Can we reliably predict response to corticosteroid treatment in severe alcoholic hepatitis?

Chokshi, Shilpa

doi:10.1002/hep4.1191

Cited by 5 publications

(6 citation statements)

References 12 publications

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“…Alcoholrelated cirrhosis is an induced immunodeficient state and the development of bacterial infection often predicts the terminal phase, increasing the probability of death to 30 % at 1 month and > 60 % by 1 year [22]. In patients with severe alcoholic hepatitis, the most florid manifestation of alcoholic liver disease, the susceptibility to infection is further heightened [21,23,24], with infection observed in up to 65 % of cases, making it the leading cause of death and the most common precipitant for acute on chronic liver failure [25]. Underpinning this disease state in alcoholic liver disease is an immunologically incongruent phenomenon.…”

Section: Immune Dysfunction In Severe Alcoholic Hepatitismentioning

confidence: 99%

Inflammation in alcohol-associated liver disease progression

et al. 2022

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Chronic alcohol consumption induces stress and damage in alcohol metabolising hepatocytes, which leads to inflammatory and fibrogenic responses. Besides these direct effects, alcohol disrupts intestinal barrier functions and induces gut microbial dysbiosis, causing translocation of bacteria or microbial products through the gut mucosa to the liver and, which induce inflammation indirectly. Inflammation is one of the key drivers of alcohol-associated liver disease progression from steatosis to severe alcoholic hepatitis. The current standard of care for the treatment of severe alcoholic hepatitis is prednisolone, aiming to reduce inflammation. Prednisolone, however improves only short-term but not long-term survival rates in those patients, and even increases the risk for bacterial infections. Thus, recent studies focus on the exploration of more specific inflammatory targets for the treatment of severe alcoholic hepatitis. These comprise, among others interference with inflammatory cytokines, modulation of macrophage phenotypes or targeting of immune cell communication, as summarized in the present overview. Although several approaches give promising results in preclinical studies, data robustness and ability to transfer experimental results to human disease is still not sufficient for effective clinical translation.

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Section: Immune Dysfunction In Severe Alcoholic Hepatitismentioning

confidence: 99%

Inflammation in alcohol-associated liver disease progression

et al. 2022

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“…Indeed, drugs such as prednisolone can increase the risk of serious infections. 139,140 Physiologically, multiple mechanisms maintain immunological homeostasis. The immune system is kept under control through a series of highly sophisticated, exquisitely fine-tuned endogenous multi-layered self-regulatory control pathways governing each facet of effector immune function and fate, to limit excessive inflammation and immune-mediated damage when a robust immune response to microbial invaders is required.…”

Section: Molecular Mechanisms Of Restoring Immune Controlmentioning

confidence: 99%

The multifactorial mechanisms of bacterial infection in decompensated cirrhosis

Merwe

Chokshi

Bernsmeier

et al. 2021

Journal of Hepatology

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Infections, due to a dysfunctional immune response, pose a great risk to patients with decompensated cirrhosis and herald the beginning of the terminal phase of this disease. Infections typically result from breaches in innate immune barriers and inadequate clearance by immune cells. This leads to bacterial and bacterial product translocation to the systemic circulation, which is already primed by ongoing hepatic inflammation in patients with cirrhosis, who are particularly prone to developing organ failure in the presence of an infection. Early identification of bacterial infection, along with the prompt use of appropriate antibiotics, have reduced the mortality associated with certain infections in patients with decompensated cirrhosis. Judicious use of antibiotic therapy remains imperative given the emergence of multidrug-resistant infections in the cirrhotic population. Important research over the last few years has identified molecular targets on immune cells that may enhance their function, and theoretically prevent infections. Clinical trials are ongoing to delineate the beneficial effects of targeted molecules from their off-target effects. Herein, we review the mechanisms that predispose patients with cirrhosis to bacterial infections, the clinical implications of infections and potential targets for the prevention or treatment of infections in this vulnerable population.

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“…To date, therapeutics have primarily focussed on (i) curtailing the infection with use of widespread antibiotics, concerningly this has promoted development of multi-drug resistant microbes ( Merli et al, 2015 ; Fernandez et al, 2016 ; EASL, 2018 ), or (ii) bridling the rampant inflammation with immunosuppressive agents. However, this latter strategy can potentiate the immunocompromised state and increase the risk of secondary infections ( Louvet et al, 2009 ; Thursz et al, 2015 ; Vergis et al, 2017 ; Chokshi, 2018 ). Targeted immunomodulatory approaches to restore the disrupted balance between protective anti-pathogen immunity and host-induced immunopathology are lacking.…”

Section: Introductionmentioning

confidence: 99%

Soluble TIM3 and Its Ligands Galectin-9 and CEACAM1 Are in Disequilibrium During Alcohol-Related Liver Disease and Promote Impairment of Anti-bacterial Immunity

et al. 2021

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Background and AimsImmunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and in vitro neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear.MethodsIn Alcoholic Hepatitis (AH; n = 19), alcohol-related cirrhosis (ARC; n = 53) and healthy control (HC; n = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-blood soluble-CR expression upon bacterial challenge. By FACS, we assessed the relationship between soluble-TIM3 and membrane-TIM3 and rescue of immunity in bacterial-challenged PBMCs.ResultsSoluble-TIM3 was the dominant plasma soluble-CR in ALD vs. HC (p = 0.00002) and multivariate analysis identified it as the main driver of differences between groups. Soluble-CRs were strongly correlated with pro-inflammatory cytokines, gut bacterial translocation markers and clinical indices of disease severity. Ethanol exposure or bacterial challenge did not induce soluble-TIM3 production from PCLS nor from whole-blood. Bacterial challenge prompted membrane-TIM3 hyperexpression on PBMCs from ALD patient’s vs. HC (p < 0.002) and was inversely correlated with plasma soluble-TIM3 levels in matched patients. TIM3 ligands soluble-Galectin-9 and soluble-CEACAM1 were elevated in ALD plasma (AH > ARC; p < 0.002). In vitro neutralization of Galectin-9 and soluble-CEACAM1 improved the defective anti-bacterial and anti-inflammatory cytokine production from E. coli-challenged PBMCs in ALD patients.ConclusionsAlcohol-related liver disease patients exhibit supra-physiological plasma levels of soluble-TIM3, particularly those with greater disease severity. This is also associated with increased levels of soluble TIM3-ligands and membrane-TIM3 expression on immune cells. Soluble-TIM3 can block the TIM3-ligand synapse and improve anti-bacterial immunity; however, the increased levels of soluble TIM3-binding ligands in patients with ALD negate any potential immunostimulatory effects. We believe that anti-TIM3 neutralizing antibodies currently in Phase I clinical trials or soluble-TIM3 should be investigated further for their ability to enhance anti-bacterial immunity. These agents could potentially represent an innovative immune-based supportive approach to rescue anti-bacterial defenses in ALD patients.

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Can we reliably predict response to corticosteroid treatment in severe alcoholic hepatitis?

Abstract: Urinary metabolites can predict corticosteroid response in SAH.

Cited by 5 publications

References 12 publications

Inflammation in alcohol-associated liver disease progression

Inflammation in alcohol-associated liver disease progression

The multifactorial mechanisms of bacterial infection in decompensated cirrhosis

Soluble TIM3 and Its Ligands Galectin-9 and CEACAM1 Are in Disequilibrium During Alcohol-Related Liver Disease and Promote Impairment of Anti-bacterial Immunity

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