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Praxis Sep 2023Cirrhosis is a common disease with high morbidity and mortality. In industrialised countries, the most common causes of cirrhosis are the alcoholic liver disease,...
Cirrhosis is a common disease with high morbidity and mortality. In industrialised countries, the most common causes of cirrhosis are the alcoholic liver disease, non-alcoholic fatty liver disease and chronic viral hepatitis. Cirrhosis is often diagnosed late, as it can be asymptomatic for a long time. Therefore, hepatopathy screening in high-risk patients and fibrosis surveillance using the ultrasound, in the presence of a chronic hepatopathy are essential. A liver biopsy is necessary to confirm the diagnosis. With optimal therapy, in some cases, cirrhosis is preventable and potentially reversible in others. In the stage of decompensation, typically characterised by ascites, patients often die from recurrent infections or hepatocellular carcinoma unless cured by liver transplantation. The prevention and treatment of complications as well as the evaluation of a transplant require cooperation with a centre hospital.
Topics: Humans; Liver Cirrhosis; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Liver Transplantation; Liver Neoplasms
PubMed: 37823811
DOI: No ID Found -
Journal of Hepatology Sep 2023Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to...
BACKGROUND & AIMS
Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood.
METHODS
HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity.
RESULTS
Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.
CONCLUSIONS
This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH.
IMPACT AND IMPLICATIONS
Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
Topics: Animals; Mice; Cellular Reprogramming; Hepatitis, Alcoholic; Hepatocytes; Inflammation; Liver
PubMed: 37088308
DOI: 10.1016/j.jhep.2023.04.013 -
Hepatology Communications Sep 2023Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring...
Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring invasive fungal infections (IFIs). These infections carry high morbidity and mortality. Multiple factors, including host immune dysfunction, barrier failures, malnutrition, and microbiome alterations, increase the risk of developing IFI. Candida remains the most common fungal pathogen causing IFI. However, other pathogens, including Aspergillus, Cryptococcus, Pneumocystis, and endemic mycoses, are being increasingly recognized. The diagnosis of IFIs can be ascertained by the direct observation or isolation of the pathogen (culture, histopathology, and cytopathology) or by detecting antigens, antibodies, or nucleic acid. Here, we provide an update on the epidemiology, pathogenesis, diagnosis, and management of IFI in patients with liver disease and liver transplantation.
Topics: Humans; Liver Diseases; Invasive Fungal Infections; Liver Transplantation; Cytology; Hepatitis, Alcoholic
PubMed: 37639701
DOI: 10.1097/HC9.0000000000000216 -
Liver International : Official Journal... Nov 2023Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways.
METHODS
We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association.
RESULTS
Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%).
CONCLUSIONS
Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Genome-Wide Association Study; Mendelian Randomization Analysis; Educational Status; Liver Cirrhosis; Liver Neoplasms; Hepatomegaly; Hepatitis, Chronic; Hepatitis, Viral, Human; Polymorphism, Single Nucleotide
PubMed: 37409353
DOI: 10.1111/liv.15669 -
Liver International : Official Journal... Oct 2023Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic... (Review)
Review
Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.
Topics: Humans; Hepatitis, Alcoholic; Pandemics; COVID-19; Liver Diseases, Alcoholic
PubMed: 37605624
DOI: 10.1111/liv.15701 -
World Journal of Hepatology Feb 2024Cytokines play pleiotropic roles in human health and disease by regulating both innate and adaptive immune responses. Interleukins (ILs), a large group of cytokines, can...
Cytokines play pleiotropic roles in human health and disease by regulating both innate and adaptive immune responses. Interleukins (ILs), a large group of cytokines, can be divided into seven families, including IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and IL-17 families. Here, we review the functions of ILs in the pathogenesis and resolution of liver diseases, such as liver inflammation (, IL-35), alcohol-related liver disease (, IL-11), non-alcoholic steatohepatitis (, IL-22), liver fibrosis (, Il-17a), and liver cancer (, IL-8). Overall, IL-1 family members are implicated in liver inflammation induced by different etiologies, such as alcohol consumption, high-fat diet, and hepatitis viruses. IL-2 family members mainly regulate T lymphocyte and NK cell proliferation and activation, and the differentiation of T cells. IL-6 family cytokines play important roles in acute phase response in liver infection, liver regeneration, and metabolic regulation, as well as lymphocyte activation. IL-8, also known as CXCL8, is activated in chronic liver diseases, which is associated with the accumulation of neutrophils and macrophages. IL-10 family members contribute key roles to liver immune tolerance and immunosuppression in liver disease. IL-12 family cytokines influence T-cell differentiation and play an essential role in autoimmune liver disease. IL-17 subfamilies contribute to infection defense, liver inflammation, and Th17 cell differentiation. ILs interact with different type I and type II cytokine receptors to regulate intracellular signaling pathways that mediate their functions. However, most clinical studies are only performed to evaluate IL-mediated therapies on alcohol and hepatitis virus infection-induced hepatitis. More pre-clinical and clinical studies are required to evaluate IL-mediated monotherapy and synergistic therapies.
