Detection of polyreactive immunoglobulin G facilitates diagnosis in children with autoimmune hepatitis.

OBJECTIVE: The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH. DESIGN: pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers (n = 285). RESULTS: IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31-73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6-20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21-34% higher accuracy than conventional autoantibodies, was positive in 43-75% of children with AIH and normal IgG and independent from treatment response. CONCLUSION: Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity.

Unmet needs in autoimmune hepatitis: Results of the prospective multicentre European Reference Network Registry (R-LIVER).

BACKGROUND AND AIMS: The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) launched the prospective, multicentre, quality-controlled R-LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment. METHODS: Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow-up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels. RESULTS: A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid-free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01-1.05]; p = .007), severe fibrosis (OR .38 [95% .16-.89], p = .026) and change of treatment within the first 6 months (OR .40 [95% CI .2-.86]; p = .018) were associated with a lesser chance of ALT normalization at 12 months follow-up. CONCLUSION: The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids.

[Treatment of autoimmune hepatitis-First-line, second-line and third-line treatment]. / Therapie der Autoimmunhepatitis ­ Erst­, Zweit- und Drittlinientherapie.

Autoimmune hepatitis (AIH) is a rare autoimmune inflammation of the liver mostly with a chronic course, which can also be acutely manifested up to acute liver failure. It affects women 3-4 times more frequently than men and can be diagnosed in all age groups. In one third of the patients a liver cirrhosis is present at the time of diagnosis. It is characterized by a hepatic inflammation pattern, a polyclonal hypergammaglobulinemia of immunoglobulin G and the detection of autoantibodies. A liver biopsy is necessary to make the diagnosis. The AIH is histologically characterized in particular by a lymphoplasmacytic infiltrate in the portal fields. In cases with a relevant disease activity, AIH is typically treated by immunosuppression. The immunosuppressive treatment is associated with a prevention of disease progression to liver cirrhosis and a better survival. The success of treatment is measured by achieving biochemical remission, i.e., normalization of the transaminase and immunoglobulin G levels as a good noninvasive predictor of a histological remission. Another treatment target is an improvement of the symptoms of the patient. The first-line treatment consists of a glucocorticoid, mostly prednisolone or in cases without advanced fibrosis budesonide, and azothioprine. For reduction of steroid-specific treatment side effects the maintenance treatment should be carried out steroid-free whenever possible. In cases of insufficient response to azothioprine or side effects a treatment attempt using antimetabolites, such as 6­mercaptopurine or mycophenolate mofetil is primarily carried out as second-line treatment. For patients who do not achieve biochemical remission through first-line or second-line treatment, a variety of medications are available for third-line treatment, e.g., rituximab, calcineurin inhibitors or antitumor necrosis factor (anti-TNF) antibodies. Third-line treatment should be carried out in expert centers and registered in the European Reference Network for Rare Liver Diseases in order to improve the currently sparse database for these forms of treatment in the future.

Association of torque teno virus viremia with liver fibrosis in the first year after liver transplantation.

Introduction: Torque teno virus (TTV) replication is controlled by immune status, mirroring a degree of immunosuppression after solid organ transplantation. TTV viraemia (TTVv) was associated with acute cellular rejection and infection within the first year after liver transplantation (LT). Long-term data on TTV after LT and correlation with graft injury from protocol biopsies are limited. Methods: One hundred plasma samples paired with graft biopsies from a prospective single-center biorepository were analyzed. Results: The median time post-LT was 23 months (range, 2-298). TTVv was detectable in 97%. TTVv decreased over time after LT and showed a significant decline from year 1 to later time points. Hence, TTVv correlated negatively with histologic liver fibrosis (liver allograft fibrosis and Ishak scores) and positively with the overall immunosuppression degree quantified by an immunosuppression score in the first year after LT. There was no association with dosages or trough levels of single immunosuppressants. The pharmacodynamic marker TTVv did not correlate with pharmacokinetic assessments of immunosuppression degree [calcineurin inhibitor (CNI) trough levels or immunosuppressant dosages]-our clinical gold standards to guide immunosuppressive therapy. TTVv was independently associated with histologically proven liver fibrosis after LT in the first year after LT in multivariate analysis. Discussion: The independent association of histological graft fibrosis with lower TTVv in year 1 underscores that a pharmacodynamic marker would be preferable to individualize immunosuppression after LT. However, a high variability of TTVv at the low immunosuppression doses given after the first year precludes TTV as a clinically useful marker after LT in the long-term liver transplant recipients.

Evaluation of immunoserological detection of anti-liver kidney microsomal, anti-soluble liver antigen and anti-mitochondrial antibodies.

