Primary Biliary Cirrhosis Patients Research Articles

Spleen Thickness Plus Platelets Can Effectively and Safely Screen for High-Risk Varices in Cirrhosis Patients.

Currently, most primary hospitals cannot routinely perform liver stiffness measurements (LSMs) and spleen stiffness measurements (SSMs), which are recommended by guidelines to exclude high-risk varices (HRVs). We tried to find more convenient indicators for HRV screening. We enrolled 213 cirrhosis patients as the training cohort (TC) and 65 primary biliary cirrhosis patients as the validation cohort (VC). We included indicators such as SSM by two-dimensional shear wave elastography, LSM by transient elastography, and other imaging and laboratory tests. Variable analysis revealed SSM, platelets (PLT), and spleen thickness (ST) as independent risk indicators for HRV. In TC, ST+PLT (ST < 42.2 mm and PLT > 113.5 × 109/L) could avoid 35.7% of the esophagogastroduodenoscopies (EGDs), with a 2.4% missed HRV rate. Although the proportion of EGDs spared by ST+PLT was less than SSM+PLT (SSM < 29.89 kPa + PLT > 113.5 × 109/L) (35.7% vs. 44.1%), it was higher than that of the Baveno VI criteria (B6) (35.7% vs. 28.2%). We did not validate SSM+PLT in VC considering our aims. ST+PLT safely spared 24.6% of EGDs in VC, identical to B6. Conclusions: The ability of ST+PLT to exclude HRVs was superior to B6 but slightly inferior to SSM+PLT. When SSM cannot be routinely performed, ST+PLT provides an extra option for patients to exclude HRVs as a more convenient model.

COMPARATIVE CHARACTERISTICS OF AMAPOSITIVE AND AMA-NEGATIVE PRIMARY BILIARY CHOLANGITIS

Primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) is one of the most significant diseases that is predominantly verified in women. The prevalence of PBC is 1.9-40.2 per 100,000 population. Antimitochondrial antibodies (AMA) are of major importance for the diagnosis of primary biliary cirrhosis (PBC), and it has also been suggested that they may be involved in the pathogenesis of the disease. Objective: The aim of this study was to characterize the clinical, biochemical parameters and response to UDCA (Paris I criteria) PBC patients depending on AMA status in the Republic of Kazakhstan. Material and methods. The study was conducted on the basis of the Research Institute of Cardiology and Internal Diseases from 2014 to 2019. A total of 212 patients with primary biliary cholangitis were recorded. Results. Among 212 patients, 171 (80.7%) were AMA-positive and 41(19,3%) - AMA-negative. Vast majority of patients in both groups were Asian (179; 84.4%) and female (206; 97.2%). Severe disease (F3/4) was revealed in 108 (63.2%) AMA-positive and in 18 (43.9 %) AMA-negative patients (p&gt;0.05). AMA-positive and AMA-negative PBC were associated with autoimmune hepatitis in 88 (51.5%) and 10 (24.4%) cases (p&lt;0.01), rheumatoid arthritis in 26 (15.2%) and 5 (12.2%), autoimmune thyroiditis in 35 (20.5%) and 4 (9.8%), vitamin D deficiency in 89 (52.1%) and 19 (46.3%), osteoporosis in 48(28.1%) and 7 (17.1%), gallstone disease in 43 (25.4%) and 8 (21.2%) respectively (p &gt;0.05). Response to ursodeoxycholic acid (UDCA) treatment according to Paris I criteria was noted in 24 out of 81 (29.6%) AMA-positive and in 9 out of 22 (40.9%) AMA-negative patients (p&gt;0.05). Conclusion. In patients with AMA-positive PBC compared with AMA-negative, there is a statistically significant high value of autoimmune hepatitis and autoimmune thyroiditis. Whereas, response to UDCA treatment according to Paris I criteria is higher in AMA-negative PBC.

Estimating restricted mean treatment effects with additive-multiplicative hazards models

ABSTRACT The difference in restricted mean survival times between two groups is often of inherent interest in epidemiologic and medical studies. In this paper, we propose a general additive-multiplicative hazards (AMHs) regression model to estimate the restricted mean treatment effects, where the survival time is subject to both dependent and independent censoring. The AMH specifies an additive and multiplicative form on the hazard functions for the survival and censored times associated with covariates, which contains the proportional hazards model and the additive hazards model. By an inverse probability censoring weights scheme, we obtain the estimators of the regression parameters and the restricted mean treatment effects. We establish the large sample properties of the proposed estimators. Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed procedures and the primary biliary cirrhosis patients data are analyzed for illustration.

