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alcoholic hepatitis:Lost in Translation

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Journal of Clinical and Translational Hepatology 2018年第1期6卷 89-96页

作者： Benjamin L. Woolbright Hartmut Jaeschke Department of Pharmacology Toxicology&TherapeuticsUniversity of Kansas Medical CenterKansas CityKansasUSA

alcoholic hepatitis is the most severe and acute form of alcoholic liver *** mortality rate associated with alcoholic hepatitis is high,largely due to the lack of suitable pharmacological *** there has been substantial research in the area,generating pharmacological interventions has been plagued by the lack of a robust mouse model both for testing and for understanding the underlying pathology.A number of major notable advances have been made in this area recently,with the goal of generating a mouse model of alcoholic *** purpose of this article is to review recent advances in modeling alcoholic liver disease both in vitro and in vivo in the mouse,and place them in the context of the greater spectrum of alcoholic liver disease,with a focus on how we can translate current advances into a high-fidelity model of alcoholic *** addition,we will review the basic mechanisms of alcoholic hepatitis as it is currently understood,focusing on recent advancements in diagnosis,prognosis and current pathophysiology,especially as it relates to the profound immune dysfunction present during alcoholic hepatitis.

关键词： alcoholic hepatitis Alcohol Liver disease Cirrhosis Prognosis Keratin-18

alcoholic hepatitis and concomitant hepatitis C virus infection

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World Journal of Gastroenterology 2014年第34期20卷 11929-11934页

作者： Mohamed Shoreibah Bhupinderjit S Anand Ashwani K Singal Division of Gastroenterology and Hepatology University of Alabama BirminghamBirminghamAL 35294-0012United States Department of Gastroenterology and Hepatology Michael DeBakey VA CenterBaylor College of MedicineHoustonTX 77030United States

hepatitis C virus(HCV)infection and alcohol abuse are two most important causes of chronic liver disease in the United *** hepatitis is a unique clinical syndrome among patients with chronic and active alcohol abuse with a potential for high short-term *** 20%of patients presenting with alcoholic hepatitis have concomitant HCV *** from alcoholic hepatitis is increased in the presence of concomitant hepatitis C due to synergistic interaction between HCV and alcohol in causing hepatocellular *** prospective randomized studies are needed to develop guidelines on the use of corticosteroids among patients with alcoholic hepatitis and concomitant HCV *** impact of antiviral therapy on mortality and outcome in the setting of alcoholic hepatitis remains a novel area for future research.

关键词： alcoholic liver disease alcoholic hepatitis hepatitis C virus infection Corticosteroids Transplantation

Molecular targets in the treatment of alcoholic hepatitis

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World Journal of Gastroenterology 2012年第39期18卷 5504-5513页

作者： Ashwin D Dhanda Richard WL Lee Peter L Collins C Anne McCune Department of Liver Medicine University Hospitals Bristol NHS Foundation TrustBS2 8HW BristolUnited Kingdom Department of Cellular and Molecular Medicine School of Clinical SciencesUniversity of BristolBS9 1TD BristolUnited Kingdom

Alcohol related costs to health and society are high. One of the most serious complications of alcohol misuse to the individual is the development of alcoholic hepatitis (AH), a clinical syndrome of jaundice and progressive inflammatory liver injury in patients with a history of recent heavy alcohol use. It has a poor outcome and few existing successful therapies. The use of glucocorticoids in patients with severe AH is still controversial and there remains a group of patients with glucocorticoid-resistant disease. However, as our understanding of the pathogenesis of the condition improves there are opportunities to develop new targeted therapies with specific actions to control liver inflammation without having a detrimental effect on the immune system as a whole. In this article we review the molecular mechanisms of AH concentrating on the activation of the innate and adaptive immune response. We consider existing treatments including glucocorticoids, anti-tumor necrosis factor therapy and pentoxifylline and their limitations. Using our knowledge of the disease pathogenesis we discuss possible novel therapeutic approaches. New targets include pro-inflammatory cytokines such as interleukin (IL)-17, chemokines and their receptors (for example IL-8, CXCL9 and CXCR3) and augmentation of anti-inflam- matory molecules such as IL-10 and IL-22. And there is also future potential to consider combination therapy to selectively modulate the immune response and gain control of disease.

