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T1871 The Prevalence of Elevated IgG4 Levels in Patients with Primary Sclerosing Cholangitis
of 0.7 mg/dL. A total of 184 patients were alive at follow-up, whereas 22 (12%) died and 5 (2.4%) were transplanted. The median FIS at baseline was 29 (10-45) and FIS at followup was 23 (7-60) with a positive correlation (p<0.001; r=0.70). FIS at baseline was 27 (1243) among survivors, 36 (12-72) in those who died (p=0.059) and 99 (41-102) in those who underwent transplantation (p=0.0009). FIS at baseline was 44 (12-88) in patients with death and/or transplantation vs. 27 (12-43) in survivors (p=0.003). A total of 13/22 (59%) of those who died had high fatigue scores at baseline compared with 9/29 (41%) with low fatigue scores (p=NS). Altogether 17/27 (63%) of those who died and/or underwent transplantation had high FIS values at baseline vs. 10/27 (37%) had low values (p=NS). Overall 6/16 (38%) of patients ≥65 years of age with high FIS scores at baseline died vs. 10/16 (64%) with low FIS scores (p=NS) and 50% of those ≤ 65 years who died had high FIS values. Conclusions: Fatigue seems to change little over time in PBC patients. Fatigue levels were higher at baseline in those who died or underwent liver transplantation. However, high fatigue levels seem to be a poor predictor of risk of mortality or need for transplantation over time.
T1870 Critical Flicker Frequency Analysis in Patients with Primary Biliary Cirrhosis Ewa Wunsch, Michal Post, Krzysztof Gutkowski, Wojciech M. Marlicz, Marek Hartleb, Piotr Milkiewicz BACKGROUND Critical flicker frequency (CFF) is a sensitive neurophysiological test in the assessment of minimal hepatic encephalopathy (Hepatology 2007;45:879-885). This modality reveals global but discrete dysfunction of central nervous system (CNS) and discloses different aspects of this dysfunction than psychometric tests. Chronic fatigue (ChF) occurs in up to 80% of patients with primary biliary cirrhosis (PBC) significantly affecting their health-related quality of life (HRQoL). Etiology of ChF remains unknown, however, it has been linked with structural changes in CNS. AIMS The aims of this work were: (i) to study CFF in patients with PBC and two control groups: subjects with alcoholic cirrhosis and healthy controls (ii) to analyze the relationships between CFF, ChF and HRQoL in patients with PBC. MATERIALS AND METHODS In total 105 subjects were studied. These included 43 (31 non-cirrhotic and 12 cirrhotic) patients with definite PBC. CFF, Fatigue Impact Score (FIS) to asses ChF and PBC-40 questionnaire to estimate HRQoL were performed in all of them. Control, age and gender matched groups for CFF analysis consisted of 31 patients with alcoholic cirrhosis without overt encephalopathy (excluded with West-Heaven score) and 41 healthy individuals. CFF was estimated with HEPAtonorm Analyzer. F-test for variance comparison and t-test for the comparison of means were used in the analysis of ChF and domains of PBC-40. Relationships between CFF, FIS and PBC-40 were assessed with Pearson's correlation test. RESULTS CFF values were significantly different (p=0.002) when all patients with PBC and healthy subjects were compared. No difference was seen between healthy controls and patients with alcoholic cirrhosis (p=0.2). In PBC group no significant difference between cirrhotics and non-cirrhotics was observed. CFF showed a trend towards a negative correlation with pruritus domain of PBC-40 when all patients with PBC were studied. This trend reached a significance in PBC cirrhotics (r=-0.77; p=0.01). No significant correlation between CFF and other domains of PBC-40 and FIS was observed. CONCLUSIONS (i) CFF analysis confirms global dysfunction of CNS in patients with PBC, which may remain independent of the degree of histological liver injury. (ii) Correlation between CFF and pruritus strengthens a concept of central rather than peripheral origin of itching in PBC. (iii) CFF does not seem to be helpful in an assessment of ChF and quality of life in patients with PBC, however, these results should be validated in larger cohorts of patients. This project was supported by the grant number N402 100 31/3038.
