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An 80-year-old woman was admitted to our hospital with complaints of jaundice and liver dysfunction. She was found to have a high titer of serum IgG4, positive rheumatoid factor and marked elevation of DUPAN-2 (11,148 U/ml). Computed tomography showed swelling of the pancreas, and endoscopic retrograde cholangiopancreatography revealed diffuse irregular narrowing of the main pancreatic duct, which are typical findings of autoimmune pancreatitis. There was no evidence of malignancy. Administration of 30 mg/day of prednisolone was started. Computed tomography showed significant regression in the size of the pancreas, and the stenosis of the main pancreatic duct was improved on ERCP. The serum level of DUPAN-2 was also markedly decreased after the treatment.

Background: It is unclear whether autoimmune cholangitis (AIC) is a separate disease entity or primary biliary cirrhosis (PBC) without antimitochondrial antibodies (AMA) since fluctuation of AMA titres by immunofluorescence (IF) is often observed during the course of PBC. The aim of this study was to determine the serial changes in AMA profiles during the course of initially diagnosed PBC or AIC., Methods: In this prospective study, 32 patients with PBC or AIC were followed-up for at least 20 months and tested for AMA by IF, enzyme-linked immunosorbent assay (ELISA), and immunoblotting (IB)., Results: When positive AMA result was defined as 'AMA by IF positive', 'AMA by IF and/or ELISA positive', and 'AMA by IB positive', the diagnosis of PBC or AIC did not change in 78%, 91%, and 97%, respectively, throughout follow-up. However, the diagnosis changed in one patient, and three patients were diagnosed as AIC throughout follow-up, despite the use of all three assays., Conclusions: Our results suggested that the diagnosis of PBC and AIC was dependent on the 'phase' of the respective disease in 22% of the patients when negative AMA result was defined as 'AMA by IF negative'. This may result in recommending IB analysis before making the diagnosis of AIC., (Copyright Blackwell Munksgaard 2005)

Aims: MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop lymphadenopathy, hypergammaglobulinaemia, serum auto-antibodies, and a generalised auto-immune disease including glomerulonephritis and arthritis, and have been used as a model for the study of systemic lupus erythematosus. Recently, MRL/lpr mice were also reported as a potentially suitable animal model of primary biliary cirrhosis (PBC). The aim of this study was to determine the suitability of MRL/Mp-lpr/lpr (MRL/lpr) mice as an experimental auto-immune-mediated cholangitis model for PBC., Methods: We investigated the serum hepatobiliary enzymes, histopathological findings, and the target antigen of antimitochondrial antibodies (AMA) in MRL/lpr mice., Results: Serum levels of total bilirubin and hepatobiliary enzymes including alanine aminotransferase (ALT), leucine aminopeptidase (LAP), and gamma-glutamyl transpeptidase (G-GTP) in older-aged (over 20 weeks old) MRL/lpr or MRL/Mp-+/+ (MRL/+) mice were not significantly higher than those in younger (8-12 weeks old) MRL/lpr, MRL/+, or older-aged control mice (C3H/HeJ and BALB/C mice). Histopathologically, 24 of 47 (51%) older-aged MRL/lpr mice showed evidence of cholangitis, compared with two of 20 (10%) younger MRL/lpr mice. Especially, epithelioid granuloma and/or bile duct loss were seen in 11 out of 47 (23%) older-aged MRL/lpr mice, whereas such findings were seen in only one of 20 (5%) younger MRL/lpr mice. None of the MRL/+, C3H/HeJ, and BALB/C mice developed cholangitis. The target antigens of AMA were not pyruvate dehydrogenase complex but 2-oxoglutarate dehydrogenase complex and/or branched-chain oxo-acid dehydrogenase complex as confirmed by immunoblotting. There was no significant correlation between the presence of AMA and severity of histological lesions in older-aged MRL/lpr mice, and there were no significant differences in these biochemical data, the proportion of mice with portal inflammation, cholangitis and AMA between male and female MRL/lpr mice., Conclusion: Although several clinical features were incompatible with PBC, the serological and histopathological features of MRL/lpr mice indicate that these mice can be used as an experimental immune-mediated cholangitis model for PBC.