关键词： alcoholic hepatitis Tumour necrosis factor-m Pentoxifylline Interleukins Chemokine receptors

Pentoxifylline versus prednisolone for severe alcoholic hepatitis:A randomized controlled trial

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World Journal of Gastroenterology 2009年第13期15卷 1613-1619页

作者： Binay Krishna De Subhabrata Gangopadhyay Deep Dutta Sumanta Das Baksi Adyapad Pani Pramit Ghosh Department of Medicine Medical College & Hospitals Department of Preventive and Social Medicine Medical College & Hospitals

AIM： To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis, and to evaluate the role of different liver function scores in predicting prognosis.METHODS： Sixty-eight patients with severe alcoholic hepatitis （Maddrey score ≥ 32） received pentoxifylline （n = 34, group Ⅰ） or prednisolone （n = 34, group Ⅱ） for 28 d in a randomized double-blind controlled study, and subsequently in an open study （with a tapering dose of prednisolone） for a total of 3 mo, and were followed up over a period of 12 mo.RESULTS： Twelve patients in group Ⅱ died at the end of 3 mo in contrast to five patients in group Ⅰ. The probability of dying at the end of 3 mo was higher in group Ⅱ as compared to group Ⅰ （35.29% vs 14.71%, P = 0.04; log rank test）. Six patients in group I developed hepatorenal syndrome as compared to none in group Ⅰ. Pentoxifylline was associated with a significantly lower model for end-stage liver disease （MELD） score at the end of 28 d of therapy （15.53± 3.63 vs 17.78± 4.56, P=0.04）. Higher baseline Maddrey score was associated with increased mortality.CONCLUSION： Reduced mortality, improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis.

关键词： alcoholic hepatitis Pentoxifylline Prednisolone Maddrey discriminant function score Model for end-stage liver disease score Glasgowalcoholic hepatitis score

Current concepts and controversies in the treatment of alcoholic hepatitis

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World Journal of Gastroenterology 2006年第43期12卷 6909-6921页

作者： Catherine Rongey Neil Kaplowitz Robert Wood Johnson Clinical Scholars Program University of California at Los Angeles 911 Broxton Avenue Los Angeles CA 90024 United States Department of Gastroenterology and Hepatology University of Southern California 2011 Zonal Avenue Los Angeles CA 90033 United States

The treatment of alcoholic hepatitis remains one of the most debated topics in medicine and a field of continued research. In this review, we discuss the evolution of scoring systems, including the recent development of the Glasgow alcoholic hepatitis score, role of liver biopsy and current treatment interventions. Studies of treatment interventions with glucocorticoids, pentoxifylline, infliximab, s-adenosyl-methionine, and colchicine are reviewed with discussion on quality. Glucocorticoids currently remain the mainstay of treatment for severe alcoholic hepatitis.

关键词： alcoholic hepatitis Treatment Glucocorticoid Biopsy Scoring system

Early mortality of alcoholic hepatitis: A review of data from placebo-controlled clinical trials

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World Journal of Gastroenterology 2010年第19期16卷 2435-2439页

作者： Yu, Chao-Hui Xu, Cheng-Fu Ye, Hua Li, Lan Li, You-Ming Zhejiang Univ Dept Gastroenterol Affiliated Hosp 1 Coll Med Hangzhou 310003 Zhejiang Peoples R China

