified by PCR and C282Y and H63D mutations determined by restriction fragment length analysis. Results: (hh= Xe ,hH=heterozygote, Wt=Wild-type) Racial origin Total" C282Y (Cy~ tTyr) H63D (His/Asp) hh hH Wt hh hH Wt Northern European 146 2 18 126 4 41 101 Celtic 83 6 14 63 2 14 67 Others 94 0 0 94 0 20 74 Total 323 8 32 283 6 75 242 Conclusion; The C282Y mutation was found exclusively in patients of Northern European and Celtic descent, and more frequently amongst Celts than other Northern Europeans (P<0.05). The His/Asp (H63D) mutation was more widely distributed, though still more common amongst Northern Europeans and Celts than others (p<0.05).
133
[ PIC10105 ]
[ P/C10/07 ]
HEPATIC PATHOLOGY IN C282Y/I-I63D COMPOUND HETEROZYGOTES M. Schtniger-Hekele, E Wrba 1, E. Penner, Ch. Miiller, E Ferenci Univ. Klinik ftir Inhere Medizin IV, University of Vienna, Austria. 1Klinisches Institut far klinische Pathologic, University of Vienna, Austria.
INHERITED TROMBOPHILIC DISORDERS IN PATIENTS WITH PORTAL VEIN THROMBOSIS L. Amitrano, M.A. Guardascione, V. Brancaccio l, M. Margaglione2, RR.J. Ames3, G. D'Andrea 2, L. Iannaccone l, A. Balzano Gastroenterology Unit, A. Cardarelli Hospital, Naples, Italy. 1Coagulation Unit, A. Cardarelli Hospital, Naples, Italy. 2Aterosclerosis and Thrombosis Unit, I.R.C.S. Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy. 3Department of Haematology, Guy's & St. Thomas' Hospital Trust, London, UK. Portal vein thrombosis (PVT) is a rare disease. Its pathogenesis is often multifactorial and may have different causes in cirrhotic (CC) and non cirrhotic CNC) patients. AIM:we investigated the presence and the role of inbedted thrombophilic disorders of coagulation in a group of CC and NC patients with PVT. METHODS: the prevalence of lupus anticoagulant, anticardiolipin antibodies (ACA), protein C deficiency, protein S deficiency, antithrombin Ill deficiency, factor V Leiden (FVL) mutation, G20210A mutation of prothromhin (PTHR A 2021o ) and TT677 mutation of methylenetetrahydrofolate reductase (MTI-IFR C. 6~...> T) were evaluated in 23 CC and 14 NC patients with PVT and compared with a population of 431 healthy controls (HC) of the same geographical area. RESULTS: no CC or NC patients had lupus anticoagulant or tested ~ositive for ACA. Patients HC (431) c c (23) NC 04) 1 (7.1%) Protein C 0 Protein S 1 (7.1°/'o) AT III 0 FVL 3 (13%) 22 (5.1%) PTHR A 2o21o 8 (34.8%) * 20 (4.7%) MTI-]FR C 677 _> T 10 (43.5%) * 3 (21.4%) 78 (18.1%) P < 0.001 CONCLUSIONS : inherited thrombophilic coagulation disorders seem to have a role in the pathogenesis of portal vein thrombosis in cirrhotic but not in non cirrotic patients.
Backoround: While hepatic pathology of homozygotic carriers of the mutation for hemochromatosis is well defined, the impact of the compound heterozygotic carrier state is unknown. Aims: To evaluate the range of hepatic pathology in compound heterozygotic patients for hemochromatosis-associated mutations C282Y/H63D of the HFE gene. Patients: In our institution within 3 years 31 patients with compound heterozygosity for C282Y/H63D were detected by molecular biology techniques. Liver biopsies were available from 14 patients. Methods: The extent of light microscopic changes of liver architecture was studied on H.E. stains. In addition, the extent and the distribution of iron deposition was studied by histochemistry (prussian blue stain) and hepatic iron was quantitatied by atom absorption spectroscopy. In addition, serum ferritin concentration and transferrin saturation was measured. Results: 10 (71%) of 14 patients reveal some type of hepatic pathology. We found only one patient with portal tract and Iobular inflammation, but fibrosis in 10 patients; In 9 of them no accompanying inflammatory reaction was noted. Stainable iron was detected in 9 (64%) patients and was found in 5 patients in 25-75% and in 4 patients in more than 75% of hepatocytes. Iron was seen in Rappaport zone 1 and 2 in all 9 patients with stainable iron and in 5 patients also in Rappaport zone 3. Mean hepatic iron was 2150 (range: 494-6813) pg/g dry weight, the mean hepatic iron index was 0.72 (range: 0.21-1.88). In 3 of 14 patients (21%) serum iron saturation was greater than 45% and serum ferritin concentration was above the upper limit of normal in 9 patients. 3 patients suffered from liver cirrhosis, two of them had also hepatocallular carcinoma, one patient had chronic hepatitis C; all other patients were clinically asymptomatic. Conclusion: Compound heterozygosity for C282Y/H63D mutations of the HFE gene is associated with significant histologic changes in the liver. Thus, liver biopsy should be performed in those patients.
