Alcohol-related liver disease (ALD) is a chronic liver injury caused by long-term excessive alcohol consumption, with complex and multifaceted pathological mechanisms. Research indicates that oxidative stress (OS), inflammatory responses, and lipid metabolic disturbances induced by alcohol and its metabolites are primary contributors to hepatocyte injury, positioning OS as a key target in ALD treatment. The main non-pharmacological treatment for ALD is alcohol abstinence, while medical treatment primarily relies on Western pharmacological interventions. However, recent research has increasingly highlighted the potential of Chinese botanical drugs in improving histological features and modulating signaling pathways associated with OS in ALD, underscoring the therapeutic potential of traditional Chinese herb medicine. Despite these promising findings, the precise mechanisms and effects of these extracts remain incompletely understood, and potential side effects must be considered. Therefore, a comprehensive analysis of herbal extracts with therapeutic effects is essential to optimize clinical administration and ensure safe, effective treatment. This review focuses on OS as a central theme, categorizing Chinese botanical drugs into six major groups-flavonoids, polyphenols, terpenoids, alkaloids, saponins, and anthraquinones-all widely used in traditional Chinese herb medicine. The review provides an overview of their botanical characteristics and therapeutic actions in the context of ALD, offering insights into OS regulation and exploring their potential as treatments for ALD. Notably, physical exercise shares overlapping mechanisms with botanical drugs in regulating OS. Combining two strategies could offer a promising integrative treatment for ALD, though further research is needed to confirm their synergistic benefits and optimize clinical applications.

Our aim was to examine the effects of combined prebiotic fiber supplementation and weight loss counseling on liver fat, body composition, subjective appetite, serum metabolomics, and intestinal microbiota in adults with MASLD.

In a double blind, placebo-controlled trial, adult participants aged 18-70 years old with MASLD were randomized to receive prebiotic (oligofructose-enriched inulin, 16 g/day; n = 22) or isocaloric placebo (maltodextrin; n = 20) for 24 weeks alongside weight loss counseling from a registered dietitian. Primary outcomes were change in intrahepatic fat % (IHF%) and hepatic injury from baseline to 24 weeks. Secondary outcomes included body composition, subjective appetite, serum lipids and cytokines, fecal microbiota, and serum metabolomics.

At baseline, participants had IHF of 14.4 ± 8.4%. The change in IHF from baseline to 24 weeks did not differ between prebiotic and placebo. Prebiotic participants had a greater decrease (p = 0.029) in percent trunk fat compared to placebo. Compared to placebo, prebiotic significantly decreased desire to eat and hunger ratings over the course of the intervention. Fecal microbiota analysis showed a significant increase in Bifidobacterium abundance with prebiotic. A pathway analysis based on untargeted serum metabolomics revealed a downregulation of taurine and hypotaurine metabolism in the placebo group which was conserved in the prebiotic group.

Adding prebiotic fiber supplementation to weight loss counseling for adults with MASLD enhanced reductions in trunk fat and had a beneficial effect on subjective appetite compared to placebo. Improvements in fecal microbial profile and taurine metabolism revealed specific beneficial effects of prebiotics in the management of MASLD.

Clinicaltrials.gov/study/NCT02568605.

Liver disease poses a significant challenge to global health, and its early diagnosis is crucial for improving treatment outcomes and patient prognosis. Since fluctuation of key biomarkers during the onset and progression of liver diseases can directly reflect liver health and normal/abnormal function, biomarker-based assays are vital tools for the early detection of liver disease. In this context, small molecule fluorescent probes have undeniably emerged as indispensable tools for diagnosis and analysis, with an ever-growing number of small molecule-based fluorescent probes being developed over recent years, with the sole aim of monitoring relevant biomarkers of liver disease. This perspective will focus on the development and application of probes developed primarily over the last 10 years for diagnosing a range liver disease-related processes. It will outline the foundational design strategies for developing promising probes, their optical response to key biomarkers, and how they have been demonstrated in proof-of-concept imaging applications. Current challenges and new developments in the field will be discussed, with the aim of providing insights and highlighting opportunities in the field.

Golgi protein 73 (GP73) is implicated in key pathogenic processes, particularly those related to inflammation and fibrogenesis. In the last years, its measurement has emerged as a promising biomarker for detection of liver fibrosis (LF), a common consequence of chronic liver disease that can progress to cirrhosis and eventually hepatocellular carcinoma. GP73 concentrations in blood appear significantly increased in LF patients, correlating with disease severity, making this biomarker a possible non-invasive alternative for detecting and monitoring this condition regardless of etiology. Understanding the molecular mechanisms involving GP73 expression could also lead to new therapeutic strategies aimed at modulating its synthesis or function to prevent or reverse LF. Despite its clinical potential, GP73 as a LF biomarker faces several challenges. The lack of demonstrated comparability among different assays as well as the lack of knowledge of individual variability can make difficult the result interpretation. Further research is therefore needed focusing on robust clinical validation of GP73 as a LF biomarker. Addressing analytical, biological, and clinical limitations will be critical to exploiting its potential for improving detection and monitoring of advanced LF.

