A1456 AASLD ABSTRACTS

6600

MUTATION ANALYSIS OF TRANSFORMING GROWTH FAC­TOR BETA TYPE I RECEPTOR, TYPE II RECEPTOR, SMAD2,SMAD4, SMAD6 AND SMAD7 IN HEPATOCELLULAR CARCI­NOMA.Susumu Kawate, Susumu Ohwada, Hamada Kunihiro, Toru Koyama,Ichiro Sakamoto, Daisuke Yoshinari, Mureo Kasahara, Naoki Tomizawa,Yoshiyuki Kawashima, Izumi Takeyoshi, Yasuo Morishita, Second Deptof Surg, Gunma Univ Sch of Med, Maebashi, Japan; Second Dept of Surg,Maebashi, Japan.

Object: Mutations of transforming growth factor beta type I receptor(TGFbRI), TGFbRII, Smad2, and Smad4 genes have been detected inseveral human cancers, but there is no report of mutation analysis of Smad6and Smad7 genes in any human cancers. Furthermore, mutations of theentire coding regions in these genes have not been analyzed in hepatocel­lular carcinoma (HCC), and the role of these genes in hepatocarcinogenesisremains unkown. We designed intron-based primer pairs for mutationanalysis of the entire coding regions in these genes, and screened HCC formutations of these genes. Materials and Methods: DNA from pairedsamples of HCC and non-tumorous liver tissue was examined for muta­tions in the complete TGFbRI, TGFbRII, Smad2, Smad4, Smad6, andSmad7 coding sequencesusing polymerase chain reaction-single-strandconformational polymorphism. Serum hepatitis B surface antigen (HBsAg)was positive in six patients, and the antibody to hepatitis C virus (HCVAb)was positive in patients. Both HBsAg and HCVAbwere negative in sixpatients. Results: We detected no mobility shifts, and sequence analysisdemonstrated no point mutations of TGFbRI, TGFbRII, Smad2, andSmad4 genes. Polymorphisms of the exon4 and intron2 of Smad6 weredetected, and polymorphisms of the exon4 and intron2 of Smad7 were alsodetected. However, we detected no point mutations of Smad6 and Smad7genes. Conclusion: Mutations of TGFbRI, TGFbRII, Smad2, Smad4,Smad6, and Smad7 genes are rare in human HCC. In order to determinewhether there are additional mechanisms leading to escape from theantimitogenic response to TGF-beta in HCC cells during tumor progres­sion, genes and proteins of other members associated with the TGF-betasignal transduction pathway must be analyzed.

6601

TREATMENT OF CHOLANGIOCARCINOMA COMPLICATINGPRIMARY SCLEROSING CHOLANGITIS: THE MAYO CLINICEXPERIENCE.Muhsin Kaya, Piet C. de Groen, Paul Angulo, Keith D. Lindor, Mayo Clin,Rochester, MN.

Delayed diagnosis and advanced stage of cirrhosis frequently precludepotentially curative resection of cholangiocarcinoma (CCA) in primarysclerosing cholangitis (PSC). AIMS: The aims of this retrospective studywere to assess the frequency of use of different treatment for these patients.METHODS: A total of 41 patients who had known CCA complicating PSCwith median age of 49 years (range, 27-75) were identified from a group of1009 patients (4%) with PSC seen over 10 years. RESULTS: Thesepatients received mainly five forms of treatment. Ten patients were treatedwith radiation therapy with or without 5-fluorouracil (5-FU), 9 with stentplacement for cholestasis, 12 with conservative treatment, 4 with surgicalresection, and 3 patients with orthotopic liver transplantation (OLT). Onepatient was treated with 5-FU alone, one was treated with photodynamictherapy and one patient with somatostatin analogue. Thirty-six patientsdied and 4 (10 %) patients survived (2 with surgical resection, I with OLT,and I with stent placement) during a median follow-up of 5.5 months(range, 1-75). One patient was lost to follow-up. CONCLUSION: In highlyselective cases, OLT and resective surgery seem to be of benefit for PSCpatients with CCA. However, these therapies are rarely applied to thesepatients because of the advanced nature of the disease at the time ofdiagnosis. Efforts should be desirable at earlier identification of potentialsurgical candidates.

6602

THE RELATION BETWEEN THE STAGE OF CHRONIC LIVERDISEASE AND THROMBOCYTE FUNCTIONS.Muhsin Kaya, Aylin Yaman, Sule Mine Bakanay, Nazmiye Kursun, SelimKarayalcin, Ankara Univ Sch of Med, Ankara, Turkey; Ankara Univ,Ankara, Turkey.

BACKGROUND: Abnormalities in thrombocyte number and function mayincrease the tendency for bleeding in the setting liver cirrhosis. AIM: Ouraim in this study is to determine the relation between the stage of liverdisease and thrombocyte function. METHODS: A total of 42 cases (23male, 19 female; with a mean age of 44.8 years) including 17 cirrhosis, 15chronic active hepatitis (CAH) and 10 healthy control were studied. In allcases complete blood count, bleeding time, prothrombin time, blood chem­istries were determined as well as maximum aggregation rate (MAR),maximum aggregation severity (MAS) and adenosine 3 phosphate (ATP)secretion upon stimulation with three different agent (ADP, collagen andristocetin) were studied. Significance of differences among groups wasdetermined by Kruskal-Wallis variance analysis test. RESULTS: Meanthrombocyte number in patients with cirrhosis was 61X 109/L, in patientswith CAH was 173X109/L, and in the control group was 191XI09/L.