Primary biliary cirrhosis (PBC) and autoimmune cholangitis (AIC) are serologic expressions of an autoimmune liver disease affecting biliary ductular cells. Previously we screened a phage-displayed random peptide library with polyclonal IgG from 2 Australian patients with PBC and derived peptides that identified a single conformational (discontinuous) epitope in the inner lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the characteristic autoantigen in PBC. Here we have used phage display to investigate the reactivity of PBC sera from 2 ethnically and geographically distinct populations, Japanese and Australian, and the 2 serologic expressions, PBC and AIC. Random 7-mer and 12-mer peptide libraries were biopanned with IgG from 3 Japanese patients with PBC and 3 with AIC who did not have anti-PDC-E2. The phage clones (phagotopes) obtained were tested by capture enzyme-linked immunosorbent assay (ELISA) for reactivity with affinity-purified anti-PDC-E2, and compared with those obtained from Australian patients with PBC. Peptide sequences of the derived phagotopes and sequences derived by biopanning with irrelevant antisera were aligned to develop a guide tree based on physicochemical similarity. Both Australian and Japanese PBC-derived phagotopes were distributed in branches of the guide tree that contained the peptide sequences MH and FV previously identified as part of an immunodominant conformational epitope of PDC-E2, indicating that epitope selection was not influenced by the racial origin of the PBC sera. Biopanning with either PBC or AIC-derived IgG yielded phagotopes that reacted with anti-PDC-E2 by capture ELISA, further establishing that there is a similar autoimmune targeting in PBC and AIC.

Objective: The diagnostic criteria of autoimmune hepatitis (AIH) were recently modified by the International Autoimmune Hepatitis Group. This study was performed to assess the impact of the revised scoring system on the diagnosis of AIH., Patients and Methods: We re-analyzed the clinical features of 89 patients diagnosed as AIH in Nagasaki Prefecture, Japan, using the revised scoring system, and compared the scores and final diagnosis with our previously published results using the original system., Results: Of the 89 patients with AIH, 40 (45%) were classified using the new system as "definite" AIH, 41 (46%) as "probable" AIH, and 8 (9%) patients were categorized as "others". Of these, 37 (42%), 35 (39%), and 4 (4%) patients who were classified as "definite", "probable", and "others" by the original system remained in the same category by the revised system, respectively. However, 3, 4, and 6 patients were re-categorized as "definite" from "probable", "others" from "probable", and "probable" from "definite", respectively. The difference in aggregate scores between the above two systems ranged from -5 to +2. The main contributing factors to the changes in aggregate AIH score were "other autoimmune disease(s)" and "interface hepatitis without lobular involvement and bridging necrosis on liver histology". However, the main contributing factors to the demotions from "definite" to "probable" and form "probable" to "others" were those related to the characteristics of biliary diseases, i.e., antimitochondrial antibody positive, biliary changes in liver histology, and alkaline phosphatase: aspartate aminotransferase ratio between 1.5 and 3.0. Moreover, two patients who had no histological evidence of AIH were both re-categorized as "others" from "probable" AIH., Conclusion: Our results indicated that the diagnosis, whether based on the revised or original system, was the same in the majority of AIH patients, but the revised scoring system excluded cases who had features suggestive of biliary diseases from "definite" AIH, and also confirmed that a diagnosis of "definite" AIH should not be made without liver histology.

Aims/background: Autoimmune cholangitis/cholangiopathy (AIC) is an enigmatic disease marked by chronic cholangitis, antinuclear antibodies (ANA) and sero-negativity for conventionally detected antimitochondrial antibodies (AMA). We examined whether AIC is a distinct entity, an AMA-negative variant of primary biliary cirrhosis (PBC), or a cholangiopathic variant of autoimmune hepatitis (AIH) by comparing the clinical, laboratory and autoantibody profiles of 21 cases of AIC, 37 cases PBC and 16 cases of AIH from selected Japanese patients., Methods: The specificities of AMA and ANA were determined by immunofluorescence, immunoblotting and enzyme inhibition assays using various mitochondrial and nuclear autoantigens, and the frequencies for these groups were compared., Results: By clinical, biochemical and histological data, AIC and PBC were similar and both were clearly distinct from AIH. Serologically, by immunofluorescence of AMA and ANA, there was polarisation. By immunoblotting, and notwithstanding the negative test for AMA, a proportion of the AIC sera reacted with the E2 subunits of the 2-oxo-acid dehydrogenase enzyme complexes, but more particularly with the lower molecular weight E2 subunits. The antinuclear reactivity in AIC was with centromere, Sp100 and nuclear pore complex proteins as in PBC, but preferentially with the nuclear pore complex., Conclusion: Our results demonstrate that AIC and PBC are similar diseases. However this duo is of interest because, usually, among sets of autoimmune syndromes, differences in serological targetting are matched by differences in clinical presentation: AIC and PBC are an exception to this.