PubMed: 38495285
DOI: 10.4254/wjh.v16.i2.140 -
Antioxidants (Basel, Switzerland) Aug 2023The liver is an organ that is particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also during the... (Review)
Review
The liver is an organ that is particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also during the biotransformation of xenobiotics. The disruption of redox balance causes oxidative stress, which affects liver function, modulates inflammatory pathways and contributes to disease. Thus, oxidative stress is implicated in acute liver injury and in the pathogenesis of prevalent infectious or metabolic chronic liver diseases such as viral hepatitis B or C, alcoholic fatty liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Moreover, oxidative stress plays a crucial role in liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Herein, we provide an overview on the effects of oxidative stress on liver pathophysiology and the mechanisms by which oxidative stress promotes liver disease.
PubMed: 37759956
DOI: 10.3390/antiox12091653 -
Primary Care Sep 2023Abnormal liver tests are one of the most common challenges in the primary care setting. Primary care practitioners order these tests for numerous reasons, including... (Review)
Review
Abnormal liver tests are one of the most common challenges in the primary care setting. Primary care practitioners order these tests for numerous reasons, including investigating abdominal signs and symptoms or suspected alcohol-use disorder, or to determine medication adverse effects. Evaluation should be guided by both the clinical presentation and the pattern of injury. In this article, we will focus on the epidemiology, pathophysiology, clinical presentation, diagnostic work-up, and management of elevated liver enzymes, with an emphasis on the most common causes of abnormal liver testing.
Topics: Humans; Liver; Liver Diseases
PubMed: 37516508
DOI: 10.1016/j.pop.2023.03.007 -
European Journal of Gastroenterology &... Sep 2023Autoimmune liver diseases include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. They are chronic, heterogenous diseases...
Autoimmune liver diseases include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. They are chronic, heterogenous diseases affecting the liver which is a key metabolic organ that ensures glucose homeostasis. It is well known that patients with other chronic liver diseases such as cirrhosis and nonalcoholic fatty liver disease (NAFLD) display glucose disturbances like insulin resistance and have an increased risk of diabetes. Previous evidence on glucose disturbances in patients with autoimmune liver disease is scarce but does point towards a potentially increased risk of type 1 diabetes and type 2 diabetes. The underlying mechanisms are unknown but may reflect genetic predisposition, concurrent NAFLD and or cirrhosis development, and treatment (steroid) related impairment of glucose homeostasis. Therefore, increased awareness and surveillance of diabetes development in patients with autoimmune liver disease may be important. Overall, detection and treatment of diabetes generally follow the usual diabetes guidelines; however, in patients with advanced liver cirrhosis, HbA1c may not be a reliable marker of average glucose levels, and treatment with insulin is generally recommended. In addition, it has recently been suggested that sodium-glucose cotransporter 2 inhibitors may be beneficial in treating refractory ascites. Further research on diabetes risk in autoimmune liver disease is warranted.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Liver Cirrhosis, Biliary; Cholangitis, Sclerosing; Liver Diseases; Autoimmune Diseases; Hepatitis, Autoimmune; Chronic Disease; Liver Cirrhosis; Glucose; Liver
PubMed: 37505973
DOI: 10.1097/MEG.0000000000002594 -
Journal of Clinical and Translational... Nov 2023Alcohol-associated liver disease (ALD) is one of the most common liver diseases and indications for liver transplantation (LT). Alcohol use disorder (AUD), a frequent... (Review)
Review
Alcohol-associated liver disease (ALD) is one of the most common liver diseases and indications for liver transplantation (LT). Alcohol use disorder (AUD), a frequent accompaniment in ALD patients, may also be associated with psychiatric comorbidities such as depression and anxiety. Identification of ALD at an earlier stage, and treatment of AUD may help prevent progression to advanced stage of ALD such as cirrhosis and alcoholic hepatitis. Screening for alcohol use and AUD treatment in ALD patients is often not performed due to several barriers at the level of patients, clinicians, and administrative levels. This review details the integrated multidisciplinary care model especially on the specific role of the hepatologist, psychiatrist, addiction counselor, and social worker in providing complete management for the dual pathology of liver disease and of AUD. Laboratory assessment, pharmacological and behavioral therapies, and recommended assessments for follow-up care by the respective specialists is outlined. We provide perspective along with the literature support, with the goal of providing team based comprehensive care of patients with ALD.
PubMed: 37719958
DOI: 10.14218/JCTH.2023.00002