Non-alcoholic and Alcohol-Associated Liver Injury

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 13907

Special Issue Editors

Department of Internal Medicine, University of Nebraska Medical Center, Veteran Affairs Medical Center, 4101 Woolworth Ave, R151, Omaha, NE 68105-8080, USA
Interests: hepatitis C, B, HIV and other viral hepatitis; alcoholic liver disease; innate immunity; antigen presentation; proteasome; protein posttranslational modifications; animal models for hepatitis study
Special Issues, Collections and Topics in MDPI journals
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
Interests: alcoholic liver disease; protein methylation; gut-liver axis in alcoholic liver disease; non-alcoholic steatohepatitis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is the expanded second edition of Non-alcoholic Liver Injury that 1st edition was resulted in publishing of 15 papers and two Webinars Non-alcohol and Non-infection-Associated Liver Diseases and Infection-Associated Liver Diseases.

Non-alcoholic liver disease is defined as liver injury of any etiology which is not induced by chronic alcohol abuse. The main histological features of most liver damage of diverse etiology are fat accumulation, steatohepatitis and progression to liver fibrosis, cirrhosis and HCC. These changes may be due to metabolic abnormalities programmed at a genetic level or triggered by extrinsic factors, including chronic infections with hepatotropic viruses and HIV. They can be also attributed to liver cancer or toxic hepatitis. In many cases, non-alcoholic liver injury is potentiated by alcohol abuse, which induces a very rapid progression to end-stage liver disease and worsens disease outcome.

For this Special Issue, “Non-alcoholic and Alcohol-Associated Liver Injury”, we encourage the submission of manuscripts on any aspects of non-alcoholic and alcohol-associated liver injury (either alone or in combination) on etiology, epidemiology, pathogenesis, organ–organ interactions, progression to end-stage liver disease, and/or treatment. We welcome the submission of review articles as well as short- and full-size original research articles to this topical Special Issue.

Prof. Dr. Natalia Osna
Prof. Dr. Kusum K. Kharbanda
Guest Editors

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Keywords

  • non-alcoholic steatohepatitis
  • alcohol-associated liver disease
  • hepatotropic infections
  • pathogenesis
  • treatment

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Published Papers (9 papers)