A Systematic Review and Meta-Analysis on Metabolic Bone Disease in Patients with Primary Sclerosing Cholangitis.

Data about the association between primary sclerosing cholangitis (PSC) and metabolic bone disease are still unclear. PSC is a chronic cholestatic liver disease (CCLD) which affects the biliary tract, and it has a highly variable natural history. We systematically searched until 28 February 2022 MEDLINE, Cochrane Central Register of Controlled Trials, the ISI Web of Science, and SCOPUS, for studies in patients with PSC. We identified 343 references to potential studies. After screening them, we included eight studies (893 PSC patients, 398 primary biliary cirrhosis (PBC) patients, and 673 healthy controls) for the present meta-analysis. Pooled analyses found no difference in BMD-LS (Z = 0.02, p-value = 0.98) between PSC patients and healthy controls. BMD-LS was statistically lower in PBC patients than in PSC patients (Mean Difference, MD, 0.06, 95% CI 0.03 to 0.09, p-value = 0.0007). The lumbar spine T-score was higher in the PSC patients compared with PBC patients (MD 0.23, 95% CI 0.04 to 0.42, p-value = 0.02). Given the limited literature available, better designed, and larger scale primary studies will be required to confirm our conclusion.

Integrated Lipidomics and Metabolomics Study of Four Chemically Induced Mouse Models of Acute Intrahepatic Cholestasis.

Lithocholic acid (LCA), alpha-naphthyl isothiocyanate (ANIT), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and ethinyl estradiol (EE) are four commonly used chemicals for the construction of acute intrahepatic cholestasis. In order to better understand the mechanisms of acute cholestasis caused by these chemicals, the metabolic characteristics of each model were summarized using lipidomics and metabolomics techniques. The results showed that the bile acid profile was altered in all models. The lipid metabolism phenotype of the LCA group was most similar to that of primary biliary cirrhosis (PBC) patients. The ANIT group and the DDC group had similar metabolic disorder characteristics, which were speculated to be related to hepatocyte necrosis and inflammatory pathway activation. The metabolic profile of the EE group was different from other models, suggesting that estrogen-induced cholestasis had its special mechanism. Ceramide and acylcarnitine accumulation was observed in all model groups, indicating that acute cholestasis was closely related to mitochondrial dysfunction. With a deeper understanding of the mechanism of acute intrahepatic cholestasis, this study also provided a reference for the selection of appropriate chemicals for cholestatic liver disease models.

[Investigation of the Contribution of Autoantibodies to Clinical Diagnosis in Liver Pathologies and the Identification of Accompanying Autoimmune Diseases].