T1868
AASLD Abstracts
Natural History of Isolated Intrahepatic Primary Sclerosing Cholangitis Phunchai Charatcharoenwitthaya, Keith D. Lindor Background & Aims: The natural history of primary sclerosing cholangitis (PSC) in patients with only intrahepatic bile duct changes remained unclear. The purpose of this study was to describe clinical features and long-term outcomes of patients with isolated intrahepatic PSC. Methods: We analyzed data from a group of 95 PSC patients who participated in a multicentric clinical trial examining the treatment efficacy of ursodeoxycholic acid and have been systemically followed up at our institution. Isolated intrahepatic PSC was defined as the disease confined to the intrahepatic portions of the biliary tree, 1 cm proximal to the hepatic confluence. Event-free survival was estimated by the Kaplan-Meier method. Results: Patients had a mean age of 42.5±12.2 years and 60% were male. Before the diagnosis of PSC, 77 (81%) patients had a history of inflammatory bowel disease. According to the Ludwig's classification, 51 (54%) patients had stage I-II, 30 had stage III, and 14 had stage IV disease at the time of diagnosis. Of these, 23 (24%) patients had PSC confined to the intrahepatic biliary system and 72 patients had diffuse changes of the intra-and extrahepatic biliary system. Clinical presentations including age, gender, coexisting inflammatory bowel disease, symptoms, liver biochemistries, Mayo risk score and histologic stage were similar between the 2 groups. Serial liver histology to compare progression rates was available in 19 of the isolated intrahepatic PSC and 52 of the diffuse PSC. There was no difference in histological progression rate between subgroups (p=.5) over a median follow-up of 61 months (range 14-184). Subsequent cholangiography performed in 16 patients with isolated intrahepatic PSC showed progression to diffuse PSC in 7 patients during a median followup of 96 months (range 9-200). Of the isolated intrahepatic PSC, one developed perihilar cholangiocarcinoma and another was diagnosed with gallbladder cancer during a median follow-up of 104 months (range 6-206). Compared with diffuse PSC patients, the probability of developing hepatobiliary malignancies among patients with isolated intrahepatic PSC was similar (p=.5). There were 15 (65%) deaths or liver transplantations in patients with isolated intrahepatic PSC and 38 (53%) in the diffuse PSC group. Survival in patients with isolated intrahepatic PSC was similar to that of diffuse PSC patients (p=.4). Conclusion: Isolated intrahepatic PSC represents a subgroup of PSC patients with a similar long-term prognosis to PSC patients with diffuse biliary involvement. This suggests that the extent of cholangiographic abnormalities in PSC does not influence the natural course of the disease.
