酒精性肝炎的防治进展

酒精性肝炎是酒精性肝病比较严重的表现形式之一,死亡率高、预后较差.本文根据国情实际和临床可操作性,结合2012年欧洲肝病学会酒精性肝病专题研究的主要目标,对酒精性肝炎的治疗和预防措施进行简要介绍.     

酒精性肝炎的治疗策略

酒精性肝炎（AH）的治疗策略是非常复杂的。一方面,个体对酒精反应的差异起重要的作用,很难一概而论;另一方面,迄今没有一个良好的、全面评价AH严重程度的方法。在所有的治疗组中有很多不确定因素,存在着一定的争论。本文就AH近来有关治疗的研究热点及我们在临床工作中的体会介绍如下。     

酒精性肝炎的治疗现状

酒精性肝炎(alcoholic hepatitis,AH)目前尚无特效的治疗药物,现有多种措施主要源于动物实验研究,然而临床随机对照试验(randomised controlled trials,RCT)结果并不理想,见表1。现从循证医学角度分析评估AH的治疗现状。     

硫普罗宁治疗酒精性肝炎56例

目的探讨凯西莱治疗酒精性肝炎的临床效果。方法对56例治疗组患者和48例对照组患者进行研究,在用药前后分别进行临床评估和检测,5项指标和附加项目3项的变化情况。结果用药30天后,治疗组各项检测指标与用药前比较有显著差异(P<0.01),与对照组比较也有显著性差异(P<0.01)。但临床症状和体证改善情况则无明显差别、临床未见明显副反应。结论凯西莱治疗酒精性肝炎是安全有效的,尤其在降低血脂,减轻肝内脂肪的沉积,改善患者肝功能的作用效果更显著,值得在临床进一步研究和试用。     

加强重症酒精性肝炎治疗的临床研究

重症酒精性肝炎（severe alcoholic hepatitis,SAH）是酒精性肝炎（AH）的严重类型,可见于短期内大量饮酒但无肝病史的人群（急性酒精中毒）,也可发生在有酒精依赖史的脂肪肝（酒精性或非酒精性）或肝硬化（包括慢性乙型肝炎）患者。     

甘利欣治疗酒精性肝炎临床观察

随着现代生活方式的改变 ,近年来 ,人们酒精摄入量逐渐增加 ,酒精性肝病发病率日趋上升。我们于 2 0 0 1年 2月至 2 0 0 3年 4月共收治了 4 6例酒精性肝炎患者 ,给予两种剂量甘利欣 (江苏正大天晴药业股份有限公司生产 )静滴治疗 ,其临床观察结果 ,报道如下。1　材料与方法1 1　病历资料　 4 6例患者 ,男 4 0例 ,女 6例 ,年龄2 6～ 6 8岁 ,平均 4 8 6岁 ,饮酒史均超过 5年 ,乙醇摄入量男性 4 0g/d ,女性 2 0g/d ,按随机化原则分为2组 ,即常规剂量组 (n =2 3) ,大剂量组 (n =2 3) ,2组中性别、年龄、病程和病情轻重方面相比 ,差异无显著性 …     

酒精性肝炎的临床特征、诊断、预后判断和治疗进展

酒精性肝炎的诊断有赖于长期、大量饮酒史,出现黄疽并且除外其他可能引起肝炎的病因.笔者对酒精性肝炎的临床特征、诊断、预后判断和治疗进展进行综述.     

酒精性肝炎的诊断与治疗策略

酒精性肝炎(alcoholic hepatitis,AH)尤其是重症酒精性肝炎(severe alcoholic hepatitis,SAH)一直是肝衰竭常见的、威胁生命的原因之一.患者常有长期大量饮酒史,肝损伤通常为亚急性,经过数周或数月才出现明显的临床表现.基本的治疗包括戒酒、营养支持和抗炎保肝.SAH的糖皮质激素...     

酒精性肝炎的诊治进展

尽管饮酒只在少部分人群中诱发酒精性肝炎和肝硬化，但每日酒精消耗量〉30g，发生酒精性肝硬化的比率明显升高。Michael等对酒精性肝炎的诊治进展进行了综述（N Engl J Med 2009，360：2578）。     

重症酒精性肝炎相关感染

重症酒精性肝炎易合并感染,与糖皮质激素的应答及预后相关。糖皮质激素可增加严重感染和真菌感染的发生。其中细菌感染以革兰阴性菌为主,侵袭性真菌感染亦不少见。早期诊断和经验性抗感染治疗是重症酒精性肝炎合并感染的重要手段,在确定多重耐药菌感染的高风险后应及时制定覆盖多重耐药菌的抗感染策略。     

New treatment options for alcoholic hepatitis

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.     

Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: Current status

The treatment of choice for patients with severe alcoholic hepatitis (AH) is use of corticosteroids.Many randomized well designed studies have been reported from all over the world on the use of corticosteroids in the treatment of AH.However,the data on the efficacy of corticosteroids in these patients have been conflicting.Initial meta-analyses also failed to show beneficial effects of corticosteroids.Based on individual data meta-analysis showing clear benefit of corticosteroids amongst patients with severe AH (modified discriminant function of 32 or more),led American College of Gastroenterology to recommend use of corticosteroids as the first line treatment option amongst patients with severe AH.However,corticosteroids are relatively contraindicated amongst patients with severe AH and coexistent sepsis,gastrointestinal bleeding,and acute pancreatitis.These patients may be candidates for second line treatment with pentoxifylline.Further,specific treatment of AH with corticosteroids far from satisfactory with as many as 40%-50% of patients failing to respond to steroids,thus classified as nonresponsive to steroids.The management of these patients is a continuing challenge for physicians.Better treatment modalities need to be developed for this group of patients in order to improve the outcome of patients with severe AH.This article describes at length the available trials on use of corticosteroids and pentoxifylline with their current status.Route of administration,dosage,adverse effects,and mechanisms of action of these two drugs are also discussed.Finally,an algorithm with clinical approach to management of patients who present with clinical syndrome of AH is described.     

