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Background: High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain., Methods: In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5., Results: ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE., Conclusion: In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia., Clinicaltrial: gov (identifier: NCT02718079)., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

End-stage liver disease and liver failure are major health problems worldwide leading to high mortality and morbidity and high healthcare costs. Currently, orthotropic liver transplantation is the only effective treatment available to the patients of end-stage liver disease. However, a serious shortage of liver donors, high cost, and risk of organ rejection are the major obstacles to liver transplantation. Because of the ability of stem cells for differentiation into any tissue type, they have huge potential in therapy of various end-stage or degenerative diseases and traumatic injuries. Stem cell therapy has the potential to provide a valuable adjunct and alternative to liver transplantation and has immense potential in the management of end stage liver disease and liver failure. Stem cell therapy can be mediated by either a direct contribution to the functional hepatocyte population with embryonic, induced pluripotent, or adult stem cells or by promotion of endogenous regenerative processes with bone marrow-derived stem cells. Initial translational studies have been encouraging and have suggested improved liver function in advanced chronic liver disease and enhanced liver regeneration after portal vein embolization and partial hepatic resection. Stem cells infusion in cirrhotic patients has improved liver parameters and could form a viable bridge to transplantation. The present review summarizes basic of stem cell biology relevant to clinicians and an update on recent advances on the management of liver diseases using stem cells.

Background: Health care workers (HCWs) constitute a high-risk population of HBV infection. There are limited data on the efficacy of vaccination in HCWs in India. This study was to evaluate the efficacy of indigenous recombinant hepatitis B vaccine, Shanvac-B, in HCWs., Methods: In 597 HCWs screened before the vaccination, 216 (36.2%) showed the presence of at least one of the markers of HBV/HCV infection. Of the remaining 381 (63.8%) HCWs who were considered for vaccination, only 153 (age 18-45 years; 48 males and 105 females) were available for final assessment. These HCWs received 20 microg of vaccine at 0, 1 and 6 months. They were asked for the reactogenicity and monitored for the seroprotective efficacy of the vaccination. Anti-HBs titres were measured after vaccination at 1, 2 and 7 months. The presence of anti-HBs titers equal to 1 MIU/ml was considered as seroconversion and that of titres greater than 10 MIU/ml as seroprotection., Results: After vaccination, 32 males (67%) and 76 females (72%) showed seroconvertion; finally 12 (25%) of the males and 47 (45%) of the females were seroprotected. Seroprotection at 2 and 7 months was more dominant in the females than in the males (96% vs. 56%, P=0.001, 100% vs. 85%, P=0.0001), respectively. Geometric mean titres of anti-HBs after vaccination were also higher in the females than in the males (257+/-19.7 vs. 29+/-1.88 MIU/ml, P=0.01, 1802+/-35.2 vs. 306+/-13.6 MIU/ml, P< or =0.05, 6465+/-72 vs. 2142+/-73.6 MIU/ml, P<0.05). Seven male HCWs showed unsatisfactory response, non-response (n=3, 6%) and hypo-response (< or =10 MIU/ml, n=4, 8%) at the end of vaccination. Smoking and alcoholism were significantly correlated with unsatisfactory response. No significant adverse effects of vaccination were observed in any HCW., Conclusions: The presence of HBsAg in HCWs indicates that a high proportion of HCWs are infected with HBV and HCV in India. Recombinant indigenous vaccine Shanvac-B is highly efficacious in HCWs, and its immunogenicity is significantly higher in females than in males. However, pre-vaccination screening of HCWs is strongly recommended in India.

Background and Aims: The mechanism of hepatitis B virus (HBV)-specific T cell hyporesponsiveness in hepatitis Be antigen (HBeAg)-positive subjects is not well understood. Inefficient antigen processing and transport to major histocompatibility complex class I molecules, namely due to low molecular weight protein (LMP) 2 and 7 and transporter associated with antigen processing (TAP) 1 and 2 genes could be playing a role., Patients and Methods: Forty patients with chronic hepatitis B (CHB) infection, hepatitis B surface antigen, and HBeAg positive; 26 with raised (Gr. I) and 14 with persistently normal ALT levels (Gr. II) and 11 healthy controls (Gr. III) were studied. Total RNA was isolated from peripheral blood mononuclear cells and mRNA expression of TAP1, TAP2, LMP2, and LMP7 genes was analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction method. Gamma interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) levels were quantified by enzyme-linked immunosorbent assay (ELISA) using log-log and linear graphs, respectively., Results: Group II CHB patients had significantly lower mRNA expression for TAP1 (p = 0.003) and LMP2 (p = 0.002) genes as compared to Gr. I patients. The mRNA expression of TAP2 and LMP7 genes was comparable between the groups. However, expression of TAP1 (p = 0.02), TAP2 (p = 0.035), and LMP2 (p = 0.041) was found to be significantly higher in Gr. III subjects compared to Gr. I and Gr. II patients. In Gr. I and II, the IFN-gamma {s54.2{9.4-165} pg/ml), (59.5{28.5-110} pg/ml)}, and TNF-alpha {12.0 (8.0-23.2)},{10.8(6.2-20.8)} pg/ml levels were comparable but were significantly (p = 0.00,0.004, respectively) higher than Gr. III subjects., Conclusions: Low expression of TAP1 and LMP2 suggests an important role of these genes in defective viral antigen processing in immune tolerant state of CHB patients. Higher IFN-gamma and TNF-alpha production in CHB are probably enough to potentiate liver injury but not enough to clear the chronic HBV infection. These novel observations could pave way for new therapeutic strategies for immune restoration in CHB infected patients.

