Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute
2016; Elsevier BV; Volume: 15; Issue: 1 Linguagem: Inglês
10.1016/j.cgh.2016.08.047
ISSN1542-7714
AutoresMack C. Mitchell, Lawrence S. Friedman, Craig J. McClain,
Tópico(s)Diet, Metabolism, and Disease
ResumoThe purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management.Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH).Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever.Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections.Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI).Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate.Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment.Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate.Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF.Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest.Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting.Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high.Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid. The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management. Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH). Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever. Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections. Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI). Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate. Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment. Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate. Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF. Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest. Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting. Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high. Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid. Acute alcoholic hepatitis (AH) is a serious form of acute decompensation of alcoholic liver disease (ALD) that develops in heavy drinkers and is characterized by rapid onset of jaundice, malaise, anorexia, tender hepatomegaly, and features of the systemic inflammatory response syndrome (SIRS). Two recent studies suggest the number of patients hospitalized in the United States with AH increased during the first decade of the 21st century.1Jinjuvadia R. Liangpunsakul S. Translational Research and Evolving Alcoholic Hepatitis Treatment Consortium. Trends in alcoholic hepatitis-related hospitalizations, financial burden, and mortality in the United States.J Clin Gastroenterol. 2015; 49: 506-511Crossref PubMed Scopus (76) Google Scholar, 2Nguyen T.A. DeShazo J.P. Thacker L.R. et al.The worsening profile of alcoholic hepatitis in the United States.Alcohol Clin Exp Research. 2016; 40: 1295-1303Crossref PubMed Scopus (21) Google Scholar Although in its most severe form AH has a high short-term mortality rate if untreated, in 2011 only 28% of more than 1600 patients admitted to U.S. hospitals were treated with glucocorticoids and 17% with pentoxifylline (PTX), suggesting a lack of widespread confidence in the 2 most frequently used therapies for AH.2Nguyen T.A. DeShazo J.P. Thacker L.R. et al.The worsening profile of alcoholic hepatitis in the United States.Alcohol Clin Exp Research. 2016; 40: 1295-1303Crossref PubMed Scopus (21) Google Scholar Patients with AH are systemically ill with a high risk of nutritional deficiency, infection, acute kidney injury (AKI), and development of multiorgan failure (MOF) syndrome.3Michelena J. Altamirano J. Abraldes J.G. et al.Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.Hepatology. 2015; 62: 762-772Crossref PubMed Scopus (195) Google Scholar Recognition of the possible complications and improved understanding of the basic mechanisms of liver injury from alcohol are essential to improve clinical outcomes for patients with severe AH. Histologic features of AH include steatosis and ballooning degeneration of hepatocytes (steatohepatitis), intrahepatic cholestasis (bilirubinostasis), chicken-wire fibrosis, Mallory-Denk bodies, and megamitochondria. Cirrhosis is present in the vast majority of those who are severely ill.4Mookerjee R.P. Lackner C. Stauber R. et al.The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.J Hepatol. 2011; 55: 1103-1111Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 5Altamirano J. Miquel R. Katoonizadeh A. et al.A histologic scoring system for prognosis of patients with alcoholic hepatitis.Gastroenterology. 2014; 146 (e1–e6): 1231-1239Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 6Crabb D.W. Bataller R. Chalasani N.P. et al.Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia.Gastroenterology. 2016; 150: 785-790Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar A recent consensus statement from the Alcoholic Hepatitis Consortium sponsored by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) provided a working definition of AH that includes onset of jaundice within 60 days of heavy consumption (>50 g/day) of alcohol for a minimum of 6 months, serum bilirubin >3 mg/dL, elevated aspartate aminotransferase (AST) (50–400 U/L), AST:ALT (alanine aminotransferase) ratio >1.5, and no other obvious cause for hepatitis.6Crabb D.W. Bataller R. Chalasani N.P. et al.Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia.Gastroenterology. 2016; 150: 785-790Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar The consensus statement proposed classifying patients with AH as definite when a liver biopsy was used to establish the diagnosis, probable when the clinical and laboratory features were present without potential confounding problems, and possible when confounding problems were present. This proposed classification is intended to improve interpretation of future treatment trials in patients with AH, because prior studies indicated that 10%–15% of subjects diagnosed with acute AH on the basis of clinical criteria alone did not have characteristic histologic features on a liver biopsy specimen. Although the exact pathogenesis of AH remains a subject of active investigation, several risk factors have been identified, including female gender, elevated body mass index, and genetic risk factors such as having the G allele of PNPLA3 (patatin-like phospholipase domain containing protein 3). Because elevated body mass index is a risk factor for both AH and nonalcoholic steatohepatitis, distinguishing these 2 entities usually rests on the amount of alcohol consumed and the rapid onset of jaundice.7Dunn W. Angulo P. Sanderson S. et al.Utility of a new model to diagnose an alcohol basis for steatohepatitis.Gastroenterology. 