The apparent coexistence of primary biliary cirrhosis (PBC) and autoimmune hepatitis in the same patient raises unresolved problems for nosology and therapy. These are exemplified by a 45-year-old Japanese woman with overlapping clinical, serological and histological features of autoimmune cholangitis and autoimmune hepatitis. The classical serological test for PBC, antimitochondrial antibody (AMA) by immunofluorescence, was atypical. By immunoblotting there was reactivity with one of the enzymes of the 2-oxo-acid dehydrogenase complex (2-OADC) family, now recognized as autoantigens responsible for AMA reactivity. Also there was reactivity by immunofluorescence for antinuclear antibodies (ANA), one showing the typical speckled pattern of anti-Sp-100 and the other the peripheral pattern of antinuclear membrane antibody, both with titres > 10(6). There was also a positive result to the lupus erythematosus (LE) cell test. Treatment with ursodeoxycholic acid was beneficial. Thus while the clinical presentation suggested the overlapping syndrome of autoimmune hepatitis and PBC, PBC eventually proved to be the likely diagnosis. We suggest that apparent cases of overlapping PBC-autoimmune cholangitis-hepatitis syndromes, after detailed testing, will mostly align with PBC.

Type 1 autoimmune hepatitis (AIH-1) is an organ-specific autoimmune liver disease for which no tissue-specific autoantigen has yet been identified. We examined the reactivity by sensitive immunoblotting with enhanced chemiluminescence (IB-ECL) of 43 sera from patients with AIH-1 and 182 sera from patients with other diseases on hepatocyte plasma membrane derived from rat or human liver (RHPM, HHPM) and separated by aqueous two-phase partition. The sera studied were from patients with AIH-1, primary biliary cirrhosis, chronic viral hepatitis, and systemic lupus erythematosus (SLE); and from normal subjects. Specificity of reactivity by IB-ECL was sought: (i) by testing sera on human or rat liver membrane; (ii) by testing sera on liver or kidney membrane; (iii) by serial titration of reactive sera; and (iv) by testing reactive sera from AIH-1 before and after successful treatment with prednisolone. The results were that in AIH-1 there were multiple reactive components which were not species-specific, since they were detected with both RHPM and HHPM, but were mostly tissue-specific for liver. There was no significant correlation between antinuclear antibodies (ANA) titer and the frequencies of sera reactivities against RHPM. Most of these reactive components were demonstrable at a lesser frequency in other liver diseases and in SLE. There was a striking decrease in reactivity by IB-ECL of AIH-1 sera with liver membrane after clinical remission, further suggesting that differences between AIH-1 and other inflammatory liver diseases and SLE are predominantly quantitative rather than qualitative. However, our study did point to candidate liver membrane antigens with molecular sizes of 136, 116, 81, and 49 kDa, additional to components previously described by others. The molecular identification of these prominent reactants with AIH-1 sera could prove informative for ascertaining pathogenesis. [ABSTRACT FROM AUTHOR]

Idiopathic retroperitoneal fibrosis (IRF) and primary biliary cirrhosis (PBC) are distinct clinical disorders which rarely occur in the same patient. We report a 79-year-old man with the coexistence of both conditions. The patient had antibodies to both centromere and mitochondria, as indicated by indirect immunofluorescence. Diagnoses of IRF and PBC were confirmed histologically. Although the association between IRF and PBC is obscure, IRF may be involved in many autoimmune diseases associated with PBC. [ABSTRACT FROM AUTHOR]