Etiology Of Primary Biliary Cirrhosis Research Articles

Primary biliary cirrhosis and psoriasis: a two-sample Mendelian randomization study.

Primary biliary cirrhosis (PBC) and psoriasis are frequently observed to co-occur in clinical settings. However, the causal associations and underlying mechanisms between PBC and psoriasis remain poorly defined. In this study, we conducted bidirectional MR analysis to explore the causal relationship between PBC and psoriasis using four MR methods: inverse-variance weighted, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses were carried out, employing different models and testing methods for comparison to assess the influence of heterogeneity and pleiotropy on our findings and to confirm the robustness of these results. A causal relationship between the risk of PBC and psoriasis was identified, as confirmed by IVW analysis (OR: 1.081, 95%CI: 1.028~1.137, P<0.05). The other three MR methods also produced similar results. However, psoriasis did not have a causal effect on PBC risk (OR: 1.022, 95%CI: 0.935~1.118, P>0.05). The intercept of MR-Egger regression was 0.0013 (P>0.05), indicating that genetic pleiotropy did not influence the results. Additionally, the leave-one-out analysis demonstrated the robustness of our MR findings. This study reveals a causal relationship between PBC and psoriasis, with PBC increasing the risk of psoriasis, but not the reverse. This potential causal relationship offers a new perspective on the etiology of PBC.

Association between chronic urinary tract infection and primary biliary cirrhosis

The etiology of primary biliary cirrhosis (PBC) remains unclear, and at present, this disease is considered to be caused by the combined effect of genetic factors, infection, autoimmunity, and environmental factors. Since infection is the major cause for PBC, scholars have been focusing on the association between chronic microbial infection. Studies have shown that Escherichia coli is the most common bacterium for urinary tract infection (UTI), and recurrent UTI has been confirmed to be a risk factor for the development and progression of autoimmune liver diseases and is closely associated with PBC. This article investigates the association between UTI and PBC and possible mechanisms.

Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune chronic liver disease with worldwide increasing morbidity. However, the etiology of PBC is still unclear. Recently, the epithelial-mesenchymal transition (EMT) and interleukin-17A (IL-17A), a pro-inflammatory cytokine, were proposed to be involved in the pathogenesis of PBC. Therefore, in this study, we aimed to clarify the roles of IL-17A and/or EMT in the onset of PBC. The results showed that the median serum IL-17A level was significantly higher in 29 PBC patients (average course of 40.69 months) than that of 11 healthy controls. The intrahepatic biliary epithelial cells (IBECs), the major target of destruction in PBC, underwent EMT in PBC patients. The immunohistochemical analysis revealed that the protein levels of IL-17A receptor were increased in IBECs and the IL-17A protein was accumulated around the IBECs in the PBC patients. These results imply that the IL-17A-mediated signaling and EMT of intrahepatic biliary epithelial cells (IBEC-EMT) are key pathogenic processes of PBC. To study the association between IL-17A and IBECs-EMT, we then examined if IL-17A induced EMT using a human cell line of IBECs (HIBECs). After the treatment with IL-17A for 48 h, HIBECs changed into bipolar cells with a fibroblastic morphology. Additionally, the results of real-time PCR and Western blot analyses demonstrated that IL-17A up-regulated the expression of a mesenchymal marker vimentin and down-regulated the expression of an epithelial marker E-cadherin in HIBECs in the dose- and time-dependent manners. These results suggest that IL-17A may play an important role in the IBECs-EMT.

Orphan drugs in development for primary biliary cirrhosis: challenges and progress

Primary biliary cirrhosis (PBC) is a chronic progressive liver disease that often leads to fibrosis, cirrhosis, and end-stage liver disease. The diagnosis is made when there is evidence of cholestasis and reactivity to the antimitochondrial antibody. The etiology of PBC is poorly understood; however, several lines of evidence suggest an environmental factor that triggers a series of immune-mediated inflammatory reactions in the bile ducts in a genetically susceptible individual. Fatigue and pruritus are the most common symptoms of PBC; however, many patients are diagnosed with PBC only based on laboratory abnormalities. The only pharmacological treatment approved for PBC is ursodeoxycholic acid (UDCA). Several controlled studies have shown that UDCA improves liver biochemistries and prolongs transplant-free survival in PBC patients. Nearly 40% of PBC patients do not respond to UDCA, and those patients are at high risk of serious adverse events, such as the development of liver failure. Therefore, newer alternative therapeutic options for PBC are needed. Obeticholic acid is a first-in-class farnesoid X receptor agonist that has been recently evaluated in PBC patients with inadequate response to UDCA, and demonstrated beneficial results in improving liver biochemistries. Several other agents (fibrates and glucocorticoids) have been previously examined in PBC patients with inad - equate response to UDCA, and preliminary results showed biochemical improvement. However, large-scale controlled clinical trials are needed to determine the long-term effects of fibrates and glucocorticoids on the clinical outcomes of PBC. Clinical trials of NGM282 (a fibroblast growth factor-19 analog) and Abatacept (a fusion protein composed of the Fc portion of immu- noglobulin G1 fused to CTLA4) are currently underway.

DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis.

BackgroundAlthough the etiology of primary biliary cirrhosis (PBC) remains enigmatic, there are several pieces of data supporting the thesis that a strong genetic predisposition and environmental factors interact to produce a selective loss of tolerance. The striking female predominance of PBC has suggested that this sex predisposition may be secondary to epigenetic alterations on the X chromosome. In the present study, we rigorously defined the X chromosome methylation profile of CD4, CD8, and CD14 cells from 30 PBC patients and 30 controls. Genomic DNA from sorted CD4, CD8, and CD14 subpopulations was isolated, sonicated, and immunoprecipitated for analysis of methylation. All products were hybridized to a custom-tiled four-plex array containing 27,728 CpG islands annotated by UCSC and 22,532 well-characterized RefSeq promoter regions. Furthermore, bisulfite sequencing was then used for validation on a subsequent group of independent samples from PBC patients and controls. Thence, expression levels of selected X-linked genes were evaluated by quantitative real-time PCR with cDNA samples from all subjects.ResultsWe report herein that a total of 20, 15, and 19 distinct gene promoters reflected a significant difference in DNA methylation in CD4+ T, CD8+ T, and CD14+ cells in patients with PBC. Interestingly, there was hypermethylation of FUNDC2 in CD8+ T cells and a striking demethylation of CXCR3 in CD4+ T cells, which inversely correlated with CXCR3 expression levels in CD4+ T cells from early-stage PBC patients.ConclusionsOur data provides a set of genes with epigenetic alteration likely to be indicators of autoimmunity and emphasizes the role of CXCR3 in the natural history of PBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0098-9) contains supplementary material, which is available to authorized users.

Does primary biliary cirrhosis cluster in time?

The aetiology of primary biliary cirrhosis (PBC) is not well established. Previously we found evidence of space–time clustering and seasonal variation in the date of diagnosis, suggesting a possible role for a transient or seasonally varying environmental factor. We examined whether a temporally varying environmental agent may be involved by analysing population-based PBC data from northeast England over 1987–2003. Using an adaptation of a method proposed by Potthoff and Whittinghill, we found significant temporal variation by date of diagnosis at the level of aggregation of one year. However, there was no evidence for general irregular (non-seasonal) temporal clustering within periods less than a year. These results provide little support for the involvement of agents occurring in geographically widespread mini-epidemics, but – taken together with studies of spatial and spatio-temporal clustering – do not preclude the role of more localised sporadic mini-epidemics. Future research should seek to elicit putative environmental agents.

Animal models of primary biliary cirrhosis.

Within the last decade, several mouse models that manifest characteristic features of primary biliary cirrhosis (PBC) with antimitochondrial antibodies (AMAs) and immune-mediated biliary duct pathology have been reported. Here, the authors discuss the current findings on two spontaneous (nonobese diabetic autoimmune biliary disease [NOD.ABD] and dominant negative transforming growth factor-β receptor II [dnTGFβRII]) and two induced (chemical xenobiotics and microbial immunization) models of PBC. These models exhibit the serological, immunological, and histopathological features of human PBC. From these animal models, it is evident that the etiology of PBC is multifactorial and requires both specific genetic predispositions and environmental insults (either xenobiotic chemicals or microbial), which lead to the breaking of tolerance and eventually liver pathology. Human PBC is likely orchestrated by multiple factors and hence no single model can fully mimic the immunopathophysiology of human PBC. Nevertheless, knowledge gained from these models has greatly advanced our understanding of the major immunological pathways as well as the etiology of PBC.

Pathophysiology and recent findings of primary biliary cirrhosis complicated by systemic sclerosis

Primary biliary cirrhosis (PBC) can be complicated by systemic sclerosis (SSc) and, more specifically, limited cutaneous SSc (lcSSc), which was previously called CREST syndrome. Moreover, combined PBC and SSc has been described in many case reports. Although neither the etiology of PBC nor that of SSc has been elucidated, some genetic and immunological factors are known to be shared. Both disorders are autoimmune fibrotic diseases characterized by increased levels of profibrotic cytokines transforming growth factor β (TGFβ) and interleukin-6, which have recently been suggested to influence T-helper 17 cells and regulatory T cells involved in acquired immunity. lcSSc is accompanied by CREST symptoms, although complete CREST cases are rare, with relatively high prevalence of Raynaud's phenomenon, sclerodactyly and telangiectasia, and lower prevalence of calcinosis and esophageal dysmotility. Because patients with anticentromere antibody positive PBC-SSc are at a high risk of developing portal hypertension, particular attention should be paid to the management of gastroesophageal varices. In addition, the management of SSc-related non-hepatic disorders, such as pulmonary fibrosis, pulmonary hypertension, heart disorder, infection and malignancy, is also important for improved outcomes. Because PBC is often complicated by rheumatic disease, hepatologists should keep the possibility of systemic disorder in mind when examining PBC patients.

Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis

Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.

Frequent detection of immunoglobulin M anti-herpes simplex viral antibody in patients with primary biliary cirrhosis

We read with great interest the article by McNally et al.,1 who reported the involvement of a seasonally varying environmental agent in the etiology of primary biliary cirrhosis (PBC), and who have reported previously that a transient environmental agent may be involved in the etiology using a space-time clustering method among cases of PBC in a defined geographical population of northeast England.2 A combination of genetic predisposition and environmental factors are thought to contribute the etiology of PBC.3 As environmental factors, certain bacterial and viral infections, including Escherichia coli, mycobacteria, and a retrovirus, are reported to be involved.4 To date, however, no specific virus has been implicated in the pathogenesis, although cases of PBC tend to cluster within areas. Herpes simplex virus (HSV) is a hepatotropic virus, but it is an uncommon cause of hepatitis in immunocompetent adults. HSV hepatitis occurs in neonatal infections, pregnancy, and immunosuppressed patients. Recently, we frequently detected immunoglobulin M (IgM) anti-HSV antibody in patients with PBC. Twenty-two (55%) of 40 patients were positive (cutoff index >1.2) for IgM anti-HSV, 13 (33%) were negative (<0.8), and five (12%) were undetermined (0.8-1.2) (Fig. 1). Nineteen of 22 patients with positive IgM anti-HSV were positive for immunoglobulin G (IgG) anti-HSV, and three were negative. Nine of 13 patients with negative IgM anti-HSV were positive for IgG anti-HSV, and four were negative. Four of five undetermined patients were positive for IgG anti-HSV, and one was negative. Immunoglobulin M anti-HSV antibody in patients with primary biliary cirrhosis. Arrows and arrowheads represent antinuclear membrane antibody positivity and anticentromere antibody positivity, respectively. Nakamura et al.5 reported that two different progression types exist in PBC and that positive anti-gp210 (antinuclear membrane) and positive anticentromere antibodies represent the hepatic failure type and portal hypertension type, respectively. All five patients with antinuclear membrane antibodies showed strong positivity (Fig. 1, arrows). Five of 13 patients with anticentromere antibodies showed weak positivity (Fig. 1, arrowheads). Our results support environmental factors involved in the etiology of PBC, although further studies should be done to evaluate whether HSV is an infectious agent or whether IgM anti-HSV is the result of a response to cross-reactive cellular proteins. Keiichi Fujiwara M.D, Ph.D.*, Osamu Yokosuka M.D., Ph.D.*, * Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

The role of the innate immune recognition system in the pathogenesis of primary biliary cirrhosis: a conceptual view

The aetiology of primary biliary cirrhosis (PBC) remains unknown. Infectious and non-infectious noxious insults in combination with tissue-specific factors may precipitate PBC. Activation of innate immune response because of impending danger signals seems to be a key event in early PBC, as evidenced by granuloma formation, eosinophilic reaction and IgM elevation. Aberrant mitophagy in 'stressed' biliary epithelia cells may initiate the immune response against mitochondrial antigens. Antimitochondrial autoantibodies recognize evolutionarily conserved molecules. The question arises, whether they are pathogenic or rather an expression of beneficial autoimmunity. The generally stable course of PBC suggests that stimulatory and inhibitory autoimmune reactions govern the inflammatory biliary process. Tissue repair and defense are the heart of innate immunity. But continuous exposure of exogenous stimuli may precipitate functional antireceptor autoantibodies that are no more protective but rather harmful. Mitophagy, apoptosis and bile duct proliferation define the inflammatory response within bile ducts. Autoantigens may be clustered in different blebs on the surface of apoptotic cells targeting a variety of membrane and non-membrane-associated antigens. Thus, the autoantibody response in PBC may target, for instance, the pro- and anti-apoptotic proteins of the Bcl-2 family or receptors of the adrenergic or cholinergic system, hereby interfering with the programme of apoptosis and the proliferation of biliary epithelial cells. Consideration of there being functional autoantibodies into the pathogenesis of PBC may help to improve our understanding of the aetiopathogenesis of PBC.