T1871 The Prevalence of Elevated IgG4 Levels in Patients with Primary Sclerosing Cholangitis Einar Bjornsson, Sven H. Almer, Hanne Prytz, Marten Werner, Per Sangfelt, Rupesh Rajani Background: Recently Immunoglobulin G4-associated cholangitis (IAC) has been described with steroid responsive biliary strictures, often in patients with autoimmune pancreatitis. Limited data exist on the prevalence of elevated IgG4 levels in patients with primary sclerosing cholangitis ( PSC) and the association with autoimmune hepatitis (AIH) and pancreatic disorders is unclear. We aimed to determine the prevalence of IgG4 in PSC and assess the reproducibility of elevated IgG4 levels. Methods: In a multicenter study, IgG4 levels were analyzed in consecutive PSC patients. Measurements were repeated if IgG4 levels were elevated. Antinuclear (ANA) and smooth muscle antibodies (SMA) were assessed in all patients. Clinical and laboratory characteristics were compared between those with elevated IgG4 (>140 mg/dl) and those with normal levels. Results: Ten out of 88 PSC patients had elevated IgG4 levels. After repeating IgG4 measurements 9/88 (10%) remained. Patients with elevated levels (IgG4 positive) were all males vs. 51/79 (65%) males among those with normal IgG4 (p=0.05). The median age was 50 years (IQR 39-66) vs. 44 (28-60) (NS) in those with elevated and normal IgG4 levels, respectively. Both groups had a median PSC duration of 9 years. The median IgG4 levels were 265 mg/dl (235-300; range 144-400) in those with IgG4 elevation and after repeated measurements 290 (170-330) (p=NS) and 35 (16-66) in those with normal IgG4. A history of pancreatic disorder was found in 4/9 (44%) (pancreatic atrophy [n=2], pancreatic mass and pancreatic cysts) in those with elevated IgG4 vs. 2/79 (2.5%) in those with normal IgG4 levels (p=0.0012). ANA levels were elevated in 2/9 (22%), SMA in 0/9 (0%) and AIH/PSC overlap syndrome had been diagnosed in 1/9 (11%), similar figures were found in those with normal IgG4 [12/79 (15%), 8/79 (10%) and 8/79 (10%] (p=NS). Alkaline phosphatase and bilirubin levels were comparable in both groups (2.1 x times upper limit of normal vs. 1.4 (p=NS) and 0.7 mg/dL vs. 0.6; p=NS), respectively. Inflammatory bowel disease was present in 6/9 (66%) vs 66/79 (84%) (p=NS). Biliary involvement was similar in the two groups; both intra- and extrahepatic in 6/9 (66%) vs. 48/79 (61%), only extrahepatic (0/9 (0%) vs. 3/79 (4%), only intrahepatic (1/9 (10%) vs. 19/79 (24%) and distal biliary strictures in 2/9 (22%) vs. 7/79 (9%) (p=NS). Conclusion: Elevated IgG4 levels were present in 10% of PSC patients with good reproducibility. History of pancreatic disorder was more common in those with elevated IgG4 levels. Autoantibodies and overlap syndrome with autoimmune hepatitis was similar in those with and without IgG4 elevation.
T1869 The Changing Face of Primary Sclerosing Cholangitis Marina Silveira, Kris V. Kowdley, Velimir A. Luketic, M. Edwyn Harrison, Timothy M. McCashland, Alex Befeler, Denise M. Harnois, Roberta A. Jorgensen, Jill C. Keach, Keith D. Lindor Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with significant morbidity and mortality. Little is known about the changes in disease presentation and severity over recent years or variability between racial groups. The goal of this study was to investigate the changing clinical presentation of PSC over a period of 15 years and to examine racial variation in patients with PSC. We examined 255 patients with PSC included in two multicenter, randomized trials. Patients enrolled between 1989 and 1995 (n=105) and randomized to either ursodeoxycholic acid (13-15 mg/kg/day) or placebo, were compared to patients enrolled between 2002 and 2007 (n=150) who were randomized to either high dose ursodeoxycholic acid (28-30 mg/kg/day) or placebo. There were significant differences in the disease characteristics over a period of 15 years. Most recently, female patients and those without inflammatory bowel disease (IBD) were older at the time of diagnosis of PSC. Overall, despite the longer duration of disease and higher prevalence of symptoms, in recent years, patients had evidence of milder liver disease. The use of magnetic resonance cholangiography as a diagnostic tool appears to explain these changes. In contrast, patients without IBD appeared to have more advanced liver disease than those with IBD, and non-Caucasians appeared to have significantly more severe liver disease than Caucasians, independent of diagnostic method employed. Conclusion: Although it remains predominantly a disease of middle-aged Caucasian men, PSC should be considered in the differential diagnosis of cholestatic liver disease in females, patients without IBD and all racial populations. The use of magnetic resonance cholangiography as a diagnostic tool appears to have altered the clinical presentation associated with PSC.
