Background. Natural killer (NK) cells are an integral part of the innate immune system. They have been suggested to play an important role in both defense against viral hepatitis and the pathogenesis ...of other liver diseases. Methods. NK cells from 134 individuals including patients with acute hepatitis B and C as well as chronic hepatitis B, C, and delta (D) patients were studied. Results. Infection with viral hepatitis was associated with increased frequencies of NK cells in the peripheral blood; that NK cells showed a less activated phenotype and were compromised in cytolotytic function and cytokine production in all viral hepatitis infections: Hepatitis virus infections did not alter NK cell differentiation, and the activity and severity of liver disease were reflected by alterations of NK cell surface receptors as demonstrated by principal component analysis. Conclusion. NK cell phenotypic and functional alterations can equally be observed in HBV, HCV, and HDV infections. Instead, patterns of NK cell alterations differ in acute and chronic infections. Thus, our data suggest a common mechanism in the alteration of NK cell phenotype and function with unique variations that depend on disease activity rather than virus-specific factors.
Progress of cholangitis to cholangiosepsis is a frequent observation in patients with secondary sclerosing cholangitis in critically ill patients (SSC-CIP). Adequate biliary drainage may reduce ...episodes of cholangiosepsis and therefore stabilize liver function and improve survival. The primary objective of the BISCIT study is to demonstrate that scheduled biliary interventions will reduce incidence of cholangiosepsis, liver transplantation, or death in patients with SSC-CIP.
A total of 104 patients will be randomized at ten study sites. Patients with SSC-CIP, confirmed by endoscopic retrograde cholangiography (ERC), will be randomized 1:1 either in the intervention group which will be treated with scheduled biliary interventions (i.e., therapeutic ERC) every 8 weeks for 6 months or in the control group which will receive standard of care. The randomization will be stratified by center. The composite primary efficacy endpoint is defined as (1) occurrence of death, (2) necessity of liver transplantation, or (3) occurrence of cholangiosepsis within 6 months following randomization.
Prospective evaluation of endoscopic treatment procedures is urgently needed to establish an evidence-based therapeutic treatment algorithm in SSC-CIP. A positive trial result could change the current standard of care for patients with SSC-CIP. The results of this study will be disseminated through presentations at international congresses, workshops, and peer-reviewed publications.
The trial was registered at ClinicalTrials.gov (NCT05396755, date of registration: May 31, 2022, last update: May 31, 2022).
Abstract Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable ...region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.
Acute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ...ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of
(TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF.
Impaired innate and-in particular-adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.
SMYD3 (SET and MYND domain-containing protein 3) is involved in histone modification, which initiates oncogenesis by activating transcription of multiple downstream genes. To investigate associations ...of variable numbers of tandem repeats (VNTR) variants in the SMYD3 gene promoter, SMYD3 serum levels and SMYD3 mRNA expression in hepatitis B virus (HBV) infection and clinical progression of related liver disease. SMYD3 VNTRs were genotyped in 756 HBV patients and 297 healthy controls. SMYD3 serum levels were measured in 293 patients and SMYD3 mRNA expression was quantified in 48 pairs of hepatocellular tumor and adjacent non-tumor liver tissues. Genotype SYMD3 VNTR 3/3 was more frequent among HCC patients than in controls (P
= 0.037). SMYD3 serum levels increased according to clinical progression of liver diseases (P = 0.01); HCC patients had higher levels than non-HCC patients (P = 0.04). Among patients with SMYD3 VNTR 3/3, HCC patients had higher SMYD3 levels than others (P < 0.05). SMYD3 mRNA expression was up-regulated in HCC tumor tissues compared to other tissues (P = 0.008). In conclusion, upregulation of SMYD3 correlates with the occurrence of HCC and SMYD3 VNTR 3/3 appears to increase the risk of HCC through increasing SMYD3 levels. SMYD3 may be an indicator for HCC development in HBV patients.
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The European Association for the Study of the Liver (EASL) guidelines recommend HCV RNA measurements at specific time points during sofosbuvir(SOF)-therapy. However, it remains ...unclear, how these results should be interpreted. We aimed to analyze whether on-treatment HCV RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays.
Samples were collected from 298 patients (HCV genotypes; GT1-5) at weeks (w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two university clinics and tested for HCV RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin (RBV) 12/24 w (n=99), pegylated-interferon-alfa (PegIFN)/SOF/RBV 12 w (n=51), SOF/simeprevir (SMV)±RBV 12 w (n=69) or SOF/daclatasvir±RBV 12/24 w (n=79).
