Early Primary Biliary Cirrhosis Research Articles

New treatments/targets for primary biliary cholangitis.

SummaryPrimary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.

Advances in noninvasive detection of esophageal varices in primary biliary cirrhosis

Primary biliary cirrhosis as autoimmune liver disease, due to conventional screening in recent years, the popularity of anti-mitochondrial antibodies to the number of patients with early primary biliary cirrhosis showed an upward trend. The development of esophageal varices is an important indicator of poor prognosis of primary biliary cirrhosis. The current assessment of esophageal variceal gold standard is endoscopy, but it is invasive examination, such as non-invasive examination to assess whether patients with esophageal varices, the selective endoscopy of the patient, can significantly reduce the patient's pain and the economic burden. In recent years, clinical studies have been carried out or carried out with non-invasive detection of patients with primary biliary cirrhosis complicated by esophageal varices. Key words: Liver cirrhosis, biliary/CO/DI; Blood glucose/CO/DI; Review

Are We Missing Early Primary Biliary Cirrhosis?

Are We Missing Early Primary Biliary Cirrhosis?

Red Blood Cell Distribution Width to Platelet Ratio is Related to Histologic Severity of Primary Biliary Cirrhosis.

We aimed to investigate whether red blood cell distribution width (RDW) and RDW to platelet ratio (RPR) were related to the histologic severity of primary biliary cirrhosis (PBC).Seventy-three treatment-naïve PBC patients who had undergone a liver biopsy between January 2010 and January 2015 were enrolled in our study. The patients’ histological stages were based on the classifications of Ludwig and Scheuer. The patients were divided into early stage (Stage I) and advanced stage (Stage II, III, and IV) hepatic fibrosis according to their histological stage. All common patient demographics, clinical characteristics, hematological parameters, liver biochemistry, and antimitochondrial M2 antibody levels (AMA-M2) were retrospectively analyzed, and RDW, RPR, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on the 4 factors (FIB-4) were calculated.A total of 28 (38.4%) patients had early stage PBC, whereas 45 (62.6%) were classified as advanced stage. Regarding age, no significant differences between the early and advanced stages were observed. Patients with advanced stage PBC had significantly higher RDW (13.6 vs 14.4; P = 0.019), conjugated bilirubin (10.1 vs 23.4; P = 0.029), and significantly lower cholinesterase (7901.1 vs 6060.8; P = 0.001) and platelets (212.6 vs 167.0; P = 0.006). However, no significant differences (P > 0.05) in other routine parameters previously evaluated in PBC, including aspartate aminotransferase (AST) and mean platelet volume, were found between the groups. The sensitivity and specificity of RDW were 33.3% and 92.9%, respectively, and the area under the receiver-operating characteristic curve (AUROC) was 0.66. However, the sensitivity and specificity of RPR were 46.7% and 96.4%, respectively, and the corresponding AUROC was 0.74 (P < 0.001). Hence, compared with preexisting indicators, RPR showed a higher AUROC than APRI (0.648; P = 0.035) and FIB-4 (0.682; P = 0.009).RDW and RPR may be a new noninvasive marker for predicting histologic severity of PBC.

The Distribution and the Fibrotic Role of Elevated Inflammatory Th17 Cells in Patients With Primary Biliary Cirrhosis.