T1872 The Simplified Diagnostic Criteria for Autoimmune Hepatitis Demonstrates Specificity When Applied to a PSC Population Natasha Chandok, Marina Silveira, Keith D. Lindor Background: The diagnosis of autoimmune hepatitis (AIH) and overlap syndromes has been the subject of intense research and debate for nearly two decades. Although the diagnostic criteria established by the International Autoimmune Hepatitis Group (IAIHG) have a sensitivity and specificity exceeding 95% in scores compatible with definite AIH, the specificity drops substantially with scores compatible with probable AIH. Moreover, the IAIHG score is cumbersome to use in clinical practice and relies on a number of autoantibodies only available in specialized laboratories. The simplified diagnostic criteria for AIH attempt to
AASLD Abstracts
A-854
T1870 Critical Flicker Frequency Analysis in Patients with Primary Biliary Cirrhosis Ewa Wunsch, Michal Post, Krzysztof Gutkowski, Wojciech M. Marlicz, Marek Hartleb, Piotr Milkiewicz BACKGROUND Critical flicker frequency (CFF) is a sensitive neurophysiological test in the assessment of minimal hepatic encephalopathy (Hepatology 2007;45:879-885). This modality reveals global but discrete dysfunction of central nervous system (CNS) and discloses different aspects of this dysfunction than psychometric tests. Chronic fatigue (ChF) occurs in up to 80% of patients with primary biliary cirrhosis (PBC) significantly affecting their health-related quality of life (HRQoL). Etiology of ChF remains unknown, however, it has been linked with structural changes in CNS. AIMS The aims of this work were: (i) to study CFF in patients with PBC and two control groups: subjects with alcoholic cirrhosis and healthy controls (ii) to analyze the relationships between CFF, ChF and HRQoL in patients with PBC. MATERIALS AND METHODS In total 105 subjects were studied. These included 43 (31 non-cirrhotic and 12 cirrhotic) patients with definite PBC. CFF, Fatigue Impact Score (FIS) to asses ChF and PBC-40 questionnaire to estimate HRQoL were performed in all of them. Control, age and gender matched groups for CFF analysis consisted of 31 patients with alcoholic cirrhosis without overt encephalopathy (excluded with West-Heaven score) and 41 healthy individuals. CFF was estimated with HEPAtonorm Analyzer. F-test for variance comparison and t-test for the comparison of means were used in the analysis of ChF and domains of PBC-40. Relationships between CFF, FIS and PBC-40 were assessed with Pearson's correlation test. RESULTS CFF values were significantly different (p=0.002) when all patients with PBC and healthy subjects were compared. No difference was seen between healthy controls and patients with alcoholic cirrhosis (p=0.2). In PBC group no significant difference between cirrhotics and non-cirrhotics was observed. CFF showed a trend towards a negative correlation with pruritus domain of PBC-40 when all patients with PBC were studied. This trend reached a significance in PBC cirrhotics (r=-0.77; p=0.01). No significant correlation between CFF and other domains of PBC-40 and FIS was observed. CONCLUSIONS (i) CFF analysis confirms global dysfunction of CNS in patients with PBC, which may remain independent of the degree of histological liver injury. (ii) Correlation between CFF and pruritus strengthens a concept of central rather than peripheral origin of itching in PBC. (iii) CFF does not seem to be helpful in an assessment of ChF and quality of life in patients with PBC, however, these results should be validated in larger cohorts of patients. This project was supported by the grant number N402 100 31/3038.
