PBC Patients Research Articles

P75 Impaired cardiorespiratory reserve in primary biliary cirrhosis patients undergoing liver transplant assessment

IntroductionIt has been previously shown that PBC patients have bioenergetic abnormality in both peripheral and cardiac muscle. In particular they exhibit significantly lower cardiac muscle phosphocreatine-to-ATP ratio (measure of cardiac...

Detection of D‐3‐phosphoglycerate dehydrogenase autoantibodies in patients with autoimmune hepatitis: Clinical significance evaluation

D-3-phosphoglycerate dehydrogenase (3-PHGDH) was identified as a putative target of autoantibodies in autoimmune hepatitis (AIH). The aims of the present study were to detect anti-3-PHGDH in patients with AIH and other chronic liver diseases and to analyze their clinical relevance. Human 3-PHGDH gene was cloned and expressed in Escherichia coli and used in enzyme-linked immunosorbent assays and Western blots. Serum from patients with AIH (n = 101), primary biliary cirrhosis (PBC, n = 122), chronic hepatitis C (CHC, n = 117), chronic hepatitis B (CHB, n = 112), and from patients with other autoimmune disease (n = 125) were investigated. The highest incidence and activity of anti-PHGDH was observed in AIH patients. Thirty-two of 40 untreated (80%) and 37 of 61 AIH patients treated with corticosteroid (60.7%) were positive. Antibody titers decreased significantly during corticosteroid treatment. 15.8% of PBC patients, 9.8% of CHB and 12.8% of CHC patients, were anti-PHGDH-positive, with less than 12% of patients positive with other autoimmune diseases via reactions with recombinant 3-PHGDH protein. Anti-PHGDH were detected in chronic liver diseases. They occur predominantly in AIH, and corticosteroid treatment seems to decrease antibody titers. Whether the antibodies are primary or secondary phenomena and whether they are related to the etiology or pathogenesis, at least in a subgroup of patients with chronic liver diseases, has still to be evaluated.

CTLA4 polymorphisms in primary biliary cirrhosis patients and first degree relatives of cretan origin

Introduction and backgroundCytotoxic T lymphocyte antigen 4 (CTLA4) encodes a coinhibitory immunoreceptor that is a key regulator of self tolerance with established genetic associations to multiple autoimmune diseases. Studies of...

CD45ROhighCD57+CD8high T cells in primary biliary cirrhosis (101.4)

Abstract Primary biliary cirrhosis (PBC) is a female predominant organ specific autoimmune disease with specific destruction of intrahepatic small biliary epithelial cells (BECs). Patients develop a multilineage response to the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody as well as autoreactive CD4 and CD8 T cell responses. Recent data from murine PBC models have suggested that liver-infiltrating CD8 T cells play a critical role in biliary destruction in PBC. Many studies suggest the augmented cytotoxicity of CD57+CD8 T lymphocytes. Therefore, we have studied the frequencies and phenotypic characterization of CD8highCD57+ T lymphocyte components in both patients with PBC and age matched controls. Our data indicate that CD45ROhighCD57+CD8high T lymphocytes from PBC patients, but not controls, have significant phenotypic alterations, including increased expression α4β7high and reduced expression of annexin V after TCR stimulation. Our data also indicate that patient CD45ROhighCD57+CD8high T cells express higher granzyme A, B, perforin, CCR5 and α4β7, reduced expression of CCR7 than other CD8high T cells. Furthermore, IFN-γ and IL-5 productions by CD57+CD8high T lymphocytes upon in vitro TCR stimulation are increased in PBC patients. In conclusion, our data demonstrate that CD45ROhighCD57+CD8high T cells are a subset of cytotoxic memory cells which play a critical role in the chronic and progressive destruction of BECs in PBC.

