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Background: Major society guidelines recommend the fibrosis‐4 index (FIB‐4) as the initial step to risk stratifying people with metabolic dysfunction‐associated steatotic liver disease (MASLD). We aimed to evaluate the proportion of people with MASLD‐related hepatocellular carcinoma (HCC) and a low FIB‐4. Methods: This cohort study included 613 consecutive adults (33% female) diagnosed with MASLD‐related HCC from January 2008 to August 2023 at seven international centres in Australia, India, Japan, South Korea, Singapore and the United States. The primary objective was to determine the proportion of participants with a low FIB‐4, defined as FIB‐4 < 1.3, or < 2 if age > 65 years, in people without cirrhosis. Results: The mean (±SD) age and body mass index were 71 (±11) years and 27 (±7) kg/m2, respectively. Overall, 235 participants (38%) did not have known cirrhosis. The median FIB‐4 was 3.90 (IQR 2.42–6.42). A total of 78 participants (13%) had a low FIB‐4. Among participants without known cirrhosis (n = 235), 62 participants (26%) had a low FIB‐4. Participants with a low FIB‐4 had larger median total tumour diameter (p < 0.001) and lower median serum alpha‐fetoprotein (p = 0.005), compared to participants without a low FIB‐4. Cirrhosis was associated with lower odds of low FIB‐4, but not other factors such as male sex, type 2 diabetes, or obesity. Conclusion: More than a quarter of those with MASLD‐related HCC without cirrhosis have a low FIB‐4. The proposed clinical care pathways may not identify these people for further evaluation. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion Primary liver cancer (PLC) is projected to be the third leading cause of cancer mortality in the United States in 2040. We examine the burden of PLC in the United States, stratified by sex, state and aetiological risk factors.Data on PLC prevalence, incidence, death and disability–adjusted life years (DALYs) were extracted from the Global Burden of Disease Study 2021. Changes in these parameters were calculated using the Joinpoint regression model.There were 47,970 cases, 31,450 incident cases, 24,770 deaths and 576,920 DALYs from PLC in the United States. The highest prevalence (16,980), incidence (12,040), death (9840) and DALYs (213,410) from PLC were due to chronic hepatitis C virus infection. From 2000 to 2021, PLC incidences increased by 141%, and PLC deaths increased by 136%. Age–standardised incidence rates (ASIRs) and death rates (ASDRs) per 100,000 population for PLC increased, primarily driven by alcohol–related liver disease (ALD) (ASIR: annual percent change [APC]: +2.40%; ASDR: APC: +2.22%) and metabolic dysfunction–associated steatotic liver disease (MASLD) (ASIR: APC: +2.32%; ASDR: APC: +2.04%).The burden of PLC in the United States has risen in the past two decades, driven mainly by ALD and followed by MASLD. These findings offer policymakers an accurate assessment of the PLC burden and emphasise the need for targeted risk factor mitigation, especially regarding alcohol related policy. [ABSTRACT FROM AUTHOR]

Aim: Acute pancreatitis is a complication of acute liver failure (ALF). This study aimed to investigate the prevalence of and clinical features associated with acute pancreatitis in patients with ALF. Methods: We retrospectively analyzed a cohort of ALF patients without hepatic encephalopathy diagnosed during a period 2011–2018, and compared clinical features between patients with acute pancreatitis and those without. Acute pancreatitis was diagnosed according to the Acute Pancreatitis Clinical Practice Guidelines 2021. A multivariate analysis was carried out to identify factors associated with acute pancreatitis. Results: There were 83 ALF patients without hepatic encephalopathy (34 men; 11 deaths; 6 liver transplants; median age, 63 years). Acute pancreatitis occurred in nine patients (10.8%). The median time duration from ALF to the onset of acute pancreatitis was 8 days. The survival rate was lower in patients with than those without acute pancreatitis (22% vs. 86%). The model for end‐stage liver disease score (hazard ratio 1.10, 95% confidence interval 1.03–1.18) was found to be a significant factor associated with acute pancreatitis, whereas triglyceride, age, and sex were not. Conclusions: A high model for end‐stage liver disease score may be a marker to stratify patients with ALF at a risk of acute pancreatitis. [ABSTRACT FROM AUTHOR]

Introduction: Adiponectin, a key adipokine, shows promise as a non‐invasive biomarker for liver cirrhosis by reflecting inflammation and metabolic changes, but conflicting findings highlight the need for a systematic review and meta‐analysis to clarify its role. Our study aimed to evaluate adiponectin levels across various stages of liver cirrhosis, compare them with other chronic liver diseases (CLD) and hepatocellular carcinoma (HCC), and assess its potential as a diagnostic and prognostic biomarker. Methods: Our systematic search was conducted on September 2023 using PubMed, EMBASE and Scopus, searching for observational studies evaluating serum and plasma adiponectin levels in liver cirrhosis. Inclusion and exclusion criteria were applied, and study quality was assessed using the Newcastle‐Ottawa Scale. To evaluate the overall effect size, we utilized a random‐effects model along with a mean difference (MD) analysis. The principal summary outcome was the MD in adiponectin levels. Results: We included 16 articles involving 2617 subjects in our qualitative and quantitative synthesis. We found significantly higher adiponectin levels in liver cirrhosis patients (8.181 [95% CI 3.676, 12.686]), especially in Child‐Pugh B individuals (13.294 [95% CI 4.955, 21.634]), compared to controls. Child‐Pugh A patients did not show significant differences compared to controls. In addition, adiponectin levels were significantly elevated in primary biliary cholangitis (PBC) patients compared to controls (8.669 [95% CI.291, 17.047]), as well as in liver cirrhosis compared to other CLD patients (4.805 [95% CI 1.247, 8.363]), including non‐alcoholic fatty liver disease (NAFLD) (8.532 [95% CI 3.422, 13.641]), but not viral hepatitis. No significant MD was observed between liver cirrhosis and HCC patients. Conclusion: Adiponectin levels are significantly elevated in liver cirrhosis, especially in advanced stages, potentially serving as a biomarker for advanced cirrhosis. Adiponectin also differentiates cirrhosis from other CLD, including NAFLD. However, its role in distinguishing cirrhosis from viral hepatitis and HCC is limited. [ABSTRACT FROM AUTHOR]