Current concepts and controversies in the treatment of alcoholic hepatitis

INTRODUCTION The treatment of alcoholic hepatitis is one of the most debated topics in medicine. The prevalence of the disease, its high fatality rate, and the elusiveness of cure keeps this disease in the forefront of topic reviews and scientific investi…     

Advances in alcoholic liver disease:An update on alcoholic hepatitis

Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality(25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material(Mallory's hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey's discriminant factor ≥ 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline.     

Molecular targets in the treatment of alcoholic hepatitis

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-inflammatory 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.     

Immune dysfunction in acute alcoholic hepatitis

Acute alcoholic hepatitis(AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogenassociated molecular particles(PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors(mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this.     

Symptoms and signs of acute alcoholic hepatitis

Although there is not one specific sign or symptom related to alcoholic hepatitis(AH),a constellation of symptoms and signs can help make the diagnosis of AH with reasonable accuracy.Documentation of chronic and active alcohol abuse is paramount in making a diagnosis of AH.Clinical presentation after abstinence for more than 3 m should raise doubts about the diagnosis of AH and dictate the need for considering other causes of liver disease,decompensation of alcoholic cirrhosis,sepsis and malignancy as the cause of patient’s clinical profile.     

Definition, epidemiology and magnitude of alcoholic hepatitis

Alcoholic liver disease(ALD) is a major cause of alcoholrelated morbidity and mortality.Its presentation ranges from fatty liver to alcoholic hepatitis(AH),cirrhosis,and hepatocellular carcinoma.Although the amount and pattern of alcohol consumption is a well recognized predisposing factor for the development of serious liver pathology,environmental factors and the host’s genetic makeup may also play significant roles that have not yet been entirely explored.Continuing alcohol consumption is a major factor that influences the survival of patients with AH.The presence of cirrhosis at presentation or its development on follow up is a major factor determining the outcome in the long run.This chapter deals with the epidemiology and magnitude of ALD in general and AH in particular.     

A meta-analysis of nutritional supplementation for management of hospitalized alcoholic hepatitis

BACKGROUND:

Alcoholic liver disease (ALD) is associated with a high risk of morbidity and mortality. Malnutrition accompanies this condition and may be both a consequence of and contributor to the pathology. Many trials have investigated the benefits of providing supplemental nutrition in the management of patients with ALD. The present study is a meta-analysis of the available evidence.

METHOD:

A meta-analysis of randomized controlled studies comparing nutritional supplementation plus a normal hospital diet versus diet alone.

RESULTS:

Seven randomized controlled studies including 262 patients with ALD were identified. Pooled analysis revealed no statistical difference in mortality between groups given special nutritional therapy versus a normal balanced diet (OR 0.80 [95% CI 0.42 to 1.52]). In addition, nutrition did not significantly improve ascites (OR 1.29 [95% CI 0.52 to 3.20]) or any biochemical parameters. However, encephalopathy showed a significant improvement or resolution (OR 0.24 [95% CI 0.06 to 0.93]).

CONCLUSION:

Nutritional supplementation provided no mortality benefit in patients with ALD, and neither ascites nor biochemical parameters significantly improved. However, encephalopathy was significantly ameliorated and, therefore, nutritional supplementation should be encouraged in that setting.     

Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians

AIM: To survey gastroenterologists and hepatologists regarding their current views on treating hepatitis C virus (HCV) infected alcoholic hepatitis (AH) patients. METHODS: A sixteen item questionnaire was electronically mailed to gastroenterologists and hepatologists. A reminder was sent after 2 mo to increase the response rate. Participation of respondents was confidential. Accessing secured web site to respond to the questionnaire was considered as informed consent. Responses received on the secured website were downloaded in an excel sheet for data analysis. RESULTS: Analyzing 416 responses to 1556 (27% response rate) emails, 57% respondents (56% gastroenterologists) reported HCV prevalence > 20% amongst AH patients. Sixty nine percent often treated AH and 46% preferred corticosteroids (CS). Proportion of respondents with consensus (75% or more respondents agreeing on question) on specific management of HCV infected AH were: routine HCV testing (94%), HCV not changing response to CS (80%) or pentoxifylline (91%), no change in approach to treating HCV infected AH (75%). None of respondent variables: age, specialty, annual number of patients seen, and HCV prevalence could predict respondent to be in consensus on any of or all 4 questions. Further, only 4% would choose CS for treating HCV infected AH as opposed to 47% while treating HCV negative AH. CONCLUSION: Gastroenterologists and hepatologists believe that AH patients be routinely checked for HCV. However, there is lack of consensus on choice of drug for treatment and outcome of HCV positive AH patients. Studies are needed to develop guidelines for management of HCV infected AH patients.