AIM: To investigate the early mortality of placebo-treated alcoholic hepatitis patients. METHODS: Mortality data about alcoholic hepatitis patients who participated in randomized placebo-controlled trials were searched from PubMed, EMBASE, and Cochrane Library, extracted and analyzed. RESULTS: A total of 661 placebo-treated patients in 19 trials were included. The overall mortality rate was 34.19% with a median observation time of 160 d (range 21-720 d). Hepatic failure, gastrointestinal bleeding and infection were the three main causes of death, accounting for 55.47%, 21.17% and 7.30% of all deaths, respectively. One-month mortality data about 324 placebo-treated alcoholic hepatitis patients in 10 trials were reported with a pooled mortality rate of 20.37%. The one-month mortality rate of patients with moderate to severe alcoholic hepatitis tended to be higherthan that of general patients (22.69% vs 10.93%, P 0.05), neither any difference was found between the studies published before and after 1990 (18.18% vs 21.88%, P > 0.05). CONCLUSION: alcoholic hepatitis is a severe liver disease with a high mortality rate, and hepatic failure, gastrointestinal bleeding and infection are the three main causes of death.

关键词： alcoholic hepatitis Mortality Placebo

Infections in alcoholic hepatitis

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Journal of Clinical and Translational Hepatology 2022年第4期10卷 718-725页

作者： Bhupinder Kaur Russell Rosenblatt Vinay Sundaram Internal Medicine Department Cedars-Sinai Medical CenterLos AngelesCAUSA Department of Gastroenterology and Hepatology Weill Cornell MedicineNew YorkNYUSA Department of Gastroenterology and Hepatology and Comprehen-sive Transplant Center Cedars-Sinai Medical CenterLos AngelesCAUSA

Severe alcoholic hepatitis (sAH) is defined by a modified discriminant function ≥32 or model for end-stage liver disease (MELD) >20. Patients with sAH are in an immu-nocompromised state attributed to cirrhosis-related immu-noparesis and corticosteroid use. Individuals with sAH often develop severe infections that adversely impact short-term prognosis. Currently, the corticosteroid prednisolone is the only treatment with proven efficacy in sAH;however, the combination of corticosteroid treatment and altered host defense in sAH has been thought to increase the risk of acquiring of bacterial, opportunistic fungal, and viral infec-tions. Newer studies have shown that corticosteroids do not increase occurrence of infections in those with sAH;unfor-tunately, the lack of response to corticosteroids may instead predispose to infection development. Prompt and appropri-ate antibiotic treatment is therefore essential to improving patient outcomes. This review highlights common infections and risk factors in patients with sAH. Additionally, current diagnostic, therapeutic, and prophylactic strategies in these patients are discussed.

关键词： alcoholic hepatitis Infections Corticosteroids STOPAH Antibiotic treatment Aspergillosis Immunodeficiency alcoholic liver disease

New treatment options for alcoholic hepatitis

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World Journal of Gastroenterology 2016年第15期22卷 3892-3906页

作者： Saggere Muralikrishna Shasthry Shiv Kumar Sarin Depart-ment of Hepatology Institute of Liver and Biliary Sciences

The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using “Omics” platforms, newer options for patients with alcoholic hepatitis are expected soon.

关键词： alcoholic liver disease alcoholic steatosis alcoholic hepatitis Gut microbiota Lipopolysaccharide Steroid non-response

Posterior reversible encephalopathy syndrome in alcoholic hepatitis:Hepatic encephalopathy a common theme

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World Journal of Gastroenterology 2017年第2期23卷 373-376页

作者： Elizabeth S John Ramy Sedhom Ishita Dalal Ranita Sharma Department of Medicine Rutgers Robert Wood Johnson Medical SchoolNew BrunswickNJ 08901United States

Posterior reversible encephalopathy syndrome(PRES) is a neuro-radiologic diagnosis that has become more widely recognized and reported over the past few decades. As such, there are a number of known risk factors that contribute to the development of this syndrome, including volatile blood pressures, renal failure, cytotoxic drugs, autoimmune disorders, pre-eclampsia, and eclampsia. This report documents the first reported case of PRES in a patient with severe alcoholic hepatitis with hepatic encephalopathy and delves into a molecular pathophysiology of the syndrome.

关键词： alcoholic hepatitis Hepatic encephalopathy Posterior reversible encephalopathy syndrome Seizure Headaches