Background: The increasing prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as non‐alcoholic fatty liver disease (NAFLD), parallels the rise in sedentary lifestyles. MASLD is the most common form of steatotic liver disease (SLD), which represents the umbrella beneath which the vast majority of chronic liver diseases fall, including alcohol‐related liver disease and their overlap. These conditions are the leading contributors to chronic liver disease, significantly impacting global morbidity and mortality. Despite the emergence of new pharmacotherapies, exercise represents the foundation of MASLD treatment. Objective: This review aims to provide an updated perspective on the role of exercise in the management of SLD, highlight its molecular and clinical benefits, and explore its benefits and safety in the stage of cirrhosis. Methods: Evidence from pre‐clinical and clinical studies was reviewed to evaluate the impact of exercise on SLD (mainly MASLD), advanced chronic liver disease stages, and its relevance in the context of evolving therapies such as Resmetirom and incretin‐based anti‐obesity medications. Conclusion: Exercise remains a cornerstone intervention in the management of MASLD, with suggested benefits even for patients who have progressed to cirrhosis. Personalized exercise regimens should be prioritized for all patients, including those receiving pharmacotherapy. Further research is needed to refine exercise protocols and investigate their impact on histologic and clinical outcomes, as well as their potential synergistic effects with emerging treatments. [ABSTRACT FROM AUTHOR]

Background and Aims: The homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha‐1 antitrypsin (AAT) deficiency and leads to liver disease via hepatocellular AAT aggregation. We systematically analysed the composition of AAT aggregates and studied the impact of bile acids. Methods: AAT inclusions were isolated from livers of PiZ overexpressing mice and PIZZ humans via fluorescence‐activated and immunomagnetic sorting (FACS/MACS), while insoluble proteins were obtained via Triton‐X extraction. Inclusion composition was evaluated through mass‐spectrometry (MS), immunoblotting and immunostaining. Hepatocytes with versus without AAT aggregates were obtained via microdissection. Serum bile acids were assessed in 57 PIZZ subjects and 19 controls. Mice were administered 2% cholic acid (CA)–supplemented chow for 7 days. Results: MS identified the key endoplasmic reticulum chaperone 78 kDa glucose‐regulated protein (GRP78) in FACS/MACS pulldowns. GRP78 was also enriched in insoluble fractions from PiZ mice versus wild types and detected in insoluble fractions/MACS isolates from PIZZ liver explants. In cultured cells/primary hepatocytes, PiZ overexpression was associated with increased GRP78 mRNA/protein levels. In human livers, hepatocytes with AAT aggregates had higher GRP78 levels than hepatocytes without. PIZZ subjects displayed higher serum bile acid levels than controls and the highest levels were seen in individuals with liver injury/fibrosis. In PiZ mice, CA‐mediated bile acid challenge resulted in increased liver injury and translocation of GRP78 into the aggregates. Conclusions: Our results demonstrate that GRP78 is sequestered within AAT inclusions. Bile acid accumulation, as seen in PIZZ subjects with liver disease, may promote GRP78 segregation and thereby augment liver damage. Trial Registration: NCT02929940 [ABSTRACT FROM AUTHOR]

Summary: Background: Several HCC risk stratification scores were developed; however, none has been prospectively validated. The primary aim is to validate the clinical utility of six HCC risk scores in large prospective study of F3‐4 patients achieving SVR following DAAs according to EASL guidelines. The secondary aim is to explore whether individualized risk stratification improves detection of HCC at early stages amenable to curative treatment. Methods: This prospective study included two cohorts: Egyptian Liver Research Institute and Hospital (ELRIAH) cohort of 463 chronic HCV patients with advanced liver disease (F3 and F4) achieved SVR with a follow‐up every 6 months according to EASL guidelines using 6 simple HCC risk scores and Tanta cohort of 492 comparable patients where individualized surveillance intervals were tailored based on HCC risk assessments using GES score as follows: low‐risk patients were followed yearly, intermediate‐risk every 6 months and high‐risk every 2–3 months. Results: All scores, except Watanabe post, successfully stratified patients into low‐, intermediate‐ and high‐risk groups, with log‐rank p‐value of 0.001 and Harrell's C ranging from 0.669 to 0.728. Clinical utility of these scores revealed that the highest percentage of patients classified as low risk was 42.5% using the GES, while the lowest was 8.9% using the aMAP. ELRIAH cohort, 25 patients developed HCC with 52% diagnosed at BCLC 0 and A. Tanta cohort, 35 patients developed HCC, with 80% diagnosed at BCLC 0 and A. Conclusion: Individualized risk stratification using HCC risk scores was associated with improved early‐stage detection and receipt of curative treatment. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: We aimed to characterise insulin‐like growth factor‐1 (IGF‐1) signalling in patients with advanced chronic liver disease (ACLD). Methods: Consecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6–9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non‐bleeding hepatic decompensation and S5: further decompensation. Results: In total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF‐1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p < 0.001). Patients with CSPH had significantly lower IGF‐1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF‐1 showed an independent negative association with body mass index (BMI; aB: −1.56; p < 0.001), enhanced liver fibrosis (ELF) test (aB: −8.43; p < 0.001), MELD (aB: −1.13; p = 0.042) and age (per 10 years; aB: −6.87; p < 0.001). IGF‐1 exhibited an excellent AUROC (0.856) for the prediction of liver‐related death at 6 months of follow‐up. Lower IGF‐1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83–0.98; p = 0.016), acute‐on‐chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68–0.93; p = 0.004) and liver‐related death (asHR: 0.76; 95% CI: 0.63–0.91; p = 0.004). Conclusion: Decreased levels of IGF‐1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF‐1 was independently linked to high BMI. Lower IGF‐1 in cirrhosis predicts decompensation, ACLF and liver‐related death. [ABSTRACT FROM AUTHOR]