Thrombocyte counts in cirrhosis group were found to be significantlylower, compared to the CAH and control group (p<O.OOI). There was no

GASTROENTEROLOGY Vol. 118, No.4

significant difference between CAH and control group for any parameter.Mean MAR and mean MAS resulting with ADP, collagen and ristocetinwere significantly lower in cirrhosis group (p<0.05). Mean ATP secretionlevels inducting with collagen and ristocetin were significantly lower incirrhosis group (P<0.05). The decrease in thrombocyte aggregation rate,aggregation severity and ATP secretion were found to be independent ofthrombocyte number. CONCLUSION: In the CAH stage of liver disease,no significant numeric or functional abnormality of thrombocytes wasdetected. But in cirrhotic stage, there was significant decrease in thrombo­cyte number and functional abnormalities without causing significant elon­gation of bleeding time.

6603

OVERLAP OF AUTOIMMUNE HEPATITIS WITH THE NEWLYMODIFIED SCORING SYSTEM.Muhsin Kaya, Paul Angulo, Keith D. Lindor, Mayo Clin, Rochester, MN.

The overlap of diagnostic criteria between autoimmune hepatitis (AIH) andprimary sclerosing cholangitis (PSC) has been reported previously to rangefrom 35% to 54%. AIM: The aim of this study was to compare thefrequency of diagnostic criteria for AIH in patients with cholangiographi­cally proven PSC using a recently modified scoring system proposed by theInternational Autoimmune Hepatitis Group for the diagnosis of AIH to theolder system. METHODS: A total of 211 untreated PSC patients including78 women and 133 men with a mean age of 43 years (range, 15-78) wereevaluated retrospectively. RESULTS: Three (1.4%) patients scored morethan IS points satisfying the diagnosis of 'definite' AIH; 13 (6%) patientsscored between 10 to IS points and could be classified as 'probable' AIHwhile the remaining 195 (93%) patients had less than 10 points allowingthe exclusion of AIH. The separation of patients with PSC plus AIH frompatients with PSC alone was mostly based on significantly higher serumlevels of total globulins, IgG, titers of autoantibodies and a higher histo­logic score (table). Using the previously published older scoring system 4(2%) patients had the diagnosis of 'definite' AIH while 40 (19%) patientshad the diagnosis of 'probable' AIH. CONCLUSIONS: The clinical Over­lap of PSC and AIH occurs uncommonly, The new scoring system seemsto better exclude the diagnosis of AIH in patients with PSC and define theoverlap between PSC and AIH, although further modification of the newscoring system may provide even better discrimination among these con­ditions and a better recognition of those few patients with to have overlap.

PSC AIH Pvalue('probable'+'Definite')

Total globulin (g/dl) 34± 0.06 3.9±01 0.01IgG(mg/dl) 1556±47 2379 ± 278 0.001ANA and/or ASMA «1:40) 03 ± 0.05 1.8±03 <0.001Total histologic score -0.8 + 0.2 018± 0.3 <0.001

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CHANGES IN LIPID PROFILE DURING COMBINATION THER­APY WITH ALPHA-INTERFERON AND RIBAVIRIN IN PA­TIENTS WITH CHRONIC HEPATITIS C. IS THERE A CORRE·LATION WITH RESPONSE TO THERAPY?Lele Kazerni-Shirazi, Harald Hofer, Peter Vukovich, Karam Kostner, Al­fred Gangl, Peter Ferenci, Univ of Vienna, Vienna, Austria.

Background: Several investigators have described changes in lipid profile(Triglycerides, ApoAI, Cholesterol) of hepatitis C patients under inter­feron monotherapy. Additionally, Apo AI levels at baseline have beenshown to be predictive for response to therapy. Data regarding alterationsin lipid metabolism under interferonlribavirin combination therapy withribavirin are lacking. Aim: Aim of this study was to evaluate changes inlipid profile under combination therapy and their possible correlation withresponse. Methods: We examined sera from 35 consecutive patients(m=26, f=9) with chronic hepatitis C enroled in a treatment trial withinterferonlribavirin combination therapy (Intron A 5-IOMU/d for 14wks,then every 2nd day, Ribavirin 100/1200 mg/d, Schering Plough Corp). Wedetermined AST, ALT, hemoglobin and fasting lipids (triglycerides, cho­lesterol) and (apo)lipoprotein (apo Al,-A2, -B, -E,-C2, lipoprotein A)levels at baseline, week 2 and every 4 weeks thereafter until week 38 (endof therapy). Results: Triglyceride levels increased significantly from base­line (B)105 ±7 to 175±27 mg/dl (week 2, p<O.OI) and 168± 13 (week 6,p<O.OOI).and stayed elevted throughout therapy. Levels ApoAl at base­line did not correlate with response to therapy, but levels dropped signif­icantly from 142±5 (B) to 121±4 (wk2, p<O.OOI) and 116±5mg/dl (wk6, p<O.OO I) and stayed decreased until the end of therapy.. Values asmeanz se, Levels of cholesterol, Lipoprotein (a) and apo A2, -B, -E,-C2did not change with therapy. Summary/Conclusions: Interferonlribavirintreatment in chronic hepatitis C transiently causes marked increases inserum triglyceride levels and decreases in apo-A1 and lipoprotein A, Asapo-AI is the main component of HDL, its decrease could reflect an HDLdrop. Together with anemia caused by ribavirin and hypertriglyceridemiathis might increase the risk in patients with silent coronary heart disease.