T1868
AASLD Abstracts
Natural History of Isolated Intrahepatic Primary Sclerosing Cholangitis Phunchai Charatcharoenwitthaya, Keith D. Lindor Background & Aims: The natural history of primary sclerosing cholangitis (PSC) in patients with only intrahepatic bile duct changes remained unclear. The purpose of this study was to describe clinical features and long-term outcomes of patients with isolated intrahepatic PSC. Methods: We analyzed data from a group of 95 PSC patients who participated in a multicentric clinical trial examining the treatment efficacy of ursodeoxycholic acid and have been systemically followed up at our institution. Isolated intrahepatic PSC was defined as the disease confined to the intrahepatic portions of the biliary tree, 1 cm proximal to the hepatic confluence. Event-free survival was estimated by the Kaplan-Meier method. Results: Patients had a mean age of 42.5±12.2 years and 60% were male. Before the diagnosis of PSC, 77 (81%) patients had a history of inflammatory bowel disease. According to the Ludwig's classification, 51 (54%) patients had stage I-II, 30 had stage III, and 14 had stage IV disease at the time of diagnosis. Of these, 23 (24%) patients had PSC confined to the intrahepatic biliary system and 72 patients had diffuse changes of the intra-and extrahepatic biliary system. Clinical presentations including age, gender, coexisting inflammatory bowel disease, symptoms, liver biochemistries, Mayo risk score and histologic stage were similar between the 2 groups. Serial liver histology to compare progression rates was available in 19 of the isolated intrahepatic PSC and 52 of the diffuse PSC. There was no difference in histological progression rate between subgroups (p=.5) over a median follow-up of 61 months (range 14-184). Subsequent cholangiography performed in 16 patients with isolated intrahepatic PSC showed progression to diffuse PSC in 7 patients during a median followup of 96 months (range 9-200). Of the isolated intrahepatic PSC, one developed perihilar cholangiocarcinoma and another was diagnosed with gallbladder cancer during a median follow-up of 104 months (range 6-206). Compared with diffuse PSC patients, the probability of developing hepatobiliary malignancies among patients with isolated intrahepatic PSC was similar (p=.5). There were 15 (65%) deaths or liver transplantations in patients with isolated intrahepatic PSC and 38 (53%) in the diffuse PSC group. Survival in patients with isolated intrahepatic PSC was similar to that of diffuse PSC patients (p=.4). Conclusion: Isolated intrahepatic PSC represents a subgroup of PSC patients with a similar long-term prognosis to PSC patients with diffuse biliary involvement. This suggests that the extent of cholangiographic abnormalities in PSC does not influence the natural course of the disease.
T1871 The Prevalence of Elevated IgG4 Levels in Patients with Primary Sclerosing Cholangitis Einar Bjornsson, Sven H. Almer, Hanne Prytz, Marten Werner, Per Sangfelt, Rupesh Rajani Background: Recently Immunoglobulin G4-associated cholangitis (IAC) has been described with steroid responsive biliary strictures, often in patients with autoimmune pancreatitis. Limited data exist on the prevalence of elevated IgG4 levels in patients with primary sclerosing cholangitis ( PSC) and the association with autoimmune hepatitis (AIH) and pancreatic disorders is unclear. We aimed to determine the prevalence of IgG4 in PSC and assess the reproducibility of elevated IgG4 levels. Methods: In a multicenter study, IgG4 levels were analyzed in consecutive PSC patients. Measurements were repeated if IgG4 levels were elevated. Antinuclear (ANA) and smooth muscle antibodies (SMA) were assessed in all patients. Clinical and laboratory characteristics were compared between those with elevated IgG4 (>140 mg/dl) and those with normal levels. Results: Ten out of 88 PSC patients had elevated IgG4 levels. After repeating IgG4 measurements 9/88 (10%) remained. Patients with elevated levels (IgG4 positive) were all males vs. 51/79 (65%) males among those with normal IgG4 (p=0.05). The median age was 50 years (IQR 39-66) vs. 44 (28-60) (NS) in those with elevated and normal IgG4 levels, respectively. Both groups had a median PSC duration of 9 years. The median