Background and objectives: Statins are used for metabolic dysfunction‐associated steatotic liver disease (MASLD) (NAFLD) treatment, but their role in this context is unclear. Genetic variants of patatin‐like phospholipase domain containing 3 (PNPLA3) are associated with MASLD susceptibility and statin treatment efficacy. Access to liver biopsies before established MASLD is limited, and statins and PNPLA3 in early liver steatosis are thus difficult to study. Methods: Liver biopsies were collected from 261 patients without known liver disease at surgery and stratified based on statin use and criteria for the metabolic syndrome (MS). Genotypes and transcript levels were measured using Illumina and Affymetrix arrays, and metabolic and lipoprotein profiles by clinical assays. Statin effects on PNPLA3, de novo lipogenesis (DNL), and lipid accumulation were further studied in vitro. Results: The PNPLA3I148M genetic variant was associated with significantly lower hepatic levels of cholesterol synthesis‐associated transcripts. Patients with MS had significantly higher hepatic levels of MASLD and lipogenesis‐associated transcripts than non‐MS patients. Patients with MS on statin therapy had significantly higher hepatic levels of PNPLA3, acetyl‐CoA carboxylase alpha, and ATP citrate lyase, and statin use was associated with higher plasma fasting glucose, insulin, and HbA1c. Exposure of hepatocyte‐like HepG2 cells to atorvastatin promoted intracellular accumulation of triglycerides and lipogenesis‐associated transcripts. Atorvastatin‐exposure of HepG2, sterol O‐acyltransferase (SOAT) 2‐only‐HepG2, primary human hepatic stellate, and hepatic stellate cell‐like LX2 cells significantly increased levels of PNPLA3 and SREBF2‐target genes, whereas knockdown of SREBF2 attenuated this effect. Conclusions: Collectively, these observations suggest statin‐associated regulation of PNPLA3 and DNL in liver. The potential interaction between PNPLA3 genotype and metabolic status should be considered in future studies in the context of statin therapy for MASLD. [ABSTRACT FROM AUTHOR]

Background: Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy. Methods: A retrospective analysis of patients with early‐stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all‐cause mortality after RFA. Results: A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non‐SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver‐related and all‐cause mortality after a median follow‐up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all‐cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45–0.996; p =.048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42–1.00; p =.049). Poor liver functional reserve (high albumin‐bilirubin grades) increased all‐cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis‐4 index were predictors for HCC recurrence, whereas SLD was not. Conclusions: Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all‐cause mortality compared to those with poor liver functional reserve. Plain Language Summary: The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease.Maintaining good liver function is an important prognostic factor for survival. [ABSTRACT FROM AUTHOR]

Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single‐dose PK (2 or 4 mg) in eight non‐cirrhotic CLD participants; Study 3 evaluated single‐dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6–42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4–85% on days 1 and 28, with 34–46% lower clearance despite a similar half‐life. The moderate HI group had a 59% higher exposure than the non‐cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17–40% after 4 weeks in participants with abnormal baseline ALP. Single‐dose PK in non‐cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well‐tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, and can lead to hepatocellular carcinoma (HCC), a leading cause of cancer‐related death. We aimed to determine the extent to which MASLD is an increasing cause of HCC in Sweden and to determine clinical characteristics associated with underlying MASLD. Using the Swedish quality registry for liver cancer (SweLiv), we identified all adults with a diagnosis of HCC in Sweden between 2012 and 2018. Baseline data were retrieved from SweLiv and other nationwide registers. Totally, 3494 patients with HCC were identified. Of them, 757 patients (22%) had MASLD‐HCC. The proportion with MASLD‐HCC increased from 19% in 2012 to 25% in 2018 (ptrend = 0.012), and MASLD was since 2017 the leading cause of HCC, surpassing hepatitis C. MASLD was the fastest growing cause of HCC with a 33% increment during the study period. Compared to other patients with HCC, those with MASLD‐HCC were older (75 vs. 67 years, p <.001), less commonly had cirrhosis (61% vs. 82%, p <.001), had larger tumours (median 5.5 vs. 4.3 cm, p <.001), and more often extrahepatic metastasis (22% vs. 16%, p <.001). Patients with HCC caused by MASLD or by other causes were equally likely to be diagnosed in an early stage (Barcelona Clinic Liver Cancer 0–A, 27% vs. 30%, p =.129). MASLD is now the leading cause of HCC in Sweden. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions To investigate the prevalence of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), and the impact of comorbidity of AIH, PBC, and PSC on hospitalization burden in patients with inflammatory bowel disease (IBD).Inpatients admitted to Peking Union Medical College Hospital from January 1, 1998 to December 31, 2021 were included. Odds ratio (OR) and the corresponding 95% confidence interval (CI) were calculated to compare the risk of AIH, PBC, and PSC between IBD and non‐IBD patients. Medical cost and length of hospitalization were compared between IBD patients with and without AIH, PBC, or PSC.Among the included 858 967 inpatients, there were 3059 patients with IBD. Additionally, there were 117 patients with AIH, 879 patients with PBC, and 35 patients with PSC, regardless of having IBD or not. Patients with IBD had a significantly higher risk of AIH (OR 4.87, 95% CI 1.20–19.71, p = 0.03) and PSC (OR 112.28, 95% CI 53.88–233.98, p < 0.01) than those without IBD. While there was no significant difference in the risk of PBC between patients with and without IBD (OR 1.60, 95% CI 0.67–3.86, p = 0.29). The medical cost of each hospitalization did not differ between IBD patients with and without AIH, PBC, or PSC.IBD patients had a higher risk of AIH and PSC. Comorbidity of AIH, PBC, or PSC has no significant effect on the average cost of each hospitalization in IBD patients. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions A novel noninvasive score, Agile‐4 score, combining liver stiffness measurements, aspartate aminotransferase/alanine aminotransferase, platelet count, diabetes status and sex has been developed for the identification of cirrhosis in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). We assessed the performance of Agile‐4 for ruling‐in/out liver cirrhosis in MASLD patients.We searched Medline, Cochrane library, Web of science, Scopus and Echosens website up to May 2024. Eligible studies assessed the accuracy of Agile‐4 for ruling‐in (≥0.565) and ruling‐out (<0.251) liver cirrhosis, using biopsy as the reference standard, at predefined thresholds. We calculated pooled sensitivity and specificity estimates for both Agile‐4 thresholds alongside 95% confidence intervals following bivariate random‐effect models. We assessed the risk of bias using Quality Assessment of Diagnostic Accuracy Studies‐2 tool.We included seven studies with 6037 participants. An Agile‐4 score ≥0.565 yielded a pooled specificity of 0.93 (95% CI, 0.86–0.97). Similarly, an Agile‐4 score <0.251 excluded cirrhosis with a summary sensitivity of 0.90 (0.80–0.95). Assuming a cirrhosis prevalence of 30%, the positive predictive value (PPV) for ruling‐in cirrhosis was 80%, while the negative predictive value for ruling‐out cirrhosis was 95%. Most studies were at high or unclear risk for bias due to concerns regarding patient selection and the blinding status of Agile‐4 score interpretation in relation to biopsy results.Agile‐4 score performs well for ruling‐in/out liver cirrhosis in MASLD patients. Owing to the relatively low PPV, sequential application of the Agile‐4 after fibrosis‐4 index (FIB‐4) testing might further enhance its performance. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) is responsible for a significant global health burden. Despite this burden, the prevalence and mortality of MASLD‐related cirrhosis remain inadequately defined, hindering effective public health strategies. This study aimed to estimate the global prevalence and mortality associated with MASLD‐related cirrhosis.A systematic search of PubMed, Ovid MEDLINE, EMBASE, Web of Science and SCOPUS was conducted using keywords related to MASLD and cirrhosis from inception of each database used through June 2024. COVIDENCE was used for abstract and manuscript review. MASLD populations were categorised into ‘general practice setting’ and ‘high risk setting’, which indicated studies from inpatient setting or those referred for liver biopsy for an indication (elevated liver enzymes). Our data extraction and quality assessment followed PRISMA guidelines. A random‐effects model was utilised for meta‐analysis.From 7924 identified articles, 35 studies comprising 513,742 patients with MASLD met the inclusion criteria. The pooled global prevalence of cirrhosis among MASLD patients was 3.26% (95% CI: 2.47%–4.31%) in general practice settings (4 studies) and 14.51% (95% CI: 11.22%–18.57%) among those in inpatient settings or referred for liver biopsy (31 studies). Regionally, higher prevalence rates in high‐risk settings were observed in North America and Australia (18.38%; 95% CI: 9.06%–33.75%), followed by Europe (10.16%; 95% CI: 5.71%–17.44%) and Asia (9.12%; 95% CI: 6.11%–13.40%) (p = 0.007). Notably, ICD‐based diagnoses indicated a significantly higher prevalence of cirrhosis (27.43%) compared to those diagnosed by liver biopsy (13.24%; p < 0.001). The pooled all‐cause mortality rate for MASLD‐cirrhosis patients was estimated at 7.91 per 100 person‐years (95% CI: 4.44–13.71) (9 studies).This meta‐analysis underscores the substantial prevalence of cirrhosis among MASLD patients and highlights significant geographic and demographic variability, calling for improved screening and management strategies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a widely prevalent type of primary liver cancer. However, strategies for pretumor intervention are still limited. In this study, a liver‐specific Zbtb7b knockout mouse model was used to evaluate the role of Zbtb7b in metabolic dysfunction‐associated steatotic liver disease (MASLD)‐related HCC development. We revealed that Zbtb7b was compensatively increased and restricted lipid deposition in the liver during MASLD progression, which protects against MASLD‐related HCC initiation. Mechanistically, Zbtb7b suppresses the expression of the long noncoding RNA H19 to attenuate hepatic de novo lipogenesis and increase fatty acid oxidation, thereby preventing lipid accumulation in hepatocytes. As a result, the proliferation and migration abilities of HCC cells are reduced. Overall, we demonstrated that Zbtb7b serves as a tumor suppressor at an early stage of HCC, thus providing a promising target for the treatment of HCC at a premalignant stage. [ABSTRACT FROM AUTHOR]

