Prevalence of primary biliary cirrhosis in adults referring hospital for annual health check-up in Southern China

Background  

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of anti-mitocondrial autoantibodies (AMA) which has an essential role also for diagnosis. In addition, also some anti-nuclear antibodies (ANA) have been shown to be highly specific PBC. The purpose of this study was to assess the prevalence of PBC among the adults referring hospital for annual health check-up in Southern China by screening sera for PBC-specific autoantibodies.     

High prevalence of lower limb atherosclerosis is linked with the gut–liver axis in patients with primary biliary cholangitis

Background and Aims

Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut–liver axis and systemic inflammation.

Methods

Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal-sized groups of women with non-alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow-mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota.

Results

PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p = .01). Factors associated with LEAD at univariate analysis were VCAM-1 (p = .002), ICAM-1 (p = .003), and TNF-alpha (p = .04) serum levels, but only VCAM-1 (OR 1.1, 95% CI 1.0–1.1; p = .04) and TNF-alpha (OR 1.12, 95% CI 0.99–1.26; p = .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF-alpha serum levels. Down-regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched-chain amino acids degradation was found in the functional gut metagenome of PBC women.

Conclusions

LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut–liver axis.     

Prevalence of Autoimmune Liver Disease Related Autoantibodies in Chinese Patients with Primary Biliary Cirrhosis

Background  

The prevalence of autoimmune liver disease (AiLD)-related autoantibodies has not been defined in Chinese patients with primary biliary cirrhosis (PBC) and therefore needs to be characterized.     

Peri-nuclear antibodies correlate with survival in Greek primary biliary cirrhosis patients

AIM:To investigate possible associations of anti-nuclear envelope antibody(ANEA)with disease severity and survival in Greek primary biliary cirrhosis(PBC)patients.METHODS:Serum samples were collected at diagnosis from 147 PBC patients(85%female),who were followed-up for a median 89.5 mo(range 1-240).ANEA were detected with indirect immunofluorescence on 1% formaldehyde fixed Hep2 cells,and anti-gp210 antibodies were detected using an enzyme linked immunosorbent assay.Findings were correlated with clinical data,histology,and survival.RESULTS:ANEA were detected in 69/147(46.9%) patients and 31/147(21%)were also anti-gp210 positive.The ANEA positive patients were at a more advanced histological stage(Ⅰ-Ⅱ/Ⅲ-Ⅳ56.5%/43.5% vs 74.4%/25.6%,P=0.005)compared to the ANEA negative ones.They had a higher antimitochondrial antibodies(AMA)titer(≤1:160/>1:160 50.7%/49.3%vs 71.8%/28.2%,P=0.001)and a lower survival time(91.7 ±50.7 mo vs 101.8±55 mo,P=0.043).Moreover,they had more advanced fibrosis,portal inflammation,interface hepatitis,and proliferation of bile ductules(P =0.008,P=0.008,P=0.019,and P=0.027,respectively).They also died more frequently of hepatic failure and/or hepatocellular carcinoma(P=0.016).ANEA positive,anti-gp210 positive patients had a difference in stage(Ⅰ-Ⅱ/Ⅲ-Ⅳ54.8%/45.2%vs 74.4%/25.6%,P= 0.006),AMA titer(≤1:160/>1:160 51.6%/48.4%vs 71.8%/28.2%,P=0.009),survival(91.1±52.9 mo vs 101.8±55 mo,P=0.009),and Mayo risk score(5.5 ±1.9 vs 5.04±1.3,P=0.04)compared to the ANEA negative patients.ANEA positive,anti-gp210 negative patients had a difference in AMA titer(≤1:160/>1:160 50%/50%vs 71.8%/28.2%,P=0.002),stage(Ⅰ-Ⅱ/Ⅲ -Ⅳ57.9%/42.1%vs 74.4%/25.6%,P=0.033),fibrosis(P=0.009),portal inflammation(P=0.018),interface hepatitis(P=0.032),and proliferation of bile ductules(P=0.031).Anti-gp210 positive patients had a worse Mayo risk score(5.5±1.9 vs 4.9±1.7,P=0.038)than the anti-gp210 negative ones.CONCLUSION:The presence of ANEA and anti-gp210 identifies a subgroup of PBC pati     

High prevalence of primary biliary cirrhosis and disease-associated autoantibodies in Japanese patients with systemic sclerosis

Objective

To investigate the prevalence of primary biliary cirrhosis (PBC) and PBC-associated autoantibodies in Japanese systemic sclerosis (SSc) patients.

Methods

Clinical data from 225 Japanese SSc patients were retrospectively obtained. Serum samples from these patients were examined for PBC-associated autoantibodies, anti-mitochondrial M2 antibodies (AMA), anti-sp100 antibodies (anti-sp100), and anti-gp210 antibodies (anti-gp210) by enzyme-linked immunosorbent assay.