With the global aging population, community-acquired pneumonia and delirium are increasingly critical health issues among the elderly. The Laboratory Frailty Index provides an objective measure of frailty. This study explores its capacity in predicting delirium and examines the interplay between frailty and nutritional status in elderly patients with community-acquired pneumonia.

This retrospective study included 481 elderly patients aged 75 and above diagnosed with community-acquired pneumonia. The Laboratory Frailty Index was calculated by dividing the sum of abnormal indicator scores by the total number of test indicators, resulting in a score ranging from 0 to 1, with higher values indicating greater frailty.

Higher Laboratory Frailty Index scores were associated with an increased risk of delirium. The index's predictive accuracy improved when combined with nutritional assessments. Patients experiencing malnutrition alongside higher frailty scores exhibited a higher risk of adverse outcomes. Nutritional status mediated the relationship between frailty and delirium, underlining the significance of addressing both variables.

The Laboratory Frailty Index is a robust predictor of delirium in elderly patients with community-acquired pneumonia. These findings provide valuable insights for the early identification and intervention of delirium in clinical settings.

The rapid evolution of artificial intelligence and the widespread embrace of digital technologies have ushered in a new era of clinical research and practice in hepatology. Although its potential is far from realization, these significant strides have generated new opportunities to address existing gaps in the delivery of care for patients with liver disease. In this review, we discuss how artificial intelligence and opportunities for multimodal data integration can improve the diagnosis, prognosis, and management of alcohol-associated liver disease. An emphasis is made on how these approaches will also benefit the detection and management of alcohol use disorder. Our discussion encompasses challenges and limitations, concluding with a glimpse into the promising future of these advancements.

Alcohol consumption is a global phenomenon and a major contributor to alcohol-associated liver disease (ALD). Detecting individuals at risk of ALD has been challenging, with only a small fraction of patients being identified at early stages compared to other chronic liver diseases. In response to this challenge, non-invasive tests (NITs) have become essential tools for the detection of ALD, offering opportunities for early identification and intervention to mitigate the disease burden. Noninvasive alcohol consumption biomarkers are crucial in estimating individuals' recent alcohol intake, providing valuable insights into their drinking patterns. Various NITs have been investigated for the initial screening of asymptomatic individuals at risk of ALD, as well as for identifying specific stages of the disease. These NITs are applied in 2 main clinical scenarios: population-based stratification for identifying and predicting liver-related symptoms and diagnosing and prognosticating compensated cirrhosis or advanced chronic liver disease in secondary or tertiary care settings. Moreover, NITs play a significant role in the prognostic assessment of patients with various manifestations of ALD, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and metabolic-associated and ALD. These tests guide appropriate treatment decisions and predict outcomes. In this review, various NITs for the early detection and monitoring of alcohol consumption were discussed. Additionally, the evaluation of NITs for screening and predicting ALD and liver complications was addressed comprehensively. Future perspectives of NITs for ALD were explored, alongside a thorough discussion of the opportunities and challenges associated with NITs for ALD screening.

There are limited prospective data among overweight and obese individuals on the prevalence of advanced fibrosis, and cirrhosis using advanced MRI-based methods in the USA. The aim of this study was to fill that gap in knowledge by prospectively determining the MRI-based prevalence of steatotic liver disease (SLD) and its subcategories, advanced fibrosis and cirrhosis among overweight and obese individuals residing in the USA.

This is a cross-sectional analysis of prospectively enrolled overweight or obese adults aged 40-75 years from primary care and community-based settings in Southern California. Participants were classified as having SLD if MRI proton density fat fraction ≥5%, and subclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-related liver disease (ALD) consistently with the new nomenclature guidance per AASLD-EASL-ALEH. Advanced fibrosis and cirrhosis were defined as magnetic resonance elastography (MRE) ≥3.63 kPa and MRE ≥4.67 kPa, respectively.

The cohort included 539 participants with mean (±SD) age of 51.5 (±13.1) years and body mass index of 32.6 (±6.2) kg/m2, respectively. The prevalence of SLD, advanced fibrosis and cirrhosis was 75%, 10.8% and 4.5%, respectively. The prevalence of MASLD, MetALD and ALD was 67.3%, 4.8% and 2.6%, respectively. There was no difference in prevalence of advanced fibrosis and cirrhosis among subcategories.

Using advanced MRI methods among community-dwelling overweight and obese adults, the prevalence of cirrhosis was 4.5%. Most common SLD subcategory was MASLD with 67% of individuals, whereas MetALD and ALD were less common. Systematic screening for advanced fibrosis among overweight/obese adults may be considered.

