Emerging Pharmacotherapies in Alcohol-Associated Hepatitis

Abstract

The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis.

Conclusion: A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.

Keywords: AH, alcohol-Associated hepatitis; ALD, Alcohol-associated liver disease; ASK-1, Apoptosis signal-regulating kinase-1; AUD, alcohol use disorder; CCL2, C–C chemokine ligand type 2; CVC, Cenicriviroc; ELAD, Extracorporeal liver assist device; FMT, Fecal Microbiota Transplant; G-CSF, Granulocyte colony-stimulating factor; HA35, Hyaluronic Acid 35KD; IL-1, interleukin 1; IL-6, interleukin 6; LCFA, saturated long-chain fatty acids; LDL, low-density lipoprotein cholesterol; LPS, Lipopolysaccharides; MCP-1, monocyte chemoattractant protein −1; MDF, Maddrey's discriminant function; MELD, Model for end-stage disease; NAC, N-acetylcysteine; NLRs, nucleotide-binding oligomerization domain-like receptors; PAMPs, Pathogen-associated molecular patterns; RCT, Randomized controlled trial; SAM, S-Adenosyl methionine; SCFA, short-chain fatty acids. 5; TLRs, Toll-like receptors; TNF, tumor necrotic factor; alcohol-associated hepatitis; anti-inflammatory; antioxidants; liver-gut axis; microbiome; sAH, severe alcohol-associated hepatitis.

Figure 1

Categories of novel agents in therapy of alcohol-associated hepatitis.