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Nature Communications Jun 2024Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing...
Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.
Topics: Non-alcoholic Fatty Liver Disease; Animals; Basic Helix-Loop-Helix Transcription Factors; Male; Macrophages; Humans; Mice; Mice, Knockout; Sphingosine; Liver; Mice, Inbred C57BL; Aryl Hydrocarbon Receptor Nuclear Translocator; Liver Cirrhosis; Disease Models, Animal
PubMed: 38834568
DOI: 10.1038/s41467-024-48954-2 -
Biomedicine & Pharmacotherapy =... Jul 2024Liver fibrosis is an intrahepatic chronic damage repair response caused by various reasons such as alcoholic liver, fatty liver, viral hepatitis, autoimmune diseases,... (Review)
Review
Liver fibrosis is an intrahepatic chronic damage repair response caused by various reasons such as alcoholic liver, fatty liver, viral hepatitis, autoimmune diseases, etc., and is closely related to the progression of liver disease. Currently, the mechanisms of liver fibrosis and its treatment are hot research topics in the field of liver disease remedy. Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential, which can ameliorate fibrosis through hepatic-directed differentiation, paracrine effects, and immunomodulation. However, the low inner-liver colonization rate, low survival rate, and short duration of intervention after stem cell transplantation have limited their wide clinical application. With the intensive research on liver fibrosis worldwide, it has been found that MSCs and MSCs-derived exosomes combined with drugs have shown better intervention efficiency than utilization of MSCs alone in many animal models of liver fibrosis. In this paper, we review the interventional effects and mechanisms of mesenchymal stem cells and their exosomes combined with drugs to alleviate hepatic fibrosis in vivo in animal models in recent years, which will provide new ideas to improve the efficacy of mesenchymal stem cells and their exosomes in treating hepatic fibrosis in the clinic.
Topics: Exosomes; Mesenchymal Stem Cells; Humans; Animals; Liver Cirrhosis; Mesenchymal Stem Cell Transplantation
PubMed: 38834005
DOI: 10.1016/j.biopha.2024.116848 -
European Journal of Gastroenterology &... Jul 2024Fatty liver disease (FLD) affects approximately 25% of global adult population. Metabolic-associated fatty liver disease (MAFLD) is a term used to emphasize components...
Fatty liver disease (FLD) affects approximately 25% of global adult population. Metabolic-associated fatty liver disease (MAFLD) is a term used to emphasize components of metabolic syndrome in FLD. MAFLD does not exclude coexistence of other liver disease, but impact of coexisting MAFLD is unclear. We investigated prevalence and characteristics of MAFLD in patients with biopsy-proven autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or toxic liver disease. Liver histopathology and clinical data from Helsinki University Hospital district (1.7 million inhabitants) between 2009 and 2019 were collected from patients with AIH, PBC, PSC, or toxic liver disease at the time of diagnosis. MAFLD was diagnosed as macrovesicular steatosis ≥5% together with obesity, type-2 diabetes, or signs of metabolic dysregulation. Of 648 patients included, steatosis was observed in 15.6% (n = 101), of which 94.1% (n = 95) was due to MAFLD. Prevalence of coexisting MAFLD in the four liver diseases varied between 12.4 and 18.2% (P = 0.483). Fibrosis was more severe in MAFLD among patients with toxic liver disease (P = 0.01). Histopathological characteristics otherwise showed similar distribution among MAFLD and non-FLD controls. Alcohol consumption was higher in MAFLD group among patients with AIH or PBC (P < 0.05 for both). In AIH, smoking was more common in patients with coexisting MAFLD (P = 0.034). Prevalence of coexisting MAFLD in other primary liver diseases is lower than reported in general population. Histopathology of MAFLD patients did not clearly differ from non-FLD ones. Alcohol and smoking were associated with MAFLD in AIH.
Topics: Humans; Male; Female; Middle Aged; Hepatitis, Autoimmune; Prevalence; Liver Cirrhosis, Biliary; Cholangitis, Sclerosing; Adult; Finland; Aged; Chemical and Drug Induced Liver Injury; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity; Metabolic Syndrome; Biopsy; Diabetes Mellitus, Type 2; Retrospective Studies; Risk Factors
PubMed: 38829946
DOI: 10.1097/MEG.0000000000002785 -
Journal of Family Medicine and Primary... Apr 2024Non-alcoholic fatty liver disease (NAFLD) is an escalating global health issue. Early detection and precise diagnosis are imperative for effective management.