T helper (Th) 17 cells were reported to have the property of proinflammation and profibrosis. We first investigate the levels of Th17 cells in primary biliary cirrhosis (PBC) patients, and then explore their distribution and fibrotic role in the disease.We compared the circulating Th17 and hepatic interleukin (IL)-17-positive cells between patients and healthy controls (HCs) at different disease stages by flow cytometry and immunohistochemistry, respectively. The levels of chemokine (c-c motif) ligand (CCL) 20 were then measured. For exploration of the reason why Th17 cells increased, CD4+CD161+ populations were sorted and cultured with IL-23 and IL-1β to analyze their proliferation and IL-17 secretions. The serum IL-23 and IL-1β were tested by enzyme-linked immunosorbent assay. The proliferation and expressions of α-smooth muscle actin and IL-8 of hepatic stellate cells (HSCs) were identified after stimulated by different concentrations of IL-17.Circulating and hepatic Th17 cells were elevated in PBC patients compared with HCs. Early PBC patients presented with more Th17 cells in periphery blood and less in the liver than advanced PBC patients. Accordingly, the levels of both serum and hepatic CCL20 for Th17 cells were higher, especially in those with advanced disease. The progenitor of Th17, CD4+CD161+ cell was increased in PBC. Moreover, the percentage of Th17 cells was positively related with CD4+CD161+ cell. After stimulation with IL-23 and IL-1β which were improved in PBC patients, CD4+CD161+ cells from PBC patients expressed more IL-17, although their proliferation were not different between 2 groups. IL-17 can promote the proliferation of HSCs at a dose-dependent method, and also increase the IL-8 expression in a dose/time-dependent way. Anti-IL-17 can neutralize the above reactions.CD4+CD161+ cells are a source of increased Th17 in PBC patients. With disease progression, Th17 population decreased in the circulation, accompanied by greater accumulation in the liver, which is regulated by CCL20 in advanced patients. IL-17 may be involved in the process of PBC fibrosis.

Pathophysiological analysis of primary biliary cirrhosis focusing on choline/phospholipid metabolism

Injury to biliary epithelial cells caused by disorders in bile composition may be the initial step in the pathogenesis of primary biliary cirrhosis (PBC). We therefore examined choline/phospholipid metabolism in livers of patients with PBC. Hepatic levels of mRNA encoded by choline metabolism-related genes in early stage PBC patients were quantified by real-time RT-PCR. Serum cholesterol and triglyceride concentrations in each lipoprotein compartment and serum/tissue choline levels were also measured. OCT1 expression was quantified by genotype (rs683369 and rs622342). Serum choline concentrations were significantly higher in PBC patients than in normal individuals, with the concentrations in the former lowered by treatment with fibrates. Hepatic choline levels were markedly lower in PBC patients than in controls. The levels of expression of genes associated with choline uptake (OCT1 and CTL1), phosphatidylcholine synthesis (PEMT and BHMT), and phosphatidylcholine transport (MDR3) were significantly upregulated in PBC compared with control livers. Serum cholesterol concentrations and the cholesterol/triglyceride ratio in serum very low density lipoprotein were markedly higher in PBC patients than in controls. In PBC liver, OCT1 protein levels were lower in patients with minor (CG/GG at rs683369 and/or CC at rs622342) than major (CC at rs683369 and AA at rs622342) genotypes of the OCT1 gene. During early stage PBC, hepatocellular choline uptake and PC synthesis become dysregulated. OCT1 genotypes may influence the pathogenesis of PBC.

Increased activated natural killer T cells in the liver of patients with advanced stage primary biliary cirrhosis.

Although growing evidence suggests a major role for T cells in the pathogenesis of primary biliary cirrhosis (PBC), the roles of natural killer (NK) and natural killer T (NKT) cells, which predominate in the liver, in the pathogenesis of PBC remain unclear. We investigated the status of NK and NKT cells in the liver and peripheral blood samples obtained from 11 patients with asymptomatic PBC diagnosed as stage I or II (early PBC) and 7 patients with symptomatic PBC who underwent liver transplantation (advanced PBC) using flow cytometry and immunohistochemical staining. The proportions of NK and NKT cells were significantly decreased in the liver of patients with early PBC compared with normal donors. However, the proportion of CD56+ NKT cells was increased in the liver of patients with advanced PBC. Moreover, the proportion of activated Fas ligand (FasL)-positive NKT cells was significantly increased in the liver of patients with advanced PBC compared with early PBC (P=0.013). We also found increased expression of FasL on lymphocytes infiltrating around the injured bile duct in advanced PBC using immunohistochemical staining. Our results suggest that activated NKT cells may contribute to the biliary epithelial cell death resulting in the progression of PBC.

Ursodeoxycholic acid influences the expression of p27kip1 but not FoxO1 in patients with non-cirrhotic primary biliary cirrhosis.