Alcohol-associated liver disease (ALD) remains a significant public health concern, accounting for at least half of cirrhosis cases in Europe. Historically, liver biopsy has been considered the gold standard method for both diagnosing and staging ALD. However, in the past 3 decades, there has been a growing interest in developing noninvasive biomarkers for identifying high-risk patients prone to develop liver-related complications, including elastography methods or blood-based biomarkers. This review aims to summarize currently available noninvasive testing methods that are clinically available for assessing patients with ALD, including notably steatosis and fibrosis.

Alcohol-associated liver disease (AALD) is a global health problem with increasing incidence with associated high morbidity and mortality. Patients with AALD have varied clinical presentation encompassing a spectrum ranging from alcoholic steatosis, alcoholic steatohepatitis to alcohol-associated fibrosis/cirrhosis, which can be either compensated or decompensated. We need uniformity in defining each of the stages of AALD, which will help in both research and patient care. Algorithmic approach using noninvasive tests like enhanced liver fibrosis score, elastography, and fibrosis-4 scores can help in early diagnosis in addition to the presence of any red flags (low albumin, low platelet count, and raised transaminases).

Alcohol-associated liver disease (ALD) is the most common cause of liver disease and an indication for liver transplantation. Identification of ALD at an earlier stage and treatment of concomitant alcohol use disorder (AUD) could potentially prevent or delay the progression to advanced stages of ALD like alcohol-associated cirrhosis and alcohol-associated hepatitis. However, screening for alcohol use is often not performed and treatment of AUD is rarely administered in ALD patients, due to several barriers at the level of patients, clinicians, and administrative levels.

Excessive alcohol consumption is a major global health concern, contributing to millions of deaths annually and a significant proportion of cirrhosis cases; however, standardized protocols for early identification of alcohol-associated liver disease are lacking. In this retrospective cohort study, we aimed to understand the prevalence and risk factors associated with elevated liver stiffness measurement (LSM) in high-risk patients with alcohol use disorder (AUD) and identify variables associated with longitudinal abstinence and outcomes.

Veterans with severe AUD without known liver disease admitted to a 35-day residential substance use treatment program were offered liver health screening, including Fibroscan evaluation. Assessment of AUD severity and liver health outcomes were evaluated longitudinally by chart review.

In a cohort of 257 veterans with severe AUD admitted to residential treatment, 185 underwent Fibroscan evaluation, and 22 were identified to have elevated LSM concerning for compensated advanced chronic liver disease. Patients with elevated LSM were more likely to remain abstinent after 1 year. About 41% of patients with LSM ≥ 10 kPa (5% of all screened patients) were confirmed to have cirrhosis on follow-up and incorporated into routine hepatology care. Screening of liver disease in high-risk populations with non-invasive imaging modalities provides an opportunity to identify patients at risk for compensated advanced chronic liver disease before decompensation. Identification of increased risk for advanced chronic liver disease may promote abstinence in patients with severe AUD. Collaboration between mental health professionals and hepatologists is critical for the integration of care for patients with AUD and liver disease.

People who drink alcohol excessively are at increased risk of developing metabolic dysfunction and alcohol-related liver disease (MetALD) or the more severe form alcohol-related liver disease (ALD). One of the most significant challenges concerns the early detection of MetALD/ALD. Previously, we have demonstrated that the lysosomal enzyme cathepsin D (CTSD) is an early marker for metabolic dysfunction-associated steatohepatitis (MASH). Here, we hypothesized that plasma CTSD can also serve as an early indicator of MetALD/ALD.

We included 303 persistent heavy drinkers classified as having MetALD or ALD (n = 152) and abstinent patients with a history of excessive drinking (n = 151). Plasma CTSD levels of patients with MetALD/ALD without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. Receiver-operating characteristic curves were generated to assess the precision of plasma CTSD levels in detecting MetALD/ALD. Lastly, plasma CTSD levels were compared between abstainers and drinkers.

Plasma CTSD levels were higher in patients with MetALD/ALD compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, liver stiffness measurement) were higher at advanced histopathological stages (assessed by liver biopsy), plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with liver stiffness measurement and AST/ALT ratio yielded enhanced diagnostic precision (AUC 0.872) in detecting MetALD/ALD in contrast to the utilization of CTSD alone (AUC 0.804). Plasma CTSD levels remained elevated in abstainers.

Elevated levels of CTSD in the circulation can serve as an early indicator of MetALD/ALD.

Alcohol-related liver disease is the leading cause of liver disease-related morbidity and mortality worldwide. However, the currently available non-invasive methods to diagnose MetALD/ALD are only able to detect advanced stages of MetALD/ALD. Here, we demonstrate that plasma levels of the lysosomal enzyme cathepsin D are already elevated at early stages of MetALD/ALD. Moreover, cathepsin D levels outperformed the currently available non-invasive methods to detect MetALD/ALD. Plasma levels of cathepsin D could therefore be a useful non-invasive marker for detection of MetALD/ALD.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions.

