Autoimmune Cholestatic Liver Disease Research Articles

Therapeutic advances for primary biliary cholangitis: the old and the new.

Primary biliary cholangitis (PBC, primary biliary cirrhosis) is an autoimmune cholestatic liver disease characterized by chronic nonsuppurative destructive cholangitis and the presence of serum antimitochondrial antibodies. Ursodeoxycholic acid is the only drug approved by the US Food and Drug Administration to treat PBC. However, one-third of patients show incomplete responses to ursodeoxycholic acid and a poor prognosis. A number of old and new medications have been used in these patients, such as fibrates, glucocorticoids, immunosuppressants, obeticholic acid, mesenchymal stem cells, biological agents (anti-interleukin-12, cytotoxic T-lymphocyte antigen 4 immunoglobulin, anti-CD20), and antifibrotic drugs. This article reviews the therapeutic advances of these old and new medications in patients with PBC.

Risk stratification in autoimmune cholestatic liver diseases: Opportunities for clinicians and trialists.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are infrequent autoimmune cholestatic liver diseases, that disproportionate to their incidence and prevalence, remain very important causes of morbidity and mortality for patients with liver disease. Mechanistic insights spanning genetic risks and biological pathways to liver injury and fibrosis have led to a renewed interest in developing therapies beyond ursodeoxycholic acid that are aimed at both slowing disease course and improving quality of life. International cohort studies have facilitated a much greater understanding of disease heterogeneity, and in so doing highlight the opportunity to provide patients with a more individualized assessment of their risk of progressive liver disease, based on clinical, laboratory, or imaging findings. This has led to a new approach to patient care that focuses on risk stratification (both high and low risk); and furthermore allows such stratification tools to help identify patient subgroups at greatest potential benefit from inclusion in clinical trials. In this article, we review the applicability and validity of risk stratification in autoimmune cholestatic liver disease, highlighting strengths and weaknesses of current and emergent approaches. (Hepatology 2016;63:644–659)

Bone disease in primary biliary cirrhosis

Primary biliary cirrhosis(PBC)is a chronic autoimmune cholestatic liver disease. Metabolic bone disease is recognized in a complication of chronic liver disease, particularly in PBC. Bone disease in PBC includes osteoporosis and, osteomalacia which is more frequent in advanced liver disease. It is important that PBC occurs mainly in middle-aged women who are highest risk group in primary osteoporosis. In patients with PBC, the dysfunction in enterohepatic circulation of bile acids is associated with the impaired absorption of fats and fat soluble vitamins. Vitamin D and K deficiency leads to osteoporosis resulting in increased risk of bone fracture. This article describes the characteristic and molecular mechanism in bone disease of PBC.

PTU-304 Cost-effectiveness of current therapies in primary biliary cirrhosis: a systematic review of economic evidence

<h3>Introduction</h3> Primary Biliary Cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease. One therapy, ursodeoxycholic acid (UDCA), is FDA approved. Many patients, however, do not respond to this treatment. Serious medical morbidity, impact on patient quality of life (QoL), and mortality are not uncommon despite UDCA therapy. This study set out to assess the economic evidence for current PBC therapies in order to inform the development and implementation of novel therapies. <h3>Method</h3> A systematic review of cost and cost-effectiveness evidence for recognised therapies in PBC was conducted. Data were extracted from relevant studies and assessed for quality in accordance with Centre for Reviews and Dissemination guidelines. <h3>Results</h3> Only two studies, both of UDCA cost-effectiveness, were identified. Although deriving data from randomised controlled trials, no justification for selection of positive UDCA effectiveness data in a broad and ambiguous field was given. A maximum of 5 years of UDCA therapy was studied. Estimates of cost ranged from US$1372 saving per year of therapy, to an extrapolated disease lifetime saving of EUR 6338 per treated patient. Both studies assessed cost from a direct hospital-based perspective only, with no inclusion of primary care costs or adjustment for QoL. <h3>Conclusion</h3> This work is the first systematic review of economic evaluations in PBC. No current or comprehensive economic evaluations of PBC treatments exist. A PBC model informed by recent advances in disease understanding is required to facilitate estimation of the economic burden of PBC and evaluation of cost-effectiveness of novel therapies currently undergoing clinical trials. <h3>Disclosure of interest</h3> None Declared.