Results

Of 225 patients, 37 (16.4%) had AMA, 13 (5.8%) had anti-sp100, and 3 (1.3%) had anti-gp210. Three patients were positive for both AMA and anti-sp100, and 2 were positive for both AMA and anti-gp210. PBC was found in 22 (9.8%) patients positive for AMA with or without anti-sp100 or anti-gp210, but not in those with anti-sp100 or anti-gp210 without AMA. Furthermore, 13 patients lacking these three antibodies were diagnosed with or suspected of PBC by liver biopsy and/or their clinical manifestation. Multivariable analysis revealed that AMA and anti-centromere antibodies were independently associated with PBC in SSc patients, while anti-sp100 and anti-gp210 were not.

Conclusions

This study has demonstrated even higher prevalence of both PBC-associated autoantibodies and PBC in the Japanese SSc population than in the Caucasian SSc population. AMA and anti-centromere antibodies are likely to indicate increasing risk of PBC in SSc patients.     

Autoantibodies to muscarinic acetylcholine receptors found in patients with primary biliary cirrhosis

Background

Autoantibodies to the human muscarinic acetylcholine receptor of the M3 type (hmAchR M3) have been suggested to play an etiopathogenic role in Sjögren's syndrome. Primary biliary cirrhosis (PBC) often is associated with this syndrome. Therefore, we studied the co-presence of hmAchR M3 autoantibodies in patients with PBC.

Methods

Frequency of hmAchR M3 autoantibodies was assessed by Western blotting analysis as well as by an ELISA using a 25-mer peptide of the 2^nd extracellular loop of hmAchR M3. Co-localization of hmAchR M3/PBC-specific autoantibodies was studied by confocal laser scanning microscopy. Finally, sera from patients with PBC as well as from healthy controls were tested.

Results

Western blotting analysis as well as results from ELISA testing revealed a significantly enhanced IgG reactivity in PBC patients in contrast to healthy controls. Co-localization of autoantibodies with the hmAchR M3 receptor-specific autoantibodies was observed in 10 out of 12 PBC-patients but none of the 5 healthy controls. Antibodies of the IgM type were not found to be affected.

Conclusions

For the first time, our data demonstrate the presence of autoantibodies to the hmAchR M3 in PBC patients. These findings might contribute to the understanding of the pathogenesis of this disease. Further studies have to focus on the functionality of hmAchR M3 autoantibodies in PBC patients.

     

Autoimmune liver diseases and diabetes: A propensity score matched analysis and a proportional meta-analysis

Background and Aims

Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Methods

We performed a case–control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age-, sex-, BMI- and ethnicity-matched controls. Next, we performed a systematic review and proportional meta-analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model.

Results

Three hundred twenty-eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%–5.7%), 1.7% (0.9%–3.1%), 3.1% (1.9%–4.8%) and of T2D 14.8% (11.1%–19.5%), 18.1% (14.6%–22.2%), 6.3% (2.8%–13.3%) in patients with AIH, PBC and PSC, respectively.

Conclusions

Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted.     

Quality of life in Dutch patients with primary biliary cholangitis: Discrepancies between patients’ perspectives and objective disease parameters

Aim

This study aims to assess the health-related quality of life (HRQoL) in a Dutch population of patients with primary biliary cholangitis (PBC) in relation to the prognosis and need for second line-therapy, based on both objective disease parameters and patients’ perspectives.

Methods

In this cross-sectional multicenter study, HRQoL was assessed by using the Dutch PBC-40 according to objective clinical parameters and patients’ perspectives on treatment and prognosis.

Results

In total, 178/269 (66%) patients responded; mean age 61.2 (SD 9.9) years and 165 (92.7%) women. The PBC-40 domain scores did not differ according to the GLOBE score response (p > 0.05 for all) or according to the POISE criteria (p > 0.05), except for the domain itch (p = 0.031). Patients who considered their survival to be impaired scored higher on all domains as compared to those expecting a normal prognosis (p < 0.05). Similarly, PBC-40 domain scores were higher among patients who considered that they were in need of additional therapy compared to those who did not (p < 0.05 for all, except for domain itch [p = 0.056]). However, 45/62 (72.6%) patients with a self-expected impaired prognosis had a GLOBE score indicative of a normal prognosis. Twenty-five of the 40 (62.5%) patients who believed they needed additional therapy were below POISE criteria.

Conclusion

The HRQoL of patients with PBC was impaired in terms of nonfavorable disease status according to the expectations of patients, but not according to objective disease parameters. Substantial discrepancies between patients’ perspectives and objective parameters were observed, which highlights the need for better patient guidance among patient with PBC.     

Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a randomised controlled trial [ISRCTN88246634]

Background  

Fatigue is a major clinical problem in many patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). An effective treatment has not been defined. Recently, a large proportion of patients with these diseases was found to have symptoms of depression. Because fatigue is a frequent symptom of depression and there is some evidence that treatment with an antidepressant improves fatigue in patients with fibromyalgia, we hypothesised that the antidepressant fluvoxamine might improve fatigue related to PBC and PSC.     

Familial Clustering and Genetic Background of Primary Biliary Cirrhosis in Japan

Background  

Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease.     

A polymorphism in the integrin ��V subunit gene affects the progression of primary biliary cirrhosis in Japanese patients

Background

Accumulating evidence indicates that multiple genetic factors are involved in the pathogenesis of primary biliary cirrhosis (PBC). The aim of this study was to investigate whether polymorphisms of the integrin ??V subunit gene (ITGAV), a component of integrin ??V??6, which plays an important role in the process of fibrosis, are associated with susceptibility to the onset and/or progression of PBC.

Methods

In the primary study, eight tag single nucleotide polymorphisms (SNPs) in ITGAV were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, direct DNA sequencing, or high-resolution melting curve analysis in 309 Japanese patients with PBC who were registered in the National Hospital Organization Study Group for Liver Disease in Japan (PBC cohort I) and 293 gender-matched healthy Japanese volunteers (control subjects). For the replication study, 35 PBC patients who progressed to end-stage hepatic failure and underwent liver transplantation (PBC cohort II) were also analyzed.

Results

Three tag SNPs (rs3911238, rs10174098, and rs1448427) in ITGAV were significantly associated with the severe progression of PBC, but not with susceptibility to the onset of PBC, in the primary study (PBC cohort I). Among these SNPs, rs1448427 was also significantly associated with the severe progression to end-stage hepatic failure in the replication study of PBC patients who underwent liver transplantation (PBC cohort II).

Conclusions

ITGAV is a genetic determinant for the severe progression of PBC in Japanese patients. Genetic polymorphisms of ITGAV may be useful for identifying high-risk Japanese PBC patients, including those who will require liver transplantation, at the time of initial diagnosis.     

Hepatic expression of endocannabinoid receptors and their novel polymorphisms in primary biliary cirrhosis

Background

The endocannabinoid system (EC) has emerged as a crucial mediator in a variety of pathophysiological conditions.

Aims

To evaluate: (1) whether the EC system is activated in the livers of patients with primary biliary cirrhosis (PBC); (2) if genetic variations in human EC receptor genes (CB1 and CB2) may be associated with a different phenotypic expression of the disease and response to therapy.

Methods

The expression of CB1 and CB2 receptors was studied by immunohistochemistry in liver biopsy specimens from 13 patients with PBC, and CB1 and CB2 mRNA expression was studied by real-time polymerase chain reaction testing (RT-PCR) in liver samples. In addition, genetic polymorphisms in the EC receptor gene were sought in 68 patients with PBC from Italy, 84 patients who were residents of the United States (US), and 70 controls matched for sex, age, and for geographical area with the Italian PBC patients. Genomic DNA was extracted from peripheral venous blood leucocytes with standard methods. PCR was used to amplify the coding regions of the CB1 and CB2 genes with specific primers.

Results

CB1 was markedly expressed in hepatocytes and biliary epithelial cells in the livers of patients with PBC; conversely in control liver samples, it was virtually absent. CB2 was expressed in hepatocytes and in cholangiocytes, whereas it was absent from mesenchymal cells. The mRNA of both CB1 and CB2 was detected in the PBC liver samples, as demonstrated by RT-PCR. The CB1 polymorphism (1359 G/A) was present in 26.5% of Italian patients, in 22.9% of healthy controls, and in 27.4% of patients from the US (p = n.s.). The CB2 polymorphism (188–189 AA/GG) was present in 24.4 versus 30.4% of Italian and US patients with PBC, respectively, and in 28.0% of Italian controls samples (p = n.s.). Logistic regression analysis showed that advanced histological stage and the lack of response to ursodeoxycholic acid treatment were significantly correlated with the CB1 polymorphism.

Conclusions

The EC system is markedly up-regulated in the livers of patients with PBC and it may exert a role regulating adaptive mechanisms in cholestasis.     