2006; 131: 1057-1063Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Some experts believe that the distinction may be artificial because preexisting fatty liver because of obesity and metabolic syndrome could provide the necessary background for additional injury caused by alcohol. AH is by its definition an inflammatory condition that is often accompanied by features of SIRS: tachycardia, tachypnea, fever, and leukocytosis. Infections are common and must be identified and treated in patients with AH, but SIRS may develop in the absence of infection. The presence of SIRS increases the risk of developing MOF, which predicts high mortality in AH.3Michelena J. Altamirano J. Abraldes J.G. et al.Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.Hepatology. 2015; 62: 762-772Crossref PubMed Scopus (195) Google Scholar Numerous basic and translational studies have identified high levels of proinflammatory cytokines in patients with AH that may be linked to an increased risk of mortality. In 1977, Maddrey et al8Maddrey W.C. Boitnott J.K. Bedine M.S. et al.Corticosteroid therapy of alcoholic hepatitis.Gastroenterology. 1978; 75: 193-199Abstract Full Text PDF PubMed Scopus (685) Google Scholar used the serum bilirubin and prothrombin time to define a group of patients with AH who had a 28-day mortality rate above 50%. This formula, known as the Maddrey Discriminant Function (MDF), was subsequently used to stratify subjects for inclusion into clinical trials. Early trials and a subsequent randomized multicenter trial indicated that only those patients with more severe manifestations of AH and MDF >32 benefited from treatment with glucocorticoids.8Maddrey W.C. Boitnott J.K. Bedine M.S. et al.Corticosteroid therapy of alcoholic hepatitis.Gastroenterology. 1978; 75: 193-199Abstract Full Text PDF PubMed Scopus (685) Google Scholar, 9Carithers J.R.L. Herlong H.F. Diehl A.M. et al.Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial.Ann Intern Med. 1989; 110: 685-690Crossref PubMed Scopus (411) Google Scholar The Model for End-Stage Liver Disease (MELD) score was also shown to predict 28-day and 90-day mortality, and the age, bilirubin, international normalized ratio, and creatinine score (ABIC score) and the Glasgow AH Score also predict 90-day mortality.10Dunn W. Jamil L.H. Brown L.S. et al.MELD accurately predicts mortality in patients with alcoholic hepatitis.Hepatology. 2005; 41: 353-358Crossref PubMed Scopus (399) Google Scholar, 11Dominguez M. Rincon D. Abraldes J.G. et al.A new scoring system for prognostic stratification of patients with alcoholic hepatitis.Am J Gastroenterol. 2008; 103: 2747-2756Crossref PubMed Scopus (233) Google Scholar, 12Forrest E.H. Morris A.J. Stewart S. et al.The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.Gut. 2007; 56: 1743-1746Crossref PubMed Scopus (105) Google Scholar All of these scoring systems have been validated to predict severe outcomes with a high degree of reliability. Although MDF >32 initially defined a group of patients with 28-day mortality rate >50%, the short-term mortality in the placebo group in recent studies (STOPAH) is much better (17%) than the mortality rate in the U.S. multicenter trial (35%), likely because of improvements in best supportive care (BSC).13Thursz M.R. Richardson P. Allison M. et al.Prednisolone or pentoxifylline for alcoholic hepatitis.N Engl J Med. 2015; 372: 1619-1628Crossref PubMed Scopus (450) Google Scholar Importantly, improved outcome with BSC alone makes direct comparisons with historical data from trials more difficult because the time when the trials were completed must be considered. The Lille score uses data obtained from the first week of treatment with prednisolone to predict whether an individual patient is likely to have a favorable outcome.14Louvet A. Naveau S. Abdelnour M. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (509) Google Scholar This information is important because prolonged use of glucocorticoids is associated with an increased risk of infection in patients with AH.13Thursz M.R. Richardson P. Allison M. et al.Prednisolone or pentoxifylline for alcoholic hepatitis.N Engl J Med. 2015; 372: 1619-1628Crossref PubMed Scopus (450) Google Scholar Combining the Lille model with the MELD score has been proposed as a further refinement.15Louvet A. Labreuche J. Artru F. et al.Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis.Gastroenterology. 2015; 149 (e8; quiz e16–e17): 398-406Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar AH is an inflammatory disease, and proinflammatory mediators such as tumor necrosis factor (TNF) play a critical role in liver injury. Gut-derived toxins such as lipopolysaccharides have been postulated to translocate across a leaky gut barrier and bind to toll-like receptors with subsequent proinflammatory cytokine production. The 2 most widely used drug therapies for severe AH both have anti-inflammatory mechanisms of action. Glucocorticoids, considered the standard of care for severe AH by many gastroenterologists/hepatologists and professional organizations, bind to receptors (GRs) in the cytoplasm. GRs subsequently translocate to the nucleus and bind to the glucocorticoid response elements in the promoter regions of glucocorticoid responsive genes to switch on expression of certain anti-inflammatory genes. Glucocorticoids can also act indirectly to repress activity of a number of relevant transcription factors (eg, nuclear factor kappa B), with subsequent downregulation of inflammatory genes. This process requires recruitment of corepressor molecules, particularly histone deacetylases-6 and -2.16De Bosscher K. Haegeman G. Minireview: latest perspectives on antiinflammatory actions of glucocorticoids.Mol Endocrinol. 2009; 23: 281-291Crossref PubMed Scopus (213) Google Scholar, 17Barnes P.J. Adcock I.M. 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Do corticosteroids reduce mortality from alcoholic hepatitis? a meta-analysis of the randomized trials.Ann Intern Med. 1990; 113: 299-307Crossref PubMed Scopus (239) Google Scholar whereas a third did not.40Christensen E. Gluud C. Glucocorticosteroids are not effective in alcoholic hepatitis.Am J Gastroenterol. 1999; 94: 3065-3066Crossref PubMed Google Scholar A 2008 Cochrane systematic review of 15 trials concluded that there was no benefit from glucocorticoids, except possibly in the group with MDF >32, primarily because of substantial variability in bias.41Rambaldi A. Saconato H.H. Christensen E. et al.Systematic review: glucocorticosteroids for alcoholic hepatitis—a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.Aliment Pharmacol Ther. 2008; 27: 1167-1178Crossref PubMed Scopus (177) Google Scholar Those trials with low bias showed benefit, whereas trials with high bias showed no benefit. PTX was reported to reduce mortality in patients with severe AH (MDF >32).47Akriviadis E. Botla R. Briggs W. et al.Pentoxifylline improves short-term survival in severe ac
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