Primary biliary cirrhosis is a generalized autoimmune epithelitis.

Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice.

High levels of soluble CTLA-4 are present in anti-mitochondrial antibody positive, but not in antibody negative patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease frequently characterized by anti-mitochondrial autoantibodies (AMA). A minority of patients are AMA-negative. Cytotoxic-T-Lymphocyte-Antigen-4 (CTLA-4) is a surface molecule expressed on activated T-cells delivering a critical negative immunoregulatory signal. A soluble form of CTLA-4 (sCTLA-4) has been detected at high concentrations in several autoimmune diseases, and its possible functional meaning has been suggested. We aimed to evaluate sCTLA-4 concentration in sera of patients with PBC and to correlate it to immunological abnormalities associated with the disease. Blood samples were collected from 82 PBC-patients diagnosed according to international criteria (44 AMA-positive/MIT3-positive and 38 AMA-negative-MIT3-negative), and 65 controls. sCTLA-4 levels were evaluated by ELISA and Western blot. Increased sCTLA-4 concentrations were found in all AMA-positive PBC-patients, but in none of the AMA-negative ones, nor in normal controls or in controls with unrelated liver diseases. sCTLA-4 presence was associated with autoantibodies against MIT3, but not with nuclear autoantibodies (sp100, gp210). This is the first study to demonstrate that levels of sCTLA-4 are elevated in sera of PBC patients. However, they are clearly restricted to patients with AMA positivity, suggesting an immunological difference with respect to AMA-negative ones.

Oxidative stress and antioxidant status in patients with autoimmune liver diseases

ObjectiveTo estimate oxidative stress and antioxidant components during different stages of autoimmune liver diseases and assess their possible implication on disease progression.MethodsWe determined several markers of oxidative injury (isoprostane, aldehydes, protein carbonyls, 3-nitrotyrosine, and myeloperoxidase) and antioxidant components (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase) in whole blood, serum, and urine in 49 patients with autoimmune cholestatic liver diseases (AC) and 36 patients with autoimmune hepatitis (AIH) and healthy subjects matched for sex and age.ResultsBoth AC and AIH patients had increased levels of all lipid and protein oxidative injury products and significantly decreased whole blood glutathione levels compared to controls. AIH patients had significantly higher levels of aldehydes and glutathione peroxidase activity and significantly lower protein carbonyl levels compared to AC patients. Protein carbonyl and isoprostane levels increased and glutathione levels decreased gradually with progression from mild fibrosis to severe fibrosis and cirrhosis in both AC and AIH patients. In addition, both cirrhotic AC and AIH patients had significantly higher protein carbonyls compared to non-cirrhotics.DiscussionWe provide novel findings in support of a major contribution of oxidant/antioxidant imbalance in the progression of liver injury in AC and AIH.

The new epidemiology of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease. Susceptibility to PBC probably arises from a combination of genetic and environmental factors. The prevalence of PBC varies both on an international and a regional level. This can be explained, in part, by differences in clinical practice and case-finding activity. It is likely, however, that substantive geographical differences exist both in terms of genetic susceptibility and environmental factors that potentially trigger the disease in genetically susceptible individuals. The study of the epidemiology of PBC has strongly supported the concept of an environmental triggering factor, but as yet no specific agent has been identified. Ongoing work to discover the environmental agent, as well as the mechanism that causes the disease will answer key questions as to the epidemiology of this complex autoimmune disease as well as providing useful information for other autoimmune conditions.

