Serum antibody specific for PBC
AMAs: AMAs, including AMAs-M2, are a specific and sensitive marker for the diagnosis of PBC[9,10,93,94]. The existing evidence shows that AMAs and AMAs-M2 have excellent diagnostic value, with high specificity and sensitivity for PBC. Compared with AMAs-M2, AMAs is a faster and more comprehensive diagnostic marker. AMAs consist of nine subtypes, four of which are associated with PBC: AMA-M2, AMA-M4, AMA-M8, and AMA-M9[9-11]. Although these four AMA subtypes have comparatively specific diagnostic value for PBC, AMA-M2 remains the foremost subtype applied as a routine diagnostic marker for PBC[9-11]. AMAs are present in 95% of PBC patients; however, 5% of patients with PBC are still AMA-negative. AMA-negative PBC patients had an observably worse prognosis in comparison with AMA-positive PBC patients; however, an obvious distinction between positive and negative PBC AMAs should not have been found on the basis of clinical manifestation, serum biochemical features, histopathological characteristics, disease process, or response to UDCA treatment. Notably, AMA-negative PBC patients had an observably decreased free survival of liver-associated complications covering liver transplant and death in comparison with AMA-positive PBC patients (P = 0.0182).
Anti-nuclear antibodies: Besides AMAs, PBC patient serum is able to demonstrate other PBC-related autoantibodies, especially anti-nuclear antibodies (ANAs) covering anti-multiple nuclear dot autoantibodies (anti-sp100, PML, NDP52, anti-sp140), anti-nuclear envelope protein autoantibodies (lamin, lamin B receptor), and anti-rim-like/membranous anti-nuclear autoantibodies (anti-gp210, anti-p62)[95-103]. Determination of AMAs and PBC-specific ANAs identified them as being associated with PBC severity[9,10]. Elevated serum concentrations of ANAs should be found in approximately 50% of PBC patients and 85% of AMA-negative PBC patients. In short, 44% of PBC patients had anti-sp100, 15.1% had PML, 25% had anti-gp210 and 25% had ACAs[97-100]. AMAs and ANAs (anti-gp210, anti-sp100, ACAs) are particularly prevalent in PBC. Although changes in most autoantibodies that occur naturally with the passage of time do not appear to associate with clinical results in PBC, changes in serum anti-sp100 antibody levels can be used as an evaluation of prognostic factors with regard to the progress of liver fibrosis diagnosed via hepatic biopsy. Sp140L is the phylogenetically nearest family member to anti-sp100 protein, and serves as an autologous antigen in PBC patients. The polymerization of anti-p62 is significantly augmented in the impaired biliary ducts of PBC and may reflect the inappropriate autophagy and subsequent senescence of biliary ducts cells in the etiopathogenesis of biliary duct injury in PBC. In clinical practice, it is vital to detect these autoantibodies in order to establish PBC diagnosis, assess disease severity, determine the PBC clinical phenotype, and calculate the long-term outcome. Positive anti-gp210 antibody and elevated vanishing biliary duct score were observable risk factors for elevated ALP predicted worsened response. Positive anti-gp210 antibody and elevated hepatitides score were observable risk factors for elevated IgM predicted worsened response. Elevation of ALP and IgM worsened response were observable risk factors for development to end-stage liver illness in the absence of jaundice. Therefore, in the classical or typical form of PBC, characterized by the chronic progressive disappearance of small intrahepatic biliary ducts with a simultaneous augment in hepatic fibrosis, anti-gp210 autoantibodies are a powerful risk factor for development to icterus and liver failure[101,105]. Age, positive anti-gp210 antibody, and positive ACAs were observable risk factors for elevated of alanine aminotransferase (ALT) worsened response. Elevation of ALT worsened response was an observable risk factor for development to end-stage hepatic illness with persistent icterus. Of PBC patients with ACAs positivity, 30% had serious bile duct damage and portal hypertension. Therefore, the presence of ACAs is a risk factor for development to hepatic cirrhosis and portal-venous hypertension[101,105,106]. Biochemical response to UDCA therapy at two years, which is affected by the serum autoantibody status of ACAs, anti-gp210, and histological and morphometric variables at baseline, may predict long-term clinical results in PBC patients. By contrast, another study showed that continuous variations of anti-sp100 titers, rather than anti-gp210 titers, might be effective for the surveillance of disease procession and UDCA treatment outcome. The study revealed a reduced rate of eGFR, an elevated possibility of chronic kidney disease (CKD), and an elevated rate of annual eGFR decline in PBC patients with ACAs compared to those without ACAs (P < 0.05, separately). ACAs may serve as an independent predictor for CKD in patients with PBC; therefore, it is important to assess ACAs and renal function in order to deter CKD evolution in PBC.
New autoantibodies: The recognition of novel autoantibodies as a non-invasive serum hallmark is still an important area of PBC research. Hu et al created a PBC-focused microarray with 21 of these recently affirmed alternatives, as well as 9 supererogatory familiar PBC autoantigens. By screening the PBC-focused microarrays with PBC patients, 6 proteins were identified as new PBC autoantigens in the presence of high specificities and sensitivities, covering hexokinase-1 (HK 1, and isoforms I and II), Kelch-like protein 7 (KLHL7), KLHL12, zinc finger, BTB domain-containing protein 2, and eukaryotic translation initiation factor 2C, subunit 1. In addition, both anti-KLHL12 and anti-HK1 antibodies with higher specificity and sensitivity were more likely to be detected in PBC in comparison with controls without PBC (P < 0.001). Anti-HK1 in combination with anti-KLHL12 in the presence of usable signs (i.e., MIT3, gp210 and sp100), improved the sensitivity of PBC diagnosis. Importantly, both anti-KLHL12 and anti-HK1 autoantibodies had been detected in 10% to 35% of AMA-negative patients with PBC, and increasing both biomarkers in routine PBC tests significantly increased the sensitivity in AMA-negative patients with PBC from 55% to 75% by means of immunoblot and from 48.3% to 68.5% with the ELISA method. Supplementing both anti-KLHL12 and anti-HK1 autoantibodies with highly specific assays for AMAs and ANA serological tests observably enhanced the serological surveillance effect and PBC diagnosis, particularly for AMA-negative patients.