1296 DEVELOPING END POINTS FOR CLINICAL TRIALS IN PBC: ALKALINE PHOSPHATASE AS A PREDICTOR OF OUTCOME

Introduction: Surrogates of treatment efficacy in PBC are of use clinically and in trials. Aim: To clarify the association between ALP values and outcome (death or liver transplant) in PBC patients treated with UDCA. Design: Retrospective analysis of 683 PBC patients followed at the Toronto Western Hospital, 1974–2009. Median follow up was 8.2 years. Results: 457 patients at baseline had complete ALP data. Median ALP was 2.52×ULN, interquartile range 1.66–4.40×ULN. Given the distribution of ALP at baseline, Cox proportional hazards analysis at baseline suggested a marginal association between ALP and outcome (P =0.06; HR 1.08; 95%CI 1.06–1.27). When categorized into tertiles or quartiles, patients in the top tertile or quartile of ALP distribution, were more likely to experience an event as compared to those in the lowest tertile/quartile: HR=2.79 (95%CI: 2.66–20.97), P = 0.01 and HR=3.15 (95%CI 2.64–46.40), P = 0.02, respectively. Similarly based on prior thresholds, associations with outcome were seen for >1.67×ULN, >1.76×ULN, >2×ULN and >3×ULN (all P 1.67×ULN, >1.76×ULN, >2×ULN and >3×ULN (all P < 0.05). We evaluated 384 patients with both baseline and year 1 data ALP data. Over this time the median fall in ALP was 40%, and interquartile range 20%-54%. Percent change in ALP as a continuous measure associated with outcome, HR=2.29 (95%CI: 1.09–4.83), P = 0.03. A 10% drop in ALP from baseline to year 1 associated with an 8% reduction in the hazard of death/transplant. Those who did not normalize were more likely to incur an event, HR=4.55 (95%CI 1.41–14.65; P = 0.01). Conclusion: ALP values are surrogates for outcome in patients with PBC.

Screening serum markers of primary biliary cirrhosis with high-throughput protein chip encoded by the human genes

Objective To screen serum markers in patients with PBC by high-throughput protein chips encoded by the human genome. Methods High-throughput protein chips (contains a total of 38 400protein spots, including 17 718 human genes encoding proteins) were used to screen sera from 21 PBC patients, 20 disease control patients and 10 normal controls. Bioinformatics software was used to analyze information and statistical software was used to analyze the data to confirm the serum markers of PBC. Results The detection rate of protein spots using anti-GST antibody on the chip was 97. 6%, and the signal intensity correlation coefficient of double protein spots was 0. 98. Four serum markers( PDHA1, DBT,DLAT and HK1 )were screened by high-throughput protein chips between PBC group and the control group with a statistically significant. The positive rate of the four markers in the three groups was 66. 67% ( 14/21), 5.00% (1/20) and 0(0/10); 57. 14% ( 12/21 ), 5.00% (1/20) and 0(0/10); 52. 38% ( 11/21 ),0(0/20) and 0(0/10); 52. 38% ( 11/21 ), 0(0/20) and 0(0/10) respectively. All the four markers were different in the three groups with statistically significant (PDHA1 :x2 = 16. 79, P ＜0. 01 ;Fisher exact test,P=0. 000; DBT:x2 =12.86, P＜0. 01;Fisher exact test, P=0. 004; DLAT and HK1:Fisher exact test,P ＜0. 01 or 0. 05). Of those markers, antibodies to PDHA1, DBT and DLAT were the component of AMAM2 which had been used as the marker of PBC. Antibody to HK1 was identified as new marker of PBC,whose sensitivity to PBC was 52. 38% and specificity was 100. 00%. There were no serum marker were screened between the AMA-M2 positive and negative PBC patients. Only antibody to CENPB was identified to be significantly expressed between the ACA positive and negative PBC patients ( Fisher exact test, P =0. 000). Conclusions High-throughput protein chip encoded by the human gene is a technology for quick and comprehensive screening of new markers of PBC. Antibodies to HK1 could be used as new marker for PBC with highly sensitivity and specificity. No serum marker is found between the AMA-M2 positive and negative PBC patients whereas only antibody to CENPB is identified as marker between the ACA positive and negative PBC patients. Key words: Liver cirrhosis, biliary; Protein array analysis; Biological markers; Autoantibodies

P02 Impaired subendocardial myofibre function in primary biliary cirrhosis

IntroductionA follow-up study1 of 770 PBC patients found that their survival was much poorer than an age- and sex-matched population (standardised mortality ratio for PBC patients was 2.87). Excluding deaths...

