The latest medical research on Gastroenterology

Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC.

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758.

PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Peginterferon-α (PegIFNα) is of limited utility during immunotolerant (IT) or immune active (IA) phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some treated patients are associated with limited/no virological responses.

To determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies.

Pre-, on- and post-treatment sera from 61 IT trial participants on PegIFNα/ entecavir therapy and 88 IA trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by pre-incubation of sera +/- recombinant-human IFNα (rhIFNα) added to Huh7 cells with measurement of interferon stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated.

Pre-incubation of on-treatment serum from 26 IT (43%) and 13 IA (15%) participants with rhIFNα markedly blunted ISG-induction in Huh7 cells. Degree of ISG-inhibition correlated with IFNα antibody titer (p<0.0001; r=0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced qHBsAg and qHBeAg declines (p<0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults (p=0.004) but nAbs in children had less impact on virological responses.

The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.

Living donor liver transplant (LDLT) is based on the principle of double equipoise. Organ shortage in Asian countries has led to development of high-volume LDLT programs with good outcomes. Safety of live liver donor is the Achilles heel of LDLT program and every effort should be made to achieve low morbidity and near zero mortality rates.

We retrospectively analyzed our prospectively maintained donor morbidity data (outcomes) of 177 donors in a new transplant program setup in western India by an experienced surgeon. The primary end point was to analyze the morbidity rates and the factors associated with it.

None of the donors in our cohort of 177 donors developed grade IV or V complication (Clavien-Dindo classification). One-fourth (1/4th) of the donors developed complications ranging from grade I to grade III(b). The rate of complications according to modified Clavien-Dindo classification is as follows: (1) grade I in 5.6% (n = 10), (2) grade II in 14.6% (n = 26), (3) grade III(a) in 3.9% (n = 7), (4) grade III(b) in 2.2% (n = 4). Three donors (1.6%) developed post-hepatectomy intra-abdominal bleeding and required re-exploration (grade IIIb). All of them recovered well post-surgery and are doing well in follow-up. The mean follow-up of the entire cohort was 2871 ± 521 days (range 1926-3736 days).

Donor safety (outcome) is determined by meticulous donor surgery and good-quality remnant.