Summary Background Purpose Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly common in the pediatric population and may increase risk for developing cardiovascular disease (CVD) in people with MASLD. Oxidized high‐density lipoprotein (oxHDL) and oxidized low‐density lipoprotein (oxLDL) are modified, pro‐atherosclerotic lipoproteins that are increased in adults with MASLD and CVD but have not been reported in adolescents with MASLD.To determine if oxLDL and oxHDL are increased in adolescents with MASLD.Fasting oxHDL and oxLDL were measured in adolescents (11–20 years) with obesity and biopsy‐confirmed MASLD (n = 47), and peers without MASLD but with obesity (Ob; n = 28), or normal weight (NW; n = 29).oxHDL was 27% higher (p < 0.05) in the MASLD group (mean ± SD: 11.9 ± 4.7 ng/mL) compared to the Ob group (9.3 ± 3.7 ng/mL, p < 0.05) but only 7% higher than the NW group (11.1 ± 3.8 ng/mL, p > 0.05). However, HDL‐C was 19% and 32% lower in the MASLD group than in the Ob and NW groups, respectively. Thus, oxHDL/HDL‐C ratio was 55% and 66% higher in MASLD compared to the Ob group (p < 0.004) and the NW group (p < 0.001), respectively. oxLDL (52.4 ± 16.0, 46.7 ± 10.1 and 47.1 ± 15.2 U/L for MASLD, Ob and NW, respectively), LDL‐C and the oxLDL/LDL‐C ratio did not differ among groups.The elevated oxHDL and oxHDL/HDL‐C in adolescents with MASLD compared to peers with Ob or NW suggests that there is some oxidative stress in MASLD independent of obesity and potential for increased CVD risk in the future. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aim Methods Results Conclusions Prognosis in autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) has historically been poor. This multicenter retrospective cohort study investigated the natural history and assessed the predictors of outcomes in patients with AIH, PBC, and PSC.AIH, PBC, and PSC patients were identified from the state‐wide Hepascore and Clinical Outcome cohort. Overall death or transplant, liver‐related mortality (liver‐related death or transplant), and liver‐related decompensation were determined using a population‐based data linkage system. Baseline Liver Outcome Score (LOS), Hepascore, and MELD were examined for predicting outcomes.Two‐hundred thirty‐seven AIH patients (24% male, median age 56.6 years [range, 14.3–94.0]), 157 PBC patients (8.3% male, median age 60.5 years [range, 25.6–87.1]), and 167 PSC patients (52.7% male, median age 55.6 years [range, 18.4–88.6]) were enrolled. Five‐year transplant‐free survival was 88% (95%CI: 81–92%) in AIH, 92% (95%CI: 85–96%) in PBC, and 61% (95%CI: 51–69%) in PSC. PSC had a significantly worse overall death or transplant, liver‐related mortality, and liver‐related decompensation when compared to AIH and PBC (p < 0.0001). LOS was a significant independent predictor of overall death or transplant, liver‐related mortality, and liver‐related decompensation among patients with AIH and PBC. LOS was a significant independent predictor of overall death or transplant in patients with PSC, and Hepascore was a significant independent predictor of liver‐related mortality and liver‐related decompensation.Outcomes for AIH and PBC are excellent but remain poor in PSC. LOS is a predictor of outcomes in autoimmune liver disease. [ABSTRACT FROM AUTHOR]

The pharmacotherapy of metabolic dysfunction‐associated steatotic liver disease (MASLD) and its progressive form, the metabolic dysfunction‐associated steatohepatitis (MASH), remains a hot topic in research and a largely unmet need in clinical practice. As the first approval of a disease‐specific drug, resmetirom, was regarded as a milestone for the management of this common liver disease, this comprehensive and updated review aimed to highlight the importance of the hepatic thyroid hormone (TH) receptor (THR)‐β signalling for the treatment of MASH, with a special focus on resmetirom. First, the genomic and non‐genomic actions of the liver‐directed THR‐β mediated mechanisms are summarized. THR‐β has a key role in hepatic lipid and carbohydrate metabolism; disruption of THR‐β signalling leads to dysmetabolism, thus promoting MASLD and possibly its progression to MASH and cirrhosis. In the clinical setting, this is translated into a significant association between primary hypothyroidism and MASLD, as confirmed by recent meta‐analyses. An association between MASLD and subclinical intrahepatic hypothyroidism (i.e. a state of relatively low hepatic triiodothyronine concentrations, with circulating TH concentrations within the normal range) is also emerging and under investigation. In line with this, the favourable results of the phase 3 placebo‐controlled MAESTRO trials led to the recent conditional approval of resmetirom by the US FDA for treating adults with MASH and moderate‐to‐advanced fibrosis. This conditional approval of resmetirom opened a new window to the management of this common and burdensome liver disease, thus bringing the global scientific community in front of new perspectives and challenges. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions Patients with alcohol‐related liver disease (ALD) might be at increased risk of acute pancreatitis (AP), but large‐scale data are lacking.Population‐based cohort study using data from the Swedish National Patient Register on 37,062 patients with ALD from 1969 to 2020. Patients were matched to ≤10 general population comparators (n = 352,931). We used logistic regression to estimate the risk of acute or chronic pancreatitis prior to ALD diagnosis and Cox regression to estimate rates for hospitalization for AP after ALD diagnosis.Median age at ALD diagnosis was 59 years; 72% were men, and 67% had cirrhosis at baseline. Overall, 7% had experienced pancreatitis before ALD diagnosis, resulting in 9‐fold higher odds of pancreatitis compared to comparators. The 10‐year cumulative incidence of hospitalization for AP was 2.7% (95%CI = 2.5–2.8) in ALD and 0.6% (95%CI = 0.58–0.63) in comparators, yielding an adjusted HR of 6.3 (95%CI = 5.8–6.9). Younger age, male sex, and diagnoses of alcohol use disorders and chronic obstructive pulmonary disease were independent risk factors for developing AP in ALD. Continued drinking after baseline was associated with a higher risk of AP (adjusted hazard ratio [aHR] 2.6, 95%CI = 2.29–2.85).ALD is associated with 9‐fold higher odds of prevalent pancreatitis compared to the general population. The hospitalization rate for AP following ALD diagnosis is 6‐fold higher. About 10% of patients with ALD have or develop AP, suggesting that assessing history of pancreatitis and its sequelae might be relevant for patients with ALD. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatotic liver disease (MASLD) refers to a broad spectrum of conditions associating fat accumulation in the liver (steatosis) with varying degrees of inflammation (hepatitis) and fibrosis, which can progress to cirrhosis and potentially cancer (hepatocellular carcinoma). The first stages of these diseases are reversible and the immune system, together with metabolic factors (obesity, insulin resistance, Western diet, etc.), can influence the disease trajectory leading to progression or regression. Dendritic cells are professional antigen‐presenting cells that constantly sense environmental stimuli and orchestrate immune responses. Herein, we discuss the existing literature on the heterogeneity of dendritic cell lineages, states, and functions, to provide a comprehensive overview of how liver dendritic cells influence the onset and evolution of MASLD. [ABSTRACT FROM AUTHOR]