P20 Functional capacity is significantly impaired in primary biliary cirrhosis and related to orthostatic symptoms

IntroductionPrimary biliary cirrhosis (PBC) is associated with a significant and diverse symptom burden independent of conventional markers of disease severity. It is unclear how this symptom load impacts upon function...

P01 UDCA response criteria identify a sub-group of PBC patients with an inherently good prognosis rather than a specific disease response

IntroductionRecent follow-up cohort studies have identified biochemical parameters in UDCA-treated patients which identify “responders” with survival identical to normal control populations, in contrast to “non-responders” who have survival indistinguishable from...

Characteristics of SLAspecific T cell response and its clinical significance in autoimmune hepatitis patients

：Objective To analyze the feature of SLA specific T cellresponse in AIH. Methods Thirtyone cases of AIH were enrolled by investigating T-cellreactivity against chemically synthesized peptides spanning the full SLA protein usingELISpot. The 31 cases of AIH included 10 anti-SLA/LP positive cases and 21 negative cases.The control groups included 30 PBC patients, 29 chronic viral hepatitis patients and 30healthy cases. The secretion of IFN-γ after PBMC stimulated by SLA peptides was observed.Results Eighteen of 31 cases with AIH [56. 08 % ( 18/31 ) ] showed the positive responseto SLA peptide pools, and only 1 of 30 patients with primary biliary cirrhosis (3.34%) and1 of 29 patients with virus hepatitis ( 3.44% ), could be elicited responses by SLApeptide pools. There wasn't positive response in healthy eases. The response frequency toSLA peptides in AIH group was significantly higher than those in PBC cases, chronic viralhepatitis cases and healthy cases (X2 = 21. 295, 20. 655, 15.988, P < 0. 01 ). Amongst18 AIH patients with positive responds to SLA pool, 8 antigen clusters including aa 1-44,aa 57-132, an 129-180,aa 177-196, aa 193-244, aa 241-268, aa 281-308 and aa 321-428 werehighlighted. The mean number of recognized peptides was 6 (2-17), indicating thepolyclonal feature. Fourteen of 18 AIH patients with positive response to SLA peptideswere subjected to live function test simultaneously when PBMC were collected. There wassignificant correlation between the breadth of recognized poptides and AST ( logarithm, r= 0. 539, P = 0. 045). Conclusions SLA peptides can induce PBMC in peripheral blood of AIHpatients to secrete IFN-γ and it is polyclonal response. The breadth of recognizedpeptides may reflect the degree of liver inflammation. Key words: Hepatitis,autoimmune; Autoantige

Update on the genetics and genomics of PBC

Despite recent progress, the pathogenic mechanisms governing PBC development, treatment response and outcome remain unknown. This deficiency is in large part due to the complex nature of PBC, wherein various environmental factors may be capable of prompting disease, but only in the context of underlying genetic susceptibility. Identification of genomic loci containing these heritable risk factors has been slowed by the rarity and late onset of PBC, which has made difficult the collection of sufficient numbers of patients and family members for meaningful genetic analyses. Advancements in our ability to catalog the genetic variation in large numbers of individuals at a genome-wide scale, coupled with unprecedented efforts to recruit PBC patients for genetic study, positions us to generate data that could fundamentally change our understanding of PBC and lead to clinical innovation. Indeed, the first genome-wide association study for PBC has been published, in which multiple genes involved with IL12 signaling, a pathway that is being targeted in treatment of other inflammatory conditions, were implicated in disease. However, this study was relatively small in the genome-wide milieu and a significantly expanded effort will be necessary to truly elucidate the genetic architecture of PBC. Moving ahead, cooperation between the groups collecting biospecimens and generating genome-wide data from large numbers of patients with PBC will be essential, not only to increase power for fine mapping and future studies of rare variants and epistasis; but to streamline efforts to perform functional validation of novel discoveries. Here we provide a brief update of the current state of genetics in PBC to form a basis for understanding the considerable progress that is likely to be made in the coming years.