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21 pages, 5031 KiB  
Article
Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies
by Diego Montoya-Durango, Mary Nancy Walter, Walter Rodriguez, Yali Wang, Julia H. Chariker, Eric C. Rouchka, Claudio Maldonado, Shirish Barve, Craig J. McClain and Leila Gobejishvili
Biology 2023, 12(10), 1321; https://doi.org/10.3390/biology12101321 - 10 Oct 2023
Viewed by 1677
Abstract
Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, [...] Read more.
Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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15 pages, 2500 KiB  
Article
MicroRNAs Signature Panel Identifies Heavy Drinkers with Alcohol-Associated Cirrhosis from Heavy Drinkers without Liver Injury
by Fathima Shihana, Mugdha V. Joglekar, Tae-Hwi Schwantes-An, Anandwardhan A. Hardikar and Devanshi Seth
Biology 2023, 12(10), 1314; https://doi.org/10.3390/biology12101314 - 08 Oct 2023
Viewed by 1013
Abstract
Background: Alcohol-associated liver disease (ALD) is the most common disorder of prolonged drinking. Mechanisms underlying cirrhosis in such patients remain unclear. MicroRNAs play regulatory role in several diseases, are affected by alcohol and may be important players in alcohol use disorders, such as [...] Read more.
Background: Alcohol-associated liver disease (ALD) is the most common disorder of prolonged drinking. Mechanisms underlying cirrhosis in such patients remain unclear. MicroRNAs play regulatory role in several diseases, are affected by alcohol and may be important players in alcohol use disorders, such as cirrhosis. Methods: We investigated serum samples from heavy chronic alcohol users (80 g/day (male) and 50 g/day (female) for ≥10 years) that were available from our previously reported GenomALC study. A subset of GenomALC drinkers with liver cirrhosis (cases, n = 24) and those without significant liver disease (drinking controls, n = 23) were included. Global microRNA profiling was performed using high-throughput real-time quantitative PCR to identify the microRNA signatures associated with cirrhosis. Ingenuity Pathway Analysis (IPA) software was utilized to identify target mRNAs of significantly altered microRNAs, and molecular pathways were analysed. Identified microRNAs were analysed for correlation with traditional liver disease biomarkers and risk gene variants previously reported from GenomALC genome-wide association study. Results: The expression of 21 microRNAs was significantly downregulated in cases compared to drinking controls (p < 0.05, ∆∆Ct > 1.5-fold). Seven microRNAs (miR-16, miR-19a, miR-27a, miR-29b, miR-101, miR-130a, and miR-191) had a highly significant correlation (p < 0.001) with INR, bilirubin and MELD score. Three microRNAs (miR-27a, miR-130a and miR-191) significantly predicted cases with AUC-ROC 0.8, 0.78 and 0.85, respectively (p < 0.020); however, INR performed best (0.97, p < 0.001). A different set of six microRNAs (miR-19a, miR-26a, miR-101, miR-151-3p, miR-221, and miR-301) showed positive correlation (ranging from 0.32 to 0.51, p < 0.05) with rs10433937:HSD17B13 gene variant, associated with the risk of cirrhosis. IPA analysis revealed mRNA targets of the significantly altered microRNAs associated with cell death/necrosis, fibrosis and increased steatosis, particularly triglyceride metabolism. Conclusions: MicroRNA signatures in drinkers distinguished those with liver cirrhosis from drinkers without liver disease. We identified mRNA targets in liver functions that were enriched for disease pathogenesis pathways. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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13 pages, 3278 KiB  
Article
Fpr2−/− Mice Developed Exacerbated Alcohol-Associated Liver Disease
by Josiah E. Hardesty, Jeffrey B. Warner, Ying L. Song, Alison Floyd, Craig J. McClain, Dennis R. Warner and Irina A. Kirpich
Biology 2023, 12(5), 639; https://doi.org/10.3390/biology12050639 - 23 Apr 2023
Viewed by 1380
Abstract
Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate [...] Read more.
Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate the role of formyl peptide receptor 2 (FPR2), a receptor for immunomodulatory signals, in the pathogenesis of ALD. WT and Fpr2−/− mice were exposed to chronic–binge ethanol administration and subsequently assessed for liver injury, inflammation, and markers of regeneration. The differentiation capacity of liver macrophages and the oxidative burst activity of neutrophils were also examined. Compared to WT, Fpr2−/− mice developed more severe liver injury and inflammation and had compromised liver regeneration in response to ethanol administration. Fpr2−/− mice had fewer hepatic monocyte-derived restorative macrophages, and neutrophils isolated from Fpr2−/− mice had diminished oxidative burst capacity. Fpr2−/− MoMF differentiation was restored when co-cultured with WT neutrophils. Loss of FPR2 led to exacerbated liver damage via multiple mechanisms, including abnormal immune responses, indicating the crucial role of FPR2 in ALD pathogenesis. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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16 pages, 2723 KiB  
Article
Lipidomic Analysis of Liver Lipid Droplets after Chronic Alcohol Consumption with and without Betaine Supplementation
by Madan Kumar Arumugam, Sathish Kumar Perumal, Karuna Rasineni, Terrence M. Donohue, Jr., Natalia A. Osna and Kusum K. Kharbanda
Biology 2023, 12(3), 462; https://doi.org/10.3390/biology12030462 - 16 Mar 2023