I P/C10/06 I
[ P/C10/08 ]
RESTRICTING HFE GENOTYPING TO PATIENTS WITH A TRANSFERRIN SATURATION >60% IS A COST EFFECTIVE SCREENING STRATEGY IN LIVER CLINIC PATIENTS S. Moodie, L. Ang, G.E. Levin, J. Stenner, V. Murdav, J.D. Maxwell St. George's Hospital and Medical School, London SW17 ORE, UK. Testing for the Cys/tyr (C282Y) genotype that is homozygous in approximately 90°/0 of patients with hereditary haemochromatosis may provide a suitable screening test. Aims: to determine the most cost effective strategy for screening patients with liver disease for genetic haemochromatosis based on serum iron markers and ethnic origin. Method~: 326 patients with significant liver disease from an ethnically mixed London population were tested for FIFE genotype. Non-fasting serum ferritin if) and transfarrin saturation (TFS) were measured in most patients. Ethnic origin was determined from family history. Genomic DNA was prepared from EDTA blood, amplified by PCR, and C282Y mutations detected by restriction fragment length analysis. Results: C282Y mutations were only found in patients of Northern European origin (including Celts), of which 140 were heterozygotes and 3.5% were homozygotes. Assuming a £5 cost for each iron marker, and £40 for genotyping, we calculated the cost per patient screened and sensitivity for detecting C282Y homozygotes Jsing the following testing sWat, Ferritin TFS Genotypins~ Sensitivity Cost All patients All patients All patients 100% £50 £18.60 If F>200mcg/l 86% All patients None £13.81 If F>200mc~/l 86% N. European None If F>200mcg/l 71% £5.82 None Celtic £9.73 IfTFS >60% 86% All patients None If TFS >60% 86% £7.75 N.European None If "ITS >600/0 £3.29 57% None Celtic Conclusions: In our study population the most cost-effective and sensitive screening strategy to detect genetic haemochromatosis was to only measure transferrin saturations in patients of Northern European origin, and to perform genotyping when the TFS is > 60%.
THE DISTRIBUTION OF HAEMOCHROMATOSIS GENE MUTATIONS WITHIN A MULTIRACIAL SOUTH LONDON POPULATION S. Moodie, L. Ang, J. Stenner, A. Fisher, V. Murda¥, J.D. Maxwell St. George's Hospital and Medical School, London SW17 ORE, UK. Recently two genotypes have been associated with around 90% of phenotypic haemochromatosis, homozygosity for Cys/Tyr (C262Y), and compound heterozygotes with His/Asp (H63D). Several population studies have shown that genetic haemochromatosis is predominately a disorder of people of European ancestry, and that the highest prevalence may be in people of Celtic origin. Aims: To determine the relationship between ethnic origin and FIFE gene mutations in an ethnically mixed population of South London. Mgth0~l~: Ethnic origin was determined from family and social history in a prospective study of 326 patients with liver disease referred to a medical clinic. Those with a parent or grandparent from Scotland, Ireland, Wales or Cornwall were classed as Celtic. Genomic DNA was prepared from EDTA blood, amplified by PCR and C282Y and H63D mutations determined by restriction fragment length analysis. Results: (hh= Xe ,hH=heterozygote, Wt=Wild-type) Racial origin Total" C282Y (Cy~ tTyr) H63D (His/Asp) hh hH Wt hh hH Wt Northern European 146 2 18 126 4 41 101 Celtic 83 6 14 63 2 14 67 Others 94 0 0 94 0 20 74 Total 323 8 32 283 6 75 242 Conclusion; The C282Y mutation was found exclusively in patients of Northern European and Celtic descent, and more frequently amongst Celts than other Northern Europeans (P<0.05). The His/Asp (H63D) mutation was more widely distributed, though still more common amongst Northern Europeans and Celts than others (p<0.05).
133