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AJR. American Journal of Roentgenology Jan 2024Alcohol-associated liver disease (ALD) continues to be a global health concern, responsible for a significant number of deaths worldwide. Although most individuals who... (Review)
Review
Alcohol-associated liver disease (ALD) continues to be a global health concern, responsible for a significant number of deaths worldwide. Although most individuals who consume alcohol do not develop ALD, heavy drinkers and binge drinkers are at increased risk. Unfortunately, ALD is often undetected until it reaches advanced stages, frequently associated with portal hypertension and hepatocellular carcinoma (HCC). ALD is now the leading indication for liver transplant. The incidence of alcohol-associated hepatitis (AH) surged during the COVID-19 pandemic. Early diagnosis of ALD is therefore important in patient management and determination of prognosis, as abstinence can halt disease progression. The spectrum of ALD includes steatosis, steatohepatitis, and cirrhosis, with steatosis the most common manifestation. Diagnostic techniques including ultrasound, CT, and MRI provide useful information for identifying ALD and excluding other causes of liver dysfunction. Heterogeneous steatosis and transient perfusion changes on CT and MRI in the clinical setting of alcohol-use disorder are diagnostic of severe AH. Elastography techniques are useful for assessing fibrosis and monitoring treatment response. These various imaging modalities are also useful in HCC surveillance and diagnosis. This review discusses the imaging modalities currently used in the evaluation of ALD, highlighting their strengths, limitations, and clinical applications.
Topics: Humans; Carcinoma, Hepatocellular; Pandemics; Liver Neoplasms; Liver Diseases, Alcoholic; Magnetic Resonance Imaging; Liver
PubMed: 37729554
DOI: 10.2214/AJR.23.29917 -
ELife Dec 2023The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45)...
The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and antigens. Further, both Ig- and -captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and -captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.
Topics: Humans; Hepatitis, Alcoholic; Escherichia coli; Immunoglobulin A; Autoantibodies; Immunoglobulin G; Immunoglobulin M
PubMed: 38055614
DOI: 10.7554/eLife.86678 -
International Journal of Molecular... Sep 2023Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several... (Review)
Review
Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities.
Topics: Humans; Hepatitis, Alcoholic; Gastrointestinal Microbiome; Liver Diseases, Alcoholic; Forecasting; Dysbiosis
PubMed: 37834256
DOI: 10.3390/ijms241914809 -
European Journal of Gastroenterology &... Oct 2023Alcohol-associated liver disease is increasing among females with an earlier onset and more severe disease at lower levels of exposure. However, there is paucity of...
BACKGROUND
Alcohol-associated liver disease is increasing among females with an earlier onset and more severe disease at lower levels of exposure. However, there is paucity of literature regarding sex differences related to alcoholic hepatitis.
METHODS
Hospitalized patients with alcoholic hepatitis were selected from the US Nationwide readmissions database 2019. In this cohort, we evaluated sex differences in baseline comorbidities, alcoholic hepatitis related complications and mortality. A subset of patients with alcoholic hepatitis who were hospitalized between January and June 2019 were identified to study sex differences in 6 month readmission rate, mortality during readmission, and composite of mortality during index hospitalization or readmission.
RESULTS
Among 112 790 patients with alcoholic hepatitis, 33.3% were female. Female patients were younger [48 (38-57) vs. 49 (39-58) years; both P < 0.001] but had higher rates of important medical and mental-health related comorbidities. Compared with males, females had higher rates of hepatic encephalopathy (11.5% vs. 10.1; P < 0.001), ascites (27.9% vs. 22.5%; P < 0.001), portal hypertension (18.5% vs. 16.4%; P < 0.001), cirrhosis (37.3% vs. 31.9%; P < 0.001), weight loss (19.0% vs. 14.5%; P < 0.001), hepatorenal syndrome (4.4% vs. 3.8%; P < 0.001), spontaneous bacterial peritonitis (1.9% vs. 1.7%; P = 0.026), sepsis (11.1% vs. 9.5%; P < 0.001), and blood transfusion (12.9% vs. 8.7%; P < 0.001). Females had a similar in-hospital mortality rate (4.3%) compared to males (4.1%; P = 0.202; adjusted odds ratio (OR) 1.02, 95% CI (cardiac index) 0.89-1.15; P = 0.994). In the subset of patients ( N = 58 688), females had a higher 6-month readmission rate (48.9% vs. 44.9%; adjusted OR 1.12 (1.06-1.18); P < 0.001), mortality during readmission (4.4% vs. 3.2%; OR 1.23 (1.08-1.40); P < 0.01), and composite of mortality during index hospitalization or readmission (8.7% vs. 7.2%; OR 1.15 (1.04-1.27); P < 0.01).
CONCLUSION
Compared to their male counterparts, females with alcoholic hepatitis were generally younger but had higher rates of comorbidities, alcoholic hepatitis related complications, rehospitalizations and associated mortality. The greater risks of alcohol-associated liver dysfunction in females indicate the need for more aggressive management.