Seasonal variation in the patient diagnosis of primary biliary cirrhosis: Further evidence for an environmental component to etiology

The etiology of primary biliary cirrhosis (PBC) is far from clear. Both genetic and environmental factors are likely to be involved. We have previously reported evidence of space-time clustering, suggesting that a transient environmental agent may be involved in etiology. To further examine whether a seasonally varying environmental agent may contribute to the etiology of PBC, we have analyzed seasonal variation with respect to month of diagnosis using population-based data from northeast England over a defined period (1987-2003). Date of diagnosis was defined as the earliest date at which the patient was found to have fulfilled any two of three diagnostic criteria (i.e., antimitochondrial antibody-positive titer ≥1 in 40, cholestatic liver blood tests, diagnostic or compatible liver histology). Monthly expected (E) numbers of cases were calculated under an assumption of a uniform distribution throughout the year. Observed counts (O) were compared with the expected numbers. The chi-squared heterogeneity test was used to test for overall nonuniform variation and also for individual months. Poisson regression analysis was used to fit a sinusoidal (i.e., harmonic) model to the data, using month of diagnosis as a covariate in the model. There was a marked peak for diagnoses in the month of June (O = 115, E = 84.7, O/E = 1.36; P = 0.001). Furthermore, there was evidence of a sinusoidal pattern with a June peak (P = 0.012). These highly novel results provide further evidence for the involvement of a seasonally varying environmental agent in the etiology of PBC.

Case–control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations

ObjectiveThe aetiology of primary biliary cirrhosis (PBC) is largely unknown. Previous studies have indicated that both environmental and genetic risk factors may be important.DesignWe undertook a large case–control study to...

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.

Environmental agents involved in the cause of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an immune mediated chronic cholestatic liver disease with a slowly progressive course It is a universal disease with a reported latitudinal gradient in prevalence and incidence. The aetiology of primary biliary cirrhosis is still unknown. It is characterized by a 60% concordance in monozygotic twins and is considered an autoimmune disease because of several features common to other autoimmune conditions and the relatively homogeneous serological and biochemical features. However geoepidemiological and clinical studies strongly imply that environmental factors also play an important role. It is accepted that the disease is clearly the result of a combination of genetic and environmental factors. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics. This review will attempt to place such factors in perspective.

Are Transient Environmental Agents Involved in the Aetiology of Primary Biliary Cirrhosis?

Are Transient Environmental Agents Involved in the Aetiology of Primary Biliary Cirrhosis?

Environmental Agents Involved in the Cause of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is an immune mediated chronic cholestatic liver disease with a slowly progressive course It is a universal disease with a reported latitudinal gradient in prevalence and incidence. The aetiology of primary biliary cirrhosis is still unknown. It is characterized by a 60% concordance in monozygotic twins and is considered an autoimmune disease because of several features common to other autoimmune conditions and the relatively homogeneous serological and biochemical features. However geoepidemiological and clinical studies strongly imply that environmental factors also play an important role. It is accepted that the disease is clearly the result of a combination of genetic and environmental factors. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics. This review will attempt to place such factors in perspective.

Treatment of Primary Biliary Cirrhosis: A new challenge?

Primary biliary cirrhosis (PBC) is characterized by unknown etiologies, anti-mitochondrial antibodies, injury of the biliary duct and the lack of a definite remedy. The etiologies of PBC have been well-discussed, including microorganisms and xenobiotics as the triggers for initiating the disease, and an abnormality of immune-tolerance. Recently, several animal models of PBC have been developed that may lead to the development of new therapies. Here, we reviewed the articles that address the etiology of PBC and the therapy for this disease for the confirmation of our current positions and future directions.

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.

Are transient environmental agents involved in the aetiology of primary biliary cirrhosis?

Recently a space-time clustering analysis of cases of primary biliary cirrhosis (PBC) was carried out, using population-based data from a defined geographical region of northeast England. Space-time clustering analysis is a specialised descriptive statistical technique an d is observed when excess cases are found in highly localised geographical areas for very limited periods of time. The analyses revealed the presence of highly statistically significant space-time clustering which could not be attributed to an artefactual occurrence. This finding was interpreted as providing supportive evidence for the involvement of transient environmental agents in aetiology [1]. This Special Issue of Disease Markers is dedicated to PBC and specifically the role that transient environmental factors may play in aetiology. Current knowledge is reviewed by seven selected invited experts (and associates) in the field. The aetiology of PBC is far from clear. In this Special Issue of Disease Markers, the role of transient environmental agents is reviewed by the seven invited contributors. They each provide their own perspective to the ongoing debate. The possibility that the putative transient agent might be an infection is considered by some of the reviewers. Epidemiological studies have indicated that infections may either trigger PBC or lead to progression. Reviewers also examine the putative role of other transient environmental factors, including chemical exposures, contaminated drinking water and lifestyle factors.