Polymorphisms in the vitamin D receptor gene and risk of primary biliary cirrhosis: A meta‐analysis

Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic autoimmune liver disease. Although many studies have evaluated the association between many functional polymorphisms in the vitamin D receptor (VDR) gene and PBC risk, debates still exist. Our aim is to evaluate the association between VDR gene polymorphisms, including TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232), and the risk of PBC by a systematic review. We searched literatures in PubMed, SCOPUS, and EMBASE until July 2013. We calculated pooled odds ratios (OR) and 95% confidence intervals (CIs) using a fixed effects model or a random effects model for the risk to PBC associated with different VDR gene polymorphisms. And the heterogeneity assumption decided the effect model. A total of six relevant studies, with 1322 PBC cases and 2264 controls, were included in this meta-analysis. The results indicated that TaqI (rs731236) polymorphism was significantly associated with PBC risk (for T vs t OR = 0.75, 95% CI 0.63, 0.89, Pz = 0.001; TT + Tt vs tt OR = 0.62, 95% CI 0.44, 0.86, Pz = 0.005; OR = 0.74, 95% CI 0.58, 0.94, Pz = 0.016 for recessive model), while ApaI (rs7975232) or BsmI (rs1544410) polymorphism did not. Based on current evidences from published studies, the cumulative effect of TaqI polymorphism in VDR was significantly associated with PBC. Larger studies with mixed ethnicity subjects and stratified by clinical and sub clinical characteristics are needed to validate our findings.

E. coliInduced Experimental Model of Primary Biliary Cirrhosis: At Last

Recurrent urinary tract infections (UTI) have been considered potential triggers of primary biliary cirrhosis (PBC), an autoimmune cholestatic liver disease characterised by progressive destruction of intrahepatic bile ducts. Additional support for the link made between PBC and UTI was based on early observations of recurrent episodes of bacteriuria in female patients with PBC. A series of large epidemiological studies demonstrated a strong correlation between recurrent UTI and PBC, initiating a series of studies investigating the role of Escherichia coli (E. coli, the most prevalent organism isolated in women with UTI) as a trigger of PBC. Immunological evidence of B- and T-cell cross-reactive responses implicating PBC-specific autoantigens and E. coli mimics have been clearly demonstrated, adding support to the notion that E. coli is a potential infectious inducer of PBC in susceptible individuals. One of the major limitations in proving the E. coli/PBC association was the lack of reliable E. coli-infected animal models of PBC. This review provides an overview of the evidence linking this infectious agent with PBC and discusses the pros and cons of a recently developed E. coli-infected animal model of PBC.

Antineutrophil cytoplasmic antibodies in bile are associated with disease activity in primary sclerosing cholangitis

Objective.Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology. The role of antineutrophil cytoplasmic antibodies (ANCAs) in the serum of patients with PSC remains unclear. We hypothesized that ANCA may be detectable in bile, potentially providing diagnostic and prognostic information. Methods.Serum and bile were prospectively collected during endoscopic retrograde cholangiography (ERC) in 72 patients with PSC and other non-PSC obstructive biliary diseases. ANCA measurements were performed by indirect immunofluorescence (IIF). Results.Immunoglobulin G (IgG) ANCA was detected significantly more often in the bile of PSC patients (15/39; 38%) than without (2/33; 6%) (p = 0.001). IgG ANCA in bile was associated with a ten times higher risk of PSC (p = 0.005). In addition, IgG ANCA positivity in bile was associated with the presence of dominant strictures (p = 0.03), cholangiographic severity (p = 0.004), number of ERC (p = 0.01) and interventions performed (p = 0.03). However, IgG ANCA in bile did not correlate with transplantation, cholangiocarcinoma or death. No association was observed between ANCA positivity in sera and ANA and ASCA positivity in sera or bile with the above-mentioned clinical features. Conclusions.The presence of ANCA in the bile of patients with PSC is a novel finding and highly suggestive of PSC. Biliary IgG ANCA correlates with the severity of bile duct strictures and the ensuing number of ERCs and interventions. Therefore, a positive ANCA status in bile may serve as a diagnostic and prognostic marker of the disease progression and biliary complications.

Is living donor liver transplantation really equivalent to deceased donor liver transplantation?

Is living donor liver transplantation really equivalent to deceased donor liver transplantation?

