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Patients with severe alcoholic hepatitis who are admitted to the hospital usually have evidence of decompensated cirrhosis with high serum bilirubin levels, low prothrombin time associated with dysfunction or failure of other organs/systems (kidney, brain, circulation).1 Spontaneous 1-month mortality is 35%.2
Pathophysiology of severe alcoholic hepatitis is incompletely understood.2–4 Alcohol consumption results in alterations of gut microbiome, increased intestinal permeability and subsequent translocation of Gram-negative bacteria. These bacteria may release pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS). In the liver, PAMPs stimulate Kupffer cells to produce high levels of proinflammatory chemokines (eg, interleukin-8 (IL-8)) or cytokines such as tumour necrosis factor α (TNF-α). TNF-α may activate cell death pathways and induce the production of reactive oxygen species (ROS) by hepatocyte mitochondria, leading to cell death. Acetaldehyde metabolism also contributes to hepatocyte ROS production. These findings led to the traditional view that excessive inflammation and oxidative stress are involved in the development of liver damage in patients with alcoholic hepatitis.
Corticosteroid therapy (40 mg of oral prednisolone per day) is now considered as the first-line treatment for severe alcoholic hepatitis.2 However, according to the Lille model ∼40% of patients with severe alcoholic hepatitis do not respond to corticosteroids,2 and this group has high 6-month mortality (close to 80%).5 This is why novel, pathophysiology-based, medical therapies should be developed for patients who do not respond to corticosteroids.
Dubuquoy et al6 provide new insights into the pathophysiology of severe alcoholic hepatitis. They investigated liver explants from patients with severe alcoholic hepatitis who underwent salvage transplantation, from patients with alcoholic cirrhosis and no alcoholic hepatitis and fragments of normal livers. …
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