Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives
Abstract
:1. Introduction
2. Pathophysiology of ALD
2.1. Alcohol Metabolism
2.2. ALD Progression
2.2.1. Alcoholic Fatty Liver (Steatosis)
2.2.2. Alcoholic Steatohepatitis (ASH)/Alcoholic Hepatitis (AH)
2.2.3. Fibrosis/Cirrhosis
2.3. ALD and Non-Alcoholic Fatty Liver Disease (NAFLD): Similarities and Differences
3. Clinical Diagnosis of ALD
4. Therapeutic Options for Various Stages of ALD
4.1. Lifestyle Modification and Nutritional Intervention
4.2. Targeted Treatments
4.2.1. Inflammation
4.2.2. Oxidative Stress
4.2.3. Hepatocellular Death
4.2.4. Hepatic Regeneration
4.3. Liver Transplantation
4.4. Potential Novel Therapeutic Targets
4.4.1. MicroRNAs
4.4.2. Gut-Liver Axis
4.4.3. G Protein-Coupled Receptors (GPCRs)
5. Conclusions and Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Similarities: Shared Signaling Pathways/Molecules between ALD and NAFLD | |||
---|---|---|---|
Cellular Response | Affected Signaling Molecules/Pathways | References | |
Hepatic fat accumulation | Increased: SREBP1c, SIRT1, ACC, SCD, DGAT Decreased: PPARs, AMPK, CPT | [42] | |
Cell death | Increased: TRAIL-R2, cell-intrinsic organelle stress, TNFα | [42,70,71,72,73] | |
Fibrogenesis | Increased: MCP1/CCR2, HMGB1/TLR4, TGFβ | [42] | |
Several forms of hepatocyte death | Increased: apoptosis, necroptosis, pyroptosis, ferroptosis | [74] | |
miRNA | Increased: miR-155 Decreased: miR-122, miR-320, miR-486, miR-705, miR-1224, miR-27b, miR-214, miR-199a, miR-192, and miR-183 | [42,75] | |
Differences: Distinct Signaling Pathways/Molecules between ALD and NAFLD | |||
Cellular Response | Affected Signaling Molecules/Pathways | References | |
ALD | NAFLD | ||
Hepatic fat accumulation | Microsteatosis > Macrosteatosis | Microsteatosis < Macrosteatosis | [76] |
Lipotoxicity | The contribution of lipotoxiciy not clearly defined | Increased | [42,77] |
Insulin resistance | Often accompanied but not clearly defined | Frequently involved and associated with hyperglycemia and type 2 diabetes | [42,78] |
Inflammation (macrophage) | Myd88 not involved in TLR4 signaling: type 1 IFNs | Myd88 recruited to TLR4 : proinflammatory cytokines | [42,53,64,79,80] |
Microbiota (in fecal) | Increased: Candida albicans, endothelin-converting enzyme | Increased: Prevotella, Porphyromonas Decreased: Bactroidetes | [42,81,82,83] |
miRNA | Increased: miR-217, miR-132 | Increased: miR-34a Decreased: let7d | [42,84,85,86,87,88,89] |
Inflammasome activation | Mostly observed in macrophages during early phase of disease progression | Occasionally observed in hepatocytes during late phase of disease progression | [42] |
Necroptosis | RIPK-3 dependent RIPK-1 independent ALT < AST | RIPK-3 independent ALT > AST | [42,57,90] |
Agents | Classification (Type of Molecule) | Mechanism of Action | Clinical Trials (Identifier) | |
---|---|---|---|---|
ALD/AH | NAFLD/NASH | |||
Anakinra (+Zinc) | Anti-inflammation: Lowers hepatic inflammation (IL-1 receptor antagonist) | NCT04072822 | ||
NCT01809132 | ||||
NCT03775109 | ||||
Metadoxine | Antioxidant: Hepatoprotection from oxidative stress (alcohol metabolism inducer) | NCT02161653 | NCT02051842 NCT02541045 | |
NCT02019056 | ||||
NCT01504295 | ||||
Emricasan (IDN-6556) | Hepatocellular protection: Lowers apoptosis (pan-caspase inhibitor) | NCT01912404 NCT01937130 | NCT02077374 | |
NCT02686762 | ||||
NCT02960204 | ||||
Selonsertib (GS-4997) | Hepatocellular protection: Lowers apoptosis (ASK1 inhibitor) | NCT02854631 | NCT03053050 | |
NCT03053063 | ||||
NCT03449446 | ||||
NCT02781584 | ||||
G-CSF | Hepatocellular regeneration: Promotes liver regeneration (Growth factor | NCT04066179 | ||
NCT01820208 | ||||
NCT03703674 | ||||
IL-22 (F-652) | Hepatocellular regeneration: Lowers inflammation and increases liver regeneration (IL-10 family cytokine) | NCT01918462 | ||
NCT02655510 | ||||
Obeticholic acid | Hepatocellular regeneration and protection: increases liver regeneration and improves cell viability and cholestasis (FXR agonist) | NCT02039219 | NCT03836937 | |
NCT01265498 | ||||
NCT02548351 | ||||
NCT02633956 | ||||
Amoxicillin clavulanate | Anti-infection and anti-inflammation: decreases the risk of infection and lowers inflammation (Antibiotics) | NCT02281929 | ||
Rifaximin | Anti-infection and anti-inflammation: decreases the risk of infection and lowers inflammation (Antibiotics) | NCT02116556 NCT02485106 | NCT02884037 | |
NCT01355575 | ||||
NCT02009592 | ||||
Cenicriviroc | Anti-inflammation: Lowers hepatic inflammation (CCR2/CCR5 dual inhibitor) | NCT03028740 | ||
NCT02217475 | ||||
NCT03059446 | ||||
NCT03517540 | ||||
Namodenoson | Anti-inflammation and anti-steatosis: Lowers hepatic inflammation and hepatic fat contents (Adenosine A3 receptor agonist) | NCT04697810 | ||
NCT02927314 |
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Ha, Y.; Jeong, I.; Kim, T.H. Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022, 10, 2530. https://doi.org/10.3390/biomedicines10102530
Ha Y, Jeong I, Kim TH. Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines. 2022; 10(10):2530. https://doi.org/10.3390/biomedicines10102530
Chicago/Turabian StyleHa, Yoonji, Inju Jeong, and Tae Hyun Kim. 2022. "Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives" Biomedicines 10, no. 10: 2530. https://doi.org/10.3390/biomedicines10102530
APA StyleHa, Y., Jeong, I., & Kim, T. H. (2022). Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines, 10(10), 2530. https://doi.org/10.3390/biomedicines10102530