CONTEXT
Non-alcoholic fatty liver disease (NAFLD) is an escalating global health issue. Early detection and precise diagnosis are imperative for effective management.
AIM
To evaluate the sociodemographic and clinical attributes of study participants concerning their ultrasound grading with FibroScan and FLI values.
SETTINGS AND DESIGN
A cross-sectional study was carried out among patients visiting gastroenterology clinics at a tertiary care hospital situated in Karachi, Pakistan.
METHODS AND MATERIAL
We included participants after written informed consent underwent an extensive array of laboratory assessments, encompassing liver function tests, lipid profile, fasting blood sugar analysis, hepatitis B and C screening, and abdominal ultrasound, while those with positive hepatitis B or C markers, documented alcohol use, or those who declined to offer informed consent were excluded from the study.
STATISTICAL ANALYSIS
Data were analyzed using SPSS version 26.
RESULTS
Around 225 patients were studied with a median age of 42 years (IQR = 34-50 years). Metabolic syndrome (MetS) was present in 61.8%. Steatosis was not found among 4.9% of patients, whereas severe steatosis was seen among 51.1% of patients. Significant variations in BMI, WC, GGT, and TG levels were identified when comparing FLI scores. The same was observed for the frequency of MetS as FLI scores increased. The agreement between FLI and ultrasound observations was found to be slight (k = 0.077, = 0.027). On the multivariable regression model, having diabetes, elevated serum glutamate pyruvate transaminase levels and mild disease on ultrasound were associated with increased odds of severe steatosis.
CONCLUSION
FLI is a good predictor of frequency of MetS and NAFLD and correlates well with increasing steatosis score (CAP) on FibroScan which can be utilized for early detection of NAFLD in primary care.
PubMed: 38827715
DOI: 10.4103/jfmpc.jfmpc_1789_23 -
Liver International : Official Journal... May 2024To examine the cardiovascular disease (CVD) risks associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and different numbers of...
BACKGROUND
To examine the cardiovascular disease (CVD) risks associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and different numbers of cardiometabolic risk factors (CMRFs) in patients with inflammatory bowel disease (IBD) based on a long-term prospective cohort.
METHODS
Prevalent IBD patients at baseline who were free of CVD, cancer, alcoholic liver disease, cancer and hepatitis B/C virus seropositive were included (N = 4204). MASLD, MASLD subtypes [pure MASLD, MASLD with increased alcohol intake (MetALD)], lean/non-lean MASLD and CMRFs at baseline were defined according to the latest criteria proposed by AASLD and EASL. The primary outcome was incident CVD, including ischaemic heart disease (IHD), heart failure (HF) and stroke. Multivariable Cox proportional hazard models were used to estimate the relationship.
RESULTS
Overall, 1528 (36.4%) were diagnosed with MASLD at baseline. During a median of 13.1-year follow-up, 503 incident CVDs were identified. Compared with IBD-only, IBD-MASLD patients had an increased risk of CVD (HR = 1.77, 95%CI: 1.26-2.49), especially in those with MetALD (HR = 2.34, 1.34-4.11) and lean MASLD (HR = 2.30, 1.13-4.66). As the number of CMRFs increased, the risks of CVD were significantly increased (p <0.001), with a 116% and 92% excess risk in MASLD with 3 CMRFs (HR = 2.16, 1.48-3.15) and ≥4 CMRFs (HR = 1.92, 1.27-2.91). Similar excess risk of incident IHD and HF was observed in IBD-MASLD, either pure MASLD or MetALD, as well as lean/non-lean MASLD.
CONCLUSIONS
MASLD is associated with increased CVD risk in IBD patients, with greater risk as number of CMRFs increased and evidently higher risk in MetALD and lean MASLD patients.