Autoantibodies are the diagnostic hallmark of autoimmune liver diseases. Indirect immunofluorescence (IFT) is the reference method for the detection of anti-mitochondrial antibodies (AMA) and anti-liver kidney microsomal type-1 (anti-LKM1) antibodies, and inhibition ELISA (iELISA) for anti-soluble liver antigen (anti-SLA) antibodies. Given the complexity of these techniques, commercial ELISAs have emerged as a practical alternative, but without head-to-head validations. This study evaluated the agreement between three commercial ELISAs and the reference techniques and the impact of polyreactive immunoglobulin G (pIgG), a recently described phenomenon in autoimmune hepatitis, on commercial ELISAs. Inter-rater reliability was assessed using Cohen-Kappa coefficient (κ). Forty-eight, 46, and 66 samples were analyzed for AMA, anti-LKM1, and anti-SLA, respectively. For AMA, one commercial assay showed high agreement (κ = 0.91 (0.78-1.00)) with the reference method, while the other two showed weak or moderate agreement. For anti-LKM1, only one commercial assay showed high agreement (κ = 0.86 (0.71-1.0)). For anti-SLA antibodies only moderate agreement was achieved (κ up to 0.71 (0.52-0.89)). There was a trend towards higher pIgG levels in false-positives in the commercial ELISAs. Patients with high suspicion of autoimmune liver diseases should be referred to reference laboratories with the capacity of performing gold standard methods if the initial ELISA-based screening was performed.

Quantification of extracellular matrix remodeling for the non-invasive identification of graft fibrosis after liver transplantation.

Detecting patients with early post-transplant fibrosis after liver transplantation (LT) is very important. Non-invasive tests are needed to avoid liver biopsies. We aimed to detect fibrosis in liver transplant recipients (LTR) using extracellular matrix (ECM) remodeling biomarkers. ECM biomarkers for type III (PRO-C3), IV (PRO-C4), VI (PRO-C6) and XVIII (PRO-C18L) collagen formation and type IV collagen degradation (C4M) were measured by ELISA in prospectively collected, cryopreserved plasma samples (n = 100) of LTR with paired liver biopsies from a protocol biopsy program. Fibrosis ≥ F2 was present in 29% of patients (median 44 months post-LT). APRI and FIB-4 neither identified significant fibrosis nor were correlated with histopathological fibrosis scores, while ECM biomarkers (AUCs 0.67-0.74) did. The median levels of PRO-C3 (15.7 vs. 11.6 ng/ml; p = 0.002) and C4M (22.9 vs. 11.6 ng/ml; p = 0.006) levels were elevated in T-cell-mediated rejection compared to normal graft function. The median levels of PRO-C4 (178.9 vs. 151.8 ng/ml; p = 0.009) and C4M (18.9 vs. 16.8 ng/ml; p = 0.004) levels were increased if donor-specific antibodies were present. PRO-C6 had the highest sensitivity (100%), NPV (100%) and negative likelihood-ratio (0) for graft fibrosis. To conclude, ECM biomarkers are helpful in identifying patients at risk of relevant graft fibrosis.

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination.

Background & Aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Impact and implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

Prospective comparison of liver stiffness measurement methods in surveillance biopsies after liver transplantation.

Background: Liver stiffness measurements (LSMs) have proven useful for non-invasive detection of fibrosis. Previous studies of LSMs after transplantation were performed in cohorts dominated by hepatitis C reinfections and indication biopsies for the evaluation of graft dysfunction. However, the diagnostic fidelity of LSMs for fibrosis is biased by inflammation e.g., during replicative hepatitis C or rejection. Materials and methods: The current study aimed for a head-to-head comparison of two different LSMs, acoustic radiation force impulse (ARFI) and transient elastography (TE), and a determination of cut-off values for the detection of advanced fibrosis (any LAF score component ≥2) in grafts undergoing surveillance biopsies (svLbx) without recurrent hepatitis C. Results: 103 svLbx were paired with valid LSMs at time of biopsy. AUROC analyses showed significant positive correlation with fibrosis for both methods (TE: AUROC = 0.819 (p < 0.001; 95%CI: 0.717-0.921); ARFI: AUROC = 0.771 (p = 0.001; 95%CI: 0.652-0.890). Patients were randomly assigned to training and validation cohorts for both LSM methods. Cut-off values were determined at 1.29 m/s (ARFI) and at 7.5 kPa (TE) in training cohorts. Sensitivity and specificity in training and validation cohorts were: TE: SEN 0.818 and 0.5; SPE 0.742 and 0.885; ARFI: SEN 0.818 and 1.0; SPE 0.75 and 0.586. LSMs were not associated with BANFF criteria for relevant graft injury. Conclusion: LSM is a good non-invasive tool to screen for advanced graft fibrosis but not for relevant graft injury in patients with (near) normal liver enzymes. Fibrosis cut-off values identified and validated in svLbx were lower than in previous cohorts using indication biopsies.

Impact of steroid withdrawal on subclinical graft injury after liver transplantation: A propensity score-matched cohort analysis.

