Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms

Abstract

Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC’s extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients.

Cell-Specific Regulation of Inflammatory Cytokines and Acute-Phase Proteins by the Glucocorticoid Receptor

“…This study was performed to understand the GR's effect on chemokine and APP expression in the liver. We hypothesized that by increasing GR activity in the liver, chemokine imbalances seen in diseases such as AH [71] could be ameliorated, thus treating or preventing the development of sepsis in this high-risk patient group [9]. To summarize our findings, GR's effect on chemokine expression is more complicated than a simple anti-inflammatory inhibition.…”

Liver-specific glucocorticoid action in alcoholic liver disease: study of glucocorticoid receptor knockout and knockin mice

“…We found that Foxo3 mRNA was down-regulated by ethanol in the WT AS mice (data not shown), which may contribute to the trend of down-regulation of GILZ in WT AS mice. In contrast to the activation of GR in acute AS, hepatic expression of GR and GR-target genes are markedly down-regulated in sAH patients (Lu, 2022). Further study on the mechanism of hepatic GR deficiency in sAH is warranted.…”

“…Marked steatohepatitis, jaundice, cholestatic liver injury, and impaired liver regeneration are hallmarks of sAH which causes high mortality (Sidhu et al, 2017, Hosseini et al, 2019). Literature suggests hepatic GR deficiency in fatty liver and AH (Ahmed et al, 2012, Nasiri et al, 2015, Lu, 2022). Most recent literature support a protective role of hepatocellular GR against steatosis during high fatty acid influx (Nasiri et al, 2015, Roqueta-Rivera et al, 2016, Quagliarini et al, 2019, Lu et al, 2022, Mueller et al, 2011).…”

“…Overeating high-fat-diet (HFD) aggravates AH and drives nonalcoholic fatty liver disease (NAFLD) (Gao et al, 2017). Literature suggests hepatic GR deficiency in NAFLD and AH (Ahmed et al, 2012, Nasiri et al, 2015, Lu, 2022). The purpose of this study was to use our novel model of mice with tamoxifen-inducible liver-specific knockout (LKO) of GR to determine the effects of hepatic deficiency of GR on alcoholic steatosis (AS) induced by high-fat diet (HFD) feeding plus binge alcohol and the alterations of GR- and ERα-target genes in AS mice with GR deficiency.…”

Development of novel liver-targeting glucocorticoid prodrugs

“…Patients with alcoholic hepatitis (AH) have severe inflammation and cholestatic liver injury [ 2 ], and severe AH (sAH) has a high mortality rate [ 3 ]. Glucocorticoids (GCs) are currently the only available drug therapy for sAH [ 4 ], however, prednisolone, the current standard of care for sAH, only marginally reduces 28-day mortality without long-term improvement [ 5 ]. Additionally, sepsis is a leading cause of death of sAH [ 6 , 7 ], and hepatic GR is essential to protect against liver failure and mortality in sepsis [ 8 ].…”