Aim of the Study: HBV‐infected individuals are also presenting with MASLD. However, the value of VCTE for detecting hepatic fibrosis and steatosis in CHB patients concurrent with MASLD is unclear. In patients with combined CHB and MASLD, we intend to assess the diagnostic efficacy of VCTE in determining the extent of fibrosis and steatosis. Methods: This retrospective study involved 368 patients diagnosed with chronic HBV infection combined with MASLD who received liver biopsy and VCTE at Xiamen City Traditional Chinese Medicine Hospital from June 2018 to June 2023. The cutoff values for liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were determined via the use of the cross‐validated area under the receiver operating characteristic (AUROC) curve analyses to identify pairwise fibrosis stage and grade, respectively. The diagnostic statistics were calculated with a 90% fixed sensitivity and 90% specificity. Results: An AUROC of 0.86 (95% CI: 0.76–0.95) was determined by a LSM cutoff value of 11.25 to identify patients with cirrhosis. Patients have the following values: sensitivity, 0.79; specificity, 0.90; PPV, 0.89; and NPV, 0.81. An AUROC of 0.84 (95% CI: 0.76–0.95) was determined by a CAP cutoff value of 313 to identify patients with severe steatotic liver. Patients have the following values: sensitivity, 0.86; specificity, 0.82; PPV, 0.82; and NPV, 0.85. Conclusion:In this investigation of adult patients diagnosed with CHB with MASLD, VCTE demonstrated a robust capability to differentiate cirrhosis and severe steatotic liver. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Discussion and Conclusions We aimed to determine acceptability and feasibility of innovative wearable alcohol biosensor monitors (ABM) for patients with alcohol‐related liver disease (ALD) and their clinicians.Patients and clinicians at a tertiary care centre participated in qualitative interviews on usability, acceptability, feasibility, efficiency/effectiveness, impact of device on behaviour/clinical practice and preferences/barriers. Interviews were audiotaped, transcribed and coded using a constant comparison method for category themes.Patients (n = 23) were 56% female, mean 44 years old, 87% White, with moderate–severe liver disease. Some felt the ABMs appearance was unappealing; others felt it provided an opportunity for openness and education of others. While some found it feasible to wear, others felt it was unrealistic to wear 24/7. Importantly, there were many positive themes on effectiveness/efficiency—participants felt the ABM could better record their alcohol use and patterns of use than they could remember. Patients felt wearing the ABM motivated abstinence, gave accountability and was a source of security.Clinicians (n = 13) were mostly hepatologists (77%), seeing on average 38 ALD patients/month. Clinicians felt seeing patterns and amounts of alcohol use could inform clinical decision making and treatments but expressed concern over the volume and complexity of data.Perspectives on ABMs for managing ALD were mixed among patients and providers. Future device designs may overcome acceptability barriers due to device appearance. However, for clinicians, the logistics of data gathering plus the complexity and volume of data produced by the ABM device requires considerable thought to make this an efficient tool for clinical use. Clinicaltrials.gov identifier NCT03533660: Alcohol biosensor monitoring for alcohol liver disease. [ABSTRACT FROM AUTHOR]

Background Method Results Conclusion Liver fibrosis progression is influenced by older age and cardiometabolic risk factors such as obesity and is associated with an increased risk of cardiovascular events. While statins may protect against cardiovascular complications, their effects in elderly individuals with obesity and liver fibrosis are unclear.The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) database was used to evaluate the effect of pravastatin on major adverse cardiovascular events in an elderly population (>70 years). Subjects were categorized by BMI: lean (<25 kg/m2), overweight (25–29.9 kg/m2) and obese (≥30 kg/m2). Liver fibrosis was assessed using the FIB‐4 index: low risk (<2.0), intermediate risk (2.0–2.66) and high risk (≥2.67). Time‐to‐event data were analysed using the Cox proportional hazards model, adjusted for confounders and compared the placebo and pravastatin groups.A total of 5.804 subjects were included. In the placebo group, the highest risk group (high FIB‐4 and obesity) had a significantly higher hazard ratio for (non‐)fatal stroke (HR 2.74; 95% CI 1.19–6.29) compared to the low FIB‐4, lean BMI group. This risk disappeared in the same pravastatin group. Pravastatin did not affect other cardiovascular endpoints. All‐cause mortality was significantly higher in subjects with lean weight and high FIB‐4 on placebo (HR 1.88; 95% CI 1.14–3.11), but not on pravastatin (HR .58; 95% CI .28–1.20).Elderly individuals with obesity and liver fibrosis are at higher risk for (non‐)fatal stroke, which is reduced with pravastatin. Pravastatin also potentially lowers all‐cause mortality in subjects with lean weight and liver fibrosis. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Type 2 diabetes increases the risk of cirrhosis and liver cancer. Noninvasive and early assessment of liver fibrosis is essential. We aimed to develop a score to aid in the initial assessment of liver fibrosis in the diabetic population.A fibrosis investigating navigator in diabetes (FIND) score was developed and validated in the NHANES dataset (2017–2020). Fibrosis was defined as a liver stiffness measurement (LSM) ≥8.0 kPa. The diagnostic accuracies of FIB‐4, NFS, LiverRisk, steatosis‐associated fibrosis estimator (SAFE) and metabolic dysfunction–associated fibrosis (MAF‐5) were compared. FIND was also externally validated in various liver diseases via biopsy as a reference in an Asian centre between 2016 and 2020. Finally, we examined the prognostic implications of the FIND index utilizing data from the UK Biobank cohort (2006–2010).The FIND score model yielded an AUROC of 0.781 for the prediction of an LSM ≥8 kPa in the validation set, which was consistently greater than that of other available models (all p < 0.05). In the whole NHANES dataset, the 85% sensitivity cut‐off of 0.16 corresponded to a NPV of 91.9%, whereas the 85% specificity cut‐off of 0.31 corresponded to a PPV of 50.6%. FIND displayed overall accuracies similar to those of the other models in staging fibrosis stages, with biopsy used as a reference. In the UK Biobank cohort, FIND >0.31 was associated with an increased risk of all‐cause and liver‐related mortality in the diabetic population in adjusted models (HR, 1.75; 95% CI, 1.62–1.89; HR, 23.59; 95% CI, 13.67–40.69).In diabetes patients, the novel FIND score performs well in identifying subjects at risk of liver fibrosis and predicting all‐cause and liver‐related mortality. [ABSTRACT FROM AUTHOR]

