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Latest article from NEJM:Latest NEJM article on AH portion on new potential treatments don’t even mention DUR-928. This means to me they at NEJM are under exposed, there is no hope for the med, or we could be sitting on potential stunning success. Here is a portion of that article: article left. Subscribe now for FULL access. REVIEW ARTICLE Alcohol-Associated Hepatitis List of authors. Ramon Bataller, M.D., Ph.D., Juan Pablo Arab, M.D., and Vijay H. Shah, M.D. December 29, 2022 N Engl J Med 2022; 387:2436-2448 DOI: 10.1056/NEJMra2207599 Editors C. Corey Hardin, M.D., Ph.D., Editor Article Figures/Media Metrics 106 References Introduction Alcohol use disorder is a major cause of advanced liver disease and liver-related hospitalization and death worldwide.1,2 Globally, alcohol is the cause of 50% of all deaths due to liver disease, and various forms of alcohol-associated liver disease (ALD) will develop in approximately 35% of patients with alcohol use disorder.3 The natural history of ALD is not well defined and is influenced by periods of heavy alcohol intake and abstinence.4 The clinical and histopathological forms of ALD range from isolated steatosis to progressive steatohepatitis with fibrosis accumulation to cirrhosis and its complications, culminating in the development of hepatocellular carcinoma.5 Most patients with ALD receive a diagnosis at an advanced stage, when the disease becomes symptomatic.6 A severe clinical profile may develop in patients with underlying ALD and active drinking, characterized by an abrupt onset of jaundice, malaise, decompensated liver disease, and coagulopathy, an entity called alcohol-associated hepatitis.7 In its severe forms, alcohol-associated hepatitis is associated with bacterial infections and the development of acute-on-chronic liver failure, multiorgan failure, and high short-term mortality (20 to 50% at 3 months).8,9 Although the prevalence of alcohol-associated hepatitis is not well known, the global incidence is probably increasing, especially among young adults (in their 20s and 30s) and women.8,10 Its incidence has increased during the coronavirus disease 2019 pandemic.11,12 During the past decade, the diagnostic criteria for alcohol-associated hepatitis have been revised. The clinical findings required for its diagnosis, the indications for transjugular liver biopsy, and the diagnostic certainty (possible, probable, and definitive alcohol-associated hepatitis) were defined by a panel of experts from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).13 Moreover, a specific histologic classification with prognostic significance was developed (Alcoholic Hepatitis Histologic Score [AHHS]).14 Specific therapy for alcohol-associated hepatitis, however, still relies on the use of glucocorticoids, which improve short-term (30-day) but not long-term survival in selected patients.15,16 From the early trials in the 1970s until the more recent Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, glucocorticoids were the only therapy for severe alcohol-associated hepatitis that consistently showed a benefit with respect to short-term survival.16-18 Translational studies have identified several key mechanisms of alcohol-associated hepatitis involving the microbiome, proinflammatory signals, and factors leading to poor hepatocyte differentiation and function.19 These discoveries have markedly stimulated the liver-disease and pharmaceutical communities to test new pathophysiological-based therapeutic approaches.20 Finally, since the transformative study by Mathurin et al.,21 an increasing number of centers worldwide are offering the possibility of early transplantation to highly selected patients with severe alcohol-associated hepatitis that does not respond to medical therapy. In this review, we discuss evolving concepts in the diagnosis and prognosis of alcohol-associated hepatitis, the current trend to treat these patients in a holistic manner involving addiction specialists, ongoing clinical trials testing new targets for therapy, and current selection criteria for early liver transplantation. Predisposing Factors and Pathogenesis Diagnosis, Prognosis, and Medical Management Early Liver Transplantation Emerging Therapies The number of clinical trials testing new pathophysiologically oriented drugs in patients with alcohol-associated hepatitis has markedly increased in recent years.20 Most studies are aimed at promoting effective liver regeneration, blocking inflammatory pathways, restoring a normal microbiome, or a combination of these. A pilot study of a recombinant fusion protein of human interleukin-22, an antiinflammatory and pro-regenerative cytokine, showed favorable outcomes as determined by Lille and MELD scores, a reduction in markers of inflammation, and increased expression of markers of hepatic regeneration.99 In addition, two open-label, randomized trials comparing granulocyte colony-stimulating factor (G-CSF) plus standard medical therapy with standard medical therapy alone in patients with severe alcohol-associated hepatitis showed an improvement in 3- and 6-month survival and a lower incidence of bacterial infections.100 A more recent European study, however, failed to show a benefit with G-CSF in patients with severe alcohol-associated hepatitis.101 The role of gut microbiota in the pathogenesis of alcohol-associated hepatitis is another area of development. A promising pilot study showed that fecal microbiome transplantation from healthy donors was associated with lower mortality than in a historical cohort.102 A study of interleukin-1 inhibition by anakinra, pentoxifylline, and zinc showed an acceptable side-effect profile, but 180-day survival did not differ significantly between the combination therapy and glucocorticoid therapy.103 Several clinical trials are now examining the role of probiotics, rifaximin, and fecal microbiome transplantation in patients with alcohol-associated hepatitis. Other targeted trials under way involve the use of antiinflammatory drugs (interleukin-1β inhibition by canakinumab), drugs targeting gut–liver axis dysfunction and dysbiosis (broad-spectrum antibiotics and bovine colostrum), antioxidants (N-acetylcysteine, metadoxine, and n–5 fatty acids), drugs targeting apoptosis (selonsertib and emricasan), phage therapy, and supplemental nutrition strategies.104 Future Directions To reduce the burden of A |
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