Clinical significance of autoantibodies to p53 protein in patients with autoimmune liver diseases

BACKGROUND:Autoantibodies to p53 (anti-p53) are rarely present in the sera of patients with autoimmune diseases or the sera of patients with malignancies.OBJECTIVE:To examine the prevalence of anti-p53 in patients with autoimmune liver disease including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), AIH/PBC overlap syndrome (AIH/PBC OS) and primary sclerosing cholangitis (PSC), and to determine the clinical significance of anti-p53 in autoimmune liver diseases.METHODS:Forty patients with AIH, 41 patients with PBC, eight patients with AIH/PBC OS and five patients with PSC were enrolled. Anti-p53 and antibodies to double-stranded DNA (anti-ds-DNA) were analyzed using commercially available ELISA kits. Demographic, laboratory and histological data were compared between the AIH groups seropositive and seronegative for anti-p53.RESULTS:Six of 40 (15.0%) patients with AIH and four of eight (50.0%) patients with AIH/PBC OS were positive for anti-p53. One of 41 (2.4%) patients with PBC was also positive for anti-p53, but all five patients with PSC were negative, indicating a significantly higher prevalence of anti-p53 in patients with AIH or AIH/PBC OS compared with patients with PBC. None of the AIH patients positive for anti-p53 progressed to hepatic failure or relapsed after immunosuppressive treatment. Titres of anti-ds-DNA in patients with AIH and AIH/PBC OS significantly correlated with titres of anti-p53 (r=0.511; P=0.0213).CONCLUSION:The emergence of anti-p53 is likely to be useful for discriminating AIH or AIH/PBC OS from PBC and helpful for predicting favourable prognoses in patients with AIH. DNA damage may trigger the production of anti-p53 in patients with AIH or AIH/PBC OS.     

Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients

Background

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.

Methods

Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction?Crestriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls.

Results

The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively.

Conclusions

CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.     

Statins in Primary Biliary Cirrhosis: Are They Safe?

Background and Aim  

Although cholesterol levels are elevated in patients with primary biliary cirrhosis (PBC), most PBC patients are not at increased risk of dying from atherosclerotic heart disease. There is, however, a subgroup, approximately 10%, who have additional disorders of lipid metabolism. They might benefit from a cholesterol-lowering agent. However, there is concern about using statins in patients with pre-existing liver disease. We therefore reviewed our experience with statins in a large cohort of PBC patients who were seen at Tufts Medical Center during the past decade.     

Waiting list mortality of patients with primary biliary cirrhosis in the Japanese transplant allocation system

Background

The present study aimed to evaluate etiology-based differences in the risk of waiting list mortality, and to compare the current Japanese transplant allocation system with the Child–Turcotte–Pugh (CTP) and the Model for End-Stage Liver Disease (MELD) scoring systems with regard to the risk of waiting list mortality in patients with primary biliary cirrhosis (PBC).

Methods

Using data derived from all adult candidates for deceased donor liver transplantation in Japan from 1997 to 2011, we assessed factors associated with waiting list mortality by the Cox proportional hazards model. The waiting list mortality risk of PBC patients was further estimated with adjustment for each scoring system.

Results

Of the 1056 patients meeting the inclusion criteria, 743 were not on the list at the end of study period; waiting list mortality was 58.1 % in this group. In multivariate analysis, increasing age and PBC were significantly associated with an increased risk of waiting list mortality. In comparison with patients with hepatitis C virus (HCV) infection, PBC patients were at 79 % increased risk and had a shorter median survival time by approximately 8 months. The relative hazard of PBC patients was statistically significant with adjustment for CTP score and medical point score, which was the priority for ranking candidates in the Japanese allocation system. However, it lost significance with adjustment for MELD score. Stratification by MELD score indicated a comparable waiting list survival time between patients with PBC and HCV.

Conclusions

PBC patients are at high risk of waiting list mortality in the current allocation system. MELD-based allocation could reduce this risk.     

The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and primary sclerosing cholangitis

Background  

In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fatigue is a major clinical problem. Abnormal amino acid (AA) patterns have been implicated in the development of fatigue in several non-hepatological conditions but for PBC and PSC no data are available. This study aimed to identify abnormalities in AA patterns and to define their relation with fatigue.     

Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008

Background  

A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.     

The ability of anti-carbonic anhydrase II antibody to distinguish autoimmune cholangitis from primary biliary cirrhosis in Japanese patients

Serum antibody against carbonic anhydrase (CA) II has been described as a serological marker for distinguishing autoimmune cholangitis (AIC) from primary biliary cirrhosis (PBC). To validate this finding in a Japanese population, we evaluated sera from patients with PBC and AIC for antibody to human CA II. An enzyme-linked immunosorbent assay was employed to quantify serum antibody against CA II in patients with PBC (n = 40), AIC (n = 23), autoimmune hepatitis (n = 10), and extrahepatic obstructive jaundice (n = 10). Compared with the finding of a 4% prevalence of anti-CAII antibody in healthy subjects (n = 24), a significantly higher prevalence of anti-CA II antibody was detected in patients with PBC (35%) and AIC (30%) (P < 0.05), but not in patients with autoimmune hepatitis and patients with obstructive jaundice. No significant difference was observed between PBC and AIC patients. These results showed that AIC and PBC would be indistinguishable by anti-CA II antibody testing in Japanese patients. However, the finding of serum anti-CA II antibody in patients with PBC and AIC supports the disease concept of autoimmune exocrinopathy. Received: July 13, 1998/Accepted: October 23, 1998