Background. Enhanced expression of cell cycle inhibitor p27kip1 suppresses cell proliferation. Ursodeoxycholic acid (UDCA) delays progression of primary biliary cirrhosis (PBC) but its effect on p27kip1 expression is uncertain. Aims. To analyze the expression of p27kip1 and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway. Materials and Methods. The examined human tissue included explanted livers from patients with cirrhotic PBC (n = 23), primary sclerosing cholangitis (PSC; n = 9), alcoholic liver disease (ALD; n = 9), and routine liver biopsies from patients with non-cirrhotic PBC (n = 26). Healthy liver samples served as controls (n = 19). Livers of FoxO-deficient mice were also studied. mRNA and protein expressions were analyzed by real-time PCR and Western blot. Results. p27kip1 expression was increased in cirrhotic and non-cirrhotic PBC. FoxO1 mRNA levels were increased in PBC (8.5-fold increase versus controls). FoxO1 protein expression in PBC was comparable to controls, but it was decreased in patients with PSC and ALD (63% and 70% reduction, respectively; both P < 0.05 versus control). UDCA-treated non-cirrhotic patients with PBC showed decreased expression of p27kip1 mRNA. Conclusion. PBC progression is characterized by a FoxO1-independent increase of p27kip1 expression. In early PBC, UDCA may enhance liver regeneration via p27kip1-dependent mechanism.

Biochemical criteria at 1 year are not robust indicators of response to ursodeoxycholic acid in early primary biliary cirrhosis: results from a 29‐year cohort study

BackgroundIn primary biliary cirrhosis (PBC), biochemical criteria at 1 year are considered surrogates of response to ursodeoxycholic acid (UDCA). However, due to the slow natural history of PBC, evaluation at 1 year may be suboptimal to assess the therapeutic response, particularly in early disease.AimTo determine whether evaluation of biochemical criteria at 1 year is a reliable surrogate of UDCA response in early PBC.MethodsWe analysed the prospectively collected data of 215 patients (untreated = 129; UDCA-treated = 86) with early PBC (normal baseline bilirubin/albumin) and a median follow-up of 8 years (range: 1–29.1). The 1-year attainment rates of the Barcelona, Paris-I, Paris-II and Toronto definitions, and their predictive relevance for a poor outcome (death, transplantation, complications of cirrhosis), were assessed either as a result of UDCA or no treatment. Independent associations with attaining each UDCA response definition were identified by multivariate analysis.ResultsUntreated patients displayed 1-year biochemical features compatible with ‘treatment response’ at rates (Barcelona: 36.4%, Paris-I: 66.7%, Toronto: 59.7%, Paris-II: 40.3%) similar to those obtained under UDCA. Depending on the definition, baseline ALP≤3xULN (OR: 4.80–35.90), AST≤2xULN (OR: 5.63–9.34) and early histological stage (OR: 3.67–3.87) were the stronger predictors for attaining the criteria. UDCA treatment was associated with attaining Barcelona (OR = 2.16) and Paris-II (OR = 2.84), but not Paris-I, and not Toronto definition when excluding late histological cases. Paris-I criteria were significantly predictive of long-term outcomes (HR = 2.83) in untreated patients.ConclusionsIn early PBC, biochemical criteria at 1 year reflect severity of the disease rather than the therapeutic response to UDCA.

Increased IL-23 and IL-17 expression by peripheral blood cells of patients with primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a typical autoimmune disease for which the pathogenesis remains unclear. IL-23 and IL-17 are pro-inflammatory cytokines of the “IL-23/IL-17 axis,” which may play a key role in the pathogenesis of autoimmune diseases. In this study, we investigated the expression of IL-23 and IL-17 in the peripheral blood of patients with PBC and its clinical significance. We used quantitative PCR to determine mRNA expressions of IL-23, IL-23 receptor, and IL-17 in peripheral blood mononuclear cells (PBMC) from PBC patients. ELISA’s were used to determine patients’ serum levels of IL-23 and IL-17. IL-23- and IL-17-producing cells in liver biopsis were also analyzed. Compared to a healthy control group, the mRNA expression levels of IL-23 p19, its corresponding receptor, IL-23R, and IL-17 in PBMC’s from PBC patients were significantly increased, and these levels were correlated with PBC disease stages. PBC patients’ serum levels of IL-23 and IL-17 were higher than those in a post-hepatic cirrhosis group and a healthy group, and were significantly higher in the early PBC disease stages than in the advanced PBC stages. There were significantly more IL23+ and IL-17+ mononuclear cells in portal areas of liver tissues in advanced stages of this disease than in the early stages. The serum levels of IL-23 and IL-17 in PBC patients were positively correlated with serum GGT levels. Thus, IL-23 and IL-17 may play an important role in the pathogenesis of PBC by promoting inflammation. Because the IL-23 and IL-17 levels in the peripheral blood of PBC patients were increased and were correlated with clinical stages, they may be indices that could be used to clinically monitor PBC.

