S. Tamura

Preemptive Treatment of Fungal Infection Based on Plasma (1 → 3)β-D-Glucan Levels after Liver Transplantation

Background:Invasive fungal infection remains a major challenge in liver transplantation and themortality rate is high. Early diagnosis and treatment are required for better results.Patients:We prospectively measured plasma (1 → 3)β-D-glucan (BDG) levels in 180 living donor liver transplant recipients for 1 year after surgery. Fungal infection was defined as proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group. Preemptive treatment (intravenous fluconazole and trimethoprim-sulfamethoxazole) was started when the BDG level was greater than 40 pg/ml.Results:Twenty-four patients (13%) were diagnosed with invasive fungal infection. The responsible pathogens included Candida spp. in 14 cases, Aspergillus fumigatus in 5, Cryptococcus neoformans in 3, and Pneumocystis jiroveci in 2. Preemptive treatment was performed in 22% of patients (n = 40). Renal impairment and mild gastrointestinal intolerance due to the drugs were observed in 28% (11/40) of patients during treatment. Among them 14 patients were diagnosed with fungal infection including seven candidiasis, five aspergillosis, and two Pneumocystis jiroveci pneumonia. The sensitivity and specificity of BDG for overall fungal infection was 58% and 83%, respectively, with a positive predictive value of 35% and a negative predictive value of 93%, and a positive likelihood ratio of 3.41 and a negative likelihood ratio of 1.98. The overall mortality for fungal infection in our series was 0.6%.Conclusion:Although the sensitivity and positive predictive value were low, the low mortality rate after fungal infection and the mild side effects of the preemptive treatment might justify our therapeutic strategy. Based on the effectiveness, this strategy warrants further investigation.

Pseudomonas aeruginosa infection after living-donor liver transplantation in adults.

Objectives. Pseudomonas aeruginosa infection is a major cause of bacterial infection after deceased‐donor liver transplantation. The incidence and risk factors of P. aeruginosa infection after living‐donor liver transplantation (LDLT), however, are not known.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

&NA; A previous genome‐wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10‐9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Preemptive Antiviral Treatment for Hepatitis C Virus After Living Donor Liver Transplantation

BACKGROUND Recurrence following liver transplantation for hepatitis C virus (HCV), which is universal, affects long-term outcomes. Treatment with interferon (IFN) and ribavirin (RBV), the only widely available options at this time, have been faced with low tolerability and overall unsatisfactory results in deceased donor liver transplantation (DDLT). However, its place after living donor liver transplantation (LDLT) remains a matter of debate. Since most LDLT cases are performed in a planned manner at a lower Model for End-stage Liver Disease (MELD) score compared to DDLT, we have aggressively applied preemptive INF/RBV in our series. PATIENTS AND METHODS We studied 122 adult recipients who underwent LDLT for HCV-related end-stage liver disease. The preemptive IFN/RBV protocol initiated treatment promptly after improvement in the patients general condition with a low-dose IFN alpha2b and RBV (400 mg/d) followed by a gradual increase in the INFalpha2b dosage. Finally, we applied pegylated IFN (1.5 ug/kg/wk) and RBV (800 mg/d). The treatment was continued for 12 months after serum HCV-RNA became negative, which was defined as the end-of-treatment response (ETR). The response was considered to be a sustained viral response (SVR) if there were negative serologic results without antiviral treatment for another 6 months. Splenectomy was performed at the time of LDLT to improve tolerability to INF/RBV. The median age of the patients was 55 yrs (range = 23-66), with male dominance (87 males and 35 females). Median MELD score was 14 (range = 6-48). The series included 72 patients with hepatocellular carcinomas, and six with HIV coinfections. In 98 cases, HCV genotype was 1b. RESULTS Overall survival at 5 years was 79%. Cumulative response rates under the protocol were ETR 56% and SVR 44% at 5 years. CONCLUSIONS Preemptive IFN/RBV therapy after LDLT for HCV is feasible with acceptable outcomes.

Model for End-stage Liver Disease and Model for End-stage Liver Disease-Na Scores Predict Both Before-Listing and Wait-List Mortality

BACKGROUND Due to the organ shortage, many patients die without transplantation, even before completing an evaluation for candidacy. We analyzed outcomes after patient referral and factors associated with mortality both before and after listing for cadaveric donor liver transplantation. METHODS We analyzed 132 consecutive patients who were evaluated for candidacy for cadaveric donor liver transplantation between 2003 and 2010. RESULTS The study included 69 men and 63 women of median age 49 years (range, 1-65). Etiologies of diseases were acute hepatic failure (n=19), liver cirrhosis due to hepatitis B or C (n=36), primary biliary cirrhosis (n=19), nonviral cirrhosis (n=14), hepatocellular carcinoma (n=13), or other causes (n=31). After evaluation for candidacy, we listed 68 (52%), subjects whereas 24 (18%) died before listing. Factors affecting death before listing were the levels of albumin (P<.001), bilirubin (P<.001), sodium (P<.001), international normalized ratio (INR; P<.001), Model for End-stage Liver Disease (MELD) score (P<.001), MELD-Na score (P<.001), and Child-Pugh-Turcotte (CPT) score (P<.001). Based on multivariate Cox regression analysis, MELD score (hazard ratio [HR] 1.201, P=.017), MELD-Na score (HR 1.244, P=.014), CPT score (HR 1.468, P=.033), and INR (HR 0.491, P=.027) were independently associated with death before listing. Among 68 listed candidates, 11 (16%) underwent transplantation, whereas 29 (43%) died without transplantation. Based on multivariate Cox regression analysis, MELD score (HR 1.102, P=.001), MELD-Na score (HR 1.128, P=.001), and CPT score (HR 1.282, P=.038) independently predicted wait-list mortality. All 11 patients who underwent cadaveric liver transplantation were alive at 29 months (range, 1-55) after transplantation. CONCLUSIONS Patients with a higher MELD, higher MELD-Na, and higher CPT score at referral were at greater risk for death without transplantation, especially before listing. Evaluation for transplantation candidacy is a time-consuming process. Therefore, earlier referral is mandatory to achieve successful listing for transplantation.

Successful treatment of disseminated Nocardia farcinica infection in a living‐donor liver transplantation recipient

Abstract: Nocardiosis is a serious infection with high mortality. We report a case of subcutaneous and neural lesions due to Nocardia farcinica infection after living‐donor liver transplantation. The neural lesion was cured with antibiotics without drainage.

NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population

Approximately 10–20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3′UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10−7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10−8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.