Cited by 3 | Viewed by 1460
Abstract
The earliest manifestation of alcohol-associated liver disease is hepatic steatosis, which is characterized by fat accumulation in specialized organelles called lipid droplets (LDs). Our previous studies reported that alcohol consumption elevates the numbers and sizes of LDs in hepatocytes, which is attenuated by [...] Read more.
The earliest manifestation of alcohol-associated liver disease is hepatic steatosis, which is characterized by fat accumulation in specialized organelles called lipid droplets (LDs). Our previous studies reported that alcohol consumption elevates the numbers and sizes of LDs in hepatocytes, which is attenuated by simultaneous treatment with the methyl group donor, betaine. Here, we examined changes in the hepatic lipidome with respect to LD size and dynamics in male Wistar rats fed for 6 weeks with control or ethanol-containing liquid diets that were supplemented with or without 10 mg betaine/mL. At the time of sacrifice, three hepatic LD fractions, LD1 (large droplets), LD2 (medium-sized droplets), and LD3 (small droplets) were isolated from each rat. Untargeted lipidomic analyses revealed that each LD fraction of ethanol-fed rats had higher phospholipids, cholesteryl esters, diacylglycerols, ceramides, and hexosylceramides compared with the corresponding fractions of pair-fed controls. Interestingly, the ratio of phosphatidylcholine to phosphatidylethanolamine (the two most abundant phospholipids on the LD surface) was lower in LD1 fraction compared with LD3 fraction, irrespective of treatment; however, this ratio was significantly lower in ethanol LD fractions compared with their respective control fractions. Betaine supplementation significantly attenuated the ethanol-induced lipidomic changes. These were mainly associated with the regulation of LD surface phospholipids, ceramides, and glycerolipid metabolism in different-sized LD fractions. In conclusion, our results show that ethanol-induced changes in the hepatic LD lipidome likely stabilizes larger-sized LDs during steatosis development. Furthermore, betaine supplementation could effectively reduce the size and dynamics of LDs to attenuate alcohol-associated hepatic steatosis. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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9 pages, 472 KiB  
Article
Outnumbered: Control Prothrombin Time in Maddrey’s Discriminant Function Impacts Steroid Use but Not Mortality in Alcoholic Hepatitis
by Marcus Healey and Richard K. Sterling
Biology 2022, 11(12), 1833; https://doi.org/10.3390/biology11121833 - 16 Dec 2022
Viewed by 1496
Abstract
Background and aims: In alcoholic hepatitis (AH), increases in the total bilirubin (TB) and the prothrombin time (PT), which are included in the Maddrey’s discriminant function (MDF) and the model for end-stage liver disease (MELD), are associated with poor outcomes. However, the impact [...] Read more.
Background and aims: In alcoholic hepatitis (AH), increases in the total bilirubin (TB) and the prothrombin time (PT), which are included in the Maddrey’s discriminant function (MDF) and the model for end-stage liver disease (MELD), are associated with poor outcomes. However, the impact of which control PT in the MDF to use compared to the MELD on the outcomes in AH is unknown. Our aim is to determine whether the choice of the control PT used in the MDF calculations has any impact on steroid use and survival when compared to the MELD in those with AH. Methods: Through retrospective chart review, we analyzed 882 subjects who were admitted from 2012 to 2020 with acute AH. Their MDF was calculated [(TB + 4.6 × (PT–control)] using the following three different control PTs: 12, 13.5, and 14.8 s, and was compared to the MELD. The primary outcomes were steroid use and 30-day survival. Results: When it was stratified by the control PT, the percentage of MDF ≥ 32 (the threshold for steroids) decreased with increasing control PT (70%, 61%, and 52%, respectively), along with decreased steroid use (91%, 84%, and 75%, respectively). Those who received steroids were not shown to have improved 30-day survival compared to those who did not receive steroids (p = 0.41). The ability of the MDF for each control PT threshold to predict 30-day survival was similar (AUROC 0.735), and was lower compared to the MELD (0.767). Conclusion: While the choice of PT control in the MDF impacted the use of steroids in AH, the use of steroids and the choice of PT control used did not impact the overall survival. Regardless of which control PT was used in the MDF, the MELD was better at predicting 30-day survival. Important information: Background: Treatment with steroids is indicated in alcoholic hepatitis (AH) with Maddrey discriminant function (MDF) ≥ 32 and the model for end-stage liver disease (MELD) ≥ 20. The impact that the control prothrombin time (PT) value that is used in MDF has on steroid use and survival in AH is poorly understood. Findings: The choice of control PT that is used when calculating the MDF impacts the use of steroids but does not impact mortality. The MELD was better than the MDF at any control PT used in predicting survival in acute AH. Implications for patient care: Providers should be aware that higher control PT’s have an effect on treatment decisions but should not generally impact survival in this population. The MELD appears to better predict 30-day survival in this population. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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Review

