Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are heterogeneous chronic autoimmune diseases that may share underlying pathogenic mechanisms. Herein, we compared simultaneously analyzed blood transcriptomes from patients with PBC, PSC, and IBD. Microarray-based measurements were conducted using RNA isolated from whole blood samples from 90, 45, 95 and 93 patients with PBC, PSC, CD, and UC, respectively, and 47 healthy controls. Expression levels of selected transcripts were analyzed by quantitative reverse-transcribed PCR using an independent cohort of 292, 71 and 727 patients with PBC, PSC, and IBD, respectively. Of 4026, 2650 and 4967 probe sets differentially expressed (adjusted p-value < 0.05) in samples from patients with PBC, PSC, and IBD, respectively, compared with healthy controls, 1946 were common to all three comparisons. Functional analyses indicated that most terms enriched for genes differentially expressed in PBC, PSC, and IBD patients compared with healthy controls were related to mitochondrial function, the vesicle endomembrane system, and GTPase-mediated processes. This study indicates that microarray-based profiling of blood gene expression supports research into the molecular mechanisms underlying disease, rather than being useful for selection of diagnostic biomarkers for use in clinical practice.
Background and AimsMetalloproteinases (MMPs) are involved in many distinct processes in the liver. Matrix metalloproteinase-3 (MMP-3) plays an important role in connective tissue remodeling, degradation of collagen (types II, III, IV, IX, and X), proteoglycans, fibronectin, laminin, and elastin. In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9. Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease, characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and liver failure. Fibrosis is the result of an imbalance between production and degradation of the extracellular matrix surrounding hepatocytes. Our aim in the present study was to determine whether the measurement of serum MMP-3 is clinically useful for assessing ongoing liver fibrosis in patients with PBC.MethodsThe MMP-3 concentration was determined in 182 PBC patients and 80 non-PBC controls using a commercially available ELISA kit.ResultsHigher concentrations of MMP-3 were found in 61% of PBC patients. PBC subjects had greater MMP-3 levels than controls: 68.9 ± 62.6 vs 21.3 ± 7.4 ng/mL, p < 0.001 for healthy subjects; 68.9 ± 62.6 vs 22.7 ± 7.6 ng/mL, p = 0.022 for autoimmune hepatitis controls; and 68.9 ± 62.6 vs 37.2 ± 17.4 ng/mL, p = 0.002 for primary sclerosing cholangitis controls. The serum MMP-3 concentration was significantly elevated in patients with higher bilirubin concentration (107.6 ± 85.8 vs 61.6 ± 46.1 ng/mL, p < 0.001) and was correlated with the level of antimitochondrial antibodies specific for PBC. The concentration of MMP-3 in sera of PBC patients was also found to correlate with the state of liver fibrosis (OR = 4.3; p < 0.01).ConclusionsOur study demonstrated significantly higher MMP-3 levels in PBC patients than in healthy and pathological controls. Increased MMP-3 concentrations were positively correlated with various clinical and immunological parameters, and advanced liver fibrosis. The level of MMP-3 was associated with hepatic dysfunction and could play a role in the pathophysiology of hepatic fibrosis in PBC.
Background Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by specific autoantibodies. We evaluated the prevalence of autoantibodies against nucleoporin p62 (anti-p62) in PBC patients' sera to determine whether it can be a marker for PBC, in comparison with other immunological and biochemical parameters. We validated the performance of our in-house ELISA technique. Methods Serum samples were collected from 135 PBC patients. Thirty patients with primary sclerosing cholangitis (PSC) and 30 with autoimmune hepatitis (AIH) were included as pathological controls, and 40 healthy blood donors served as healthy controls. The presence of anti-p62 was determined by an in-house ELISA using a recombinant protein. We calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratio (LR+ and LR−) of our in-house ELISA for diagnosing PBC based on anti-p62. Findings were correlated with biochemical data and survival. Results Anti-p62 was detected in 32 PBC patients (23.7%). Specificity and PPV of anti-p62 for PBC were 99% and 97%, respectively. The difference between proportions of anti-p62-positive patients and controls was 0.23 (95% confidence interval [CI]: 0.03–0.40; P <0.0001); LR+ and LR− were 23.7 and 0.77, respectively. The presence of anti-p62 was associated with higher levels of bilirubin and alkaline phosphatase ( P <0.001). The odds ratio for survival was 2.44 (95% CI: 0.87–6.87; P =0.091). Conclusions Anti-p62 may be regarded as a significant serological marker of PBC.
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by immune-mediated destruction of intrahepatic bile ducts and the presence of specific antibodies. The aim of the study was to examine the diagnostic significance of antibodies against promyelocytic leukemia nuclear body (PML NB) components such as Sp100, Sp140, and PML in a cohort of PBC patients and compare the results with biochemical and histological parameters. Serum samples were collected from 93 PBC patients. Anti-Sp100 and anti-PML antibodies were assessed using commercially available kits, anti-Sp140 using developed “in-house” ELISA test. Anti-Sp140, anti-Sp100, and anti-PML antibodies were present in 25 (27%), 37 (40%), and 29 (31%) PBC patients, respectively. Anti-PML NB positive patients also showed increased concentration of bilirubin and alkaline phosphatase (p < 0.05). In the group with the presence of at least two types of these antibodies, more frequent deaths or transplantations were observed. A correlation between the presence of antibodies and histological grade (OR = 2.55 p = 0.039) was established. Patients with bilirubin > 1.1 mg/dL at the time of diagnosis had a significantly shorter time of survival than patients with bilirubin ≤ 1.1 mg/dL (HR 5.7; 95% C.I., 2.7, 12.3; p < 0.001). Our data confirm very high specificity of anti-PML NB antibodies, which can expand the laboratory diagnostic capabilities of PBC. We found an association between positive reactivity of autoantibodies directed against components of PML nuclear bodies and higher concentrations of bilirubin and alkaline phosphatase, but the main prognostic marker of survival remains serum bilirubin.
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