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The incidence and prognostic significance of major clinical events in primary sclerosing cholangitis
Posters
P/C09/05
]
OSTEOPOROSIS IS NOT A SPECIFIC COMPLICATION OF PRIMARY BILIARY CIRRHOSIS (PBC) J.L. Newton l, D. Rawlings2, M.I. Prince 1, O.EW. James 1, M.E Bassendine I D.EJ. Jones l ~Centre for Liver Research, University of Newcastle, UK. 2Regional Medical Physics Department, University of Newcastle, UK. In recent years the diagnosis of PBC has increasingly been made in the earlier, non-cholestatic stages of disease. Accepted wisdom to date has been that PBC is frequently complicated by osteopomsis. In this study we set out to ask whether osteoporosis remains a complication of PBC in its broader spectrum of severity. All 272 patients in our cohort with definite or probable PBC who had undergone bone bone density measurement (BDM) were identified. In this large unselected group of PBC patients mean z scores (number of standard deviations from an age and sex matched norm) at neck of femur (NOF) and lumbar spine (LS) at the time of first BDM (7_+6 years after PBC diagnosis) were -0.1_+1.4 and 0.1+1.4 respectively. A minonty of PBC patients had osteoporosis (z score <-2.0) at first BDM (n=18). This was no more prevalent, however, than would be expected in an age/sax matched population. A total of 957 scans were performed (0.35 per patient year of follow-up). 220 patients had 2 or more scans. In the 51 of these patients (who were clinically representative of the whole group) who had received no PBC or bone related treatment during follow-up the %BDM changes per year at NOF and LS were 1.6_+3.2 and 0.1-+2.2 respectively. No variance in this "natural" rate of BDM change was seen in patients receiving PBC modulating agents (including prednisolone and UDCA) or osteoporosis prophylaxis/therapy. Significant improvement at LS was seen in patients (n=16) undergoing liver transplantation. No patients developed de novo osteoporosis over the first 5 years of follow-up. If BDM had been performed every 5 years rather than annually in this group no cases of osteoporosis would have been missed, but 628 unnecessary scans would have been avoided.
P/C09/06 ] ESTABLISHMENT OF A SIMPLE ELISA FOR THE MEASUREMENT OF ANTI-SLA/LP AUTOANTIBODIES I. Wies l, R. Kneusel2, T. Simon2, K.H. Meyer zum Btischenfelde1, P.R. Galle 1, B. Liedvogel 2, A.W. Lohse 1 II. Dept. of Medicine, Joh. Gutenberg-Univ. Mainz, Germany. 2Diarect AG, Freiburg, Germany. Antibodies to a soluble liver antigen (SLA) and antibodies to liver-pancreas antigen (LP) were shown to be the same antibodies recognizing a recently cloned 422 amino-acid long cytosolic protein of as yet unknown function. Anti-SLA/LP autoantibodies can be detected in about 20 % o f patients with autoimmune hepatitis, and seem to occur exclusively in autoimmune liver disease underlining their diagnostic importance, However, the lack of a standardized diagnostic assay has hampered further study of these autoantibodies. The aim of the present study was the establishment of a simple diagnostic assay using the recombinant anti-SLA/LP target antigen, named the autoimmune hepatitis specific antigen (AHSA). The short isoform of the AHSA antigen was expressed in E. coil with a C-terminal hexa-histidine tag and purified by nickel metal chelate chromatography. Purified AHSA was coated onto ELISA plates at a concentration of 0,2 ~tg / well and postcoated with 1% BSA. 100 Stl of patient sera were added at a dilution of 1 : 100, incubated for 60 min at room temperature, washed three times with PBST and bound antibodies detected using peroxidase labelled anti-human IgG and substrate ABTS. 38 out of 41 anti-SLA/LP positive sera were found to be highly positive in the ELISA, the other three sera showing borderline values. None out o f 57 control sera tested positive. The three borderline anti-SLA/LP sera also showed only low or minimal reactivity both in the original inhibition anti-SLA ELISA and in Western blotting analysis. This study confirms the role o f the recombinant AHSA as the central target antigen of anti-SLA/LP autoantibodies and demonstrates the establishment of simple and reliable diagnostic immunoassays for the routine detection of the antibodies in patient sera.