Methotrexate in Patients with Primary Biliary Cirrhosis Who Respond Incompletely to Treatment With Ursodeoxycholic Acid

Approximately 35% of PBC patients have progressive disease despite treatment with UDCA. We offered treatment with methotrexate and colchicine to PBC patients who had not responded fully to UDCA, after at least 1 year of treatment. A total of 91 PBC patients failed to respond adequately to UDCA, defined as patients whose liver biopsies showed persistent interface hepatitis and whose serum alkaline phosphatase levels remained more than 50% above normal after at least 12 months on UDCA. We added colchicine (0.6 mg orally twice daily) for 6 months. If there was no decrease in alkaline phosphatase, methotrexate (0.25 mg/kg lean body weight orally per week) was added. Liver biopsies were performed at least three times: at diagnosis, after a patient had been on UDCA for at least 1 year (mean 3.4 years), and after a patient had been on methotrexate for at least 6 months (mean 2.2 years). A fourth liver biopsy was performed in 51 patients after they had been on methotrexate for at least another year (mean 3.5 years). From the time that methotrexate was begun until the final visit, there were significant decreases in the mean levels of alkaline phosphatase, 323 to 151, ALT, 73 to 39, fibrosis, 2.5 to 2.0, and inflammation scores, 2.0 to 1.0, (p < 0.0001 for all). Based on pre-specified definitions, 73 patients (80%) responded to methotrexate while 18 (20%) did not. In 91 PBC patients who responded incompletely to UDCA, colchicine and methotrexate significantly improved liver enzyme tests and liver histology.

S1873 The use of Liver Biopsy Evaluation in Determination of Autoimmune Hepatitis vs. Drug-Induced Liver Injury

Background/Aims: There has been increased interest in the potential role of B cells and antimitochondrial antibodies in PBC. Indeed a new paradigm in PBC includes the potential of B cells to act as both regulatory elements and as components of the inflammasone induced by apoptosis of biliary cells. We submit that a rigorous dissection of the inflammatory infiltrate in PBC will provide further insight on these issues. Materials and Methods: We took advantage of well-characterized Mabs to CD3, CD4, CD8, CD20, CD38, CD56, CD68, and pan-keratin antigens, and immunohistochemistry (IHC), to study the distribution of liver infiltrating CD38-positive plasma cells in 26 consecutive patients with PBC (AMA positive in 20 and negative in 6), all of whom had detailed staged clinical data. All data was “blindly” evaluated. We simultaneously studied 10 ageand gender-matched patients with chronic hepatitis C as a control. Results: Noteworthy within the IHC data was the presence of an intense coronal arrangement (CR) of CD38-positive cells around interlobular bile ducts, generally in specimens with chronic non-suppurative destractive cholangitis (CNSDC). In contrast, CD20-positive B lymphocytes (precursor cells of plasma cells) were found scattered and/or aggregated within the lymphoplasmocytic infiltration. Such CD20positive B cells also occasionally formed follicle-like aggregations but importantly were not observed in the proximity of CNSDC. PBC patients with CR demonstrated significantly higher titers of AMA (119.5±16.1 vs. 59.7±17.1, p=0.018) and lower levels of total cholesterol (TC) (195.1±9.0 vs. 223.6±9.6, p=0.04) than those without CR. Interestingly the CR correlated with titer of AMA (r=0.46), IgM (r=0.32), the presence of CNSDC (r=0.32) and inversely with age (r=-0.37), γ-GTP (r=-0.38) and TC (r=-0.41). In contrast, CD4and CD8-positive T lymphocyte infiltration was noted either in proximity of, or within the degenerated cholangioepithelium, suggesting the participation of these cells in the destructive processes of interlobular bile ducts. No CR was found in control subjects. Conclusion: The presence of CD38+ plasma cells surrounding biliary epithelium has clinical and serologic significance; further it correlates with disease progression exemplified by TC decrease and the development of florid duct lesions. These data further highlight the functional significance of B cells/ plasma cells; it also reflects a multilineage loss of tolerance in PBC. We submit that study of B cells in PBC should go beyond simple measurement of AMA titer and include rigorous phenotypical and functional dissection of the liver specific B cell lineage populations.