HCV RNA levels during the first 4weeks of SOF/RBV therapy were significantly lower in GT3 patients who achieved SVR compared with those who relapsed. All GT3 patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ⩾45IU/ml (p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR: 100% vs. 29%; p=0.0002). In contrast, HCV RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens.
Residual HCV RNA was frequently detected by ART at later stages of therapy. However, SVR rates remained high in these patients. At the end of SOF/SMV±RBV therapy HCV RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR.
HCV RNA levels assessed at week 2 of SOF/RBV therapy can predict relapse in GT3-patients. Detectable HCV RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension.
We analyzed the predictive value of hepatitis C virus (HCV) RNA levels measured at different time points for treatment efficacy. We found that the level of HCV RNA measured at week 2 of antiviral therapy can be used to predict treatment success in patients with HCV genotype 3 infection treated with sofosbuvir and ribavirin but not in patients treated with other sofosbuvir-based regimens. Low level HCV RNA is frequently detected by the RealTime HCV assay during later stages of antiviral therapy. However, this is not associated with reoccurrence of HCV RNA after the end of treatment.
HCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) ...infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center.
All consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12.
208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12.
P/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.
Mortality due to COVID-19 is not increased in immunosuppressed individuals after liver transplantation (OLT) compared to individuals without immunosuppression. Data on long-term protective immunity ...against SARS-CoV-2 in immunosuppressed convalescents, is limited. We prospectively measured immune responses against SARS-CoV-2 by quantifying antibodies against 4 different antigens (spike protein 1 and 2, receptor binding domain, nucleocapsid) and T cell responses by IFN-γ ELISPOT against 4 antigens (membrane, nucleocapsid, spike protein 1 and 2) in 24 OLT convalescents with immunosuppressive therapy longitudinally in the first year after COVID-19 including a booster vaccination in comparison to a matched cohort of non-immunosuppressed convalescents (non-IS-Con). Pre-pandemic OLT samples were retrieved from our prospective OLT biorepository (n = 16). No relevant T cell reactivity or immunoglobulin G (IgG) against SARS-CoV-2 were detectable in pre-pandemic samples of OLT recipients despite reactivity against endemic corona-viruses. OLT convalescents had a lower prevalence of IgG against nucleocapsid (54% vs. 90%) but not against spike protein domains (98–100% vs. 100%) after vaccination in the second half-year after COVID-19 compared to non-IS-Con. Also, concentrations of anti-nucleocapsid IgG were lower in OLT convalescents than in non-IS-Con. Concentration of IgG against spike protein domains was significantly increased by a booster vaccination in OLT convalescents. But concentration of IgG against two of three spike protein domains remains slightly lower compared to non-IS-Con finally. However, none of these differences was mirrored by the cellular immunity against SARS-CoV-2 that remained stable during the first year after COVID-19 and was not further stimulated by a corona vaccination in OLT convalescents. In conclusion, despite lower concentrations of anti-SARS-CoV-2 IgG in OLT convalescents anti-SARS-CoV-2 cellular immunity was as robust as in non-IS-Con.
Liver cancer is an emerging global health issue, with rising incidence in both the United States and the economically developing world. Although Guatemala experiences the highest rates of this ...disease in the Western hemisphere and a unique 1:1 distribution in men and women, few studies have focused on this population. Thus, we determined the prevalence and correlates of aflatoxin B1 (AFB1) exposure and hepatitis virus infection in Guatemalan adults. Healthy men and women aged ≥40 years (n = 461), residing in five departments of Guatemala, were enrolled in a cross-sectional study from May-October of 2016. Serum AFB1-albumin adducts were quantified using isotope dilution mass spectrometry. Multivariate linear regression was used to assess relationships between AFB1-albumin adduct levels and demographic factors. Biomarkers of hepatitis B virus and hepatitis C virus infection were assessed by immunoassay and analyzed by Fisher's exact test. AFB1-albumin adducts were detected in 100% of participants, with a median of 8.4 pg/mg albumin (range, 0.2-814.8). Exposure was significantly higher (p<0.05) in male, rural, low-income, and less-educated participants than in female, urban, and higher socioeconomic status participants. Hepatitis B and C seropositivity was low (0.9% and 0.5%, respectively). Substantial AFB1 exposure exists in Guatemalan adults, concurrent with low prevalence of hepatitis virus seropositivity. Quantitatively, AFB1 exposures are similar to those previously found to increase risk for liver cancer in Asia and Africa. Mitigation of AFB1 exposure may reduce liver cancer incidence and mortality in Guatemala, warranting further investigation.
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