Introduction: Interleukin (IL)-18 plays an important dual role in Th1 polarization and viral clearance, as well as in the development of liver fibrosis. Single-nucleotide promoter polymorphisms influence the transcription of IL-18 mRNA. Promoter polymorphisms are linked to delayed virus clearance and disease susceptibility in many diseases. However, there is no information about their role in hepatitis C virus (HCV) infection., Aim: To investigate the association between -607 or -137 polymorphism with susceptibility and severity of HCV infection., Patients and Methods: Two hundred and four serologically proven patients with chronic HCV infection and 350 matched healthy controls were included in this study. Patients were segregated in 2 groups: group A with mild liver disease and group B with severe liver disease on the basis of histological activity index (HAI 5) and hepatic fibrosis score (2). IL-18 promoter genotyping was performed with sequence-specific primers., Results: There was no significant difference in the frequencies of -607 and -137 allelic distribution in patients and controls. The -607 A/A allele was more common in group A patients with mild liver disease than in patients with severe liver disease on the basis of HAI (38.6% vs. 21%, P = 0.05; odds ratio [OR] = 0.424, confidence interval [CI] = 0.233-0.773; R (2) = 0.631) and stage of fibrosis (38.7% vs. 16.7%, P = 0.008; OR = 0282, CI = 0.134-0.596; R (2) = 0.434)., Conclusions: IL-18 promoter polymorphism at -607 position with A/A allele is a potential protective marker, as it is associated with milder liver disease in patients with chronic HCV infection.

Background and Aim: The risk of acquiring hepatitis B virus (HBV) infection through exposure to blood or its products is highest amongst health care workers (HCWs). Despite potential risks, a proportion of HCWs never get vaccinated. India is second to China in the numbers of people with chronic HBV. This study aimed to investigate the vaccination practices and the prevalence of HBV infection in HCWs in India., Methods: A total of 2162 HCWs were screened for the presence of serological markers of HBV and hepatitis C virus (HCV). Occult HBV infection was tested by detection of HBV-DNA for surface and core regions by nested polymerase chain reaction in HBsAg-negative and IgG anti-hepatitis core antigen-positive subjects., Results: Only 1198 (55.4%) of the 2162 HCWs screened had been vaccinated; and 964 (44.6%) were not vaccination-status conscious; of these HCWs, 600 (27.7%) had never been vaccinated and 364 (16.4%) were unaware of their vaccination status. Protective (> 10 IU/mL) anti-hepatitis B surface (anti-HBs) antigen titers were seen in only 61.7%. The anti-HBs titers were found to be lower with the passage of time; the median anti-HBs titers in subjects who were vaccinated > 10 years ago were significantly lower than those who had been vaccinated < 5 years ago (P < 0.001). One percent of HCWs were HBsAg-positive, and 24.7% of 700 HCWs screened had past exposure (IgG-anti-HBc-positive). Occult HBV was detected in 5% of 120 positive subjects with past exposure; all had anti-HBs titers > 10 IU/mL., Conclusions: Even today, 28% HCWs in India are unvaccinated and 17% are unaware of their vaccination status. This data suggests that use of hepatitis B immune globulin be mandatory in needle-pricked HCWs in India, and that implementation of awareness strategies is urgent. Since the anti-HBs titers decline in a fair proportion, there is justification for giving a booster dose of vaccine 10 years after primary vaccination to HCWs in India.

The non-response to hepatitis B vaccine in health care workers (HCWs) is reported to vary between 5 and 40%. The underlying cellular and molecular events for unresponsiveness to HBV vaccine have not yet been characterized at any great extent. In the current study, we examined the CD150 surface expression levels and its association with polyclonally activated and HBV specific stimulated cellular proliferations in responders and non-responders. CD150 was identified as upregulated expression marker with suppressive regulatory cell function on all activated T cells by gene chip analysis. We found the overall weak cellular proliferation in response to specific and non-specific agents in non-responders. This is significantly associated with enhanced surface expression of CD150 in the non-responders. A strong expression of CD150 with weak cellular proliferation could be used as a predictive marker for non-responsiveness.

We have been investigating whether alloantigen-specific CD4(+)25+ regulatory T cells can be identified for use in treating graft-versus-host disease. CD150, which is upregulated on the surface of all activated T lymphocytes, was identified as a candidate marker for alloantigen-activated CD4(+)25+ regulatory T cells by gene chip analysis. Freshly isolated CD4(+)25+ cells had only low cell-surface expression of CD150, comparable to that of CD4(+)25- T cells. Increased CD150 expression was observed on all T cells after coculture with allogeneic stimulator cells. When purified CD4(+)25+ cells were precultured with allogeneic stimulator cells, then sorted into CD150+ and CD150- subsets, allosuppressive activity was contained primarily in the CD150+ fraction. These cells also suppressed the proliferation of alloantigen-activated autologous T cells, and they could be expanded in vitro without loss of their suppressive capacity. These results suggest that CD150 can be used as a marker for the identification of purified alloantigen-activated CD4(+)25+ regulatory T cells.