S1871 The Association of Low Level of Both Vitamin a and Retinol Binding Protein With the Liver Complications in Patients With Primary Sclerosing Cholangitis

Background/Aims: There has been increased interest in the potential role of B cells and antimitochondrial antibodies in PBC. Indeed a new paradigm in PBC includes the potential of B cells to act as both regulatory elements and as components of the inflammasone induced by apoptosis of biliary cells. We submit that a rigorous dissection of the inflammatory infiltrate in PBC will provide further insight on these issues. Materials and Methods: We took advantage of well-characterized Mabs to CD3, CD4, CD8, CD20, CD38, CD56, CD68, and pan-keratin antigens, and immunohistochemistry (IHC), to study the distribution of liver infiltrating CD38-positive plasma cells in 26 consecutive patients with PBC (AMA positive in 20 and negative in 6), all of whom had detailed staged clinical data. All data was “blindly” evaluated. We simultaneously studied 10 ageand gender-matched patients with chronic hepatitis C as a control. Results: Noteworthy within the IHC data was the presence of an intense coronal arrangement (CR) of CD38-positive cells around interlobular bile ducts, generally in specimens with chronic non-suppurative destractive cholangitis (CNSDC). In contrast, CD20-positive B lymphocytes (precursor cells of plasma cells) were found scattered and/or aggregated within the lymphoplasmocytic infiltration. Such CD20positive B cells also occasionally formed follicle-like aggregations but importantly were not observed in the proximity of CNSDC. PBC patients with CR demonstrated significantly higher titers of AMA (119.5±16.1 vs. 59.7±17.1, p=0.018) and lower levels of total cholesterol (TC) (195.1±9.0 vs. 223.6±9.6, p=0.04) than those without CR. Interestingly the CR correlated with titer of AMA (r=0.46), IgM (r=0.32), the presence of CNSDC (r=0.32) and inversely with age (r=-0.37), γ-GTP (r=-0.38) and TC (r=-0.41). In contrast, CD4and CD8-positive T lymphocyte infiltration was noted either in proximity of, or within the degenerated cholangioepithelium, suggesting the participation of these cells in the destructive processes of interlobular bile ducts. No CR was found in control subjects. Conclusion: The presence of CD38+ plasma cells surrounding biliary epithelium has clinical and serologic significance; further it correlates with disease progression exemplified by TC decrease and the development of florid duct lesions. These data further highlight the functional significance of B cells/ plasma cells; it also reflects a multilineage loss of tolerance in PBC. We submit that study of B cells in PBC should go beyond simple measurement of AMA titer and include rigorous phenotypical and functional dissection of the liver specific B cell lineage populations.

S1874 Drug-Induced Autoimmune Hepatitis: Clinical Characteristics and Prognosis

Background/Aims: There has been increased interest in the potential role of B cells and antimitochondrial antibodies in PBC. Indeed a new paradigm in PBC includes the potential of B cells to act as both regulatory elements and as components of the inflammasone induced by apoptosis of biliary cells. We submit that a rigorous dissection of the inflammatory infiltrate in PBC will provide further insight on these issues. Materials and Methods: We took advantage of well-characterized Mabs to CD3, CD4, CD8, CD20, CD38, CD56, CD68, and pan-keratin antigens, and immunohistochemistry (IHC), to study the distribution of liver infiltrating CD38-positive plasma cells in 26 consecutive patients with PBC (AMA positive in 20 and negative in 6), all of whom had detailed staged clinical data. All data was “blindly” evaluated. We simultaneously studied 10 ageand gender-matched patients with chronic hepatitis C as a control. Results: Noteworthy within the IHC data was the presence of an intense coronal arrangement (CR) of CD38-positive cells around interlobular bile ducts, generally in specimens with chronic non-suppurative destractive cholangitis (CNSDC). In contrast, CD20-positive B lymphocytes (precursor cells of plasma cells) were found scattered and/or aggregated within the lymphoplasmocytic infiltration. Such CD20positive B cells also occasionally formed follicle-like aggregations but importantly were not observed in the proximity of CNSDC. PBC patients with CR demonstrated significantly higher titers of AMA (119.5±16.1 vs. 59.7±17.1, p=0.018) and lower levels of total cholesterol (TC) (195.1±9.0 vs. 223.6±9.6, p=0.04) than those without CR. Interestingly the CR correlated with titer of AMA (r=0.46), IgM (r=0.32), the presence of CNSDC (r=0.32) and inversely with age (r=-0.37), γ-GTP (r=-0.38) and TC (r=-0.41). In contrast, CD4and CD8-positive T lymphocyte infiltration was noted either in proximity of, or within the degenerated cholangioepithelium, suggesting the participation of these cells in the destructive processes of interlobular bile ducts. No CR was found in control subjects. Conclusion: The presence of CD38+ plasma cells surrounding biliary epithelium has clinical and serologic significance; further it correlates with disease progression exemplified by TC decrease and the development of florid duct lesions. These data further highlight the functional significance of B cells/ plasma cells; it also reflects a multilineage loss of tolerance in PBC. We submit that study of B cells in PBC should go beyond simple measurement of AMA titer and include rigorous phenotypical and functional dissection of the liver specific B cell lineage populations.

