The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis.

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materials: We analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). Results: Analysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D' = 0.92 vs D' = 0.50 respectively; P = 1.3x10-8). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 - 17.4) U/mL vs 21.3 (16.5 - 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 - 44.8) U/mL vs 8.8 (6.1 - 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. Conclusion: This study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1.

A Double-Blind, Randomized Placebo-Controlled Trial of Probiotic Lactobacillus casei Shirota in Stable Cirrhotic Patients.

Background: In cirrhosis, a pathological gut microbiome has been linked with immune dysfunction. A pilot study of probiotic Lactobacillus casei Shirota (LcS) in alcoholic cirrhosis demonstrated significant improvement in neutrophil function. This study aimed to evaluate the efficacy of LcS on neutrophil function and significant infection rates in patients with cirrhosis. Methods: 92 cirrhotic patients (Child-Pugh score ≤10) were randomized to receive LcS or placebo, three times daily for six months. Primary end-points were incidence of significant infection and neutrophil function. Secondary end-points were cytokine profile, endotoxin, bacterial DNA positivity, intestinal permeability and quality of life. Results: Rates of infection, decompensation or neutrophil function did not differ between placebo and probiotic groups. LcS significantly reduced plasma monocyte chemotactic protein-1 and, on subgroup analysis, plasma interleukin-1ß (alcoholic cirrhosis), interleukin-17a and macrophage inflammatory protein-1ß (non-alcoholic cirrhosis), compared with placebo. No significant differences in intestinal permeability, bacterial translocation or metabolomic profile were observed. Conclusion: LcS supplementation in patients with early cirrhosis is safe. Although no significant infections were observed in either group, LcS improved cytokine profile towards an anti-inflammatory phenotype, an effect which appears to be independent of bacterial translocation.

Long-term outcome in patients with acute liver failure.

BACKGROUND & AIMS: Acute liver failure patients who meet poor prognostic criteria have high early mortality without emergency liver transplantation. A recent study however, reported that patients that survive spontaneously have a poorer outcome compared with patients undergoing transplantation. In this single centre study, we aimed to confirm or refute this observation. METHODS: Early survivors (acute liver failure patients who survived 90 days after the ICU admission) were assessed for long-term outcomes in four distinctive cohorts, incorporating aetiology (Acetaminophen overdose or non-Acetaminophen overdose), and management strategy (conservative or liver transplantation). Chi Squared or Fisher test were used to compare outcomes among the four cohorts (P < 0.05) and Kaplan-Meier curve (Log Rank test) to represent cumulative survival. RESULTS: Two hundred consecutive acute liver failure patients between 1990 and 2014 were included; mean age 38.3, ±12.8, male 70, 35%. 124/200 (62%) early survivors were identified; 13/124 (10.5%) acetaminophen patients underwent transplantation and 48/124 (38.7%) survived spontaneously; 36/124 (29.0%) non-acetaminophen underwent transplantation and 27/124 (21.8%) survived spontaneously. A total of 11/124 (8.9%) died subsequently (median survival 5.3± IQR 9.1), three spontaneous survivors and eight transplanted patients (P = 0.025); of the eight transplanted patients, six died of transplant related complications and two of suicide. CONCLUSION: The results of this study suggest that although liver transplantation is a life-saving procedure for acute liver failure patients, they have a worse long-term outcome compared with spontaneous survivors. Novel therapies to increase the percentage of spontaneous survivors are urgently needed.

Development of an organ failure score in acute liver failure for transplant selection and identification of patients at high risk of futility.

INTRODUCTION: King's College Hospital criteria are currently used to select liver transplant candidates in acetaminophen-related acute liver failure (ALF). Although widely accepted, they show a poor sensitivity in predicting pre-transplant mortality and cannot predict the outcome after surgery. In this study we aimed to develop a new prognostic score that can allow patient selection for liver transplantation more appropriately and identify patients at high risk of futile transplantation. METHODS: We analysed consecutive patients admitted to the Royal Free and Beaujon Hospitals between 1990 and 2015. Clinical and laboratory data at admission were collected. Predictors of 3-month mortality in the non-transplanted patients admitted to the Royal Free Hospital were used to develop the new score, which was then validated against the Beaujon cohort. The Beaujon-transplanted group was also used to assess the ability of the new score in identifying patients at high risk of transplant futility. RESULTS: 152 patients were included of who 44 were transplanted. SOFA, CLIF-C OF and CLIF-ACLF scores were the best predictors of 3-month mortality among non-transplanted patients. CLIF-C OF score and high dosages of norepinephrine requirement were the only significant predictors of 3-month mortality in the non-transplanted patients, and therefore were included in the ALF-OFs score. In non-transplanted patients, ALF-OFs showed good performance in both exploratory (AUC = 0.89; sensitivity = 82.6%; specificity = 89.5%) and the validation cohort (AUC = 0.988; sensitivity = 100%; specificity = 92.3%). ALF-OFs score was also able to identify patients at high risk of transplant futility (AUC = 0.917; sensitivity = 100%; specificity = 79.2%). CONCLUSION: ALF-OFs is a new prognostic score in acetaminophen-related ALF that can predict both the need for liver transplant and high risk of transplant futility, improving candidate selection for liver transplantation.

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis.

BACKGROUND: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. METHODS AND FINDINGS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. CONCLUSIONS: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.

Can antiretroviral therapy modify the clinical course of HDV infection in HIV-positive patients?

BACKGROUND: Infection with hepatitis delta virus (HDV) affects approximately 6-14.5% of patients coinfected with HIV-1 and HBV, showing a more aggressive clinical course compared with an HIV-negative population. There is no universally approved treatment for chronic hepatitis D (CHD) in HIV-infected patients. Antiretroviral therapy (ART) containing tenofovir has been recently associated with HDV suppression. Our aim was to evaluate whether the outcome of CHD in HIV-infected patients can be favourably influenced by ART including reverse transcriptase inhibitors. METHODS: The clinical course of four HBV/HDV/HIV-coinfected patients receiving ART were retrospectively examined. RESULTS: HDV RNA became undetectable in all patients after a variable period of ART along with the disappearance of hepatitis B surface antigen in two of them, and an increase in CD4(+) T-cell count. In all patients, virological changes were associated with improved liver function tests and clinical features. CONCLUSIONS: We suggest that ART regimens including drugs active against HBV could have beneficial effects on the clinical course of CHD in patients with HIV-1 by favouring immunological reconstitution.