To evaluate the efficacy of the 18F-AlF-NOTA-RGD2 positron emission tomography (PET)/computed tomography (CT) molecular probe for the noninvasive staging of liver fibrosis in mini pigs, a potential alternative to invasive diagnostic methods was revealed. This study used 18F-AlF-NOTA-RGD2 PET/CT imaging of mini pigs to assess liver fibrosis. The methods included synthesis and quality control of the molecular probe, establishment of an animal model of liver fibrosis, blood serum enzymatic tests, histopathological examination, PET/CT imaging, collagen content and expression, and mitochondrial reserve function assessment. The 18F-AlF-NOTA-RGD2 PET/CT molecular probe effectively differentiated various stages of liver fibrosis in mini pigs. Blood serum enzymatic tests revealed distinct stages of liver fibrosis, revealing significant increases in AST, ALT, TBIL, and DBIL levels as fibrosis advanced. Notably, ALT levels increased markedly in severe fibrosis patients. A gradual increase in collagen deposition and increasing α-SMA RNA expression and protein levels effectively differentiated between mild and severe fibrosis stages. Pathological examinations and Sirius Red staining confirmed these findings, highlighting substantial increases in collagen accumulation. PET/CT imaging results aligned with histopathological findings, showing that increased radiotracer uptake correlated with fibrosis severity. Assessments of mitochondrial function revealed a decrease in total liver glutathione content and mitochondrial reserve capacity, especially in patients with severe fibrosis. The 18F-AlF-NOTA-RGD2 PET/CT molecular probe is a promising tool for the noninvasive assessment of liver fibrosis, offering potential benefits over traditional diagnostic methods in hepatology.

In this study, we aimed to explore the clinical significance of serum CK18-M65 and CK18-M30 levels in patients with chronic hepatitis B (CHB) complicated by nonalcoholic steatohepatitis (NASH) and liver fibrosis. The observation and control groups comprised 133 patients with CHB complicated by NASH and 50 healthy patients from our hospital, respectively. Liver function indices, including alanine aminotransferase, glutamic aminotransferase, γ-glutamyltransferase, total bilirubin, total protein, and total cholesterol, were determined using an automatic biochemical analyzer. Hyaluronic acid, type III procollagen, type IV collagen, laminin, and CK18-M65 and M30 levels were detected using ELISA. Serum CK18-M65 and M30 levels in patients with CHB complicated by NASH were positively correlated with the liver fibrosis stage (P < .05). While serum CK18-M65 demonstrated a low diagnostic value for liver fibrosis in the S0-1 stage, it exhibited good diagnostic value for S2-3 stage liver fibrosis. Serum CK18-M30 displayed good diagnostic value for S0-1 and S2-3 hepatic fibrosis, particularly for S2-3 hepatic fibrosis. Elevated serum CK18-M65 and CK18-M30 levels in patients with CHB complicated with NASH suggest their potential utility in evaluating the progression of liver fibrosis in this population. In particular, CK18-M30 exhibits superior diagnostic efficiency.

Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD.

Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below -1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria.

A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34-0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00-1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97-1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD.

The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

Alcoholic liver disease (ALD) encompasses a spectrum of liver conditions, including liver steatosis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). microRNAs (miRNAs) have garnered significant interest as potential biomarkers for ALD.

We searched PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) systemically from inception to June 2024. All extracted data was stratified according to the stages of ALD. The vote-counting strategy performed a meta-analysis on miRNA expression profiles.

We included 40 studies. In serum of individuals with alcohol-use vs. no alcohol-use, miRNA-122 and miRNA-155 were upregulated, and miRNA-146a was downregulated. In patients with ALD vs. healthy controls, miRNA-122 and miRNA-155 were also upregulated, and miRNA-146a was downregulated. However, in patients with AH vs. healthy individuals, only the serum miRNA-122 level was upregulated. Due to insufficient data on diagnostic accuracy, we failed to conclude the ability of miRNAs to distinguish between different stages of ALD-related liver fibrosis. The results for ALD-related HCC were also insufficient and controversial.

Circulating miRNA-122 was the most promising biomarker to manage individuals with ALD. More studies were needed for the diagnostic accuracy of miRNAs in ALD.

This protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/prospero/) with registration number CRD42023391931.

