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.

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Background and Aim Primary biliary cholangitis (PBC) patients who are refractory to ursodeoxycholic acid (UDCA) are at risk for progression to cirrhosis and liver failure. Bezafibrate could be an alternative second‐line therapeutic option in these patients. This study aimed to evaluate the long‐term outcome(s) of combined UDCA and bezafibrate therapy in UDCA‐refractory PBC patients and identify prognostic factors. Methods Among 445 patients treated with UDCA, 150 patients inadequately responded to UDCA monotherapy and received long‐term UDCA plus bezafibrate (median, 15 years). Data from these patients were used for this retrospective analysis. Results Combination therapy resulted in significant improvements in serum biochemistry and liver transplantation risk estimated using the UK‐PBC‐risk and the GLOBE scores. The cumulative normalization rates of alkaline phosphatase, gamma‐glutamyltransferase, and immunoglobulin M (IgM) were significantly higher in patients without cirrhosis‐related symptoms or liver‐related events than in those with them. Overall, IgM constantly emerged as a significant factor associated with cirrhosis‐related symptoms and liver‐related events at all time points. Cumulative survival rates were significantly lower in patients with IgM ≥ 240 mg/dL than in patients with IgM < 240 mg/dL. Thus, normalization of IgM levels was a good surrogate predictor of long‐term prognosis. None of the patients discontinued combination therapy due to any adverse events during the follow‐up period. Conclusions Our findings point to the beneficial effects of long‐term UDCA plus bezafibrate combination therapy for UDCA‐refractory PBC patients, and IgM response can be a useful predictive biomarker of long‐term clinical outcomes.

We developed a small portable sensor device using a p-type semiconductor cuprous bromide (CuBr) thin film to measure breath ammonia in real time with highsensitivity and selectivity. Breath ammonia is reportedly associated with chronic liver disease (CLD). We aimed to assess the practical utility of the novel CuBr sensor device for exhaled breath ammonia and the correlation between breath and blood ammonia in CLD patients. This was a feasibility and pilot clinical study of 21 CLD patients and 18 healthy volunteers. Breath ammonia was directly and quickly measured using the novel CuBr sensor device and compared with blood ammonia measured at the same time. CLD patients had significantly higher breath ammonia levels than healthy subjects (p = 1.51 × 10−3), with the level of significance being similar to that for blood ammonia levels (p= 0.024). Significant differences were found in breath and blood ammonia between the healthy and cirrhosis groups (p = 2.97 × 10−3 and 3.76 × 10−3, respectively). Significant, positive correlations between breath and blood ammonia were noted in the CLD group (R = 0.747, p = 1.00 × 10−4), healthy/CLD group (R = 0.741, p = 6.75 × 10−8), and cirrhosis group (R = 0.744, p = 9.52 × 10−4). In conclusion, the newly developed, easy-to-use, and small portable CuBr sensor device was able to non-invasively measure breath ammonia in real time. Breath ammonia measured using the device was correlated with blood ammonia and the presence of liver cirrhosis, and might be an alternative surrogate biomarker to blood ammonia.

Objective We aimed to investigate the association between the digit symbol test (DST) and clinical characteristics, including the nutritional status of liver cirrhosis patients. Methods Fifty-nine cirrhotic patients without a history of overt hepatic encephalopathy were retrospectively evaluated. We examined neuropsychological abnormalities (NPAs) using the DST. We also estimated the detailed nutritional status using the Food Frequency Questionnaire (FFQ). The patients were divided into two groups according to their DST status: patients with normal DST scores (DST-Nor group, n=45) and those with abnormal DST scores (DST-Abn group, n=14). The clinical and nutritional findings of the two groups were compared. Results Overall, 14 (23.7%) patients had a DST abnormality. There were significant differences between the two groups in serum albumin (Alb; p=0.0043), valine (Val; p=0.0016), leucine (Leu; p=0.0078), isoleucine (Ile; p=0.0022), the molar ratio of total branched-chain amino acids to tyrosine (BTR; p=0.00025), total-bilirubin (T-Bil; p=0.0071), prothrombin time(%) (PT; p=0.028), and serum sodium (Na; p=0.035). A multivariate analysis found the BTR to be the only independent predictor of a DST abnormality (hazard ratio, 9.24; p＜0.031). An FFQ analysis, revealed that the nutritional findings of patients with and without a DST abnormality, were similar. Conclusion The BTR was useful for predicting the risk of NPAs, as defined by a DST abnormality. The risk of NPAs may be estimated by monitoring the BTR.