Autoantibodies are frequently detected in the presence of autoimmune liver diseases (ALD) [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)] and are widely used to classify the disease clinically. The aim of this study was to investigate the contribution of autoantibodies for the diagnosis of ALD and the identification of other accompanying systemic autoimmune rheumatic diseases (SARD). In addition, it was aimed to compare the results of indirect immunofluorescence (IIF) antinuclear antibody (ANA) patterns and extractable nuclear antigen (ENA) antibodies. A total of 593 patients, including 544 patients with high liver function tests from general surgery/gastroenterology clinics and 49 patients referred from internal medicine/rheumatology clinics to investigate ALD, were included in the study. HBsAg and anti-HCV test results of the patients were found to be negative. ANA, anti-mitochondrial antibody (AMA)/anti-liver-kidney microsomal antibody (LKM), anti-smooth muscle antibody (ASMA), antineutrophil cytoplasmic antibody (ANCA) assays were performed by indirect immunofluorescence method (IIF) (Euroimmune AG, Luebeck, Germany). Extractable nuclear antigen (ENA) (nRNP/Sm, Sm, SS-A, SS-B, Scl-70, Jo-1, dsDNA, nucleosome, histone, ribosomal P-protein, AMA-M2, Ro-52, PM-Scl, CENP-B, PCNA, DFS70) and liver profiles [soluble liver antigen\liver pancreas antigen (SLA/LP), liver cytosolic antigen1(LC-1), LKM-1, anti-mitochondrial antibody M2(AMA-M2)] (Euroimmune AG, Luebeck, Germany) were detected by immunoblot (IB) method. Demographic characteristics, clinical data, presence of systemic autoimmune rheumatic diseases (SARD), radiological and laboratory findings were determined from the medical records. Autoantibody tests were found to be negative in 461 (77.7%) of 593 patients (mean age= 53.3 ± 15.6, age range= 18-90), and were positive in 132 (22.3%) (86.4% female) of the patients. Of the patients with positive autoantibodies, 60.6% (80/132) were diagnosed as PBS and 1.5% (2/132) were diagnosed as AIH (positive anti-LC-1 and anti-LKM1 antibodies). Fourteen of the patients (10.6%) with centromere, nuclear membrane (NM), multiple nuclear dot (MND) staining patterns and elevated liver enzymes could not be diagnosed as a specific disease and were followed up. PBS (13/30) was detected in approximately half of the patients diagnosed with SARD. The most common accompanying SARD in PBC patients was Sjögren's syndrome (SS) (7.5%, 6/80), followed by rheumatoid arthritis (RA) (5.0%, 4/80), scleroderma (2.5%, 2/80), and systemic lupus erythematosus (SLE) (1.3%, 1/80) respectively. The most common pattern was the AMA staining pattern (34.8%, 46/132) among the autoantibody positive patients. AMA and ANA staining patterns were detected together in 31.1% (41/132) of the patients. In the ENA profile results of these patients, the most common profile detected was anti-Ro-52 (65.9%, 27/41), followed by anti-SSA (34.1%, 14/41), anti-SSB (22.0%, 9/41) and anti-CENP-B (12.2%, 5/41) autoantibodies , respectively. ANA patterns were detected in 32.6% (43/132) of the patients (NM 9.1%, centromere 9.1%, MND 6.8%, respectively). In our study, 87.5% (70/80) of the patients diagnosed as PBS were found to have AMA positivity and 12.5% (10/80) of them had ANA positivity (such as NM, CNN, centromere). The characteristics, laboratory and radiological findings of the patients with isolated AMA positivity alone (Group 1) and patients with multiple patterns/autoantibodies (Group 2) were compared. In patients with multiple patterns/autoantibodies (Group 2), the presence of cirrhosis and liver heterogeneity were found to be higher than Group 1 (p= 0.049). ALD associated autoantibodies can be detected before years from the clinical disease. ALD may be associated with various SARD. Detection of ALD-related autoantibodies in patients diagnosed with SARD can provide early diagnosis of these patients. These autoantibodies guide both diagnosis and prognosis as in PBC. Collaboration between the laboratory specialist and the clinician is critical in the diagnosis, management and early recognition of these patients before clinical disease.

Serum Ghrelin Concentration in Patients With Primary Biliary Cirrhosis (PBC).

Introduction: The appetite-modulating hormone ghrelin may have a role in the etiology of anorexia which is a serious concern in patients with primary biliary cirrhosis (PBC). This study aims to assess the difference in ghrelin level between cases of PBC and healthy controls matched for age and gender, and to evaluate the level of ghrelin in relation to clinical and laboratory findings among cases.Methods: Twenty patients with primary biliary cirrhosis and 30 healthy controls matched by gender and age were recruited. The severity of liver disease was determined using the Child-Pugh grading system. Clinical comorbidities such as a history of ascites, gastrointestinal bleeding, and encephalopathy were evaluated. A commercial enzyme-linked immunosorbent assay was used to measure total ghrelin. Results: PBC cases had a significantly higher average level of ghrelin (2305.3 ± 639.4) pg/mL compared to controls (682 ± 197.3) pg/mL. Furthermore, the minimum reported level in cases was 1258 pg/mL compared to 326 pg/mL in controls, while the maximum level nearly tripled the control’s maximum level. In PBC patients, plasma levels of total ghrelin showed a weak positive correlation with age, an inverse correlation with body mass index, and were not associated with gender. The level was significantly higher than those in the controls. Ghrelin was associated with the severity of cirrhosis. Levels of serum ghrelin were higher in patients with associated comorbidities such as a history of ascites, gastrointestinal bleeding, and encephalopathy.Conclusions: Our study demonstrated elevated serum ghrelin levels in patients with primary biliary cirrhosis. Serum ghrelin was associated with the degree of severity and the presence of related comorbidities. Patients with primary biliary cirrhosis remain anorexic and catabolic despite elevated ghrelin levels, suggesting tissue resistance to this anabolic peptide which could be crucial to understanding anorexia and cachexia in primary biliary cirrhosis.