64 ANTIGEN-SPECIFIC REGULATORY T-CELLS IN AUTOIMMUNE HEPATITIS TYPE 2: CYTOKINE PROFILE AND EFFECT OF SEMI-MATURE DENDRITIC CELLS ON SUPPRESSOR FUNCTION

Primary Biliary Cirrhosis is an autoimmune liver disease that predominantly affects middle-aged women, characterized by lymphocytic infiltration in portal tracts and destruction of intrahepatic small bile ducts, causing liver fibrosis and eventually liver failure. The histopathology is presumably mediated by CD8 T cells. Here, we describe a novel mouse model which shows gender differences similar to the female predominance observed in PBC patients. Adoptive cell transfer experiments of OVA-specific CD8+ T cells into K14-Ovap transgenic mice were performed. K14-Ovap mice express the antigenic SINFEKL peptide (residues 257–264 of OVA) under the control of human keratinocyte-specific promoter which directs expression in biliary epithelial cells. OT1 CD8+ T cells were injected intraperitoneally in male and female mice and survival rate, serum transaminases and histologic sections of the liver were analysed. Serum transaminase levels were significantly increased in female recipient mice in comparison to PBS control animals after adoptive transfer of 4×106 OT1 CD8+ T cells (**p < 0.009). In contrast transaminase levels of male mice recipient did not increase even after transfer of 10×106 OT1 CD8+ T cells. After adoptive transfer of 4×106 OT1 CD8+ T cells, histopathologic examinations of female mice showed peribiliary lymphocytic infiltrates and granuloma like lesions, whereas in male mice no histological lesions were seen. On day 6 after adoptive transfer of 20×106 and 10×106 OT1 CD8+ T cells 100% of female recipient mice died. Survival rate increased with transfer of lower cells numbers (4×106 survival rate of 80%). Male mice which received the corresponding cell numbers survived. In previously described models of PBC the immunopathology develops equally in male and female mice, in contrast to the female predominance in humans. In our model female mice showed a higher susceptibility against OT1 CD8+ T cell mediated hepatobiliary injury. We here describe an inducible, gender affected, immune-mediated model of PBC which could serve as an important tool to study gender effects on early autoimmune liver injury.

原発性胆汁性肝硬変が疑われる症例における抗ミトコンドリア抗体測定〜IFとM2のどちらを用いるべきか〜

For Antimitochondrial antibodies (AMA) testing, both indirect immunofluorescense (IF) and ELISA (M2) are currently used. Herein we aimed to suggest which is better for AMA testing in clinical setting. Recent nation-wide surveillances for PBC demonstrated that AMA testing with M2 has been prevailed instead of IF. On the other hand, 3-5% of PBC patients had M2-negative but IF-positive AMA, and these patients might not be diagnosed as PBC if only M2 would have been tested. In another PBC cohort at our hospital we failed to detect any difference between patients with only IF-positive and those with M2-positive. Therefore, M2 should be used for screening for AMA, and if M2 was negative AMA should be reexamined with IF.

