Autoimmune hepatitis with histologic cholangitis: A variant syndrome or an under-recognized manifestation of classical disease?

drug withdrawal (25% vs 25%), treatment failure (16% vs 23%), progression to cirrhosis (35% vs 19%), and death from liver failure or requirement for liver transplantation (8% vs 12%) occurred as frequently in women and men during comparableperiods (100-+9 months vs 102-+20 months). Women with HLA DR4 responded better to corticosteroid therapy than men and women without HLA DR4 by failing treatment less often (5% vs 21%, p=O.OO5) and requiring liver transplantation less frequently (2% vs 11%, p = 0.03). Men failed treatment more often than women only if they had HLA DR3 and the women had HLA DR4 (25% vs 4%, p=O.O2). Men with HLA DR3 and TNF-308 ANGA died of liver failure or required liver transplantation more frequently than women with HLA DR4 and TNF-308 GG (25% vs 3%, p=O.04), but TNF-3O8 ANAG did not have an independenteffect on the outcome in men. Similarly, each polymorphism of the promoter genes alone or in combination did not have a synergistic effect on treatment responsein either gender. Conclusions. Men and women have different clinical manifestations, but similar responsesto corticosteroid therapy. Women with AIH have HLA DR4 more commonly than men. HLA DR4-positive women have a better response to therapy than men and women without HLA DR4. Known polymorphisms of autoimmune promoter genes do not have an independentor synergistic effect on outcome.

PBC

Controls

ALC

Type

Yers.-lysate

CRT

RNA-pol

CD4/IFNy CD4/IL~ CD8/IFNy CD8/IL-4 CD4/IFNy CD4/IL-4 CD8/IFNy CDB/IL-4 CD4/IFNy CD4/IL-4 CD8/IFNy CD8/IL-4

45% (n=18) 21% (n=19) 44% (n=20) 26% (n=19) 66% (n=21) 23.8%(n=21) 61.9%(n=21) 19% (n=21) 53% (n=13) 7.6% (n=13) 38,4%(n=8) 0% (n=13)

20% (n=2O) 28.5%(n=21) 14% (n=20) 38% (n=21) 23.8%(n=21) 4.7% (n=21) 23.8%(n=21) 0% (n=21) 0% (n=13) 0% (n=13) 0% (n=13) 0% (n=13)

15% (n=2O) 43% (n=21) 25% (n=20) 42% (n=21) 28.6%(n=21) 14.3%(n=21) 28.5%(n=21) 14.3%(n=21) 23% (n=13) 0% (n=13) 23% (n=13) 7.6%(n=13)

1826 1824

Clincal Effect Of Long-Term (32 Weeks) Eieosapentate Administation In Primary Biliary Cirrhosis Koichiro Takagi, Morio Takahashi, Hiroshi Takada,Yoshinori Kitazumi, Takeshi Arima, Satoshi Kanozawa,Toshimi Anzai, Miho Takano, Fumihiro Kiumi, Univ Hosp at Koshigaya, Dokkyo Univ Sch, KoshigayaJapan BACKGROUNDS:Epidemiologicalresearchfound that populationswith high fish consumption have lower prevalenceof auto-immune diseases.The beneficialeffect of Eicosapentate(EPA), which is abundant in fish, in auto-immune diseasessuch as SLE and RA has been clinically demonstrated.We previously reportedthe beneficialeffect of short term (up to 8 weeks) EPA on laboratory data, such as total bile acids, of patients with primary bUiary cirrhosis (PBC). We have now extendedour study of EPAto 32 weeksof administration. METHODS:1. Patients with biopsy-documentedPBCwho were given UDCA600 mg qd for at least 24 weeks without labolatory data improvement were eligible for the study after they gave informed consent. Eight consecutivestudy patients were then given EPA 600 mg orally TID in addition to UDCA. Blood was obtained before and at 4, 8, 32 weeks weeks after study initiation for AST, ALT, total bile acids and bile acid isozymes, gammaGTP,total cholesterol, and triglycerides determinations. RESULTS: At 32 weeks after EPA co-administration, total bile acids were reduced significantly by 62.5% (24.4 +/-5.9 vs 65.1 +/-22.6, p
Utilily Of 6 Mercaptopurine Metabolite Analysis In The Management Of Children With Autoimmune Hepatitis Carolina Rumbo, Benjamin L. Shneider, Mount Sinai Sch of Medicine, New York, NY Background:Azathioprine (AZA) and 6-mercaptopurine(GMP) are used as adjunctive therapy in the treatment of autoimmune hepatitis (AIH). Potential complications such as neutropenia and hepatotoxicity make utilization of these agents problematic, especially in patients with hypersplenism associatedwith cirrhosis. Aim: To determine6MP metabolite levels and correlate with therapeutic effects, medication induced toxicity and adherenceto medication. Methods: From May 2000 to November 2000, a group of 14 pediatric patients with AIH was prospectively examined. AZA or 6MP was prescribed at an initial dose of 0.7 to 2.0 mg/kg/ day. In addition to routine biochemicalstudies, 6 thioguanine (6TG) and 6 methylmercaptopurine (6MMP) were assessed.Red blood cell thiopurine methyltransferase(RBCTMP'r) enzyme activity was assessedin six patients.AZA dose was adjustedaccordingto 6TG level (therapeutic = 200-450). Results: 31 sampleswere obtained from 14 patients; eight patients had hypersplenism when treatment was started. In 8 samples (6 patients) 6TG levels were in the therapeutic range and were associatedwith biochemical quiescence. No adjustment in dose was made. In 12 samples (7 patients) 6TG were in sub-therapeutic range (47-183), dosing was increased without complication. In 5 samples (4 patients) AZA doses did not correlate with 6TG levels (dose 0.85-2.15 mg/kg/day; 6TG level 15-98), in 4/4 patients non-adherence was admitted. In 2 samples (2 patients) the 6TG level was in the toxic range (491-695) accompanied by neutropenia; this required discontinuation of AZA in one case and dose reduction in the other; in both cases neutropenia resolved. In a third case, AZA was held due to neutropenia,6TG level was subtherapeutic,and treatment was safely restarted. RBC TMPT enzyme activity was measured in 6 patients, all levels were normal. In all patients, including three in which 6TG levels were greater than 350, 6MMP was undetectable. For adherent patients as a group, no correlation existed betweenmedicationdosing (mg/kg) and 6TG level. Therapeutic 6TG levels were observedwith AZA doses of 1.00 to 2.15 mg/kg. Subtherapeutic 6TG levels were observed with AZA doses of 0.8 to 2.5 mg/kg. Conclusion: Measurementof 6MP metabolite levels appears to be especially useful in the management of children with AIH. The absenceof measurable 6MMP despite normal red blood cell TMPT enzymeactivity suggests that hepatic enzyme activity might be clinically relevant in AIH.