Covering the Cover

Patient-centric, orthogonal, genetic, and pharmacologic approaches identify sequential inhibition of XPO1 and ATR that may yield therapeutic benefit in TP53-mutant CRC. Impressive advances in sequencing technologies and bioinformatic approaches have identified numerous potentially clinically relevant, intervenable genetic alterations in many cancers, including colorectal cancer (CRC). The challenge remains to identify relevant functional alterations and prioritize those with the highest therapeutic or diagnostic potential from such compendiums. In this issue of Gastroenterology, Inoue et al used a patient-centric functional genomics approach to identify new clinically actionable therapeutic targets in CRC (see Graphical Abstract) by pairing in vivo functional genomics with in vitro drug screening in patient-derived samples. The investigators used patient-derived CRC xenografts (PDXs) to perform a short hairpin RNA screen with 196 genes targeted by FDA-approved compounds. Concurrently, a 262-compound in vitro screen was performed and correlated with the in vivo results. These orthogonal approaches yielded genetic targets with high clinical therapeutic potential. Identification of several known targets, namely, PSMD1, PLK1, HDAC2.3, CDK4/6, and mTOR, supported the validity of this approach, as did target concordance between genetic and pharmacologic screening strategies. Exportin 1 (XPO1), a nuclear-cytoplasmic exporter, was identified as a novel target in this dual screening strategy. XPO1 levels were increased in all 4 CRC PDX models, in CRC cell lines, and in TCGA datasets, where high expression correlated with poor prognosis in CRC patients. Importantly, XPO1 inhibitors are under clinical investigation. Both genetic and pharmacologic inhibition of XPO1 by KPT-330 attenuated growth of CRC PDX-derived samples via induction of TP53-independent DNA damage responses. Importantly, recovery from KPT-330-treated TP53-mutant lines increased ATM and ATR phosphorylation as well as activation of downstream targets, which suggests G2/M checkpoint engagement. XPO1 inhibition with the XTR inhibitor AZD-6738 strikingly attenuated recovery in a TP53-mutant context. Sequential XPO1/ATR inhibition in a TP53-mutant CRC PDX model resulted in DNA damage, tumor shrinkage, and increased overall survival. These results warrant future efficacy experiments in immunocompetent preclinical models. Nevertheless, this critical study highlights the value of combining orthogonal genetic and pharmacologic approaches to identify potential clinically actionable targets in cancer. See page 196. A novel skin-to-pruriceptor neuron miR-146a pathway is responsible for pruritis in patients with cholestatic liver disease. Pruritis commonly occurs in cholestatic disease and can be intense, persistent, and debilitating. Therapeutic options are marginally effective at best. While it is widely thought that the accumulation of bile acids in the dermis is contributory, the precise molecular mechanism has not been fully elucidated. Lysophosphatidylcholine (LPC) hydrolyzed to lysophosphatidic acid (LPA) is correlated with itch severity in patients suffering from cholestatic disease. Earlier work implicated TRPV1 and TRPA1, members of the TRP ion channel family, in LPA-mediated pruritis. In this issue of Gastroenterology, Chen et al investigate the mechanism of cholestatic disease–induced pruritis with the use of mouse and nonhuman primate models. Treatment with the TRPV4 inhibitors GSK205 and HC067047 or keratinocyte-specific TRPV4 deletion reduced LPC-induced scratching in mice. Patch-clamp recordings in HEK293 cells engineered to express TRPV4 revealed that LPC directly interacted with a binding pocket in the TRPV4 carboxy terminus. This TRPV4:LPC interaction resulted in ERK phosphorylation in both human and mouse keratinocytes. Subsequent modeling using an inducible Braf transgenic mouse model demonstrated increased pERK and scratching behavior with transgene induction. Paracrine secretion of miR-146a by keratinocytes was LPC-, TRPV4-, and MEK/ERK-dependent and resulted in scratching phenotype via TRPV1 activation in primary pruriceptors. Both LPC and miR-146a were increased in cholestatic mouse models and primary biliary cirrhosis patients with cholestatic itch. Finally, rhesus monkeys injected with either LPC or miR-146a triggered scratching behavior. These studies identify a new signaling pathway from the skin to sensory neurons triggering pruritis which could lead to new therapeutics, potentially via modulation of miR-146 levels in patients with pruritic cholestatic disease. See page 301. TAK-101, gliadin encapsulated in negatively charged nanoparticles, prevents gluten-induced immune activation in celiac disease. Gluten induces immune activation leading to enteropathy in celiac disease. TAK-101 is composed of gliadin encapsulated in negatively charged poly(D,L-lactide-co-glycolide) nanoparticles designed to induce tolerogenic inhibition (Figure 1). In this issue of Gastroenterology, Kelly and Murray report a phase 1 safety study and phase 2a randomized double-blind trial of TAK-101 among biopsy-confirmed celiac disease patients. Thirty-three patients on a gluten-free diet underwent a 14-day gluten challenge after 2 intravenous doses of placebo or TAK-101. No serious adverse events were observed. TAK-101 induced an 88% reduction in change from baseline in circulating gliadin-specific interferon-γ–producing cells (2.01 vs 17.58; P = .006). The Vh:Cd ratio decreased in the placebo group but not in the TAK-101 group. TAK-101 also reduced circulating effector memory T cells. These findings suggest that antigen-specific immune tolerance can be induced pharmacologically, preventing gluten-induced immune activation. The results support further clinical development of this novel agent in celiac disease and offer proof of principle for inducing immune tolerance as a therapeutic strategy for other immune-mediated diseases. See page 66. Thermal ablation after endoscopic mucosal resection is associated with low risk of residual or recurrent adenoma for large nonpedunculated colorectal polyps in an international prospective trial. Thermal ablation of the defect margin after endoscopic mucosal resection for large (≥20 mm) nonpedunculated colorectal polyps reduces residual or recurrent adenoma at surveillance colonoscopy in a randomized trial. In this issue of Gastroenterology, Sidhu et al reported real-world clinical effectiveness of this treatment modality (Figure 2). A total of 1049 patients with 1049 large nonpedunculated polyps from 2016 to 2020 were enrolled in an international multicenter prospective trial. The median size of the polyps was 35 mm, with 54% located in the right colon. Thermal ablation was achieved in 989 patients (95%). Among those patients, residual or recurrent adenoma was identified in 1.4% during surveillance colonoscopy at a median interval of 6 months. Thermal ablation was incomplete in 5% of patients. Among those with incomplete thermal ablation, residual or recurrent adenoma was identified in 27.1% during surveillance colonoscopy. This study shows that thermal ablation after endoscopic mucosal resection is associated with a low rate of residual or recurrent adenoma in a real-world setting. See page 163.