Subclinical graft injuries in orthotopic liver transplantation may threaten long-term graft survival and could be the result of chronic under-immunosuppression. It is not known whether steroid withdrawal increases the risk of subclinical immune responses against the graft. This retrospective single-center study aimed to assess the risk of subclinical graft damage after steroid withdrawal within the first nine months after orthotopic liver transplantation in the first three years after transplantation in a prospective cohort of surveillance biopsies using a propensity score matching analysis. Of 355 patients, 109 patients underwent surveillance biopsies between eleven and 36 months after liver transplantation. Thirty-seven patients discontinue steroids within the first nine months and 72 later than nine months after transplantation. The matching led to 28 patients per group. Patients with autoimmune hepatitis, primary biliary cholangitis, and hepatocarcinoma were excluded by the propensity score matching unintentionally. Patients who discontinued steroids had a trend toward lower levels of immunosuppression at the time of surveillance biopsy. Steroid withdrawal in the first nine months was not associated with an increased risk of subclinical T cell-mediated rejection, graft inflammation, or liver graft fibrosis in the matched cohort with patients with a low frequency of autoimmune liver diseases. There were also no differences in the development of metabolic diseases. In conclusion, steroid withdrawal within the first nine months after transplantation, as assessed by surveillance biopsies, does not increase the risk of subclinical graft injuries or fibrosis at least in liver transplant recipient without or a low prevalence of autoimmune liver diseases.

No association of serum ferritin levels with advanced liver fibrosis in untreated German patients with autoimmune hepatitis.

In the January 2022 issue of BMC Gastroenterology, Chen et al. report an association between serum ferritin levels and the presence of advanced liver fibrosis in patients with treatment-naïve autoimmune hepatitis (AIH). The odds ratio for ferritin in this study was marginally above 1.0. We analyzed our own published data from a German cohort for an association between ferritin levels and the presence of advanced fibrosis in treatment-naïve AIH and were not able to validate the findings of Cheng et al.

Reduced humoral but stable cellular SARS-CoV-2-specific immunity in liver transplant recipients in the first year after COVID-19.

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.

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.

Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation.

Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.

Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.

BACKGROUND & AIMS: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis. METHODS: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation. RESULTS: Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. CONCLUSION: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver. LAY SUMMARY: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.

Liver-first strategy for a combined lung and liver transplant in patients with cystic fibrosis.

OBJECTIVES: A combined lung and liver transplant in patients with cystic fibrosis (CF) is an uncommon procedure. The goal of this study was to compare long-term outcomes between patients with CF who underwent either a combined lung-liver or a lung-only transplant. METHODS: This is a retrospective single-centre study of patients with CF who underwent a lung transplant between January 2005 and May 2020. Since 2006, our preference for a combined lung-liver transplant was to transplant the liver first and then the lung. Outcomes were compared using the Kaplan-Meier analysis and the log-rank test. Median follow-up was 53 (23-97) months. RESULTS: During the study period, among 357 patients with CF who underwent a lung transplant, 14 (4%) required a lung-liver transplant whereas 343 (96%) had a lung-only transplant. Lung cold ischaemic time was longer in the lung-liver transplant group, but no patient in this group showed primary graft dysfunction at 72 h after the transplant. Prevalence of anti-human leucocyte antigen donor-specific antibodies was 7.1% vs 13.7% in the lung-liver versus the lung-only transplant group (P = 0.42). At 5 years, lung graft survival (78% vs 69%) and freedom from chronic lung allograft dysfunction (79% vs 62%) did not differ between the lung-liver versus the lung-only groups (P = 0.45 and P = 0.55, respectively). Freedom from lung biopsy-confirmed rejection was significantly higher in patients undergoing a lung-liver transplant (91% vs 50%; P = 0.027). CONCLUSIONS: A lung-liver transplant did not impair lung graft function. The lower prevalence of donor-specific antibodies and the better freedom from lung biopsy-confirmed rejection suggest tolerogenic effects of the liver graft.

Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review.

Autoimmune Hepatitis (AIH) is a heterogenous, mostly chronic liver disease that affects people of all age groups, women more often than men. The aim of therapy is to prevent cirrhosis, as it mainly accounts for liver-related mortality in patients with AIH. Rates of remission are high in patients with AIH, but life-long immunosuppressive therapy is required. AIH is hypothesized to originate from immunologic reactivity targeted against mostly unknown self-antigens, potentially triggered by viral infections among other factors. While AIH does not follow a Mendelian inheritance pattern, part of the risk of developing AIH or worse disease course, is attributed to specific genetic risk factors. Major associations for the risk of development of AIH were found for HLA-DRB1*03:01 and HLA-DRB1*04:01 in adult AIH in the only genome-wide association study on AIH. However, other potential risk loci in SH2B3, CARD10 and KIR genes were described. This review covers the current knowledge on genetic risk factors in adult and pediatric AIH.

Distinct Immune Imprints of Post-Liver Transplantation Hepatitis C Persist Despite Viral Clearance.

Recurrence or de novo infection of hepatitis C virus (HCV) after liver transplantation (LT) has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of HCV LT is unknown. We studied 74 protein biomarkers in the plasma of LT patients receiving antiviral therapy. In addition, deep immune phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed. We found that LT patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL)-18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-beta, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants. Interestingly, patients who cleared HCV after LT did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence. Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets after LT are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV after LT did not trigger rejection episodes in many patients.