ManagementTreatment of Severe Alcoholic Hepatitis
Section snippets
Who to Treat: Stratification of Patients by Disease Severity
Encephalopathy, renal failure, coagulopathy (based on prothrombin time), and serum levels of bilirubin have served as independent prognostic factors for AH since the early 1970s.5, 9, 10 However, Maddrey et al2 used discriminant analysis to produce a scoring system that reliably defined individuals at highest risk for death in the short term. In the original study describing the DF, a cut-off value of 93 was used to identify patients who died. Subsequently, the scoring system was changed (to
Corticosteroids
From 1971 through 2014 there were 13 randomized trials and 4 meta-analyses that investigated the effects of corticosteroids in patients with AH.14, 15, 16, 17 Although these studies produced many results, controversy persisted over the use of corticosteroid therapy in these patients. Advocates cited reductions in short- to medium-term mortality, whereas detractors raised concerns about the risks of sepsis and gastrointestinal hemorrhage.
The largest placebo-controlled study of the effects of
Pentoxifylline
Pentoxifylline, a phosphodiesterase inhibitor, is believed to inhibit production of tumor necrosis factor (TNF). The efficacy of pentoxifylline monotherapy in patients with AH has been compared with that of placebo and prednisolone (Table 1). The efficacy of the combination of prednisolone and pentoxifylline has been compared with that of prednisolone or pentoxifylline monotherapy. These studies have produced conflicting results.
Five randomized controlled trials have compared the efficacy of
N-Acetylcysteine and Antioxidants
Oxidative stress increases in livers of patients with AH, and levels of antioxidants such as glutathione or N-acetylcysteine (NAC) are decreased in patients with hepatic failure. Several studies therefore have tested the safety and efficacy of NAC, either alone or in combination with other antioxidants, in patients with AH (Table 2).
Moreno et al38 compared the effect of enteral nutritional support alone with that of nutritional support with intravenous NAC for 14 days in patients with
Meta-Analyses of Efficacy
Results from meta-analyses of studies of patients with AH vary, depending on which studies are included (high quality vs all trials) and who assessed the quality of the study and performed the meta-analysis.45, 46 Furthermore, until recently, meta-analyses compared 2 treatment options (such as prednisolone vs placebo or pentoxifylline vs placebo). However, a recent network meta-analysis compared outcomes among multiple treatments,17 based on 22 high-quality studies comprising more than 2500
Liver Transplantation
Liver transplantation is the ultimate treatment for patients with liver failure. Liver transplantation is accepted for patients with alcoholic cirrhosis, and excessive alcohol consumption is a factor in approximately 20% of transplants performed in the United States and in 30%–50% of transplants performed in Europe.47, 48, 49 Most countries require 6 months of abstinence before liver transplantation for patients with a history of excessive alcohol use. The problem with requiring prolonged
Abstinence
AH is actually 2 diseases: a liver disease in patients with alcohol use disorder. Gastroenterologists focus on the liver disease, which is the most frequent cause of death during the first 6 months after the onset of AH. However, alcohol use disorder is the most common cause of death after 6 months. The obvious conclusion that a return to alcohol use after an episode of AH would be harmful was shown decades ago and has been confirmed in recent studies.51 In the STOPAH trial, drinking alcohol at
Ineffective Treatment Strategies
Many strategies that have attempted to alter pathways associated with the pathogenesis of AH have failed to increase survival (Table 3).28, 40, 43, 46, 53, 54, 55, 56, 57, 58, 59 Although most trials enrolled small numbers of patients, the lack of efficacy has reduced enthusiasm for follow-up studies.
Future Therapeutic Strategies
Multiple treatments are being evaluated in patients with AH (Table 4). Absorbable and nonabsorbable antibiotics could decrease bacterial growth—potentially decreasing absorption of endotoxin and other inflammatory bacterial products. Absorbable antibiotics also may decrease infections or sepsis, particularly among patients receiving corticosteroids. Probiotics may alter the intestinal microbiome to be less hepatotoxic. Binding of endotoxin by use of antibodies to lipopolysaccharide also is
Future Directions
Our current recommendations for treatment of AH are shown in Figure 1. Infection and septicemia are common among patients with AH. Some patients have infections at the time of admission, which might have contributed to the development of AH. In other patients, infections develop after admission or after initiation of treatment with corticosteroids; these can increase short-term mortality.66 A high level of lipopolysaccharide in serum is associated with the development of the systemic
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Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver Disease
2024, American Journal of PathologyNutrition in liver disease
2023, Comprehensive Guide to Hepatitis AdvancesAlcohol and Acute-on-Chronic Liver Failure
2022, Journal of Clinical and Experimental HepatologyCitation Excerpt :Extracorporeal liver support in the form of plasma exchange (APACHE; NCT03702920) and strategies targeting albumin exchange and endotoxin removal (DIALIVE; NCT03065699) are currently being studied after trials on albumin dialysis (MARS) and extracorporeal cellular therapy (ELAD) failed to improve short-term survival, compared to the standard medical therapy.65–67 Despite their role as first-line treatment, corticosteroids exhibit a wide heterogeneity in their efficacy of improving survival rates in severe AH.68 From six randomised clinical trials assessing the impact of corticosteroids on survival after 28-days, only two69,70 showed significantly improved survival rates while four provided no evidence of benefit probably due to lack of adequate patient stratification.71–74
Plasma-Signature-Model for End-Stage Liver Disease Score to Predict Survival in Severe Alcoholic Hepatitis
2022, Clinical Gastroenterology and HepatologyBarriers for Liver Transplant in Patients with Alcohol-Related Hepatitis
2022, Journal of Clinical and Experimental HepatologyCitation Excerpt :Transplant providers struggle to quantify an often subjective set of data, especially since psychosocial factors are difficult to ascertain and are dynamic in nature. From a strictly medical perspective, clinicians have developed models to help prognosticate the morbidity and mortality of patients with AH.17,18 However, these models often fall short and fail to accurately capture the individual patient’s course.
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2021, Clinics in Liver Disease
Conflicts of interest The authors disclose no conflicts.
Funding Supported by U01 AA21884, U01 AA21886, and U01 AA018389 from the National Institutes of Health/National Institutes on Alcohol Abuse and Alcoholism (T.R.M.).
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Authors share co-first authorship.