Dynamic prediction and analysis based on restricted mean survival time in survival analysis with nonproportional hazards

Background and objectiveIn the process of clinical diagnosis and treatment, the restricted mean survival time (RMST), which reflects the life expectancy of patients up to a specified time, can be used as an appropriate outcome measure. However, the RMST only calculates the mean survival time of patients within a period of time after the start of follow-up and may not accurately portray the change in a patient's life expectancy over time. MethodsThe life expectancy can be adjusted for the time the patient has already survived and defined as the conditional restricted mean survival time (cRMST). A dynamic RMST model based on the cRMST can be established by incorporating time-dependent covariates and covariates with time-varying effects. We analyzed data from a study of primary biliary cirrhosis (PBC) to illustrate the use of the dynamic RMST model, and a simulation study was designed to test the advantages of the proposed approach. The predictive performance was evaluated using the C-index and the prediction error. ResultsConsidering both the example results and the simulation results, the proposed dynamic RMST model, which can explore the dynamic effects of prognostic factors on survival time, has better predictive performance than the RMST model. Three PBC patient examples were used to illustrate how the predicted cRMST changed at different prediction times during follow-up. ConclusionsThe use of the dynamic RMST model based on the cRMST allows for the optimization of evidence-based decision-making by updating personalized dynamic life expectancy for patients.

Paricalcitol inhibits oxidative stress-induced cell senescence of the bile duct epithelium dependent on modulating Sirt1 pathway in cholestatic mice

BackgroundClinical studies indicate that vitamin D receptor (VDR) expression is reduced in primary biliary cirrhosis patient livers. However, the mechanism by which activated VDR effect cholestatic liver injury remains unclear. MethodsMice were injected intraperitoneally with the VDR agonist paricalcitol or a vehicle 3 days prior to bile duct ligation (BDL) and for 5 or 28 days after surgery. The analyses of liver morphology and necrotic areas were based on H&E staining. Serum biochemical indicators of liver damage were analyzed by commercial kits. The mechanisms of paricalcitol on cholestatic liver injury were determined by Western blot analysis. ResultsParicalcitol ameliorated the BDL-induced liver damage in mice. Paricalcitol increased the proliferation of BECs to promote the repair of the bile duct. Paricalcitol also reduced the BDL-induced oxidative stress level in the mice. Mechanistic analysis revealed that paricalcitol decreased the number of SA-β-gal-positive cells and downregulated the expression of p53, p21 and p16 proteins which was associated with reducing oxidative stress. Additionally, paricalcitol exerted the inhibitory effect of cell senescence was through reducing DNA damage and promoting DNA repair. Interesting, we found that paricalcitol prevented the downregulation of oxidative stress-induced Sirt1 expression in the BDL mice and t-BHP-induced BECs models. Moreover, paricalcitol suppressed cell senescence through a Sirt1-dependent pathway. These results were confirmed by antioxidant ALCAR and the Sirt1 inhibitor EX-527. ConclusionParicalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 pathway.