128
P/C09/07 ] HIGH PREVALENCE OF AUTOIMMUNE HEPATITIS (AIH) AMONG PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) H.R. van Buuren, H.J.E van Hoogstraten, T Terkivatan, S.W. Schalm, EP. Vleggaar Department of Hepatogastroenterology, University Hospital, Rotterdam, The Netherlands. It has been well established that AIH and PSC can occur simultaneously or consecutively. Only few studies have assessed the actual prevalence of this overlap syndrome. The aim of this study was to assess the prevalence of AIH among patients with PSC. A detailed retrospective analysis was undertaken of all consecutive patients with a diagnosis of PSC, based on characteristic cholangiograpnic abnormalities, seen in our centre since 1976. AIH was diagnosed according to conventional clinical, laboratory, immunological and histological criteria. In addition, the numerical consensus scoring system for the diagnosis of AIH (both the original and the recently revised system) were applied. Diagnosis of the overlap syndrome was established for nine (6 males; mean age at presentation with either AIH or PSC 27 (range 7-54) yrs) (8%) of a total of 113 PSC patients. According to the AH-I scoring system 8/9 cases were classified as definitive AIH and 1/9 as probable AIH; application of the revised system yielded the same results. Four patie~ats initially presented with AIH and in five cases PSC was diagnosed first. Eight patients also suffered from influnmmtory bowel disease. All patients responded to immunosuppressive therapy; long-term remission was achieved in 3 cases. Three patients underwent liver transplantation 4 months, 7 and 9 yrs. resp. after presentation. In conclusion, this study found a prevalence rate of 8% of AIH among patients with PSC, a figure substantially nigher than reported previously by Czaja etal) (3.4%) and Boberg et al2 (1,8%). Selection bias related to referral patterns may be the most likely explanation for these diverging results. Recognition of patients with the AIH-PSC overlap syndrome is of climcal significance considering the important therapeutic consequences. Czaja AJ etal. Dig Dis Sci 1996;41:305-14 2 Boberg KM et al. Hepatology 1996;23:1369-76
P/C09/08 ] THE INCIDENCE AND PROGNOSTIC SIGNIFICANCE OF MAJOR CLINICAL EVENTS IN PRIMARY SCLEROSING CHOLANGITIS EP. Vleggaar I, B.E. Hansen l, G.P. Van Berge Henegouwen2, H.R. van Buuren 1 tDept, of Hepatogastroenterology, University Hospital Rotterdam, The Netherlands. 2Dept. of Hepatogastroenterology, University Hospital Utrecht, The Netherlands. The incidence and prognostic significance of major clinical complications in PSC, including the development of dominant bile duct stenosis, cholangio- and colorectal carcinoma, cholangitis and de-novo inflammatory bowel disease (IBD) have been poorly documented. These aspects were assessed in a cohort of 163 patients (67% males; median age 33 (12-72) yrs) followed for a median period of 6.6 (0.04-21) yrs. When PSC was diagnosed 59% had IBD (63% ulcerative colitis; 21% Cmhn's disease; 16% indeterminate colitis). The median transplantation-free survival was 13.5 yrs and was better for asymptomatic (15.3 yrs) than for symptomatic patients (7.6 yrs) (p=0.0002 log-rank). 20-yr incidence of dominant bile duct strictures and cholangiocarcinoma was 17% and 35% resp. 15-yr incidence of de-novo IBD was 32%. For the total cohort of patients and for those with IBD at presentation, 15-yr incidence if colorectal cancer was 9% and 14% resp. 20-yr incidence of either colorectal or chulangiecarcinoma was 25%. Multivariate analysis revealed that age (RR 1.03; 95% CI 1.009-1.06) and symptomatic presentation (RR 2.2; 95%-CI 1.13-4.3) were independent prognostic factors of decreased transplantation-free survival. Time-dependant analyses showed that the development of dominant bile duct strictures and cholangitis were associated with decreased survival. These results underline that PSC is a progressive disease associated with a markedly decreased life expectancy. Patients diagnosed in the context of IBD associated with liver test abnormalities but without symptoms can be expected to run a more benign course. Patients with PSC carry a nigh risk for developing cancer.