Clinicopathological Significance of Serum Fractalkine in Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC), characterized by cholangitis and loss of intrahepatic small bile ducts, predominantly affects middle-aged females. We have reported that fractalkine expression associated with chronic inflammation is observed in the damaged bile ducts and periductal vessels of PBC patients, which is closely associated with chronic cholangitis. We investigated the association between serum fractalkine levels and clinicopathological findings in PBC patients. Liver biopsy specimens before ursodeoxycholic acid treatment and serum samples at the time of liver biopsy and 1 and 2 years after treatment were obtained from 68 PBC patients (M/F = 14/54). Serum fractalkine levels were measured by enzyme-linked immunosorbent assay, and their association with clinicopathological findings (liver function data, autoantibodies, cholangitis activity, hepatitis activity, fibrosis, bile duct loss, and orcein-positive granules) was analyzed. Serum fractalkine levels were in the range of 0.1-33.2 ng/ml (average, 3.2 ng/ml). They were increased in PBC patients with high degrees of cholangitis activity, a mild degree of hepatitis activity, fibrosis, orcein-positive granules, and early stages. In cases with high serum fractalkine levels, those who exhibited good biochemical responses to treatment mostly showed improved serum fractalkine levels after treatment. Serum fractalkine levels of PBC patients were high in cases with marked cholangitis activity at early stages. In addition, they closely correlated with the effect of therapy, indicating that fractalkine plays a role in the pathogenesis of initial cholangitis in early stage PBC and consequent chronic cholangitis. Thus, our results suggest that fractalkine is a good candidate for molecular-targeted treatment.

A validated clinical tool for the prediction of varices in PBC: The Newcastle Varices in PBC Score

Gastro-oesophageal varices (GOV) can occur in early stage primary biliary cirrhosis (PBC), making it difficult to identify the appropriate time to begin screening with oesophageo-gastro-duodenoscopy (OGD). Our aim was to develop and validate a clinical tool to predict the probability of finding GOV in PBC patients. A cross-sectional retrospective study analysing clinical data of 330 PBC patients who underwent an OGD at the Freeman Hospital, Newcastle was used to create a predictive tool, the Newcastle Varices in PBC (NVP) Score, that was externally validated in PBC patients from Cambridge (UK) and Toronto (Canada). 48% of the Newcastle, 31% of the Cambridge, and 22% of the Toronto cohorts of PBC patients had GOV. Twenty-five percent (95% CI 18-32%) of the Newcastle cohort had GOV diagnosed at an index variceal bleed. Of the others, 37% (95% CI 28-46%) bled after a median of 1.5 years (IQR 3.75). Transplant-free survival was significantly better in those without GOV than in those with GOV (p<0.001), but similar in patients with GOV that bled and those that did not (p=0.1). The NVP score (%Probability)=1/[1+exp^-(9.186+0.001*alkaline phosphatase in IU-0.178*albumin in g/L-0.015*platelet × 10(9)) was validated in 2 external cohorts and was highly discriminant (AUROC 0.86). Cost consequences analyses revealed the NVP score to be as accurate as, but more economical than using either OGD directly or other risk scores for screening PBC patients. The NVP score is an inexpensive, non-invasive, externally validated tool that accurately predicts GOV in PBC.

Keratin 19 Demonstration of Canal of Hering Loss in Primary Biliary Cirrhosis: “Minimal Change PBC”?

