Alcoholic Liver Disease
Better-designed controlled clinical trials are probably necessary to resolve the controversy and avoid a possible type I error. Acute confusional state following liver transplantation for alcoholic liver disease. Determinants of long-term outcome in severe alcoholic hepatitis.
Overview and Prognosis of Alcoholic Liver Disease
In general, enteral nutrition is preferable over parenteral supplementation, and protein should be supplied to provide positive nitrogen balance. Occasionally, the patient may be asymptomatic. Indeed, experimental liver damage in both rats and mice is protected by betaine supplementation [ 70 ]. Relation between liver pathology and prognosis in patients with portal hypertension. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisone. Free radicals initiate lipid peroxidation, which causes inflammation and fibrosis. Probably the most extensive studies on the nutritional status of patients with liver disease are large studies by the VA Cooperative Studies Program dealing with patients having AH [ 31 ].
The analysis was conducted on an intention-to-treat basis. The comparison of mortality at 28 days between treated and untreated groups was performed with the use of logistic regression, with adjustments for risk category high or intermediate and factorial design. Mortality and rates of liver transplantation at 90 days and 1 year were compared with the use of the same strategy. A test for treatment interaction was performed as a secondary analysis.
Cox proportional-hazards regression was used to compare 1-year survival among the groups, and Kaplan—Meier curves for 1-year survival were plotted. All P values were two-sided. A univariate logistic-regression analysis was performed for the end points of day mortality, day mortality, and 1-year mortality. Separate models were fitted for conventional prognostic scores discriminant function, Model for End-Stage Liver Disease score, Glasgow alcoholic hepatitis score, and Lille score and for clinical and laboratory variables, to investigate whether they were significant predictors of mortality.
Over a 3-year period, patients were screened, and after the application of eligibility criteria, patients were randomly assigned to one of the four treatment groups: All the patients were followed for 12 months or until the time of their death, with the exception of patients enrolled at the end of the trial. Owing to limitations on funding, the trial was stopped after all enrolled patients had completed at least 28 days of follow-up.
At the time the trial was stopped, 33 patients who underwent randomization during the last 90 days of the trial could not be included in the day or month analyses. In addition, there were patients who underwent randomization within 90 days to 12 months before the end of trial who could not be included in month analyses. The four groups were well matched with regard to their baseline characteristics, including laboratory values Table 1. Kaplan—Meier survival curves show a nonsignificant survival advantage during the first 28 days among patients who received prednisolone as compared with those who did not receive prednisolone odds ratio, 0.
No significant survival advantage was seen for patients who received pentoxifylline as compared with those who did not receive pentoxifylline odds ratio, 1. Survival curves for all four study groups up to 1 year are also shown Panel C.
In the prespecified analysis of the primary outcome a logistic-regression analysis that was adjusted for the risk category [high or intermediate] used in the randomization and for the factorial design , the odds ratio for day mortality among patients who received pentoxifylline those in the pentoxifylline—placebo group or those in the prednisolone—pentoxifylline group , as compared with patients who did not receive pentoxifylline was 1.
Neither prednisolone nor pentoxifylline was found to influence mortality or the need for liver transplantation at 90 days or 1 year Table 2. Kaplan—Meier curves for survival in each treatment group and for survival with prednisolone versus no prednisolone and with pentoxifylline versus no pentoxifylline are provided in Figure 1.
The baseline variables that influenced day mortality in univariate analyses included age, encephalopathy, white-cell count, prothrombin ratio, and serum levels of bilirubin, creatinine, and urea Table 3. In multivariate analyses, age, encephalopathy, white-cell count, prothrombin ratio, and serum levels of bilirubin, creatinine, and urea remained significant. In a secondary analysis, in which a multivariate logistic-regression model was used that adjusted for these prognostic variables, we found that the odds ratio for day mortality among the patients who received prednisolone, as compared with those who did not, was 0.
However, the effect of prednisolone on mortality at 90 days odds ratio, 1. The occurrence of gastrointestinal bleeding, sepsis, or renal failure before randomization did not affect mortality during the trial. Controversy over the use of glucocorticoids in severe alcoholic hepatitis has persisted for many years despite the results of meta-analyses of selected trials. However, in a secondary analysis that included adjustments for baseline determinants of prognosis, a significant advantage with respect to day mortality was seen with prednisolone.