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26 pages, 17705 KiB  
Review
Mitochondrial Dysfunction-Associated Mechanisms in the Development of Chronic Liver Diseases
by Madan Kumar Arumugam, Thiyagarajan Gopal, Rakhee Rathnam Kalari Kandy, Lokesh Kumar Boopathy, Sathish Kumar Perumal, Murali Ganesan, Karuna Rasineni, Terrence M. Donohue, Jr., Natalia A. Osna and Kusum K. Kharbanda
Biology 2023, 12(10), 1311; https://doi.org/10.3390/biology12101311 - 05 Oct 2023
Cited by 2 | Viewed by 1766
Abstract
The liver is a major metabolic organ that performs many essential biological functions such as detoxification and the synthesis of proteins and biochemicals necessary for digestion and growth. Any disruption in normal liver function can lead to the development of more severe liver [...] Read more.
The liver is a major metabolic organ that performs many essential biological functions such as detoxification and the synthesis of proteins and biochemicals necessary for digestion and growth. Any disruption in normal liver function can lead to the development of more severe liver disorders. Overall, about 3 million Americans have some type of liver disease and 5.5 million people have progressive liver disease or cirrhosis, in which scar tissue replaces the healthy liver tissue. An estimated 20% to 30% of adults have excess fat in their livers, a condition called steatosis. The most common etiologies for steatosis development are (1) high caloric intake that causes non-alcoholic fatty liver disease (NAFLD) and (2) excessive alcohol consumption, which results in alcohol-associated liver disease (ALD). NAFLD is now termed “metabolic-dysfunction-associated steatotic liver disease” (MASLD), which reflects its association with the metabolic syndrome and conditions including diabetes, high blood pressure, high cholesterol and obesity. ALD represents a spectrum of liver injury that ranges from hepatic steatosis to more advanced liver pathologies, including alcoholic hepatitis (AH), alcohol-associated cirrhosis (AC) and acute AH, presenting as acute-on-chronic liver failure. The predominant liver cells, hepatocytes, comprise more than 70% of the total liver mass in human adults and are the basic metabolic cells. Mitochondria are intracellular organelles that are the principal sources of energy in hepatocytes and play a major role in oxidative metabolism and sustaining liver cell energy needs. In addition to regulating cellular energy homeostasis, mitochondria perform other key physiologic and metabolic activities, including ion homeostasis, reactive oxygen species (ROS) generation, redox signaling and participation in cell injury/death. Here, we discuss the main mechanism of mitochondrial dysfunction in chronic liver disease and some treatment strategies available for targeting mitochondria. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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19 pages, 985 KiB  
Review
A Pathogenic Role of Non-Parenchymal Liver Cells in Alcohol-Associated Liver Disease of Infectious and Non-Infectious Origin
by Kusum K. Kharbanda, Shilpa Chokshi, Irina Tikhanovich, Steven A. Weinman, Moses New-Aaron, Murali Ganesan and Natalia A. Osna
Biology 2023, 12(2), 255; https://doi.org/10.3390/biology12020255 - 06 Feb 2023
Cited by 3 | Viewed by 1570
Abstract
Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on [...] Read more.
Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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Other