Liver biopsy is important for diagnosing primary biliary cirrhosis (PBC). Prior investigations suggest that immunostaining for biliary keratin 19 (K19) may show the earliest changes suspicious for PBC, namely, loss of the canals of Hering (CoH). We aimed to study the clinical outcomes of patients whose biopsy specimens appeared histologically near normal or with minimal inflammatory changes, but in which K19 staining revealed widespread periportal CoH loss, a finding we termed "minimal change PBC." Ten patients were identified prospectively as having nearly normal or mildly inflamed biopsy specimens without diagnostic or suggestive histologic features of PBC, but with near complete CoH loss; six had available follow-up clinical data, one had follow-up biopsy. Controls for clinical and/or K19 analysis included six normal livers and biopsy specimens from 10 patients with confirmed early PBC, 10 with early stage chronic hepatitis C (CHC), and nine with resolving, self-limited hepatitis (RSLH). Staining for K19 in normal controls, livers with "minimal change" PBC, CHC, and RSLH showed 9.2 ± 6.0, 0.44 ± 0.37 (P < 0.0001), 5.7 ± 4.6 (n.s.), 4.1 ± 2.1 (P < 0.02) CoH per portal tract, respectively. Patients with available clinical follow up, compared to patients with diagnostic early-stage PBC biopsies, showed identical treatment responses to ursodeoxycholic acid, similar rates and types of nonhepatic autoimmune diseases, and/or subsequent development of autoimmune hepatitis overlap syndrome. We suggest that CoH loss demonstrated by K19 immunostaining is an early feature in PBC. Clinical findings in the years following biopsy, including response to ursodeoxycholic acid, show identical changes to patients with biopsy confirmed PBC. We suggest that this "minimal change" feature may support a clinical diagnosis of PBC even in the absence of characteristic, granulomatous, duct destructive lesions.

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.

Restless leg syndrome is a treatable cause of sleep disturbance and fatigue in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) patients frequently describe sleep problems. The cause remains unclear and treatment is challenging. Restless leg syndrome (RLS) is a common sleep disorder. In this study, we systematically screened PBC patients for the presence of RLS. Participants were recruited from our specialist PBC clinical service. Subjects completed the International Restless Leg Syndrome Study Group rating scale (IRLSS) a validated measure of the presence of RLS and its severity. Those fulfilling diagnostic criteria for RLS underwent foot actigraphy (CamNtech Actiwatch) to objectively assess periodic limb movement index (PLMI) (normal <5/h). Restless leg syndrome was assessed in 42 consecutive early stage PBC patients. Twelve (29%) fulfilled the IRLSS criteria for RLS. Scores were significantly higher in PBC compared to controls (P = 0.005). Twenty-four patients were further assessed with foot actigraphy for 3 nights (12 with subjective RLS symptoms and 12 with no RLS symptoms). Thirteen of twenty-four subjects had PLMI >5/h and four had moderate or severe PLMI >15/h. All moderate or severe PLMI subjects had subjective symptoms of moderate or severe RLS. No patients had PLMI >10 in the absence of RLS symptoms. Eleven PBC patients with symptomatic RLS went on to have treatment. Sixty-three per cent had clear benefit in restless leg symptoms and associated symptoms of fatigue. Restless leg syndrome symptoms are common and underdiagnosed in PBC patients. RLS represents a potential therapy for PBC patients with daytime sleepiness, fatigue and unpleasant lower limb symptoms and this is worthy of further studies in larger cohorts.

Clinical significance of autoantibodies directed against nuclear and cytoplasmic antigens in autoimmune liver disease

Previous research carried out in the area of autoimmune liver disease and autoantibody specificity has not been conclusive, and correlation between the two in most situations remains unclear. This study aims to facilitate a consensus on these autoantibodies in an unselected patient population and their relationship to autoimmune liver disease (AILD). The study detected two autoantibodies that show reasonable specificity for primary biliary cirrhosis (PBC), anti-sp100 and anti-gp210, and it may be clinically useful to report any antimitochondrial antibody (AMA) detected, as this may be a sign of very early PBC. The inter-methodological differences in assays available for detection of the autoantibodies were also noted. Care must be taken when selecting methods to detect these autoantibodies.