PubMed: 38819640
DOI: 10.1111/liv.15999 -
Biomarker Research May 2024Liver disease is a complex group of diseases with high morbidity and mortality rates, emerging as a major global health concern. Recent studies have highlighted the... (Review)
Review
Liver disease is a complex group of diseases with high morbidity and mortality rates, emerging as a major global health concern. Recent studies have highlighted the involvement of fibrinogen-like proteins, specifically fibrinogen-like protein 1 (FGL1) and fibrinogen-like protein 2 (FGL2), in the regulation of various liver diseases. FGL1 plays a crucial role in promoting hepatocyte growth, regulating lipid metabolism, and influencing the tumor microenvironment (TME), contributing significantly to liver repair, non-alcoholic fatty liver disease (NAFLD), and liver cancer. On the other hand, FGL2 is a multifunctional protein known for its role in modulating prothrombin activity and inducing immune tolerance, impacting viral hepatitis, liver fibrosis, hepatocellular carcinoma (HCC), and liver transplantation. Understanding the functions and mechanisms of fibrinogen-like proteins is essential for the development of effective therapeutic approaches for liver diseases. Additionally, FGL1 has demonstrated potential as a disease biomarker in radiation and drug-induced liver injury as well as HCC, while FGL2 shows promise as a biomarker in viral hepatitis and liver transplantation. The expression levels of these molecules offer exciting prospects for disease assessment. This review provides an overview of the structure and roles of FGL1 and FGL2 in different liver conditions, emphasizing the intricate molecular regulatory processes and advancements in targeted therapies. Furthermore, it explores the potential benefits and challenges of targeting FGL1 and FGL2 for liver disease treatment and the prospects of fibrinogen-like proteins as biomarkers for liver disease, offering insights for future research in this field.
PubMed: 38816776
DOI: 10.1186/s40364-024-00601-0 -
Digestive Diseases and Sciences May 2024Alcoholic hepatitis (AH) is a serious complication of alcohol consumption with high morbidity and mortality, particularly in the United States where alcohol-related...
INTRODUCTION
Alcoholic hepatitis (AH) is a serious complication of alcohol consumption with high morbidity and mortality, particularly in the United States where alcohol-related liver diseases rank as one of the leading causes of preventable death. Our study aims to analyze the morbidity and mortality of AH across racial groups and project hospitalization trends up to 2028, thereby informing public health initiatives.
METHODS
We conducted a cross-sectional study utilizing data from the Nationwide Inpatient Sample (NIS) spanning 2012 to 2021. The study population comprised hospitalizations identified using specific ICD-9-CM and ICD-10-CM codes for AH. We assessed hospitalizations, in-hospital mortality rates, length of stay (LOS), and morbidities related to alcoholic hepatitis adjusting for sociodemographic factors and hospital characteristics. Statistical analyses were performed using Stata and R software, employing logistic and linear regression analyses, and SARIMA models for forecasting.
RESULTS
Our results indicated a predominantly White cohort (68%), with a notable increase in AH hospitalizations among Hispanics (129.1% from 2012 to 2021). Racial disparities were observed in inpatient mortality, liver transplant accessibility, and the occurrence of in-hospital complications. The study forecasts a continued rise in hospitalizations across all racial groups, with Hispanics experiencing the sharpest increase.
CONCLUSION
Our study reveals a disproportionate rise in the AH burden among Hispanics with projections indicating a persistent upward trend through 2028. These findings highlight the need for targeted public health strategies and improved healthcare access to mitigate the increasing AH burden and address disparities in care and outcomes.
PubMed: 38811506
DOI: 10.1007/s10620-024-08462-1 -
Biomaterials Oct 2024Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with...
Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.
Topics: gamma-Glutamyltransferase; Animals; Humans; Carcinoma, Hepatocellular; Photoacoustic Techniques; Liver Neoplasms; Liver Diseases; Optical Imaging; Mice; Male; Mice, Inbred BALB C; Liver; Fluorescent Dyes
PubMed: 38810386
DOI: 10.1016/j.biomaterials.2024.122635 -
Clinical Journal of Gastroenterology May 2024This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic...
This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5-7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory-Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient's hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis.
PubMed: 38809500
DOI: 10.1007/s12328-024-01988-x -
Cureus Apr 2024Acute hepatitis can result from a wide variety of noninfectious causes that include, but are not limited to, drugs (drug-induced hepatitis), alcohol (alcoholic...
Acute hepatitis can result from a wide variety of noninfectious causes that include, but are not limited to, drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis, primary biliary cholangitis), or as a result of indirect insult secondary to biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock, or metastatic disease. In clinical settings, these causes are not uncommon to overlap with each other or are masked by obviously visible causes in medical history. We reported our scenario of a patient who has a heavy history of alcohol use and presented with alcohol withdrawal symptoms and a marked elevation of liver enzymes. Interestingly, further investigations suggested Wilson's disease could be an underlying culprit of acute hepatitis in this patient. This case again emphasized that Wilson's disease can be masked under multiple causes and various scenarios, which alerts clinicians that a broad approach should be made for every case of acute hepatitis.
PubMed: 38803772
DOI: 10.7759/cureus.59025