TGF-β/Smad signaling pathway plays an important role in the pathogenesis and progression of liver fibrosis. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+) dependent enzyme and responsible for deacetylating the proteins. Increasing numbers of reports have shown that the molecular mechanism of SIRT1 as an effective therapeutic target for liver fibrosis but the transformation is not very clear. In the present study, liver fibrotic tissues were screened by staining with Masson, hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) for histopathological observation from the liver biopsy of seventy-seven rhesus monkey, which fixed with 4% paraformaldehyde (PFA) after treatment with high-fat diet (HFD) for two years. And the liver function was further determined by serum biochemical tests. The mRNA levels and protein expression of rat hepatic stellate (HSC-T6) cells were determined after treatment with Resveratrol (RSV) and Nicotinamide (NAM), respectively. The results showed that with the increasing of hepatic fibrosis in rhesus monkeys, the liver function impaired, and the transforming growth factor-β1 (TGF-β1), p-Smad3 (p-Smad3) and alpha-smooth muscle actin (α-SMA) was up-regulated, while SIRT1 and Smad7 were down-regulated. Moreover, when stimulated the HSC-T6 with RSV to activate SIRT1 for 6, 12, and 24 h, the results showed that RSV promoted the expression of smad7, while the expression of TGF-β1, p-Smad3 and α-SMA were inhibited. In contrast, when the cells stimulated with NAM to inhibit SIRT1 for 6, 12, and 24 h, the Smad7 expression was decreased, while TGF-β1, p-Smad3, and α-SMA expressions were increased. These results indicate that SIRT1 acts as an important protective factor for liver fibrosis, which may be attributed to inhibiting the signaling pathway of TGF-β/Smad in hepatic fibrosis of the rhesus monkey.

Alcohol-associated liver disease is currently the leading cause of liver transplantation and liver deaths both in Europe and the United States. Efficacious treatments exist for alcohol use disorder, but they are seldomly prescribed for patients who need them. Besides, the presence of liver cirrhosis can complicate pharmacological treatment choices. In this review, we discuss established and innovative treatment strategies to treat unhealthy alcohol use in patients with alcohol-associated liver disease. We also describe the experience of our own institutions, Hospital Universitari Germans Trias i Pujol in Badalona (Spain) and Yale-New Haven Health and Yale Medicine (Connecticut. United States of America).

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Protein corona, a layer of biomolecules primarily comprising proteins, forms dynamically on nanoparticles in biological fluids and is crucial for predicting nanomedicine safety and efficacy. The protein composition of the corona layer is typically analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Our recent study, involving identical samples analyzed by 17 proteomics facilities, highlighted significant data variability, with only 1.8% of proteins consistently identified across these centers. Here, we implement an aggregated database search unifying parameters such as variable modifications, enzyme specificity, number of allowed missed cleavages and a stringent 1% false discovery rate at the protein and peptide levels. Such uniform search dramatically harmonizes the proteomics data, increasing the reproducibility and the percentage of consistency-identified unique proteins across distinct cores. Specifically, out of the 717 quantified proteins, 253 (35.3%) are shared among the top 5 facilities (and 16.2% among top 11 facilities). Furthermore, we note that reduction and alkylation are important steps in protein corona sample processing and as expected, omitting these steps reduces the number of total quantified peptides by around 20%. These findings underscore the need for standardized procedures in protein corona analysis, which is vital for advancing clinical applications of nanoscale biotechnologies.

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.

Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.

Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%-50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%-60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.

An association between environmental pollutants and alcohol-related liver disease (ALD) has not been determined until now. The objectives of this study were to examine the association of the pollutants with ALD, and whether the pollutants together increased the risk of ALD.

Data were extracted from the Korea National Health and Nutrition Examination Survey (2010-2013 and 2016-2017; n = 11,993). Blood levels of lead, cadmium, and mercury were measured. ALD was defined by a combination of excessive alcohol consumption and ALD/non-alcoholic fatty liver disease index > 0. The aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 score were used to evaluate ALD FIB.

The odds ratios (ORs) of ALD for the highest versus the lowest quartiles of exposure were for lead, 7.39 (95% confidence interval [CI], 5.51-9.91); cadmium, 1.68 (95% CI, 1.32-2.14); and mercury, 5.03 (95% CI, 3.88-6.53). Adjusting for age, gender, smoking, occupation, education, and personal income attenuated the associations but indicated significant positive trends (all Ptrend < 0.001). A positive additive interaction between cadmium and lead was observed. The relative excess OR due to the interaction was 0.96 (95% CI, 0.41-1.51); synergy index = 2.92 (95% CI, 0.97-8.80). Among 951 subjects with ALD, advanced FIB was associated with lead and cadmium (OR, 3.46, 95% CI, 1.84-6.53; OR, 8.50, 95% CI, 2.54-28.42, respectively), but not with mercury. The effect estimates for lead and cadmium remained significant even after adjustment for daily alcohol intake.

Blood levels of lead, cadmium, and mercury were significantly associated not only with the risk of ALD but also with ALD FIB. Cadmium and lead have synergistic effects that increase the risk of ALD.

The first two causes of liver cirrhosis and hepatocellular carcinoma are alcoholic and dysmetabolic. In the early stages alcohol related liver disease (ALD) is silent. For this reason, more efforts should be made to identify early individuals with hazardous/harmful alcohol consumption (AC). Alcohol use disorder identification test (AUDIT) is a validated test.