Prevalence and associated factors with esophageal varices in early primary biliary cirrhosis

Recent routine testing for anti-mitochondrial antibodies has increased the number of patients with early primary biliary cirrhosis (PBC). The prevalence and clinical significance of esophageal varices in those patients remains obscure. A systematic cohort analysis of 256 PBC patients was performed to clarify the prevalence, characteristics, and prognosis of the patients with early PBC and esophageal varices. Twenty-two patients had esophageal varices at the time of diagnosis: 5.5% (12/217) with early disease of histological stage 1 or 2, and 25.6% (10/39) with advanced disease of stage 3 or 4. Immediate treatments were required for two patients with early PBC: one for bleeding varices, and the other for large varices. The overall survival of the patients with early PBC and esophageal varices at diagnosis did not significantly differ from that of patients without esophageal varices (P = 0.66). High alkaline phosphatase (ALP) ratios (odds ratio = 2.3) and low platelet counts (odds ratio = 0.77) were significantly associated with the presence of esophageal varices in the patients with early PBC. Significant associations of these two factors with the development of esophageal varices during follow-up were also revealed (odds ratio = 1.4 and 0.88, respectively). The patients with early PBC and high ALP ratios ≥ 1.9 had significantly high risks of developing esophageal varices during follow-up (P = 0.022). High ALP ratios and low platelet counts at diagnosis and decreased platelet counts during follow-up are useful predictors of esophageal varices in patients with early PBC.

378 Investigation of Platelet Function in Patients With Early Primary Biliary Cirrhosis Using Rotem Thrombelastography and Flow Cytometry. Comparison With Healthy Controls

378 Investigation of Platelet Function in Patients With Early Primary Biliary Cirrhosis Using Rotem Thrombelastography and Flow Cytometry. Comparison With Healthy Controls

Pathogenesis of biliary tract injury in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. The pathogenesis of PBC, predominance of female, or the reason why biliary duct is selectively involved, however, remains unknown. Infectious or non-infectious noxious insults such as xenobiotic chemicals may precipitate in the individual having a genetic background of PBC. Activation of innate immune response seems to be a key event in early PBC, leading to the autoimmune injury of small intrahepatic bile duct. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). In PBC, dysregulated biliary innate immunity, namely hyper-responsiveness to PAMPs, is associated with the pathogenesis of cholangiopathy. Moreover, the targeted biliary epithelial cells (BEC) may play an active role in the perpetuation of autoimmunity by attracting immune cells via chemokine secretion. Biliary innate immune responses induce the production of two chemokines, CX3CL1 (fractalkine) and several Th1 shift chemokines, causing the migration of inflammatory cells including NK cells. TLR 4 ligand-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-α) synthesized by TLR 3 ligand-stimulated monocytes. These findings give new insights in the pathogenesis of this mysterious disease, PBC.

Varices in Early Histological Stage Primary Biliary Cirrhosis

Esophageal varices (EV) in early histological stages of primary biliary cirrhosis (PBC) have been recognized but not well defined. We sought to determine the prevalence, clinical characteristics, and predictors of EV in early-stage PBC, as well as to evaluate the effectiveness of recent guidelines regarding EV screening in PBC patients. We retrospectively reviewed the charts of 325 PBC patients who had undergone complete evaluation before enrollment into 2 large clinical trials at the Mayo Clinic. Nineteen percent (62/325) of our patient population had EV on esophagogastroduodenoscopy; 6% (8/127) of early-stage PBC patients had EV. Ninety five percent of our PBC patients with varices met at least one of the following conditions: male sex, low albumin (<3.5 g/dL), elevated bilirubin level (≥1.2 mg/dL), and/or prolonged prothrombin time (≥12.9 s). The sensitivity and specificity of these variables in combination to predict the presence of varices were 95% and 55%, respectively. Serum bilirubin ≥1.2 mg/dL and albumin <3.5 were independent predictors of varices with hazard values of 5.4 and 3.5 respectively. EV can occur in a minority of early-stage PBC patients. Various models may be used to identify PBC patients who are candidates for screening esophagogastroduodenoscopy for EV. Based on adequate performance and its simplicity, we propose that male sex, low albumin, elevated bilirubin, and/or prolonged prothrombin time be used as a model to noninvasively predict EV. Further validation is required.