IgG4 levels were 265 mg/dl (235-300; range 144-400) in those with IgG4 elevation and after repeated measurements 290 (170-330) (p=NS) and 35 (16-66) in those with normal IgG4. A history of pancreatic disorder was found in 4/9 (44%) (pancreatic atrophy [n=2], pancreatic mass and pancreatic cysts) in those with elevated IgG4 vs. 2/79 (2.5%) in those with normal IgG4 levels (p=0.0012). ANA levels were elevated in 2/9 (22%), SMA in 0/9 (0%) and AIH/PSC overlap syndrome had been diagnosed in 1/9 (11%), similar figures were found in those with normal IgG4 [12/79 (15%), 8/79 (10%) and 8/79 (10%] (p=NS). Alkaline phosphatase and bilirubin levels were comparable in both groups (2.1 x times upper limit of normal vs. 1.4 (p=NS) and 0.7 mg/dL vs. 0.6; p=NS), respectively. Inflammatory bowel disease was present in 6/9 (66%) vs 66/79 (84%) (p=NS). Biliary involvement was similar in the two groups; both intra- and extrahepatic in 6/9 (66%) vs. 48/79 (61%), only extrahepatic (0/9 (0%) vs. 3/79 (4%), only intrahepatic (1/9 (10%) vs. 19/79 (24%) and distal biliary strictures in 2/9 (22%) vs. 7/79 (9%) (p=NS). Conclusion: Elevated IgG4 levels were present in 10% of PSC patients with good reproducibility. History of pancreatic disorder was more common in those with elevated IgG4 levels. Autoantibodies and overlap syndrome with autoimmune hepatitis was similar in those with and without IgG4 elevation.
T1869 The Changing Face of Primary Sclerosing Cholangitis Marina Silveira, Kris V. Kowdley, Velimir A. Luketic, M. Edwyn Harrison, Timothy M. McCashland, Alex Befeler, Denise M. Harnois, Roberta A. Jorgensen, Jill C. Keach, Keith D. Lindor Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with significant morbidity and mortality. Little is known about the changes in disease presentation and severity over recent years or variability between racial groups. The goal of this study was to investigate the changing clinical presentation of PSC over a period of 15 years and to examine racial variation in patients with PSC. We examined 255 patients with PSC included in two multicenter, randomized trials. Patients enrolled between 1989 and 1995 (n=105) and randomized to either ursodeoxycholic acid (13-15 mg/kg/day) or placebo, were compared to patients enrolled between 2002 and 2007 (n=150) who were randomized to either high dose ursodeoxycholic acid (28-30 mg/kg/day) or placebo. There were significant differences in the disease characteristics over a period of 15 years. Most recently, female patients and those without inflammatory bowel disease (IBD) were older at the time of diagnosis of PSC. Overall, despite the longer duration of disease and higher prevalence of symptoms, in recent years, patients had evidence of milder liver disease. The use of magnetic resonance cholangiography as a diagnostic tool appears to explain these changes. In contrast, patients without IBD appeared to have more advanced liver disease than those with IBD, and non-Caucasians appeared to have significantly more severe liver disease than Caucasians, independent of diagnostic method employed. Conclusion: Although it remains predominantly a disease of middle-aged Caucasian men, PSC should be considered in the differential diagnosis of cholestatic liver disease in females, patients without IBD and all racial populations. The use of magnetic resonance cholangiography as a diagnostic tool appears to have altered the clinical presentation associated with PSC.
T1872 The Simplified Diagnostic Criteria for Autoimmune Hepatitis Demonstrates Specificity When Applied to a PSC Population Natasha Chandok, Marina Silveira, Keith D. Lindor Background: The diagnosis of autoimmune hepatitis (AIH) and overlap syndromes has been the subject of intense research and debate for nearly two decades. Although the diagnostic criteria established by the International Autoimmune Hepatitis Group (IAIHG) have a sensitivity and specificity exceeding 95% in scores compatible with definite AIH, the specificity drops substantially with scores compatible with probable AIH. Moreover, the IAIHG score is cumbersome to use in clinical practice and relies on a number of autoantibodies only available in specialized laboratories. The simplified diagnostic criteria for AIH attempt to
AASLD Abstracts
A-854