Anti-neutrophil cytoplasmic antibodies in bile are associated with disease activity in primary sclerosing cholangitis

Objective. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology. The role of antineutrophil cytoplasmic antibodies (ANCAs) in the serum of patients with PSC remains unclear. We hypothesized that ANCA may be detectable in bile, potentially providing diagnostic and prognostic information. Methods. Serum and bile were prospectively collected during endoscopic retrograde cholangiography (ERC) in 72 patients with PSC and other nonPSC obstructive biliary diseases. ANCA measurements were performed by indirect immunofluorescence (IIF). Results. Immunoglobulin G (IgG) ANCA was detected significantly more often in the bile of PSC patients (15/39; 38%) than without (2/33; 6%) (p = 0.001). IgG ANCA in bile was associated with a ten times higher risk of PSC (p = 0.005). In addition, IgG ANCA positivity in bile was associated with the presence of dominant strictures (p = 0.03), cholangiographic severity (p = 0.004), number of ERC (p = 0.01) and interventions performed (p = 0.03). However, IgG ANCA in bile did not correlate with transplantation, cholangiocarcinoma or death. No association was observed between ANCA positivity in sera and ANA and ASCA positivity in sera or bile with the above-mentioned clinical features. Conclusions. The presence of ANCA in the bile of patients with PSC is a novel finding and highly suggestive of PSC. Biliary IgG ANCA correlates with the severity of bile duct strictures and the ensuing number of ERCs and interventions. Therefore, a positive ANCA status in bile may serve as a diagnostic and prognostic marker of the disease progression and biliary complications.

Primary biliary cirrhosis and hereditary hemorrhagic telangiectasia: When two rare diseases coexist

Primary biliary cirrhosis is a slowly progressive cholestatic autoimmune liver disease that mainly affects middle-aged women with an estimated prevalence ranging from 6.7 to 402 cases per million. Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber disease, is an autosomal dominant disorder characterized by angiodysplastic lesions (telangiectases and arteriovenous malformations) that can affect many organs, including liver, with a prevalence of 1-2 cases per 10000. We describe the coexistence, for the first time to our knowledge, of these two rare diseases in a 50-year old Caucasian woman. In this setting, the relevance of an accurate medical history, the role of liver histology and the characterization of liver involvement through dynamic imaging techniques can be emphasized.

The Immunophysiology and Apoptosis of Biliary Epithelial Cells: Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Biliary epithelial cells (BECs) provide the first line of defense against lumenal microbes in the biliary system. BECs express a variety of pathogen recognition receptors and can activate several intracellular signaling cascades to initiate antimicrobial defenses, including production of several anti-microbial peptides, cytokines, chemokines, and adhesion molecules. BECs also secrete immunoglobulin A and interact with other cells through expression and release of adhesion molecules and immune mediators. Recently, several reports suggest a correlation between apoptosis and autoimmunity through ineffective clearance of self-antigens. Primary biliary cirrhosis (PBC) is a slowly progressive, autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated destruction of BECs. We have demonstrated that the AMA self-antigen, namely the E2 subunit of the pyruvate dehydrogenase complex, is detectable in its antigenically reactive form within apoptotic blebs from human intrahepatic biliary epithelial cells and activates innate immune responses. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and the presence of concentric fibrosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis. However, apoptosis does not appear to play a central role in PSC. Despite both diseases involving immune-mediated injury to bile ducts, apoptosis occurs more commonly overall in PBC where it likely plays a unique role.

