The knowns and unknowns of treatment for alcoholic hepatitis

Abstract

Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often arises in patients with a background of chronic liver disease and it is characterised by the rapid onset of jaundice and the development of myriad complications. Medical therapy for severe alcoholic hepatitis relies on corticosteroids, which have modest effectiveness. Abstinence from alcohol is critically important in patients with alcoholic hepatitis, but recidivism is high. Because of the absence of effective medical treatments for alcoholic hepatitis and alcohol dependency, there is a pressing need to develop new and effective therapeutics. Supported by promising preliminary and preclinical studies, many ongoing clinical trials of new therapies for alcoholic hepatitis are currently underway and are discussed further in this Series paper.

Figure 1:. Pathophysiology of Alcoholic Hepatitis and Mechanisms of Action of Novel Therapeutic Agents

The pathogenesis of alcoholic hepatitis involves the interplay of multiple complex mechanisms. A. Chronic alcohol use causes changes in the gut microbiome composition (dysbiosis) and breakdown of gut barrier function. LPS and other bacterial products can potently activate the innate immune system and are collectively called Pathogen-Associated Molecular Patterns (PAMPs). Increased gut permeability allows for the translocation of bacteria and PAMPs to the liver via splanchnic vasculature. Multiple therapeutics, including antibiotics, fecal transplantation, bovine colostrum, and hyperimmunized bovine colostrum IMM-124E target dysbiosis and reduce endotoxemia. B. Excessive alcohol consumption leads to liver injury by multiple mechanisms. The toxic metabolites of ethanol, particularly acetaldehyde, cause direct hepatocyte oxidative injury as well as injury via formation of protein/DNA adducts. Ethanol metabolites also cause mitochondrial dysfunction and lipid peroxidation which leads to steatosis. Activated immune cells induce cell-mediated cytotoxicity by release of reactive oxygen species (ROS), further exacerbating oxidative injury. Antioxidants have been trialed in alcoholic hepatitis to attenuate oxidative stress. Zinc, in addition to being an antioxidant, is also protective against mitochondrial dysfunction and apoptosis. Cholestasis is another target for alcoholic hepatitis therapy. Obeticholic acid (OCA) is currently in trial as an agonist to the farnesoid X receptor (FXR), which has activity against bile synthesis. The injured liver has two different clinical outcomes, cell death and organ failure vs. liver regeneration and recovery. Hepatocyte injury activates apoptosis and necrosis pathways and releases Damage-Associated Molecular Patterns (DAMPs), which are cell derived molecules capable of activating the immune system. Emricasan and Selonsertib are two inhibitors to apoptosis signaling studied in alcoholic hepatitis. Liver injury also stimulates liver regeneration. Many cytokines, including TNFα and Interleukin-6 (IL-6), are potent activators of liver regeneration. Another cytokine, IL-22, has also been shown to stimulate liver regeneration. Growth colony stimulating factor (G-CSF) and its derivative pegylated G-CSF have shown promising results in multiple early clinical trials. C. The accumulation of DAMPs and PAMPs in the liver activates resident liver immune cells, particularly Kupffer cells, by activation of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs). Receptor activation enhances NFκB signaling and results in expression of pro-inflammatory molecules, including IL-1β. Pro-IL-1β undergo cleavage by caspase-1, which is activated by the inflammasome complex, to become activated IL-1β. An inhibitor to IL-1β, Anakinra, is currently studied in clinical trials. TNFα inhibitors, including Infliximab, have been tested in clinical trials. Pentoxifylline is another extensively studied compound in the treatment of alcoholic hepatitis. It suppresses NFκB signaling and reduces the production of cytokines, including TNFα. Chemokine receptors, such as C-C chemokine receptors (CCRs), promote inflammatory signaling via stimulation of the NFκB pathway, and a CCR2/CCR5 inhibitor, Cenicriviroc, has been proposed as another target for alcoholic hepatitis therapy. Inflammatory cytokines and chemokines released by Kupffer cells and other liver cells recruit circulating immune cells such as neutrophils and monocytes and promote chemotaxis and infiltration into liver parenchyma. Immune cell infiltration causes secondary cell-mediated injury to the liver parenchymal cells by oxidative injury as described above.

Figure 2:

Current Clinical Treatment Algorithm for Alcoholic Hepatitis