Showing papers by "Michael A. Heneghan published in 2017"

Expert clinical management of autoimmune hepatitis in the real world

Abstract: SummaryBackground High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. Aim To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. Methods A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. Results Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. Conclusions There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Concurrent extrahepatic autoimmunity in autoimmune hepatitis: implications for diagnosis, clinical course and long-term outcomes

Abstract: Concurrent extrahepatic autoimmune disease (CEHAID) associated with autoimmune hepatitis (AIH) have been incorporated into the diagnostic criteria stipulated by the International Autoimmune Hepatitis Group (IAIHG). Large comprehensive cohort data on the extrahepatic autoimmunity in AIH remain scanty AIM: To systematically assess features and clinical impact of CEHAID on AIH METHODS: Clinical records of 562 patients with AIH from two tertiary centres in the United Kingdom were retrospectively reviewed RESULTS: Prevalence of CEHAID in patients with AIH were 42%. Autoimmune thyroid disease was the commonest CEHAID associated with AIH (101/562, 18%). Autoimmune skin diseases were more prevalent in AIH-2 than AIH-1 (21.9% vs.7%, p=0.009). Personal history of CEHAID was more commonly found in AIH patients with than without first degree family history of CEHAID [(48/86, 55.8% vs 169/446, 37.9%), p=0.002]. AIH patients with CEHAID were more often female [201/236 (85.2%), p=0.008], had higher post-treatment IAIHG score (22 vs. 20, p<0.001), less reactivity to smooth muscle antibodies (49.8% vs 65%, p<0.001), more likely to have mild fibrosis at diagnosis (20.9% vs. 6.5%, p<0.001), less often had ascites (6.3% vs. 13.6%, p=0.008) and coagulopathy (1.18 vs. 1.27, p=0.013) at presentation. Presence of CEHAID, however, did not significantly affect disease progression, prognosis and survival in AIH CONCLUSIONS: Our study confirms the strong association of CEHAID with AIH. Association between personal and familial extrahepatic autoimmunity especially among first degree relatives was evident. Presence of CEHAID may influence clinical phenotype of AIH at presentation but without notable impact on the long term clinical outcomes

Developing a donation after cardiac death risk index for adult and pediatric liver transplantation

Abstract: Developing a donation after cardiac death risk index for adult and pediatric liver transplantation

STAT4-associated natural killer cell tolerance following liver transplantation

Abstract: Objective Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype. Design Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing. Results NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV. Conclusions LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease.

Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis.

Abstract: Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+ CD25- cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4+ CD25- cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+ CD25- cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .

Impact of comorbidity on waiting list and post-transplant outcomes in patients undergoing liver retransplantation.

Abstract: Impact of comorbidity on waiting list and post-transplant outcomes in patients undergoing liver retransplantation

Interlobar Artery Resistive Index predicts Acute-on-Chronic Liver Failure Syndrome in Cirrhotic Patients with Acute Decompensation.

Abstract: Introduction Patients with acutely decompensated (AD) cirrhosis are at risk for developing acute-on-chronic liver failure (ACLF) syndrome. This syndrome is associated with a high short-term mortality rate. The aim of our study was to identify reliable early predictors of developing ACLF in cirrhotic patients with AD. Patients and Methods We assessed 84 cirrhotic patients admitted for AD without ACLF on admission. We performed routine blood testing and detailed ultrasound Doppler studies of systemic arteries and mayor abdominal veins and arteries. We also calculated liver-specific and intensive care unit predictive scores. The area under the ROC curve (AUROC) was calculated for all variables that were significantly different between patients who developed ACLF and those who did not. Sensitivity, specificity, positive and negative predictive values, as well as diagnostic accuracy predicting the short-term development of ACLF were determined. Results of the 84 patients, 23 developed ACLF whereas 61 did not. In the univariate analysis, serum levels of creatinine and urea, prothrombin time ratio, MELD score, portal vein and femoral artery flow velocity as well as the renal and interlobar artery resistive indices (RI) were associated with the short-term development of ACLF. However, only interlobar artery RI had independent predictive value in the multivariate analysis. The AUROC value for RI of the interlobar arteries was 0.9971. Conclusion On the first day of admission, ultrasound measurement of the RI of the interlobar arteries recognizes with high predictive accuracy those cirrhotic patients admitted with AD who will develop ACLF during hospital admission.