Serum BAFF and APRIL levels in patients with PBC

B-cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are known to be involved in the occurrence of autoimmune diseases. We assessed serum levels of these cytokines in PBC patients. Serum BAFF levels were significantly higher in PBC patients than in healthy controls (1253.9+/-741.4 vs. 722.8+/-199.2 pg/ml; p<0.0001) and HCV-infected patients (1253.9+/-741.4 vs. 871.0+/-251.1 pg/ml; p=0.015). Whereas changes in serum APRIL levels were not significant among these groups, there was a significant correlation between BAFF and AST (R=0.278, p=0.003) or total bilirubin (R=0.363, p=0.0006) in PBC patients. Furthermore, serum BAFF levels were elevated in PBC patients with advanced interface hepatitis. Our data indicate that serum levels of BAFF and APRIL are differentially regulated and serum BAFF levels are significantly elevated in PBC patients. These findings suggest that BAFF may serve as a modulator of the clinical and/or serological manifestation in PBC patients.

Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment

ObjectivePrimary biliary cirrhosis (PBC) is frequently associated with hypercholesterolemia and with an increased cardiovascular morbidity and mortality. Statins lower serum cholesterol levels and may thus improve the cardiovascular risk in PBC patients. The aim of our study was to prospectively examine the efficacy of low-dose atorvastatin on cholestasis as well as cardiovascular risk markers such as dyslipidemia and vascular function in patients with PBC. MethodsNineteen patients with early-stage (biopsy proven and AMA positive) PBC and low-density lipoprotein cholesterol (LDL-C) above 130mg/dL were included in this single-center study and treated with atorvastatin 10mg per day for one year. ResultsConcentrations of total cholesterol, LDL-C, LDL triglycerides, oxLDL, IgG and sVCAM-1 decreased significantly after 48 weeks of atorvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery as an indicator of vascular function significantly increased, while carotid artery intima-media thickness and vascular wall stiffness did not progress under treatment. No statistical differences in liver enzymes were observed except a transient increase of alkaline phosphatase. ConclusionTreatment with low-dose atorvastatin is safe in early-stage PBC, effectively reduces total cholesterol, LDL-C, LDL triglycerides, oxLDL and sVCAM-1 and improves vascular function as reflected by FMD, without affecting cholestasis progression. Therefore, statin therapy should be considered in PBC patients with additional risk factors for cardiovascular disease.

Autoantibodies to asialoglycoprotein receptor (ASGPR) measured by a novel ELISA—Revival of a disease-activity marker in autoimmune hepatitis

Background The liver-specific ASGPR is an autoantigen in autoimmune hepatitis (AIH) patients. Anti-ASGPR antibody correlates with disease activity, however, only in-house assays have been reported so far. Methods Rabbit ASGPR was purified by affinity chromatography on galactose-Sepharose and used for standardised detection of anti-ASGPR by ELISA. Anti-ASGPR IgG was measured in sera from 45 patients with AIH, PBC ( n = 43), alcoholic liver disease ( n = 13), HBV infection ( n = 35), HCV infection ( n = 53), and 118 blood donors. Anti-ASGPR was correlated with biochemical parameters of disease activity in 22 AIH patients with consecutive samples. Results Twenty-one of 30 untreated (70%) and five of 15 treated AIH patients (30%) showed elevated anti-ASGPR at first presentation. Only one blood donor demonstrated anti-ASGPR. ALD and PBC patients were all negative. ROC curve analysis of AIH and disease-control patients revealed a sensitivity of 77.8% and a specificity of 99.4%. Three (8.6%) of 35 HBV and 7 (13.2%) of 53 HCV patients demonstrated elevated anti-ASGPR. In AIH patients, anti-ASPGR correlated with liver-transaminases levels. In 22 follow-up patients, elevation of anti-ASPGR preceded liver-transaminases increase. Conclusions The novel anti-ASGPR ELISA is a readily available and specific diagnostic tool for anti-ASGPR detection in AIH. Quantification of anti-ASGPR is helpful in monitoring disease activity.