Serum biochemical sign in PBC: The enhanced serum activity of ALP, gamma-glutamyltransferase (γ-GT), ALT, AST, total bilirubin (TBIL), and bile acids can be detected in most patients with PBC[9,10,47,111-113]. Evidence from several studies has shown that the presence of elevated serum activity of ALP is not only an obvious guidepost of intrahepatic cholestasis, but also a pronounced succedaneous hallmark PBC severity[111-113]. A Japanese study showed that elevated serum ALP levels were not only markedly related to the presence of esophageal varicosities in PBC patients with early histological stage, but also associated with the progression of esophageal varicosities during the follow-up period. In addition, a meta-analysis of individual patient information from 4845 PBC cases covering 15 European and North American countries demonstrated that serum levels of ALP and TBIL detected at research enrollment and every year for 5 years were significantly related to clinical results. The study result showed that serum levels of ALP and TBIL may predict clinical results (i.e., hepatic transplant or dying) of PBC patients, and could serve as alternative terminal points in treatment tests. In addition, a study in China showed that, among serum biolabeling in PBC patients, the serum concentrations of bile acids were augmented with the development of PBC, while the concentrations of carnitines were reduced with the development of PBC; these factors, high serum levels of ALP, TBIL, and bile acids, are markedly associated with progressive PBC and worsened outcomes.
Serum immunoglobulins in PBC: PBC patients characteristically show elevated serum levels of IgM[9,10]. Environmental factors, but not genetic ones, are considered to play an important role in the pathogenesis of high serum IgM in PBC. In addition, serum IgG2 and IgG3 levels were most prominently increased in PBC. However, evidence of decreased serum levels of IgA, IgM, and IgG in a PBC patient seems to demonstrate that immunoglobulin-mediated etiopathogenesis may be unessential for the development of PBC.
Serum markers of infection in PBC: As a screening test, serum from 69 PBC patients were detected for IgG-antibodies against Toxoplasma gondii (anti-T. gondii), Helicobacter pylori (anti-H. pylori), Epstein-Barr virus (anti-EBV), cytomegalovirus (anti-CMV), anti-HBV and anti-HCV. The results demonstrated that the prevalence rates of 4 anti-infectious agent antibodies: Scilicet anti-T. gondii (P < 0.0001), anti-H. pylori (P < 0.01), EBV early antigen (P < 0.0001), and anti-CMV (P < 0.05) in PBC patients was observably higher than in the controls. The coexistence of the 4 anti-infectious agent antibodies was comparatively ordinary in PBC, but the infection burden was infrequent in normal controls (P < 0.0001). In addition, peculiar contagion reciprocities that potentially accelerate PBC patient risk were also pointed out. Seropositivity of ammodytoxin A was negatively related to hepatic cirrhosis among patients with PBC (P < 0.05).
Serum biomarkers in PBC: Serum microRNAs (miRNAs), which are sufficiently steady and control RNase-mediated degeneration in body fluids, have been used as novel potential biomarkers for many illnesses. However, the expression spectrum of serum miRNAs in patients with PBC is poorly understood. Recently, a miRNA panel (hsa-miR-122-5p, hsa-miR-141-3p, and hsa-miR-26b-5p) was confirmed to have prominent diagnostic accuracy for PBC (sensitivity = 80.5%, specificity = 88.3%). There was a remarkable difference between expression profiles of the miRNA panel, those of serum ALP (P < 0.001), and those of serum ANAs (P = 0.0282). Seventeen miRNAs were confirmed to be distinctively expressed in peripheral blood mononuclear cells from PBC patients. In addition, the downregulated expression of hsa-miR-505-3p and miR-197-3p can be used as biological markers of PBC. Functional bioinformatics analysis showed prediction of microRNA target genes involved in multiple signaling passageways and biological processes. In general, serum biological markers for inchoate diagnosis of PBC are a new subject of ongoing research.
Serum predictive marker in PBC: Non-invasive predictive markers of hepatic fibrosis in PBC patients should be used for predicting illness development. The Wisteria floribunda agglutinin-positive Mac-2-binding protein [WFA (+)-M2BP] could serve as an effortless and dependable non-invasive succedaneous serum glycol-biomarker for the diagnosis of hepatic fibrosis in PBC. Serum WFA (+)-M2BP was not only considered to be better than the other non-invasive markers in determining the important and serious fibrosis stages of PBC, but was also forcefully and separately related to clinical result. Serum FGF19 is related to hepatic illness severity, and can also be used as a potential predictive marker of chronic cholestatic hepatic lesion in PBC. Serum ANAs, total cholesterol, and bile acids are predictors of liver failure in PBC. Elevated serum levels of fractalkine in patients with PBC could serve as predictive markers of cholangitis activity at early stages. Comparative proteomics analysis demonstrated not only obvious elevated serum levels of vitronectin in AMA-negative PBC patients compared to those of AMA-positive PBC (P < 0.01), but also a potential association with the more serious bile duct destruction found in this group. Serum hyaluronan is considered a hopeful hallmark for the estimation of hepatic fibrosis in PBC. In addition, serum cartilage oligomeric matrix protein might be a novel non-invasive biomarker for estimating PBC and the risk of HCC.