OptBand: optimization-based confidence bands for functions to characterize time-to-event distributions

Classical simultaneous confidence bands for survival functions (i.e., Hall–Wellner, equal precision, and empirical likelihood bands) are derived from transformations of the asymptotic Brownian nature of the Nelson–Aalen or Kaplan–Meier estimators. Due to the properties of Brownian motion, a theoretical derivation of the highest confidence density region cannot be obtained in closed form. Instead, we provide confidence bands derived from a related optimization problem with local time processes. These bands can be applied to the one-sample problem regarding both cumulative hazard and survival functions. In addition, we present a solution to the two-sample problem for testing differences in cumulative hazard functions. The finite sample performance of the proposed method is assessed by Monte Carlo simulation studies. The proposed bands are applied to clinical trial data to assess survival times for primary biliary cirrhosis patients treated with D-penicillamine.

Bile Acid Profiles Are Distinct among Patients with Different Etiologies of Chronic Liver Disease

A significant increase of bile acid (BA) levels has been recognized as a general metabolic phenotype of diverse liver diseases. Monitoring of BA profiles has been proposed for etiology differentiation on liver injury. Here, we quantitatively profiled serum BAs of healthy controls and 719 patients with chronic liver disease of five etiologies, hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), alcohol-induced liver disease (ALD), and primary biliary cirrhosis (PBC), and investigated the generality and specificity of different etiologies. The raw data have been deposited into MetaboLights (ID: MTBLS2459). We found that patients with HBV, HCV, and NASH appeared to be more similar, and ALD and PBC patients clustered together. BA profiles, consisting of a total concentration of the 21 quantified BAs [total BAs (TBAs)], 21 BA proportions, and 24 BA relevant variables, were highly different among the etiologies. Specifically, the total BAs was higher in ALD and PBC patients compared with the other three groups. The proportion of conjugated deoxycholates was the highest in HBV-infected patients. The ratio of 12α-hydroxylated (12α-OH) to non-12α-OH BAs was the highest in NASH patients. The proportion of taurine-conjugated BAs was the highest in ALD patients. For PBC patients, the proportion of ursodeoxycholate species was the highest, and the ratio of primary to secondary BAs was the lowest. Comparatively, the difference of BA profiles among cirrhosis patients was consistent but weaker than that of all patients. The correlations between BA profiles and clinical indices were also quite different in different pathological groups, both in all patients and in patients with cirrhosis. Overall, our findings suggested that BA compositions are distinct among patients with different etiologies of chronic liver disease, and some BA-relevant variables are of clinical potentials for liver injury type differentiation, although further validations on more etiologies and populations are needed.

Manganese and copper levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis

The liver and the biliary tree form the main excretory route of manganese (Mn) and copper (Cu). Cholestasis, can lead to the accumulation of these trace elements in the organism, resulting in toxicity to the basal ganglia of the central nervous system. The aim of our study was to reveal the influence of long-term cholestasis on the Mn and Cu levels in the blood of patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We recruited patients with PBC (n = 20) and PSC (n = 32). A control group (n = 40) was also set up. We also examined serum bile acid concentrations and liver enzyme activities. We did not observe any significant differences in any of these parameters between the PBC and PSC groups. The Mn and Cu levels in the PBC and PSC patients differed significantly from the that in the control group (p < 0.0001 and p < .021, respectively). Patients in whom the laboratory cholestasis markers normalized during ursodeoxycholic acid treatment (18/52;35%) presented with significantly lower levels of Mn and Cu (p = .015 and p = .012, respectively). Ten PSC patients showed normal levels of Mn and Cu six months after liver transplantation. Fine tremors, rigidity, dysarthria, and hypomimia were reported in nine (23%), eight (20%), four (10%), and eight (20%) patients, respectively. In addition to monitoring the cholestasis levels, liver function, and Mn and Cu levels during the long-term treatment of PBC and PSC patients, it is important to also regularly monitor the occurrence and development of extrapyramidal symptoms of Parkinson’s-like syndromes.

Making apples from oranges: Comparing noncollapsible effect estimators and their standard errors after adjustment for different covariate sets.

We revisit the well‐known but often misunderstood issue of (non)collapsibility of effect measures in regression models for binary and time‐to‐event outcomes. We describe an existing simple but largely ignored procedure for marginalizing estimates of conditional odds ratios and propose a similar procedure for marginalizing estimates of conditional hazard ratios (allowing for right censoring), demonstrating its performance in simulation studies and in a reanalysis of data from a small randomized trial in primary biliary cirrhosis patients. In addition, we aim to provide an educational summary of issues surrounding (non)collapsibility from a causal inference perspective and to promote the idea that the words conditional and adjusted (likewise marginal and unadjusted) should not be used interchangeably.