ASL3 (Ligurian Local Health Company 3) has included the AUDIT renamed Glu-Glu Test on its institutional website dedicated to citizens. The renaming was carried out to bring citizens closer to the test with greater ease, especially younger citizens. At the end of the compilation of the test, the calculator provides the citizen with his score: in relation to his possible risk band, provides him with the appropriate advice. In case of a score higher than 7, ultrasonography and elastography (2D-SWE) are proposed.

From December 15, 2021, to July 15, 2022, 270 asymptomatic subjects requested a medical examination autonomously, without the indication of a health worker. In 167 patients the score found hazardous AC, in 65 harmful AC and in 38 alcohol addiction. In case of hazardous AC, fibrosis grade 1-2 was evidenced in 16.7%, fibrosis grade 3 in 4.8% and fibrosis grade 4 in 3.6% of subjects. In case of harmful AC fibrosis grade 1-2 was evidenced in 37%, grade 3 in 9%, grade 4 in 6%. In this group an HCC nodule was diagnosed. In case of alcohol addiction, fibrosis grade 1-2 was evidenced in 73.6%, grade 3 in 10.5% and grade 4 in 10.5%.

This preliminary experience clearly tells us that it is possible to make an early diagnosis of fibrosis and HCC starting from the AC reported autonomously by citizens.

Increased matrix stiffness is a common phenomenon in solid tumor tissue and is regulated by both tumor and mesenchymal cells. The increase in collagen and lysyl oxidase family proteins in the extracellular matrix leads to deposition, contraction, and crosslinking of the stroma, promoting increased matrix stiffness in tumors. Matrix stiffness is critical to the progression of various solid tumors. As a mechanical factor in the tumor microenvironment, matrix stiffness is involved in tumor progression, promoting biological processes such as tumor cell proliferation, invasion, metastasis, angiogenesis, drug resistance, and immune escape. Reducing tissue stiffness can slow down tumor progression. Therefore targeting matrix stiffness is a potential option for tumor therapy. This article reviews the detailed mechanisms of matrix stiffness in different malignant tumor phenotypes and potential tumor therapies targeting matrix stiffness. Understanding the role and mechanisms of matrix stiffness in tumors could provide theoretical insights into the treatment of tumors and assist in the clinical development of new drug therapies.

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.

Ethyl glucuronide (EtG), ethyl sulfate (EtS) and phosphatidylethanol (PEth) are considered specific direct biomarkers for detecting alcohol consumption. However, PEth, which is produced in red blood cells (RBC), varies considerably between patients for unknown reasons. We here studied various confounders of PEth elimination including fibrosis after alcohol withdrawal.

EtG, EtS and PEth together with routine laboratory and clinical parameters were studied in 100 Caucasian heavy drinkers prior and after alcohol detoxification. In addition, fibrosis stage and degree of steatosis were assessed by transient elastography (Fibroscan, Echosens, Paris).

All three biomarkers were highly correlated (0.61-0.72) with initial serum alcohol levels, but only PEth correlated with daily alcohol consumption. After alcohol withdrawal, PEth significantly decreased within 6.1 days from 1708 to 810 ng/mL (half-life varied from 1.6 to 15.2 days). Both levels of serum alcohol but also EtG and EtS were higher in patients with liver cirrhosis as compared to patients without fibrosis despite comparable alcohol consumption suggesting a decreased alcohol elimination in patients with cirrhosis. PEth was also elevated in cirrhosis but not significantly. In contrast, PEth elimination rate was significantly higher in patients with enhanced RBC turnover and signs of alcohol-mediated hemolytic anemia with elevated ferritin, LDH and increased mean corpuscular volume (MCV).

We here demonstrate that alcohol elimination is decreased in patients with liver cirrhosis. In patients with cirrhosis, PEth levels are both affected in opposite directions by enhanced red blood cell turnover and elevated alcohol levels. Our data have important implications for the use and interpretation of PEth in the clinical setting.

Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care.

A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives.

The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided.

It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD.

Interleukin 6 (IL-6) is pleiotropic cytokine with pathological pro-inflammatory effects in various acute, chronic and infectious diseases. It is involved in a variety of biological processes including immune regulation, hematopoiesis, tissue repair, inflammation, oncogenesis, metabolic control, and sleep. Due to its important role as a biomarker of many types of diseases, its detection in small amounts and with high selectivity is of particular importance in medical and biological fields. Laboratory methods including enzyme-linked immunoassays (ELISAs) and chemiluminescent immunoassays (CLIAs) are the most common conventional methods for IL-6 detection. However, these techniques suffer from the complexity of the method, the expensiveness, and the time-consuming process of obtaining the results. In recent years, too many attempts have been conducted to provide simple, rapid, economical, and user-friendly analytical approaches to monitor IL-6. In this regard, biosensors are considered desirable tools for IL-6 detection because of their special features such as high sensitivity, rapid detection time, ease of use, and ease of miniaturization. In this review, current progresses in different types of optical biosensors as the most favorable types of biosensors for the detection of IL-6 are discussed, evaluated, and compared.

Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a perspective on the status of trials in hepatology and a vantage point into the emerging capabilities and external forces that will shape the conduct of clinical trials in the future. The adaptations to clinical trial operations in response to the disruptions by the COVID-19 pandemic and opportunities for innovation in hepatology trials are emphasized. Future trials in hepatology will be driven by unmet therapeutic needs and fueled by technological advances incorporating digital capabilities with expanded participant-derived data collection, computing, and analytics. Their design will embrace innovative trial designs adapted to these advances and that emphasize broader and more inclusive participant engagement. Their conduct will be further shaped by evolving regulatory needs and the emergence of new stakeholders in the clinical trials ecosystem. The evolution of clinical trials will offer unique opportunities to advance new therapeutics that will ultimately improve the lives of patients with liver diseases.

The fibrosis-4 score is a marker of liver fibrosis and has been confirmed to be associated with the prognosis of various diseases. There is no study exploring the prognostic value of the fibrosis-4 score in traumatic brain injury (TBI) patients. We design this study to explore the association between the fibrosis-4 score and mortality from TBI. TBI patients from the Medical Information Mart for Intensive Care-III database were extracted for the study. Univariate and multivariate logistic regressions were sequentially performed to analyze the association between fibrosis-4 and mortality in TBI. The area under the receiver operating characteristic curve (AUC) was drawn to evaluate the prognostic value of fibrosis-4 and other scores. A total of 1018 TBI patients were included, with a 30-day mortality of 24.2%. Non-survivors had older age, lower Glasgow Coma Scale (GCS), and higher injury severity score (ISS) than survivors. The aspartate aminotransferase platelet ratio index (APRI) and fibrosis-4 score were significantly higher in non-survivors. Univariate logistic regression showed that age, GCS, ISS, white blood cell, hemoglobin, fibrosis-4 score, subarachnoid hemorrhage, and anticoagulants were associated with the mortality of TBI patients. Multivariate logistic regression presented that age, GCS, ISS, fibrosis-4 score, subarachnoid hemorrhage, and anticoagulants were independent risk factors of mortality in TBI patients after adjusting for confounding effects. The AUC of the GCS, ISS, APRI, and fibrosis-4 score for predicting mortality was 0.711, 0.625, 0.592, and 0.627, respectively. Composed of age, GCS, ISS, fibrosis-4 score, subarachnoid hemorrhage, and anticoagulants, the predictive model had the highest AUC value of 0.790. The fibrosis-4 score is an independent risk factor for mortality in TBI. The model incorporating fibrosis-4 performs well in predicting the prognosis of TBI patients.

The progression of alcohol-associated liver disease (ALD) in its early precirrhotic stages can be a silent process. Serum keratin 18 levels (K18-M65) predict severe events and mortality in advanced stages of ALD, but data on this biomarker in early stages are scarce. We evaluated the diagnostic accuracy of K18-M65 levels in identifying early forms of ALD.

We prospectively evaluated two cohorts of actively drinking patients with alcohol use disorder (AUD) following a rehabilitation program (training (n = 162) and validation (n = 78)) and matched healthy controls (n = 21). Clinical, laboratory, and imaging data were used to distinguish AUD patients with simple steatosis (minimal ALD) and steatohepatitis/fibrosis (early ALD). We measured serum K18-M65 levels and assessed their ability to predict early ALD.

High levels of K18-M65 characterized AUD patients with early ALD, while levels in the minimal ALD group were similar to those in healthy controls. K18-M65 levels distinguished minimal liver disease from early ALD (AUROC = 0.8704; p < 0.0001) with an optimal cutoff at 265.9 U/L. K18-M65 levels strongly correlated with transaminases and predicted early ALD (OR 25.81; 95% CI 3.166-336.1; p < 0.0001), controlled attenuation parameter, and liver stiffness independently from transaminases and other potential confounders. K18-M65 levels did not discriminate between fibrosis and steatohepatitis but correlated with histological signs of hepatocellular injury and inflammation (all p < 0.05). The K18-M65 cutoff detected early ALD in the validation cohort with high accuracy (sensitivity 86.67%, specificity 96.67%) and a very high positive likelihood ratio (28.6; 95% CI 4.14-197.73).

Serum K18-M65 levels can be used as a biomarker to detect early ALD stages with excellent predictive value.