P/C09/05
]
OSTEOPOROSIS IS NOT A SPECIFIC COMPLICATION OF PRIMARY BILIARY CIRRHOSIS (PBC) J.L. Newton l, D. Rawlings2, M.I. Prince 1, O.EW. James 1, M.E Bassendine I D.EJ. Jones l ~Centre for Liver Research, University of Newcastle, UK. 2Regional Medical Physics Department, University of Newcastle, UK. In recent years the diagnosis of PBC has increasingly been made in the earlier, non-cholestatic stages of disease. Accepted wisdom to date has been that PBC is frequently complicated by osteopomsis. In this study we set out to ask whether osteoporosis remains a complication of PBC in its broader spectrum of severity. All 272 patients in our cohort with definite or probable PBC who had undergone bone bone density measurement (BDM) were identified. In this large unselected group of PBC patients mean z scores (number of standard deviations from an age and sex matched norm) at neck of femur (NOF) and lumbar spine (LS) at the time of first BDM (7_+6 years after PBC diagnosis) were -0.1_+1.4 and 0.1+1.4 respectively. A minonty of PBC patients had osteoporosis (z score <-2.0) at first BDM (n=18). This was no more prevalent, however, than would be expected in an age/sax matched population. A total of 957 scans were performed (0.35 per patient year of follow-up). 220 patients had 2 or more scans. In the 51 of these patients (who were clinically representative of the whole group) who had received no PBC or bone related treatment during follow-up the %BDM changes per year at NOF and LS were 1.6_+3.2 and 0.1-+2.2 respectively. No variance in this "natural" rate of BDM change was seen in patients receiving PBC modulating agents (including prednisolone and UDCA) or osteoporosis prophylaxis/therapy. Significant improvement at LS was seen in patients (n=16) undergoing liver transplantation. No patients developed de novo osteoporosis over the first 5 years of follow-up. If BDM had been performed every 5 years rather than annually in this group no cases of osteoporosis would have been missed, but 628 unnecessary scans would have been avoided.
P/C09/06 ] ESTABLISHMENT OF A SIMPLE ELISA FOR THE MEASUREMENT OF ANTI-SLA/LP AUTOANTIBODIES I. Wies l, R. Kneusel2, T. Simon2, K.H. Meyer zum Btischenfelde1, P.R. Galle 1, B. Liedvogel 2, A.W. Lohse 1 II. Dept. of Medicine, Joh. Gutenberg-Univ. Mainz, Germany. 2Diarect AG, Freiburg, Germany. Antibodies to a soluble liver antigen (SLA) and antibodies to liver-pancreas antigen (LP) were shown to be the same antibodies recognizing a recently cloned 422 amino-acid long cytosolic protein of as yet unknown function. Anti-SLA/LP autoantibodies can be detected in about 20 % o f patients with autoimmune hepatitis, and seem to occur exclusively in autoimmune liver disease underlining their diagnostic importance, However, the lack of a standardized diagnostic assay has hampered further study of these autoantibodies. The aim of the present study was the establishment of a simple diagnostic assay using the recombinant anti-SLA/LP target antigen, named the autoimmune hepatitis specific antigen (AHSA). The short isoform of the AHSA antigen was expressed in E. coil with a C-terminal hexa-histidine tag and purified by nickel metal chelate chromatography. Purified AHSA was coated onto ELISA plates at a concentration of 0,2 ~tg / well and postcoated with 1% BSA. 100 Stl of patient sera were added at a dilution of 1 : 100, incubated for 60 min at room temperature, washed three times with PBST and bound antibodies detected using peroxidase labelled anti-human IgG and substrate ABTS. 38 out of 41 anti-SLA/LP positive sera were found to be highly positive in the ELISA, the other three sera showing borderline values. None out o f 57 control sera tested positive. The three borderline anti-SLA/LP sera also showed only low or minimal reactivity both in the original inhibition anti-SLA ELISA and in Western blotting analysis. This study confirms the role o f the recombinant AHSA as the central target antigen of anti-SLA/LP autoantibodies and demonstrates the establishment of simple and reliable diagnostic immunoassays for the routine detection of the antibodies in patient sera.
