Treatment of Severe Alcoholic Hepatitis

doi:10.1053/j.gastro.2016.02.074

Gastroenterology

Volume 150, Issue 8, June 2016, Pages 1823-1834

https://doi.org/10.1053/j.gastro.2016.02.074 Get rights and content

Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected—no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.

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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Cited by (50)

Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver Disease
2024, American Journal of Pathology
Alcohol-associated liver disease (ALD) is a serious public health problem with limited pharmacologic options. The goal of the current study was to investigate the efficacy of pharmacologic inhibition of soluble epoxide hydrolase (sEH), an enzyme involved in lipid metabolism, in experimental ALD, and to examine the underlying mechanisms. C57BL/6J male mice were subjected to acute-on-chronic ethanol (EtOH) feeding with or without the sEH inhibitor 4-[[trans-4-[[[[4-trifluoromethoxy phenyl]amino]carbonyl]-amino]cyclohexyl]oxy]-benzoic acid (TUCB). Liver injury was assessed by multiple end points. Liver epoxy fatty acids and dihydroxy fatty acids were measured by targeted metabolomics. Whole-liver RNA sequencing was performed, and free modified RNA bases were measured by mass spectrometry. EtOH-induced liver injury was ameliorated by TUCB treatment as evidenced by reduced plasma alanine aminotransferase levels and was associated with attenuated alcohol-induced endoplasmic reticulum stress, reduced neutrophil infiltration, and increased numbers of hepatic M2 macrophages. TUCB altered liver epoxy and dihydroxy fatty acids and led to a unique hepatic transcriptional profile characterized by decreased expression of genes involved in apoptosis, inflammation, fibrosis, and carcinogenesis. Several modified RNA bases were robustly changed by TUCB, including N⁶-methyladenosine and 2-methylthio-N⁶-threonylcarbamoyladenosine. These findings show the beneficial effects of sEH inhibition by TUCB in experimental EtOH-induced liver injury, warranting further mechanistic studies to explore the underlying mechanisms, and highlighting the translational potential of sEH as a drug target for this disease.
Nutrition in liver disease
2023, Comprehensive Guide to Hepatitis Advances
The important role of nutrition in the trajectory of chronic liver disease has long been recognized as exemplified by the fact that nutritional status was one of the variables of the original prognostic score introduced by Child and Turcotte. Yet, not all hepatologists consider nutrition issues relevant in the management of their patients. In this chapter, the scientific and evidence base for nutritional metabolic management in patients with liver disease is reviewed including appropriate recommendations.
Alcohol and Acute-on-Chronic Liver Failure
2022, Journal of Clinical and Experimental Hepatology
Citation 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
Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.
Plasma-Signature-Model for End-Stage Liver Disease Score to Predict Survival in Severe Alcoholic Hepatitis
2022, Clinical Gastroenterology and Hepatology
Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature–MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein–based surrogate of the gene signature and independently validate its prognostic capability.
All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome–based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients.
The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature–MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15–9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices.
The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.
Barriers for Liver Transplant in Patients with Alcohol-Related Hepatitis
2022, Journal of Clinical and Experimental Hepatology
Citation 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.
Liver transplantation (LT) for alcohol-related liver disease has historically been reserved for patients who have been six months abstinent. Given the increasing incidence of alcohol-related hepatitis (AH) and dismal survival in patients who fail medical therapy, transplant centers are extending their acceptance criteria for patients with less than 6 months of sobriety. We sought to determine the barriers for listing.
We conducted a retrospective chart review of all inpatient LT referrals for a diagnosis of AH between September 2019 and December 2020. LT evaluations were performed by a multidisciplinary team. Descriptive statistics were reported using mean and standard deviation (SD) or percentage where appropriate.
During our study period, 82 patients were evaluated for LT. Of these 82 patients, 62 were declined for liver transplantation. The mean (SD) age of the 62-patient cohort was 44 years (10.7), and most patients were men. The mean (SD) number of reasons for denial was 2 (0.97). Four patients had medical contraindications for transplant. Twenty-seven (44%) and 35 (56%) patients lacked insight and were at risk of alcohol relapse, respectively. Forty-three (69%) and fourteen (22.5%) patients had insufficient social support and an inability to maintain a therapeutic relationship with the transplant team, respectively.
Patients are more likely denied for psychosocial factors than medical comorbidities. The majority were due to lack of insight, insufficient social support, and inability to maintain a therapeutic relationship with the transplant team. Resources should be allocated to address these issues.
Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required?
2021, Clinics in Liver Disease

View all citing articles on Scopus

: 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.).

^∗: Authors share co-first authorship.

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ManagementTreatment of Severe Alcoholic Hepatitis

Section snippets

Who to Treat: Stratification of Patients by Disease Severity

Corticosteroids

Pentoxifylline

N-Acetylcysteine and Antioxidants

Meta-Analyses of Efficacy

Liver Transplantation

Abstinence

Ineffective Treatment Strategies

Future Therapeutic Strategies

Future Directions

Gastroenterology

J Hepatol

J Hepatol

Gastroenterology

Hepatology

Am J Clin Nutr

Am J Clin Nutr

Lancet

J Hepatol

J Hepatol

Gastroenterology

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Lancet

Gastroenterology

Am J Gastroenterol

J Hepatol

J Hepatol

J Hepatol

Hepatology

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Alcoholic hepatitis

N Engl J Med

Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis

Gut

Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial

JAMA

Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis

N Engl J Med

Prednisolone or pentoxifylline for alcoholic hepatitis

N Engl J Med

Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone

N Engl J Med

Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial

N Engl J Med

MELD accurately predicts mortality in patients with alcoholic hepatitis

Hepatology

Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis

Gastroenterology

Management
Treatment of Severe Alcoholic Hepatitis