Autoantibody profile in eosinophilic granulomatosis and polyangiitis: predominance of anti-alpha-enolase antibodies.

To evaluate the autoantibody profile in eosinophilic granulomatosis and polyangiitis (EGPA) patients. 33 EGPA patients were tested for anti-neutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), rheumatoid factor (RF), anti-alpha-enolase antibodies, and anti-eosinophil peroxidase (EPO) antibodies. Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), hypereosinophilic syndrome (HES), rheumatoid arthritis (RA), primary biliary cirrhosis (PBC) patients and healthy subjects were tested as a control group. Anti-alpha-enolase antibodies were positive in 82% of EGPA patients at high titers. Although a high sensitivity was shown for an anti-alpha-enolase antibody titer above 1/100 (82%), the specificity for EGPA remained low (44%) (AUC=0.653, p=0.008). Anti-alpha-enolase antibodies predominated in males with EGPA (p=0.048) and were associated with skin involvement (p=0.040). Most of the EGPA patients positive for anti-alpha enolase antibodies (20 out of 27) had a negative indirect immunofluorescence test (IFT) for ANCA. ANCA were positive in 8 EGPA patients (24%) with a perinuclear pattern in all but one patient. The ANCA-target antigen was myeloperoxidase (MPO) and/or alpha-enolase. A usually fine-speckled ANA pattern was observed in 42% of the EGPA patients. RF was positive in 1 (6%) of the 18 EGPA patients tested. There was no association between the presence and levels of autoantibodies and EGPA disease activity. None of the patients and controls was positive for anti-EPO antibodies. Alpha-enolase may be a target of autoimmunity in EGPA patients and shows usually negative ANCA IFT results.

A62 CANADIAN POPULATION-BASED EVALUATION OF THE NATURAL HISTORY OF PRIMARY BILIARY CHOLANGITIS OVER THE LAST DECADE

Abstract Background Few studies have evaluated the epidemiology of primary biliary cirrhosis (PBC) in North America. Ursodeoxycholic acid (URSO) improves outcomes amongst PBC patients. Aims Therefore, we undertook this study to determine the epidemiology of PBC in Canada, and impact of URSO on clinical outcomes, two decades after URSO approval in North America. Methods We used our previously validated coding algorithm to identify PBC patients in population based administrative databases in the Calgary Health Zone (population ~1.5 million) from 2005–2015. Multiple sources of data including inpatient, ambulatory, physician billing, laboratory, and pharmaceutical were linked. Annual prevalence and incidence were estimated using Poisson regression. Age/sex adjusted rate ratios were calculated. We used Cox regression models to estimate: all-cause mortality, liver transplant and decompensated cirrhosis free survival. In our models, we adjusted for demographic and clinical variables including response to URSO. Results During the study period over 11 years, the overall annual age/sex adjusted PBC incidence was 29.5 cases per million (48.3 and 9.9 per million for women and men, respectively). The highest incidence rate was observed among women aged 60–79 (90.9 per million) with an incidence rate ratio of 10.4 (95%: 6.83–15.9) compared to those aged 20–39. While incidence rate remained stable, prevalence rate increased significantly from 242 to 343 cases/ million, between 2005 and 2015 (P&amp;lt;0.01). Prevalence rate was highest at 965 cases/ million amongst women aged 60–79. We identified 299 incident PBC cases with a median follow up of 5.1 years (IQR 2.9–8.3). 87 (29.1%) of these incident cases developed decompensated cirrhosis or HCC, 10 patients (3.4%) underwent liver transplantation, and 44 (14.7%) patients died. The annual mortality rate was 2.9% (95%CI: 2.1- 3.8) compared to 3.4% (2.3–4.9%) a decade ago (P=0.04). The estimated 5-year survival rate was 87.6% (82.6- 91.3). Standardized mortality rate was 3.2 (95%CI: 2.2–4.1). Overall, 25% of our incident cohort were not prescribed URSO. Patients not prescribed URSO were more likely to be male, older age, have normal ALP and had decompensated cirrhosis at diagnosis (P&amp;lt;0.01 for all). Among those who used URSO, response rate was 86%. Response to URSO was an independent predictor of reduced risk of decompensated cirrhosis and liver transplant, and higher survival (aHR: 0.46, 0.29–0.74). Conclusions PBC prevalence is increasing in this North American population. While mortality rate decreases in our PBC cohort, survival was suboptimal compared to the general population, mainly due to late presentation at diagnosis. Therefore, better surveillance and early detection of possible PBC patients in the primary care setting are essential to improve PBC outcomes. Funding Agencies None

The expression and clinical significance of serum IL-17 in patients with primary biliary cirrhosis.

