HEPATOLOGY Vol. 34, No. 4, Pt. 2, 2001 AASLD ABSTRACTS 507A

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HEPATIC INVOLVEMENT IN TURNER SYNDROME: IDIOPATHIC AND HETEROGENEOUS LESIONS SUGGESTING A ROLE FOR VASCULAR ORIGIN. Dominique Roulot, Avicenne Hosp, Bobigny France; Claude Degott, geaujon Hosp, Beaujon France; Olivier Chazouilleres, Saint-Antoine Hosp, Paris France; kaurent Castera, Jean Verdier Hosp, Bondy France; Frederic Oberti, Angers Hosp, Angers France; Nicolas Carbonell, Saint-Antoine Hosp, Paris France; Said Benferhat, Beaujon Hosp, Beaujon France; Paul Cales, An- gers Hosp, Angers France; Dominique Valla, Beaujon Hosp, Beaujon France

Background & Aims: Liver tests abnormalities have been reported with a high prevalence (20 to 80%) in patients with Turner syndrome (TS). However, the nature and etiology of underlying histological lesions are poorly known. The aim of this study was to characterize hepatic anatomical features and their outcome in patients with TS. Methods : 23 patients (mean age 43216 yrs) followed since the time of discovery of liver tests abnormalities until 2001 (mean follow-up 8.625.6 yrs) were studied. Etiological investigations, including viral tests, auto-antibodies, ferritine- mia, ceruloplasmin, alpha-l-antitrypsin, ultrasound, ERCP (n=9) were performed in all patients. 20 patients underwent a liver biopsy. In one patient who underwent orthotopic liver transplantation (OLT), the entire explanted liver was examined. Results : 20 patients had increased transaminasis levels (AST 2.020.8 N; ALT 2.5-+1.7 N), 21 elevated GGT (1.7+-1.2 N) and 16 elevated AP (5.7+-1.7 N). No etiology for chronic liver disease was found in 21 patients. None of the patient had biliary tree lesions. Discontinuation of oestroprogestative therapy in 6 patients was not associated with improvement of liver tests. Histological lesions were: a) mac- rovesicular steatosis (n= 10), mild fibrosis (n= 19), inflammatory lesions (n= 12), non alcoholic steato-hepatitis (NASH) (n= 3), b) biliary canalicular lesions: concen- tric fibrosis(n=5), ductular proliferation (n=4), c) vascular lesions including nod- ular regenerative hyperplasia (n=4), peliosis (n= 1), hepatoportal sclerosis (n= 1) and incomplete septaI cirrhosis (n = 2). Patients were divided into 2 groups accord- ing to the existence of architectural abnormalities, group 1 (n = 7): septal fibrosis and nodular regeneration ; group 2 (n=13): normal liver architecture. In patients of group 1 as compared with those of group 2: portal hypertension and aortic vascular malformations (bicuspidy and coarctation) were significantly more frequent: 6/7 vs 0/13, (p=0.005) ; 5/7 vs 1/13, (p<0.001), respectively ; GGT values tended to be higher, and prothrombin time to be lower, however, the difference did not reach :statistical significance. During follow-up, 2 patients in group 1 developed liver [allure leading to death in one and to OLT in the other one. Conclusion : Although iheterogeneous, hepatic involvement in Turner syndrome is characterized by a high frequency of architectural abnormalities (30%). The association of such abnormal- ities with aortic malformations suggests a role for vascular origin, possibly hepatic microcirculation alterations. These lesions should be search for in the management of patients with Turner syndrome and liver test abnormalities because of potential :severe outcome.

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GENETIC MAPPING OF A LOCUS FOR FAMILIAL HYPERCHOLANE- MIA. Victoria E Carlton, University of California, San Francisco, San Fran- cisco, CA; Erik Puffenberger, Clinic for Special Children, Strasburg, PA; A S Knisely, King's College Hospital, London Uk; Benjamin Shneider, Mount Sinai School of Medicine, New York, NY; D Holmes Morton, Clinic for Special Children, Strasburg, PA; Gerald Salen, UMDNJ-New Jersey MedicaI School, East Orange, NJ; Laura Bull, University of Cahfornia, San Francisco, San Fran- cisco, CA

We have previously identified several Amish children with elevated serum bile acid concentrations and failure to thrive. The index case, who has been exten- sively studied, shows low biliary and hepatic bile acid levels and increased hepatic bile acid synthesis. The severity of the disease is variable. Serum bile acid levels show large fluctuations in these children, from 5 to 149/xg/ml, with most measurements over 30/zg/ml (normal is 1.1 b~g/ml). The disease presen- tation suggests a defect in the hepatic uptake of conjugated bile acids; patients respond well to ursodeoxycholic acid therapy. The inheritance pattern is con- sistent with a highly penetrant, autosomal recessive disease. We have com- pleted a genome screen using 800 highly potymorphic markers and 22 DNA samples from 6 Amish families. For our initial analysis we are using a conser- vative approach by considering affected only those 5 patients who meet the following strict criteria: at least two serum bile acid measurements over 30 #g/ml (the child must have been over one year old for at teast one of the measurements) and absence of jaundice. Three additional patients who do not meet these criteria have been genotyped and may be used in further analyses. As all of these patients are from an isoIated population, the Amish, we are using a linkage disequlibrium approach to map the gene; we expect that the patients have inherited the disease-causing mutation from one (or possibly two) com- mon ancestor(s) who introduced the mutation(s) into the population. Hence at the disease locus and in the flanking DNA, the patients will be genetically identical, sharing a common haplotype (or two, if two ancestors introduced mutations). Markers near the disease locus will show excess allele sharing. Analysis has been completed for the 400 markers initially genotyped, which span the genome with an average spacing of 10 cM. We have identified 22 regions containing markers for which a single allele occurs with high fre- quency on patient chromosomes and are typing additional markers in these regions to identify potential shared haplotypes. Data for the additional 400 markers are currently being analyzed; These data, when combined with the data for the initial 400 markers, will cover the genome at a higher resolution, with an average spacing of 5 cM.