The survival differences may have been a chance finding or may represent a benefit of prednisolone for short-term mortality that did not translate to longer-term benefit. Although we used the same threshold of disease severity that has been used in most other trials of alcoholic hepatitis a score of 32 or higher for discriminant function , the day mortality overall in STOPAH was appreciably lower than the day mortality in the trials included in the meta-analysis by Mathurin et al.
The use of liver biopsy to provide histologic confirmation of alcoholic steatohepatitis remains controversial. A recognized drawback of glucocorticoid use in patients with alcoholic hepatitis is increased susceptibility to infection. Investigators attributed deaths to infection in of cases Since infection plays such an important role in the outcome of alcoholic hepatitis, it is worth noting that in a trial published in , the addition of N -acetylcysteine to prednisolone was associated with a reduced rate of infection.
The results of this trial showed that after 28 days, neither prednisolone nor pentoxifylline influenced mortality. Furthermore, the cumulative mortality at 90 days and at 1 year in this group of patients is alarming. However, data on alcohol consumption are difficult to collect, and this fact is reflected in the high proportion of missing data. No matter what the exact figures are, more clearly needs to be done to prevent recidivism in this group of patients.
The findings suggest that the administration of 40 mg of prednisolone daily for 1 month may have a beneficial effect on short-term mortality but not on the medium-term or long-term outcome of alcoholic hepatitis.
Disclosure forms provided by the authors are available with the full text of this article at NEJM. Allison, receiving consulting fees from Norgine. No other potential conflict of interest relevant to this article was reported. From Imperial College M. Richardson and Aintree Hospital S. Address reprint requests to Dr. N Engl J Med ; Corticosteroid therapy of alcoholic hepatitis. European Association for the Study of Liver. EASL clinical practical guidelines: J Hepatol ; Aliment Pharmacol Ther ; Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone.
A randomized trial of prednisolone in patients with severe alcoholic hepatitis. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone.
Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: Pentoxifylline for alcoholic hepatitis. Cochrane Database Syst Rev ;4: Pentoxifylline versus prednisolone for severe alcoholic hepatitis: World J Gastroenterol ; Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis COPE trial.
Dig Dis Sci ; Determinants of long-term outcome in severe alcoholic hepatitis. Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians. With abstinence, morphologic changes of the fatty liver usually revert to normal. Although the short-term prognosis in patients with alcoholic steatosis is excellent, with longer follow-up it has been found that cirrhosis develops more commonly in alcohol abusers with fatty liver changes than in those with normal liver histology.
Hepatic encephalopathy, derangement in renal function, hyperbilirubinemia, and prolonged prothrombin time are seen more often in patients who succumb to the illness than in those who survive. The Lille model LilleModel is another prognostic scoring system that incorporates 6 reproducible clinical variables, including change in bilirubin in the first week during steroid therapy for severe alcoholic hepatitis.
It is more accurate than the Child, Maddrey, Glasgow, or MELD scores in predicting death at 6 months in patients with severe alcoholic hepatitis.
Cirrhosis has historically been considered an irreversible outcome following severe and prolonged liver damage. However, studies involving patients with liver disease from many distinct causes have shown convincingly that fibrosis and cirrhosis might have a component of reversibility. Patients with fatty liver typically are either asymptomatic or present with nonspecific symptoms that do not suggest acute liver disease.
Supporting features on physical examination include an enlarged and smooth, but rarely tender, liver. In the absence of a superimposed hepatic process, stigmata of chronic liver disease such as spider angiomas, ascites, or asterixis are likely absent. Alcoholic hepatitis is a syndrome with a spectrum of severity, and therefore manifesting symptoms vary. Symptoms may be nonspecific and mild and include anorexia and weight loss, abdominal pain and distention, or nausea and vomiting. Alternatively, more severe and specific symptoms can include encephalopathy and hepatic failure.
Physical findings include hepatomegaly, jaundice, ascites, spider angiomas, fever, and encephalopathy. Established alcoholic cirrhosis can manifest with decompensation without a preceding history of fatty liver or alcoholic hepatitis.
