Soichiro Shibata

Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis

OBJECTIVES:Noninvasive markers of liver fibrosis in patients with primary biliary cirrhosis (PBC) are needed for predicting disease progression. As the Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) was recently established as a liver fibrosis glycobiomarker in chronic hepatitis C, we assessed its efficacy in evaluating liver fibrosis stage and disease progression in PBC.METHODS:A total of 137 patients with PBC who underwent liver biopsy and serological tests for WFA+-M2BP were enrolled. All patients were treated with ursodeoxycholic acid. Clinical data were compared with those for other noninvasive markers (aspartate aminotransferase-to-platelet ratio, FIB-4 index, aspartate aminotransferase/alanine aminotransferase ratio, Forn’s index, and Mayo score) for estimating liver fibrosis using receiver operating characteristic analysis. The association between WFA+-M2BP and clinical outcome (liver decompensation, liver transplantation, or death) was evaluated using the Cox proportional hazards model with stepwise method.RESULTS:WFA+-M2BP was independently associated with liver fibrosis stage as determined by liver biopsy. The cutoff values of WFA+-M2BP for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.7, 1.0, 1.4, and 2.0, respectively. The area under the receiver operating characteristic curve values for significant fibrosis, severe fibrosis, and cirrhosis were 0.979, 0.933, and 0.965, respectively. WFA+-M2BP was significantly superior to the other indices for the determination of significant and severe fibrosis stages. Furthermore, the WFA+-M2BP level at enrollment was strongly and independently associated with clinical outcome (hazard ratio 18.59, P=0.021).CONCLUSIONS:Baseline measurements of WFA+-M2BP represent a simple and reliable noninvasive surrogate marker of liver fibrosis and prognosis in patients with PBC.

Colonic diverticular hemorrhage: the hood method for detecting responsible diverticula and endoscopic band ligation for hemostasis

BACKGROUND AND STUDY AIMS Although colonic diverticular hemorrhage is a common cause of lower gastrointestinal bleeding, the low rate of detection of the diverticula responsible for bleeding, together with inadequate evaluation of endoscopic hemostasis, remain unsatisfactory. PATIENTS AND METHODS Over 3 years, we employed the hood method to diagnose diverticular hemorrhage in 53 patients and applied endoscopic band ligation (EBL) for hemostasis in 27 patients with responsible diverticula. RESULTS The hood method revealed active bleeding in 13 patients (24.5%), nonbleeding visible vessels in 14 patients (26.4%), and presumptive diverticular hemorrhage in 26 patients (49.1%). The nonbleeding visible vessels were located in the diverticular dome in 13 patients and at the diverticular orifice in one patient. EBL was performed in 27 patients, and a hemostasis rate of 96.3% was achieved. In 9 of 12 patients treated with EBL, follow-up colonoscopy revealed resolution of the responsible diverticula. CONCLUSIONS The hood method improves the detection rate of diverticula responsible for bleeding by revealing potential nonbleeding visible vessels in the diverticular dome. EBL may become an effective procedure for hemostasis of colonic diverticular hemorrhage.

Association of Serum Autotaxin Levels with Liver Fibrosis in Patients with Chronic Hepatitis C

Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn’s index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P < 0.01). Serum ATX concentration increased significantly according to liver fibrosis stage in overall and both genders (P < 0.001). The cutoff values of ATX for prediction of fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.8, 1.1, 1.3, and 1.7 mg/L, respectively, in male patients and 0.9, 1.7, 1.8, and 2.0 mg/L, respectively, in female patients. The area under the receiver operating characteristic curve for ATX to diagnose fibrosis of ≥F2 (0.861) in male patients was superior to those of FIB-4 index and Forn’s index (P < 0.001), while that in female patients (0.801) was comparable with those of the other markers. ATX therefore represents a novel non-invasive biomarker for liver fibrosis in HCV-infected patients.

Serum levels of interleukin-22 and hepatitis B core-related antigen are associated with treatment response to entecavir therapy in chronic hepatitis B

We sought to clarify the associations between serum cytokines and chemokines, hepatitis B surface antigen (HBsAg), hepatitis B core‐related antigen (HBcrAg), and hepatitis B virus (HBV) DNA and response to entecavir therapy in chronic hepatitis B.

Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein may predict liver fibrosis and progression to hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Serum glycosylated Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP) is a reliable, non‐invasive marker of liver fibrosis. This study assessed the ability of WFA+‐M2BP to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection and evaluated WFA+‐M2BP as a predictor of hepatocellular carcinoma (HCC) development.