1311 NONALCOHOLIC FATTY LIVER DISEASE IS NOT MORE FREQUENT AMONG HYPERTENSIVES AND NON-DIPPERS

Arterial hypertension (AH) and nonalcoholic fatty liver disease (NAFLD) are both components of the metabolic syndrome although their concurrence is uncertain. Normal variation of blood pressure (BP) is characterized by a nighttime dip of 10–20%. The association of non-dipping status and NAFLD is also controversial. The aims of our study were to investigate the possible association of NAFLD and insulin resistance to AH and the effect of the dipping profile. Patients and Methods: 186 consecutive patients, referred to the Hypertensive Unit were included. Exclusion criteria: alcohol >40gr/d and >20gr/d for men and women, respectively, diabetes mellitus, viral or autoimmune hepatitis, cholestatic and druginduced liver disease. AH was defined as mean 24-hour ambulatory BP values >130/80mmHg. Dippers and non-dippers were defined according to whether nighttime BP drop was ≥ or < 10%, respectively. Body mass index (BMI), waist/hip ratio and blood results were evaluated. 24-hour BP monitoring, cardiac and abdominal ultrasounds were also performed. Results: 173 patients were eligible for analysis (82 with AH), mean age: 54.3±10.1 years (mean±SD). Patients with and without steatosis on ultrasound differed with respect to BMI (30.0±5.2 vs 25.6±3.8 kg/m, p < 0.0001), waist/hip ratio (103.1±13.2 vs 87.1±11.7 cm, p =0.002), triglycerides (135.9±62.4 vs 98.7±58.2mg%, p = 0.028), HOMA-IR (3.5±3.0 vs 1.5±0.8, p = 0.0004) and gGT (25.8±18.4 vs 16.0±7.7 IU/L, p = 0.025) whereas the frequency of hypertension was not different (52 vs 37%, p = 0.061). Characteristics of NAFLD were not different among hyperand normotensives. Among hypertensives, no differences were identified in the distribution of study parameters between dippers (N=48) and non-dippers (N=34). A more detailed analysis, after exclusion of reverse and extreme dippers, did not alter the results. Conclusions: 1. There is a trend for patients with steatosis to have AH (p =0.061) 2. All parameters related to NAFLD did not differ among patients with and without AH 3. Dipping status in patients with AH does not seem to be associated to NAFLD.

Overlapping of Primary Biliary Cirrhosis and Small Duct Primary Sclerosing Cholangitis: First Case Report

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both autoimmune cholestatic liver disease and the association of these two conditions in the same patient is very rare. We report the case of a female patient presenting with a cholestatic liver disease and a panel of autoantibodies specific for PBC, including antibodies to mitochondrial E2-pyruvate dehydrogenase, gp-210 and Sp-100. Beside these findings, the liver biopsy revealed concentric fibrosis of small biliary ducts and the magnetic resonance cholangiography presented no abnormal findings. Diagnosis of small duct PSC/PBC overlapping was done. No description of this association was found in the literature. Clinical and serological features of this unusual finding are discussed.

Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.

Infectious Agents and Xenobiotics in the Etiology of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC)is a chronic autoimmune cholestatic liver disease that manifests a latitudinal gradient in prevalence and incidence. The mechanisms leading to the initiation and perpetuation of PBC remain largely enigmatic, although it is established that a combination of genetic predisposition and environmental stimulation is required. PBC is also characterized by a high concordance rate in monozygotic twins and is considered a model autoimmune disease because of several features common to other conditions and the relatively homogeneous serological and biochemical features. From a diagnostic standpoint, PBC is characterized by the highest specificity of serum autoantibodies directed at mitochondrial proteins. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics that will be critically discussed in the present review article.

PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York.

Various environmental factors have been proposed as triggers of primary biliary cirrhosis (PBC), a progressive autoimmune cholestatic liver disease which is characterised by the destruction of the small intrahepatic bile ducts. Support for their pathogenic role in PBC is provided by epidemiological studies reporting familial clustering and clusters of the disease within a given geographical area. The seminal study by Triger reporting that the great majority of PBC cases in the English city of Sheffield drank water from a specific water reservoir, has been followed by studies reporting disease 'hot spots' within a restricted geographic region of the former coal mining area of Newcastle. The New York study reporting an increased risk and significant clustering of PBC cases near toxic federal waste disposal sites has added strength to the notion that environmental factors, possibly in the form of infectious agents or toxic/chemical environmental factors in areas of contaminated land, water or polluted air may play a key role in the development of the disease. This review discusses the findings of reports investigating environmental factors which may contribute to the cause of primary biliary cirrhosis.