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SIGNIFICANCE OF HFE GENE MUTATIONS IN CHRONIC HEPATITIS C: H63D AND C282Y HETEROZYGOSITY ARE INDEPENDENT RISK ]FACTORS FOR LIVER FIBROSIS AND CIRRHOSIS. Andreas Erhardt, Hei- nrich-Heine-University Duesseldorf, Duesseldorf Germany; Andrea Mas- chner-Olberg, Heinrich-Heine University, Duesseldorf Germany; Claudia Mel- lenthin, Guenther Kappert, Ortwin Adams, Andreas Donner, Heinrich-Heine- University, Duesseldorf Germany; Claus Nierderau, Heinrich-Heine- University, Dueseldorf Germany; Dieter Haenssinger, Heinrich-Heine- University, Duesseldorf Germany

Background and Aims: The impact of HFE mutations on iron indices and the course of HCV infection was studied. Methods: Iron indices (ferritin, trans- terrin saturation [TS], serum iron), the C282Y and H63D mutations were determined in 296 healthy controls and 350 patients with chronic HCV. HCV genotypes were available in 273 and liver histologies in 182 patients. Results: Allele frequencies of the C282Y and H63D mutation did not differ between I-ICV patients and controls (7.2% vs. 6.2%, n.s.; 14.9% vs. 16.4%, n.s.). Higher iron indices were found in men but not in women with chronic HCV compared to healthy controls. HCV patients with at least one HFE gene mutation had higher ferritin (377+39/xg/L vs. I90-+16/zg/L, p<0.0005), TS (41-+2% vs. 32.1%, p<0.0005) and serum iron (i50-+6 p~g/dL vs. 123-+4 /xg/dL, p<0.0005) compared to HCV patients with wildtype HFE alleles. By multivar- iate regression analysis odds ratios for the development liver cirrhosis were 6.7 and 3.9 for patients with C282Y or H63D heterozygosity compared to HFE wildtype patients. Considering alI HCV patients with at least one HFE muta- tion odds ratio of 6.i for liver fibrosis and 5.1 for cirrhosis were calculated. Conclusion: HFE gene mutations, even in case of H63D heterozygosity, are independent risk factors for liver fibrosis and cirrhosis in HCV infected indi- viduals. Thus, screening for HFE gene mutations and phlebotomy should be considered in patients with HCV infection.

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USEFULNESS OF LIGHT AND ELECTRON MICROSCOPY IN THE DIAG- NOSIS OF NONALCOHOLIC STEATOHEPATITIS (NASH). Gabriella Verucchi, Luciano Attard, Malattie Infettive Policlinico S Orsola Malpighi, Bologna Italy; Ornella Leone, Dip to Oncologico ed Ematologico, Policlinico S Orsola - M, Bologna Italy; Paolo Costigliola, Malattie Infettive Policlinico S Orsola Malpighi, Bologna Italy; Gianandrea Pasquinelli, Dip to Oncologico ed Ematologico, Policlinico S Orsola - M, Bologna Italy; Cristina Behrami, Malat- tie Infettive Policlinico S Orsola Malpighi, Bologna Italy; Barbara Fabbrizio, Dip to Oncologico ed Ematologico , Policlinio S Orsola Malpi, Bologna Italy; Francesco Chiodo, Malattie lnfettive Policlinico SOrsola Malpighi, Bologna Italy

Aim: To study by light and electron microscopy the liver morphology of pa- tients with suspected NASH. Methods: 1 lpatients (6Males, 5Females), mean age 51,4years (range 38-63) have been selected. All had ipertransaminasemia (ALT>AST) and fatty liver by ultrasound. Alcohol and other causes of liver disease were escluded. Results: the histological criteria of NASH were present in 9/1 lcases, in 1/9patients features of chronic active hepatitis were also doc- umented. The 2 patients without NASH showed only steatosis. In 7/9(77.8%) NASH, steatosis was of mixed type (all grade3), while macrovescicular type was present in 2/9(22.2%) (one gradel, one grade2). Spotted loci of necrosis associated with inflammatory cells was observed in all. Fibrosis was present in 8/9(88.9%) of the cases (2 slight and focal, 4 gradel, 2 grade3). All morpho- logical features of NASH were milder in patients with macrovescicnlar type. Among the various uhrastructural features only the presence of mitochondrial damage correlated with the histological diagnosis of NASH. 77.7% of NASH patients showed pleomorphic mitochondria with matrix condensation and crystalline inclusions. ITO cell hypertrophy was documented in 77.8% of the NASH patients. Apoptotic hepatocytes and sinusoidal wall lymphocytes were observed in 22.2% of NASH pts only thus reflecting the focal nature of hepatitis in NASH disease. Discussion: Histological examination is crucial to diagnose NASH and is clinically useful for defining the evolutive stage of the disease. Hepatocyte mitochondria are pleomorphic with an high percentage of crystal- line inclusions of unknown composition. Whether this reflects a primitive or secondary mitochondrial damage is still matter of debate.