Controlled attenuation parameter is correlated with actual hepatic fat content in patients with non-alcoholic fatty liver disease with none-to-mild obesity and liver fibrosis.

Aim: Non‐invasive steatosis‐quantifying methods are required for non‐alcoholic fatty liver disease (NAFLD) patients in order to monitor disease severity and assess therapeutic efficacy. Controlled attenuation parameter (CAP) evaluated with vibration‐controlled transient elastography can predict the presence of steatosis, but its application to absolute hepatic fat quantitation remains unclear. The aim of this st\udy was to examine whether CAP is correlated with real hepatic fat content in NAFLD patients.

STAT4 Gene Polymorphisms Are Associated with Susceptibility and ANA Status in Primary Biliary Cirrhosis

Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4) genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P = 9.4 × 10−3, rs11889341; P = 1.2 × 10−3, rs7574865; P = 4.0 × 10−4, rs8179673; P = 2.0 × 10−4, and rs10181656; P = 4.2 × 10−5). Three risk alleles (rs7574865; P = 0.040, rs8179673; P = 0.032, and rs10181656; P = 0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.

Serum Cell Death Biomarkers for Prediction of Liver Fibrosis and Poor Prognosis in Primary Biliary Cirrhosis

The development of simple, noninvasive markers of liver fibrosis is urgently needed for primary biliary cirrhosis (PBC). This study examined the ability of several serum biomarkers of cell death to estimate fibrosis and prognosis in PBC. A cohort of 130 patients with biopsy-proven PBC and 90 healthy subjects were enrolled. We assessed the utility of the M30 ELISA, which detects caspase-cleaved cytokeratin-18 (CK-18) fragments and is representative of apoptotic cell death, as well as the M65 and newly developed M65 Epideath (M65ED) ELISAs, which detect total CK-18 as indicators of overall cell death, in predicting clinically relevant fibrosis stage. All 3 cell death biomarkers were significantly higher in patients with PBC than in healthy controls and were significantly correlated with fibrosis stage. The areas under the receiver operating characteristic curve for the M65 and M65ED assays for differentiation among significant fibrosis, severe fibrosis, and cirrhosis were 0.66 and 0.76, 0.66 and 0.73, and 0.74 and 0.82, respectively. In multivariate analysis, high M65ED (hazard ratio 6.13; 95% confidence interval 1.18–31.69; P = 0.031) and severe fibrosis (hazard ratio 7.45; 95% confidence interval 1.82–30.51; P = 0.005) were independently associated with liver-related death, transplantation, or decompensation. High serum M65ED was also significantly associated with poor outcome in PBC (log-rank test; P = 0.001). Noninvasive cell death biomarkers appear to be clinically useful in predicting fibrosis in PBC. Moreover, the M65ED assay may represent a new surrogate marker of adverse disease outcome.

KIR, HLA, and IL28B Variant Predict Response to Antiviral Therapy in Genotype 1 Chronic Hepatitis C Patients in Japan

Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.

Mutations of pre-core and basal core promoter before and after hepatitis B e antigen seroconversion.

AIM To investigate the role of pre-core and basal core promoter (BCP) mutations before and after hepatitis B e antigen (HBeAg) seroconversion. METHODS The proportion of pre-core (G1896A) and basal core promoter (A1762T and G1764A) mutant viruses and serum levels of hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg), and HB core-related antigen were analyzed in chronic hepatitis B patients before and after HBeAg seroconversion (n = 25), in those who were persistently HBeAg positive (n = 18), and in those who were persistently anti-HBe positive (n = 43). All patients were infected with HBV genotype C and were followed for a median of 9 years. RESULTS Although the pre-core mutant became predominant (24% to 65%, P = 0.022) in the HBeAg seroconversion group during follow-up, the proportion of the basal core promoter mutation did not change. Median HBV viral markers were significantly higher in patients without the mutations in an HBeAg positive status (HBV DNA: P = 0.003; HBsAg: P < 0.001; HB core-related antigen: P = 0.001). In contrast, HBV DNA (P = 0.012) and HBsAg (P = 0.041) levels were significantly higher in patients with the pre-core mutation in an anti-HBe positive status. CONCLUSION There is an opposite association of the pre-core mutation with viral load before and after HBeAg seroconversion in patients with HBV infection.