Chronic liver diseases (CLDs) are a major public health problem. Despite the progress achieved in fighting against viral hepatitis, the emergence of non-alcoholic fatty liver disease might pose a serious challenge to the public's health in the coming decades. Medical management of CLDs represents a substantial burden on the public health infrastructures. The health care cost of these diseases is an additional burden that weighs heavily on the economies of developing countries. Effective management of CLDs requires the adoption of reliable and cost-effective screening and diagnosing methods to ensure early detection and accurate clinical assessment of these diseases. Vibrational spectroscopies have emerged as universal analytical methods with promising applications in various industrial and biomedical fields. These revolutionary analytical techniques rely on analyzing the interaction between a light beam and the test sample to generate a spectral fingerprint. This latter is defined by the analyte's chemical structure and the molecular vibrations of its functional groups. Raman spectroscopy and surface-enhanced Raman spectroscopy have been used in combination with various chemometric tests to diagnose a wide range of malignant, metabolic and infectious diseases. The aim of the current review is to cast light on the use of these optical sensing methods in the diagnosis of CLDs. The vast majority of research works that investigated the potential application of these spectroscopic techniques in screening and detecting CLDs were discussed here. The advantages and limitations of these modern analytical methods, as compared with the routine and gold standard diagnostic approaches, were also reviewed in details.

Fibrosis of the liver is a degenerative alteration that occurs in the majority of chronic liver disorders. Further progression can lead to cirrhosis, liver failure, and hepatocellular carcinoma, which can seriously affect the health and lives of patients. The field of liver fibrosis research has flourished in the last 20 years, with approximately 9000 articles retrieved from the Web of Science Core Collection database alone. In order to identify future research hotspots and potential paths in a thorough and scientifically reliable manner, it is important to organize and visualize the research on this topic from a holistic and very general perspective. This study used bibliometric analysis with CiteSpace and VOSviewer software to provide a quantitative analysis, hotspot mining, and commentary of articles published in the field of liver fibrosis over the last 20 years. This bibliometric analysis contains a total of 8994 articles with 45667 authors from 6872 institutions in 97 countries, published in 1371 journals and citing 156 309 references. The literature volume has steadily increased over the last 20 years. Research has focused on gastroenterology and hepatology, pharmacology and pharmacy, and medicine, research, and experimental areas. We found that the pathological mechanisms, diagnostic and quantitative methods, etiology, and antifibrotic strategies constitute the knowledge structure of liver fibrosis. Finding mechanisms for liver fibrosis regression, identifying precise noninvasive diagnostic and prognostic biomarkers, and creating efficient liver fibrosis patient treatments are the main goals of current research.

Dysregulation of immune checkpoint regulators has been reported in alcoholic liver disease (ALD). This study was designed to assess the serum levels of cytokines and chemokines associated with ALD and uncover the possible disease correlations with the soluble TIM-3 and LAG-3.

The soluble TIM-3 and LAG-3 levels were measured by enzyme-linked immunoassay, and 14 cytokines and chemokines were measured using Luminex-based multiplex assay in 111 male ALD patients and 45 healthy controls (HCs).

Our results showed that soluble TIM-3 was significantly increased (p < 0.001) while soluble LAG-3 was significantly decreased (p < 0.001) in ALD group compared to HCs. Among the 14 cytokines and chemokines assessed, granulocyte-colony stimulating factor (G-CSF) (p = 0.003) and interferon γ-induced protein (IP)-10 (p < 0.001) were significantly increased, while interleukin (IL)-4 (p = 0.005) and IL-12 (p40) (p = 0.001) were significantly decreased in the ALD group. Kaplan-Meier analysis showed that overall survival decreased in higher TIM-3 level individuals.

Our results showed that TIM-3, LAG-3, and IP-10 appear to be important for clinical diagnosis of ALD and ALD severity and may represent potential therapeutic targets in ALD.

The prevalence of metabolism-related fatty liver disease (MAFLD) has been rarely reported in hospital staffs. The aim of this study was to assess the prevalence and risk factors for MAFLD in hospital staffs aged ≥18 years.

Based on type B ultrasonic, hospital staffs who underwent medical examinations at the second Affiliated Hospital of Hainan Medical University from January 2022 to March 2022 were classified into health control group (661 subjects) and MAFLD group (223 subjects), demographic, biochemical and blood examination information were compared between 2 groups. Independent risk factors for MAFLD were determined by logistic regression. Predictive values of risk factors of MAFLD were evaluated by receiver operating characteristic (ROC) curves.

The prevalence of MAFLD was 33.7%. Older age (OR=1.08, p<0.001), H. pylori infection (OR=0.234, p=0.02), triglyceride-glucose (TyG) (OR=7.001, p<0.001), low-density lipoprotein cholesterol (LDL-C) (OR=2.076, p=0.028), red blood cell (RBC) (OR=2.386, p=0.001), eating out (OR=0.048, p=0.001), regular exercise (OR=23.017, p<0.001), and overweight (OR=3.891, p=0.003) were independently associated factors for MAFLD. The AUC of model predicting MAFLD is 0.910 [95% CI (0.886, 0.934)], with 0.794 sensitivity, 0.908 specificity. The diagnostic value of model was higher in the female MAFLD group after stratified analysis according to gender. The model showed that TyG was the factor contributing more to MAFLD. The diagnostic value of TyG was higher in the female MAFLD group than male MAFLD group.

The prevalence of MAFLD among hospital staffs was 33.7%. TyG can be used to predict MAFLD especially for female hospital staffs for early intervention.