1827 Autoimmune Hepatitis With Histologic Cholangitis: A Variant Syndrome Or An Under-Recognized ManifectaDon Of Classical Disease? Albert J. Czaja, Herschel A. Carpenter, Mayo Clin, Rochester, MN Background/Objective.Bile duct changes are not included within the histologic spectrum of classical autoimmune hepatitis (AIH), and their occurrence may reflect a variant syndrome with a different clinical expression and outcome. Our aim was to assess the frequency and significance of bile duct injury in type 1 AIH. Methods. Liver biopsy specimens from 84 patients were reviewed under code, and the findings correlated with clinical features and treatment response. All patients satisfied international criteria for definite (79 patients) or probable (5 patients) AIH. None had antimitochondrial antibodies, and their mean diagnostic score for AIH pre-treatment was 18.7-+0.2. Results. Twenty patients (24%) had bile duct changes, including 15 who had changes at presentationand 5 who manifestedthem 52+22 months later. Fivepatients had destructivecholangitis, including two who also had ductopenia; 11 patients had nondestructive cholangitis, including one with ductopenia; 3 patients had ductopenia only; and one patient had portal fibrosis and ductular proliferation. Patients with and without bile duct changes had similar serum aspartate aminotransferase(564+101 U/L vs 536-+52 U/L), bilirobin (5.5-+1.4 mg/dL vs 3.9-+0.6 mg/dL), and alkaline phosphatase (349-+80 vs 339-+24 U/L) levels, and comparablefrequencies of HLA DR3 (55% vs 52%), DR4 (50% vs 38%), and A1-B8-DR3 phenotype(45% vs 45%). Cumulativediagnostic scores for AIH were lower in the patients with bile duct changes (17.3-+0.6 vs 19.1-+0.2, p-
1825 Specific Th-2-type Reaction of T-lymphocytes of PBC Patients to Calreticulin and Bacterial RNA-polymerase Mathias Oelke, Anja Tuczek, Dirk Behringer, Heidrun Maennle, Doerte Jensen, KaiWolfgang Roesler, Wolfgang Kreisel, Medical Clin, Freiburg Germany Introduction: Previously we had shown that about 1/3 of patients with PBC have antibodies to the/~-subunit of bacterial RNA-polymerase(RNA-pol). 2/3 have antibodies to the stress protein calreticulin (CRT). We investigatedwhether peripheralT-lymphocytes of patients with PSC react with these proteins. Methods: From PBMC we isolated monocytes which were cultured and differentiated to dendritic cells under the influence of IL-4, GM-CSFand TGFp. After 6 days the antigens to be tested were added. After a 16 h incubation during which the antigens were processed, dendritic cells and autologous T-cells were incubated for 6 h. Stimulation of T-cells was determined by the cytokin secretion assay: By FACS-analysisthe percentage of the following types of T-cells were measured: CD4+/IL-4-secreting, CD4+/ IFNy-secreting, CD8+/IL-4-secreting, CD8+/IFNy-secreting. We used a lysate from Yersinia enterocolitica (Yers.-lysate), human CRT and RNA-pclymerasefrom E. coil as antigens. A reaction was regardedas positive, if we found an at least two-fold increaseof the percentage of positive cells in comparison to unstimuleted cells. Results: The percentage of positive reactions to the antigens was determined in patients with PBC, alcoholic liver cirrhosis and in healthy controls. The results are indicated in the table. Conclusion: There is a preferential Th2-type reaction of peripheralT-lymphocytes in PBC patients. This type of reactionto highly conserved proteins seems to be disease-specific.

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