Alternatively, alcoholic cirrhosis may be diagnosed concurrently with acute alcoholic hepatitis. The symptoms and signs of alcoholic cirrhosis do not help to differentiate it from other causes of cirrhosis. Patients may present with jaundice, pruritus, abnormal laboratory findings eg, thrombocytopenia, hypoalbuminemia, coagulopathy , or complications of portal hypertension, such as variceal bleeding, ascites, or hepatic encephalopathy.
Fatty liver is usually diagnosed in the asymptomatic patient who is undergoing evaluation for abnormal liver function tests; typically, aminotransferase levels are less than twice the upper limit of normal. No laboratory test is diagnostic of fatty liver. Characteristic ultrasonographic findings include a hyperechoic liver with or without hepatomegaly. Liver biopsy is rarely needed to diagnose fatty liver in the appropriate clinical setting, but it may be useful in excluding steatohepatitis or fibrosis.
Typical histologic findings of fatty liver include fat accumulation in hepatocytes that is often macrovesicular, but it is occasionally microvesicular Figure 1. The centrilobular region of the hepatic acinus is most commonly affected. In severe fatty liver, however, fat is distributed throughout the acinus.
Attribution of fatty liver to alcohol use therefore requires a detailed and accurate patient history. The diagnosis of alcoholic hepatitis is also based on a thorough history, physical examination, and review of laboratory tests. Other common and nonspecific laboratory abnormalities include anemia and leukocytosis.
Liver biopsy is occasionally necessary to secure the diagnosis. The classic histologic features of alcoholic hepatitis include inflammation and necrosis, which are most prominent in the centrilobular region of the hepatic acinus Figure 2. Hepatocytes are classically ballooned, which causes compression of the sinusoid and reversible portal hypertension.
The inflammatory cell infiltrate, located primarily in the sinusoids and close to necrotic hepatocytes, consists of polymorphonuclear cells and mononuclear cells. In addition to inflammation and necrosis, many patients with alcoholic hepatitis have fatty infiltration and Mallory bodies, which are intracellular perinuclear aggregations of intermediate filaments that are eosinophilic on hematoxylin-eosin staining. Neither fatty infiltration nor Mallory bodies are specific for alcoholic hepatitis or necessary for the diagnosis.
The diagnosis of alcoholic cirrhosis rests on finding the classic signs and symptoms of end-stage liver disease in a patient with a history of significant alcohol intake. Patients tend to underreport their alcohol consumption, and discussions with family members and close friends can provide a more accurate estimation of alcohol intake. Patients can present with any or all complications of portal hypertension, including ascites, variceal bleeding, and hepatic encephalopathy. The histology of end-stage alcoholic cirrhosis, in the absence of acute alcoholic hepatitis, resembles that of advanced liver disease from many other causes, without any distinct pathologic findings Figure 3.
The overall clinical diagnosis of alcoholic liver disease, using a combination of physical findings, laboratory values, and clinical acumen, is relatively accurate Table 3. However, liver biopsy can be justified in selected cases, especially when the diagnosis is in question. The foundation of therapy for alcoholic liver disease is abstinence. Patients are often unable to achieve complete and durable alcohol abstinence without assistance, and referral to a chemical dependency team is appropriate.
Hospitalization is indicated to expedite a diagnostic evaluation of patients with jaundice, encephalopathy, or ascites of unknown cause. In addition, patients with known alcoholic liver disease who present with renal failure, fever, inadequate oral intake to maintain hydration, or rapidly deteriorating liver function, as demonstrated by progressive encephalopathy or coagulopathy, should be hospitalized.
Supportive care for all patients includes adequate nutrition. Almost all patients with alcoholic hepatitis have some degree of malnutrition, but estimating the severity of malnutrition remains a challenge because sensitive and specific clinical or laboratory parameters are lacking. The nutritionist plays a valuable role in assessing the degree of malnutrition and guiding nutritional supplementation in malnourished alcoholic patients.
The degree of malnutrition correlates directly with short-term 1-month and long-term 1-year mortality. In general, enteral nutrition is preferable over parenteral supplementation, and protein should be supplied to provide positive nitrogen balance.
Branched-chain amino acids are useful as a supplement to maintain positive nitrogen balance in patients who do not tolerate liberal protein intake because of the development of encephalopathy; however, the expense limits routine use in all alcoholic malnourished patients.
