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Review
. 2022 Sep 21;12(4):266-288.
doi: 10.3390/jox12040019.

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

Hong Lu  1
Affiliations
Review

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

Hong Lu. J Xenobiot. .

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.

Keywords: alcoholic hepatitis; glucocorticoid; glucocorticoid receptor; glucocorticoid resistance; mineralocorticoid receptor; protein kinase C.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Data mining of (A) microarray and (B) RNA-sequencing analyses of hepatic mRNAs in humans with severe alcoholic hepatitis (AH). The mRNA expression of microarray (GSE28619) and RNA-sequencing (GSE142530) data were retrieved from GEO DataSets and normalized to β-actin, with values of normal human livers set as 1.0. (A) N = 7 normal livers and 15 AH livers, (B) N = 12 normal livers, 10 AH livers, and 6 alcoholic cirrhosis (AC) livers. Mean ± SE. * p < 0.05 versus normal livers.
Figure 2
Figure 2
Data mining of (A) microarray and (B) RNA-sequencing analyses of hepatic mRNAs in humans with severe alcoholic hepatitis (AH). The mRNA expression of microarray (GSE28619) and RNA-sequencing (GSE142530) data were retrieved from GEO DataSetsand normalized to β-actin, with values of normal human livers set as 1.0. (A) N = 7 normal livers and 15 AH livers, (B) N = 12 normal livers, 10 AH livers, and 6 alcoholic cirrhosis (AC) livers. Mean ± SE. * p < 0.05 versus normal livers.
Figure 3
Figure 3
Diagram of glucocorticoid (GC) therapy and the roles of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in alcoholic hepatitis (AH). Ethanol activates GR via enhancing its nuclear translocation. Endogenous GCs are activated by 11-β-dehydrogenase isozyme 1 (HSD11β1) to act as GR agonists, whereas GCs are inactivated by HSD11β2 to prevent unwanted activation of MR by GCs in tissues such as kidney and brain. Bile acids (BAs) potently inhibit HSD11β1, resulting in attenuated hepatic activation of GCs and induction of GR target genes. Inhibition of HSD11β2 by BAs can lead to undesired activation of MR by GCs (e.g., prednisolone) and aggravated alcohol abuse, inflammation, and acute kidney injury (AKI). Protein kinase C δ (PKCδ) is activated by diverse stresses, such as lipopolysaccharide (LPS), tumor necrosis factor (TNF), transforming growth factor beta (TGFβ), BAs, and ethanol, and PKCδ, in turn, inhibits hepatocyte nuclear factor 4α (HNF4α), Sirtuin-1 (SIRT1), and GR, master regulators of metabolic homeostasis. SIRT1 is also a key coactivator of GR. GR directly induces HNF4α, and GR can increase SIRT1 activity via induction of nicotinamide phosphoribosyl-transferase (NAMPT) and the resultant increased production of nicotinamide adenine dinucleotide (NAD+), an essential cofactor for SIRT1. Ethanol activation of PKCδ causes proteasomal degradation of dual specificity protein phosphatase 1 (DUSP1), sustained c-Jun N-terminal kinase (JNK) activation, impaired autophagy, and hepatocyte apoptosis. Activation of JNK inhibits GR via direct phosphorylation of GR. In contrast, activation of GR induces DUSP1 to inhibit the activation of JNK. Ethanol also activates calpain to inhibit GR and promote cell death. Marked down-regulation of C-X-C Motif Chemokine Ligand 2 (CXCL2) and induction of CXCL1 and CXCL8 is a key characteristic that distinguishes sAH from other forms of alcoholic liver diseases, such as alcoholic cirrhosis (Figure 2B). GR in hepatocytes induces CXCL2 and down-regulates CXCL1 and CXCL8 to help maintain neutrophil homeostasis. CXCL2 synergizes with granulocyte-colony-stimulating factor (G-CSF) to rapidly mobilize hematopoietic stem cells (HSC), which plays an important role in liver regeneration/repair.
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