The year 2024 is the year of new clinical practice and management guidelines for chronic hepatitis B virus (HBV) infection. World Health Organization (WHO) published the updated HBV guidelines in March 2024. In contrast, two key international societies for liver diseases, including the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL), are currently in the process of updating their clinical practice guidelines for HBV. In 2022, China published their HBV guidelines, regarded as one of the most uncompromising ones as the threshold to start antiviral treatment is set at detectable HBV DNA above 10–20 IU/mL. In this chapter, the latest developments in the HBV guidelines with a specific focus on the Chinese & WHO guidelines are discussed. Specifically, the pros and cons of lowering treatment thresholds and the benefits of treating more people to avoid the complications of chronic hepatitis B, specifically HCC, are reviewed. [ABSTRACT FROM AUTHOR]

This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction‐associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction‐associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver. [ABSTRACT FROM AUTHOR]

H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) remain elusive. Here, a genome‐wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)‐induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP‐Seq and RNA‐Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1‐promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF‐κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs‐Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs‐Allo robustly alleviates HFD‐induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac‐TDO2‐NF‐κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aim Methods Results Conclusions The T cell receptor (TCR) can recognize a vast number of antigens and is closely associated with the pathogenesis of various diseases including autoimmune diseases and malignancies. However, the clinical significance of the TCR repertoire and its post‐treatment changes remain unclear in liver diseases.We performed next‐generation sequencing (NGS)‐based TCR analysis using DNA obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors (HD, n = 5), primary biliary cholangitis (PBC, n = 5), autoimmune hepatitis (AIH, n = 5), and hepatocellular carcinoma (HCC, n = 5) and evaluated the changes after treatment.Baseline TCR repertoire analysis demonstrated that TCR clonotype usage is restricted and diversity is low in all three disease groups (PBC, AIH, and HCC), particularly in PBC and AIH compared to HD (p < 0.05). Following treatment, clonotype usage and diversity did not change significantly, except in AIH, where diversity decreased further (p < 0.05 for clone Shannon diversity and clone evenness). Disease‐specific usage of TCR beta genes and specific changes after therapy were observed in all groups. Analysis of clonotypes shared with other individuals (public clonotypes) revealed that nine public clonotypes in PBC, eight in AIH, and eight in HCC disappeared after treatment. Motif analysis identified one characteristic motif (NQPQH) in PBC.The diversity of the TCR repertoire, TCR beta chain usage, clonotypes, and motifs and their post‐treatment changes are disease‐specific in each liver disease, indicating that further TCR repertoire studies are needed to accelerate the understanding of liver disease pathogenesis from an immunological perspective. [ABSTRACT FROM AUTHOR]

Background: Patients with substance use disorders present with many risk factors for liver disease—including alcohol, hepatitis C virus infection, and obesity—and should thus be screened for compensated advanced chronic liver disease (cACLD). Such screening could potentially be performed by outpatient addiction clinics. In this study, we aimed to assess the feasibility, acceptability, and results of cACLD screening using transient elastography (TE) among all patients attending routine follow‐up visits at addiction clinics, regardless of their liver disease risk factors. Methods: Liver fibrosis evaluation using TE was offered to every patient consulting two different addiction clinics in France, between December 2020 and September 2021, during dedicated half‐day screening sessions. The screening was proposed during the patient's routine care and was performed immediately after the scheduled consultation. Patients with a liver stiffness measurement over 8 kPa were referred to a hepatology visit in the addiction clinic within 2–4 weeks. Results: Screening was offered to 227 patients and was accepted by 116 (51%) patients. Twelve patients had a liver stiffness over 8 kPa, and nine of these patients attended the recommended specialist hepatology visit. Five patients (4.3% of those screened) were diagnosed with cACLD. Patients' acceptance of the screening was associated with older age, being on one's own or professionally inactive, and presenting with alcohol use disorder. Conclusion: Overall, our results demonstrated that opportunistic cACLD screening using TE in outpatient addiction clinics was feasible and acceptable, with good results. [ABSTRACT FROM AUTHOR]