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10 pages, 1955 KiB  
Brief Report
Reduction in Obesity-Related Hepatic Fibrosis by SR1664
by Benita L. McVicker, Ronda L. Simpson, Frederick G. Hamel and Robert G. Bennett
Biology 2023, 12(10), 1287; https://doi.org/10.3390/biology12101287 - 26 Sep 2023
Viewed by 911
Abstract
Peroxisome-proliferator-activated receptor gamma (PPARγ) is a transcription factor with adipogenic, insulin-sensitizing, and antifibrotic properties. Strong PPARγ activators, such as the thiazolidinediones, can induce unwanted effects such as edema, weight gain, and bone loss, and therefore selective modulators of PPARγ are in development. We [...] Read more.
Peroxisome-proliferator-activated receptor gamma (PPARγ) is a transcription factor with adipogenic, insulin-sensitizing, and antifibrotic properties. Strong PPARγ activators, such as the thiazolidinediones, can induce unwanted effects such as edema, weight gain, and bone loss, and therefore selective modulators of PPARγ are in development. We previously reported that one selective PPARγ modulator, SR1664, reduced toxin-induced hepatic fibrosis and the activation of hepatic stellate cells (HSCs), the main collagen-producing liver cell in fibrosis. In this study, we used a high fat and high carbohydrate (HFHC) model of hepatic steatosis and fibrosis to determine the effect of SR1664. Mice were placed on a standard chow or HFHC diet for 16 weeks, with SR1664 or control treatment for the final 4 weeks. SR1664 did not alter weight gain or fasting insulin or glucose levels. The size of lipid droplets in the HFHC group was reduced by SR1664, but there was no effect on total liver triglyceride levels. The degree of fibrosis was significantly reduced by SR1664 in mice on the HFHC diet, and this was accompanied by a decrease in activated HSC. In summary, SR1664 improved insulin sensitivity and reduced fibrosis in the HFHC diet, suggesting selective PPARγ modulation is effective in obesity-related liver fibrosis. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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12 pages, 2210 KiB  
Systematic Review
Alcohol Use and the Risk of Colorectal Liver Metastasis: A Systematic Mapping Review
by Roshan Sapkota, Joseph Zakaria, Emily Glenn, Heather Richard, Ahmad Rimawi, Martin Tobi and Benita McVicker
Biology 2023, 12(2), 257; https://doi.org/10.3390/biology12020257 - 06 Feb 2023
Cited by 1 | Viewed by 1685
Abstract
The consumption of alcohol has long been associated with the development of liver disease as well as cancers including colorectal cancer (CRC). Leading healthcare concerns include the prevalent use of alcohol and the high burden of CRC mortality. Many CRC deaths are attributed [...] Read more.
The consumption of alcohol has long been associated with the development of liver disease as well as cancers including colorectal cancer (CRC). Leading healthcare concerns include the prevalent use of alcohol and the high burden of CRC mortality. Many CRC deaths are attributed to the development of colorectal liver metastasis (CRLM) as the liver is the foremost site of CRC spread. However, an association has not been defined for the role of alcohol intake and related liver injury with the development of CRLM. Here, a mapping review of recent research was undertaken to evaluate the relationship between alcohol consumption and the risk of CRLM. The literature search revealed 14 articles meeting the inclusion criteria that included patient database analyses and preclinical studies. Most of the human data analyses found alcohol use independently associates with worse CRC outcomes. The preclinical evaluations identified several pathways involved in the alcohol-mediated promotion of CRLM burden and CRC cell metastatic behavior. The limited number of studies identified exposes a significant need for more prospective analyses to define the role of alcohol intake and advanced CRC as well as the translation of preclinical research to fully characterize targetable mechanisms for the generation of new therapeutic options. Full article
(This article belongs to the Special Issue Non-alcoholic and Alcohol-Associated Liver Injury)
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