Topics: Humans; Male; Female; Hepatitis, Alcoholic; Sex Characteristics; Retrospective Studies; Hospitalization; Liver Cirrhosis
PubMed: 37577797
DOI: 10.1097/MEG.0000000000002612 -
Cell Adhesion & Migration Dec 2023Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex... (Review)
Review
Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Targeted Therapy; Mutation
PubMed: 37726886
DOI: 10.1080/19336918.2023.2258539 -
Drugs Nov 2023Alcohol is a prominent cause of liver disease worldwide with higher prevalence in developed nations. The spectrum of alcohol-associated liver disease (ALD) encompasses a... (Review)
Review
Alcohol is a prominent cause of liver disease worldwide with higher prevalence in developed nations. The spectrum of alcohol-associated liver disease (ALD) encompasses a diverse range of clinical entities, from asymptomatic isolated steatosis to decompensated cirrhosis, and in some cases, acute or chronic liver failure. Consequently, it is important for healthcare practitioners to maintain awareness and systematically screen for ALD. The optimal evaluation and management of ALD necessitates a collaborative approach, incorporating a multidisciplinary team and accounting for concurrent medical conditions. A repertoire of therapeutic interventions exists to support patients in achieving alcohol cessation and sustaining remission, with complete abstinence being the ultimate objective. This review explores the existing therapeutic options for ALD acknowledging geographical discrepancies in accessibility. Recent innovations, including the inclusion of alcohol consumption biomarkers into clinical protocols and the expansion of liver transplantation eligibility to encompass severe alcohol-associated hepatitis, are explored.
Topics: Humans; Liver Diseases, Alcoholic; Liver Transplantation; Fatty Liver
PubMed: 37747685
DOI: 10.1007/s40265-023-01939-9 -
Journal of Gastroenterology and... Aug 2023The socioeconomic burden of alcohol-related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol-related liver... (Review)
Review
The socioeconomic burden of alcohol-related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol-related liver disease are rarely diagnosed in the earlier phase of the disease spectrum. Alcoholic hepatitis is a distinct syndrome with life-threatening signs of systemic inflammation. In severe alcoholic hepatitis, prednisolone is indicated as the first-line treatment even with the possibility of various complications. Early liver transplantation can be another option for highly selected patients with a null response to prednisolone. Most importantly, abstinence is the mainstay of long-term care, but relapse is frequent among patients. Recent findings on the pathogenesis of alcoholic hepatitis have enabled us to discover new therapeutic targets. Preventing hepatic inflammation, reducing oxidative stress, improving gut dysbiosis, and enhancing liver regeneration are the main targets of emerging therapies. Herein, we review the pathogenesis, current treatment, and barriers to successful clinical trials of alcoholic hepatitis. Additionally, clinical trials for alcoholic hepatitis, either ongoing or recently completed, will be briefly introduced.
Topics: Humans; Hepatitis, Alcoholic; Liver Diseases, Alcoholic; Prednisolone; Liver Transplantation; Inflammation
PubMed: 37300449
DOI: 10.1111/jgh.16257 -
Liver International : Official Journal... Nov 2023This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal... (Review)
Review
This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal cells. Their presence and accumulation are considered to be a major pathological hallmark of the health and fate of liver parenchymal cells that leads to overall tissue deterioration and eventually results in organ failure. The first description on giant mitochondria dates back to the 1960s, coinciding with the availability of the first generation of electron microscopes in clinical diagnostic laboratories. Detailed accounts on their ultrastructure have mostly been described in patients suffering from alcoholic liver disease, chronic hepatitis, hepatocellular carcinoma and non-alcoholic fatty liver disease. Interestingly, from this extensive literature survey, it became apparent that giant mitochondria or megamitochondria present themselves with or without highly organised crystal-like intramitochondrial inclusions. The origin, formation and potential role of giant mitochondria remain to-date largely unanswered. Likewise, the biochemical composition of the well-organised crystal-like inclusions and their possible impact on mitochondrial function is unclear. Herein, concepts about the possible mechanism of their formation and three-dimensional architecture will be approached. We will furthermore discuss their importance in diagnostics, including future research outlooks and potential therapeutic interventions to cure liver disease where giant mitochondria are implemented.
Topics: Humans; Mitochondrial Swelling; Mitochondria, Liver; Liver Diseases, Alcoholic; Non-alcoholic Fatty Liver Disease; Hepatitis, Chronic; Liver
PubMed: 37615254
DOI: 10.1111/liv.15711 -
Dysregulated meta-organismal metabolism of aromatic amino acids in alcohol-associated liver disease.Hepatology Communications Nov 2023Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated... (Comparative Study)
Comparative Study
BACKGROUND
Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated liver disease (ALD) have been characterized, less is known about the interactions between host metabolism and circulating microbe-derived metabolites during the progression of ALD.
METHODS
A large panel of gut microbiome-derived metabolites of aromatic amino acids was quantified by stable isotope dilution liquid chromatography with online tandem mass spectrometry in plasma from healthy controls (n = 29), heavy drinkers (n = 10), patients with moderate (n = 16) or severe alcohol-associated hepatitis (n = 40), and alcohol-associated cirrhosis (n = 10).
RESULTS
The tryptophan metabolites, serotonin and indole-3-propionic acid, and tyrosine metabolites, p-cresol sulfate, and p-cresol glucuronide, were decreased in patients with ALD. Patients with severe alcohol-associated hepatitis and alcohol-associated cirrhosis had the largest decrease in concentrations of tryptophan and tyrosine-derived metabolites compared to healthy control. Western blot analysis and interrogation of bulk RNA sequencing data from patients with various liver pathologies revealed perturbations in hepatic expression of phase II metabolism enzymes involved in sulfonation and glucuronidation in patients with severe forms of ALD.
CONCLUSIONS
We identified several metabolites decreased in ALD and disruptions of hepatic phase II metabolism. These results indicate that patients with more advanced stages of ALD, including severe alcohol-associated hepatitis and alcohol-associated cirrhosis, had complex perturbations in metabolite concentrations that likely reflect both changes in the composition of the gut microbiome community and the ability of the host to enzymatically modify the gut-derived metabolites.
Topics: Humans; Amino Acids, Aromatic; Hepatitis; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Tryptophan; Tyrosine; Gastrointestinal Microbiome; Hepatitis, Alcoholic; Liver
PubMed: 37820283
DOI: 10.1097/HC9.0000000000000284