We aimed to investigate the expression and clinical significance of interleukin 17 (IL-17) in patients with primary biliary cirrhosis (PBC). PBC patients (n=127), patients without PBC (n=100) were selected from January 2015 to December 2015.The measure of IL-17 level was performed by cytometric beads array (CBA), immunohistochemistry and real-time PCR (QRT-PCR). The expression levels of serum IL-17, IL-6, IFN-γ, TNF-α and IL-10 in PBC groups were significantly higher than control group, a positively correlation between IL-17 and ALT, ALP, GGT, CIV was observed in PBC patients (r=0.350, P=0.013; r=0.373, P=0.008; r=0.337, P=0.017; r=0.349, P=0.021). In addition, IL-17 mRNA expression level in PBC group was higher than control group. Immunohistochemical results suggest that positive cells did not appear in normal tissues, while they appeared in the PBC liver tissue, mainly in the bile duct. This study shows that IL-17 over expressed in PBC patients, it played a pro-inflammatory effect in the pathogenesis of PBC, most probably as a targeting drug research.

Fatigue in chronic hepatitis B patients is significant and associates with autonomic dysfunction

BackgroundFatigue is an important clinical finding in patients with chronic hepatitis virus infection. However, studies assessing fatigue in patients with chronic hepatitis B (CHB) are very limited. This study aimed to quantify the severity of fatigue in patients with CHB, to determine whether perceived fatigue reflects impairment of functional ability, and to explore potential causes.MethodsA total of 133 patients with histologically proven CHB and 59 community controls were assessed using the fatigue impact scale (FIS).ResultsThe degree of fatigue was significantly higher in patients with CHB than in controls (mean (range) FIS 24.9 (0–91) vs. 15.7 (0–31), p < 0.001). Fatigue experienced by patients with CHB was similar to that in primary biliary cirrhosis (PBC) (n = 20) (FIS 22.2 vs. 20.9, p = 0.28). No association was found between FIS and biochemistry and histological parameters of liver disease severity. Significant associations were found between fatigue severity and cognitive impairment (r = 0.39, p < 0.001), daytime somnolence (r = 0.32, p < 0.001), scores of the Chronic Liver Disease Questionnaire (r = − 0.31, p < 0.001), and autonomic symptoms (r = 0.43, p < 0.001). The level of autonomic symptom was the only factor independently associated with the degree of fatigue.ConclusionFatigue is a significant problem of functional ability impairment in CHB and similar in degree to that in PBC patients. Fatigue in patients with CHB appears to be unrelated to the severity of liver disease but is associated with significant autonomic symptoms.

Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis

Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.

Analysis and functional study on lncRNA expression profile in primary biliary cirrhosis patients

Objective Analyzing the lncRNA expression profile in peripheral blood mononuclear cells (PBMC) of primary biliary cirrhosis (PBC) patients to provide new ideas for the pathogenesis, clinical diagnosis and treatment of PBC. Methods Collected peripheral blood from 30 PBC patients and 30 healthy volunteers, then separated PBMC. Four cases from each group were selected for long-noncoding RNA (lncRNA) expression microarray detection. Reverse transcription-PCR technology in a larger sample size was used to verify the microarray results. Bioinformatic analysis such as Cis- / Trans- target genes Gene ontology (GO) and pathway analysis, co-expression networks were conducted in order to provide a theoretical basis in the pathogenesis of PBC. Transfecting small interfering RNAs(siRNAs) for linc-pbc to see changes in the expression of nuclear receptor 4A group 3(NR4A3) and forkhead boxP3(FOXP3) and cell apoptosis in transfected PBMC. Results Compared to the healthy group, 749 lncRNA and 230 coding messenger RNA(mRNA) genes were abnormally expressed. Interestingly, NR4A3 gene was down-regulated by 78%. While linc-pbc, which was about 20 000 bp downstream of NR4A3 gene, increased 2.56-fold. Then design siRNA for linc-pbc. After transfection, mRNA and protein levels of NR4A3 and FOXP3 were up-regulated. Conclusions By recruiting PRC2 complex, linc-pbc may increased the methylation level of NR4A3 gene promoter region, thus decreasing the expression of NR4A3 in PBC patients and reduced NR4A3 futher downregulated the expression of FOXP3 and reduced the amounts of immunosuppressive Treg cells in peripheral blood and liver tissue, breaking the equilibrium state of immune tolerance, and promoted the occurrence and development of the disease.(Chin J Lab Med, 2018, 41: 374-379) Key words: Liver cirrhosis, biliary; RNA, long noncoding; DNA-binding proteins