For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Serum WFA(+)-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.

Signaling via TLRs results in dendritic cell (DC) activation/maturation and plays a critical role in the outcome of primary immune responses. So far, no data exist concerning TLR expression by liver DC, generally regarded as less immunostimulatory than secondary lymphoid tissue DC. Because the liver lies directly downstream from the gut, it is constantly exposed to bacterial LPS, a TLR4 ligand. We examined TLR4 expression by freshly isolated, flow-sorted C57BL/10 mouse liver DC compared with spleen DC. Real-time PCR revealed that liver CD11c+CD8α− (myeloid) and CD11c+CD8α+ (“lymphoid-related”) DC expressed lower TLR4 mRNA compared with their splenic counterparts. Lower TLR4 expression correlated with reduced capacity of LPS (10 ng/ml) but not anti-CD40-stimulated liver DC to induce naive allogeneic (C3H/HeJ) T cell proliferation. By contrast to LPS-stimulated splenic DC, these LPS-activated hepatic DC induced alloantigen-specific T cell hyporesponsiveness in vitro, correlated with deficient Th1 (IFN-γ) and Th2 (IL-4) responses. When higher LPS concentrations (≥100 ng/ml) were tested, the capacity of liver DC to induce proliferation of T cells and Th1-type responses was enhanced, but remained inferior to that of splenic DC. Hepatic DC activated by LPS in vivo were inferior allogeneic T cell stimulators compared with splenic DC, whereas adoptive transfer of LPS-stimulated (10 ng/ml) liver DC induced skewing toward Th2 responses. These data suggest that comparatively low expression of TLR4 by liver DC may limit their response to specific ligands, resulting in reduced or altered activation of hepatic adaptive immune responses.

Background/AimThe definition of muscle atrophy (pre-sarcopenia) and its diagnostic criteria have not been well reported. To elucidate the frequency of pre-sarcopenia in chronic liver disease (CLD), we examined clinical features of Japanese CLD patients using abdominal computed tomography (CT) findings.MethodsWe enrolled 988 CLD (736 with naïve hepatocellular carcinoma) and 372 normal control subjects (NCs). The psoas muscle area index [PI, psoas muscle area at the mid-L3 level in CT (cm2)/height (m)2] was calculated using personal computer software. The cut-off level for pre-sarcopenia was defined as less than two standard deviations (SDs) below the mean PI value in the NCs under 55 years old [males, 45.6 ± 5.7 years (n = 61), 4.24 cm2/m2; females, 47.0 ± 6.1 years (n = 49), 2.50 cm2/m2]. Elderly was defined as 65 years or older. Clinical features were retrospectively evaluated.ResultsIn the CLD group (HCV:HBV:HBV and HCV:alcohol:non-HBV and HCV = 652:88:7:82:159), pre-sarcopenia was observed in 15.3 % of patients with chronic hepatitis (CH), 24.4 % of those with liver cirrhosis (LC) Child-Pugh A, 37.7 % of those with LC Child-Pugh B, and 37.1 % of those with LC Child-Pugh C. A comparison between NC and CH by age (<55, 55–64, 65–74, ≥75 years) showed that the frequency of pre-sarcopenia was higher in CH regardless of age (1.8 vs. 3.6 %, 3.2 vs. 15.9 %, 4.9 vs. 13.4 %, 14.3 vs. 20.2 %, respectively). PI values showed correlations with BMI (r = 0.361), age (r = −0.167), albumin (r = 0.115), and branched-chain amino acids (r = 0.199) (P < 0.01).ConclusionRetrospective evaluate for pre-sarcopenia was easy to perform with CT findings. Nutrition and exercise instruction should be considered for early stage and even non-elderly CLD as well as LC.

Muscle wasting is an important prognostic factor in patients treated with sorafenib.