Nutritional supplementation is generally associated with an improvement in liver test results, but only rarely with a mortality benefit. The use of corticosteroids as specific therapy for alcoholic hepatitis has generated a good deal of interest. The rationale behind this approach is the possible role of the immune system in initiating and perpetuating hepatic damage. The data suggest a significant decrease in short-term day mortality in patients randomized to prednisolone, but only those with more-severe liver dysfunction, as manifested by hepatic encephalopathy or a markedly abnormal discriminant function.
Results from other randomized, controlled trials have been contradictory. Christensen and Gluud 27 found no effect of corticosteroids on mortality.
Most recent trials of corticosteroids for alcoholic hepatitis have excluded patients with certain coexisting conditions, such as gastrointestinal bleeding, active infection, diabetes, viral hepatitis, or acute pancreatitis, and therefore the applicability of these study findings is limited. Practice guidelines 19 support the use of corticosteroids in patients in whom the diagnosis of severe alcoholic hepatitis is certain.
Pentoxifylline, an oral phosphodiesterase inhibitor, is also an inhibitor of TNF synthesis. Elevated TNF levels have been associated with higher mortality from alcoholic hepatitis.
Other therapies that have been investigated in the treatment of alcoholic hepatitis but not found to be beneficial include propylthiouracil; 31 infliximab; 32 insulin and glucagon; 33, 34 calcium channel blockers; 35 antioxidants such as vitamin E, 36 S-adenosyl-L-methionine SAMe , 37 or silymarin, 38 which is the active ingredient in milk thistle.
Treatment of the patient with alcoholic cirrhosis mirrors the care of patients with any other type of cirrhosis, and includes prevention and management of ascites, spontaneous bacterial peritonitis, variceal bleeding, encephalopathy, malnutrition, and hepatocellular carcinoma.
Once advanced cirrhosis has occurred with evidence of decompensation ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding , the patient should be referred to a transplantation center.
Acute alcoholic hepatitis is generally considered a contraindication to liver transplantation. For more than a decade, alcoholic cirrhosis has been the second leading indication for liver transplantation in the United States. Most transplantation centers currently require patients with a history of alcohol abuse to have documented abstinence of at least 6 months before undergoing transplantation.
This requirement theoretically has a dual advantage of predicting long-term sobriety and allowing recovery of liver function from acute alcoholic hepatitis.
This 6-month abstinence rule might not have much prognostic significance in predicting recidivism, however. As emphasized in the most recent national practice guidelines, 19 health care providers must be attentive for signs of covert alcohol abuse. Many patients do not openly disclose an accurate history of alcohol use. In addition, no physical examination finding or laboratory abnormality is specific for alcoholic liver disease.
All patients should therefore be screened for alcohol abuse or dependency. Dependency is defined by physical tolerance and symptoms of withdrawal. Clinicians should screen all patients for harmful patterns of alcohol use. All patients with alcohol-related liver disease should abstain from alcohol. Liver transplantation remains an option for select patients with end-stage liver disease due to alcohol.
Alcoholic Liver Disease Kyrsten D. Definition Liver disease related to alcohol consumption fits into 1 of 3 categories: Yes Variable Generally no. Alcohol consumption and alcoholic liver disease: Evidence of a threshold level of effects of ethanol. Alcohol Clin Exp Res ;17 5: Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse.
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What would you like to print? Pilot data from a small US open-label trial of etanercept, a TNF receptor antagonist, also showed safety in patients with less severe AH, and a multicenter trail studying this agent is being funded by the National Institutes of Health [ 41 ]. Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis.
Alcoholic liver disease is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver , alcoholic hepatitis , and chronic hepatitis with liver fibrosis or cirrhosis.
However, two meta-analyses have what are the side effects of low testosterone shown any convincing benefit associated with pentoxifylline. Fatty change and alcoholic alcoholic liver failure steroids with abstinence can be reversible. In humans with mild alcoholic hepatitis, silymarin improves liver steroide test results. J Hepatol ; Clinical diagnosis was chosen because the use of liver biopsy in this group of patients is uncommon, and the aim was to recruit a large steroidw of participants whose condition would reflect as closely as possible the condition of patients seen lvier clinical practice. Less than half of those who develop SBP can be expected to survive 1 year, while the median survival of patients with hepatorenal syndrome is less than 2 weeks [ 1920 ]. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites.
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