128
P/C09/07 ] HIGH PREVALENCE OF AUTOIMMUNE HEPATITIS (AIH) AMONG PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) H.R. van Buuren, H.J.E van Hoogstraten, T Terkivatan, S.W. Schalm, EP. Vleggaar Department of Hepatogastroenterology, University Hospital, Rotterdam, The Netherlands. It has been well established that AIH and PSC can occur simultaneously or consecutively. Only few studies have assessed the actual prevalence of this overlap syndrome. The aim of this study was to assess the prevalence of AIH among patients with PSC. A detailed retrospective analysis was undertaken of all consecutive patients with a diagnosis of PSC, based on characteristic cholangiograpnic abnormalities, seen in our centre since 1976. AIH was diagnosed according to conventional clinical, laboratory, immunological and histological criteria. In addition, the numerical consensus scoring system for the diagnosis of AIH (both the original and the recently revised system) were applied. Diagnosis of the overlap syndrome was established for nine (6 males; mean age at presentation with either AIH or PSC 27 (range 7-54) yrs) (8%) of a total of 113 PSC patients. According to the AH-I scoring system 8/9 cases were classified as definitive AIH and 1/9 as probable AIH; application of the revised system yielded the same results. Four patie~ats initially presented with AIH and in five cases PSC was diagnosed first. Eight patients also suffered from influnmmtory bowel disease. All patients responded to immunosuppressive therapy; long-term remission was achieved in 3 cases. Three patients underwent liver transplantation 4 months, 7 and 9 yrs. resp. after presentation. In conclusion, this study found a prevalence rate of 8% of AIH among patients with PSC, a figure substantially nigher than reported previously by Czaja etal) (3.4%) and Boberg et al2 (1,8%). Selection bias related to referral patterns may be the most likely explanation for these diverging results. Recognition of patients with the AIH-PSC overlap syndrome is of climcal significance considering the important therapeutic consequences. Czaja AJ etal. Dig Dis Sci 1996;41:305-14 2 Boberg KM et al. Hepatology 1996;23:1369-76
P/C09/08 ] THE INCIDENCE AND PROGNOSTIC SIGNIFICANCE OF MAJOR CLINICAL EVENTS IN PRIMARY SCLEROSING CHOLANGITIS EP. Vleggaar I, B.E. Hansen l, G.P. Van Berge Henegouwen2, H.R. van Buuren 1 tDept, of Hepatogastroenterology, University Hospital Rotterdam, The Netherlands. 2Dept. of Hepatogastroenterology, University Hospital Utrecht, The Netherlands. The incidence and prognostic significance of major clinical complications in PSC, including the development of dominant bile duct stenosis, cholangio- and colorectal carcinoma, cholangitis and de-novo inflammatory bowel disease (IBD) have been poorly documented. These aspects were assessed in a cohort of 163 patients (67% males; median age 33 (12-72) yrs) followed for a median period of 6.6 (0.04-21) yrs. When PSC was diagnosed 59% had IBD (63% ulcerative colitis; 21% Cmhn's disease; 16% indeterminate colitis). The median transplantation-free survival was 13.5 yrs and was better for asymptomatic (15.3 yrs) than for symptomatic patients (7.6 yrs) (p=0.0002 log-rank). 20-yr incidence of dominant bile duct strictures and cholangiocarcinoma was 17% and 35% resp. 15-yr incidence of de-novo IBD was 32%. For the total cohort of patients and for those with IBD at presentation, 15-yr incidence if colorectal cancer was 9% and 14% resp. 20-yr incidence of either colorectal or chulangiecarcinoma was 25%. Multivariate analysis revealed that age (RR 1.03; 95% CI 1.009-1.06) and symptomatic presentation (RR 2.2; 95%-CI 1.13-4.3) were independent prognostic factors of decreased transplantation-free survival. Time-dependant analyses showed that the development of dominant bile duct strictures and cholangitis were associated with decreased survival. These results underline that PSC is a progressive disease associated with a markedly decreased life expectancy. Patients diagnosed in the context of IBD associated with liver test abnormalities but without symptoms can be expected to run a more benign course. Patients with PSC carry a nigh risk for developing cancer.