Aim: In patients with Fontan‐associated liver disease (FALD), gamma‐glutamyl transferase (GGT) levels are often elevated, however, its clinical importance is unclear. We investigated the relationship between the clinical course of FALD and GGT levels. Methods: We enrolled 145 patients with FALD who underwent right‐heart catheterization (RHC) and visited our department. Ursodeoxycholic acid (UDCA) was administered to 62 of the patients. Patients with GGT levels <50 and ≥50 U/L were compared. Follow‐up RHC was undertaken in 76 patients. Cases in which GGT levels decreased by ≥10% or <50 U/L were defined as improved (n = 33). Results: Patients with GGT levels ≥50 U/L had significantly lower levels of albumin and higher levels of alanine transaminase (ALT) but no significant differences in RHC factors. Over a 4.6‐year period, 43.4% showed improvement in GGT levels. Improved cases had significantly lower total bilirubin (1.1 vs. 1.6 mg/dL), AST (22 vs. 28 U/L), and ALT (18 vs. 27 U/L) levels than nonimproved cases (n = 29, p < 0.05), and the change in platelet count (−0.5 vs. −3.0 × 10−4/μL) was significantly lower in the latter (p = 0.03). The improvement rate was significantly higher in UDCA‐treated cases (55.2%) with GGT levels ≥50 U/L compared to cases not treated with UDCA (18.2%, p = 0.04). Conclusion: In cases of FALD with no improvement in GGT level, the platelet count decreased over time, suggesting progression of fibrosis. Physicians should be aware of the importance of a high GGT level in patients with FALD. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to identify the genetic risk factors from donors or recipients that contribute to postliver transplantation (LT) steatotic liver disease (SLD), focusing on the genetic risk score (GRS) based on single nucleotide polymorphisms (SNPs) in SLD patients. Methods: This retrospective study included 55 Japanese SLD recipients and their respective donors. Genotyping of PNPLA3, TM6SF2, and HSD17B13 was undertaken, and the combined GRS was calculated. The relationship between the GRS and the incidence of posttransplant SLD was also evaluated. Results: The SLD recipients had a high prevalence of post‐LT graft steatosis/steatohepatitis (76.4% and 58.2%, respectively). Although the recipients had a high frequency of risk alleles, there was no relationship between the number of risk alleles for each SNP and the incidence of posttransplant SLD. In contrast, an increased number of risk alleles for any SNP in the donor was correlated with high incidence rates of both post‐LT steatosis and steatohepatitis. A multivariable analysis showed that a high donor GRS was an independent risk factor for graft steatosis (odds ratio 8.77; 95% CI, 1.94–52.94; p = 0.009). Similarly, a high donor GRS was an independent risk factor (odds ratio 6.76; 95% CI, 1.84–30.78; p = 0.007) for post‐LT graft steatohepatitis. Conclusions: Donor risk alleles of PNPLA3, TM6SF2, and HSD17B13, rather than recipient risk alleles, have been implicated in the development of posttransplant SLD. The combination of these donor risk alleles into a GRS could predict the development of posttransplant SLD. [ABSTRACT FROM AUTHOR]

Background and Aim: The prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasing worldwide, coinciding with aging population. However, limited studies have evaluated its incidence and progression to advanced fibrosis in the elderly population. Therefore, our study aimed to investigate the incidence of MASLD and advanced fibrosis in this age group. Methods: We included 878 686 individuals aged ≥60 years from the Korea National Health Insurance Service‐Senior cohort. After excluding participants with preexisting MASLD, 329 388 individuals were finally analyzed. Participants were categorized into four groups based on the presence of overweight/obesity and additional risk factors (aRF) included in the cardiometabolic diagnostic criteria of MASLD. Results: The overall incidence of MASLD was 1.94 per 100 person‐years, and the incidence of advanced fibrosis in MASLD patients was 1.78 per 100 person‐years. MASLD development was significantly higher in overweight/obese patients (2.65 per 100 person‐years) compared to lean patients (1.09 per 100 person‐years), and this trend persisted after stratification by the presence of aRF. Similarly, the incidence of advanced fibrosis among MASLD patients was higher in overweight/obese individuals (2.06 per 100 person‐years) compared to lean counterparts (0.87 per 100 person‐years), irrespective of aRF. Conclusions: The lower incidence of MASLD in the elderly population compared to the general population underscores the importance of identifying age‐specific risk factors. Overweight/obesity emerged as a robust predictor of MASLD development and advanced fibrosis. Additionally, the presence of additional cardiometabolic risk factors further increased the risk of incident MASLD and advanced fibrosis among the elderly. [ABSTRACT FROM AUTHOR]

Background: Liver steatosis (LS) and liver fibrosis (LF) can increase the risk of cardiovascular disease in people with HIV, but their prevalence and associated factors are poorly understood. This study aimed to assess the prevalence of and factors associated with LS and LF in a large cohort of people with HIV. Methods: We conducted a cross‐sectional study of consecutive people with HIV attending the Clinic of Barcelona from September 2022 to September 2023, excluding those with chronic B or/and C hepatitis virus coinfection. LS was assessed using the Hepatic Steatosis Index (HSI) and Fatty Liver Index (FLI), and LF was assessed using the Non‐Alcoholic Fatty Liver Disease Fibrosis Score (NFS), Fibrosis‐4 score (FIB‐4), and the European AIDS Clinical Society (EACS) algorithm in both the whole cohort (cohort 1) and in a specific cohort more susceptible to liver disease (cohort 2). We identified independent variables associated with LS and LF using logistic regression. Results: Cohort 1 included 4664 people with HIV; 76% and 37% of them had available HSI and FLI data, LS was present in 28% and 19%, respectively. LF risk was present in 1%, 2%, and 1% of people with HIV according to NFS, FIB‐4, and EACS algorithm scores, respectively. Cohort 2 included 1345 people with HIV; 60% and 30% of them had available HSI and FLI data, LS affected 55% and 43% and LF 2%, 5%, or 3%, respectively. Factors associated with LS included current CD4 cell count, diabetes, and hypertension, whereas LF was associated with previous exposure to dideoxynucleoside drugs and current CD4 to LF. Current integrase strand transfer inhibitor (INSTI) therapy appeared protective for LF in cohort 1. Conclusions: In this study, one in four people with HIV had LS, and the prevalence rose to one in two in those with cardiovascular risk factors. The prevalence of LF was low, but it should be considered in older people with HIV with low CD4 counts or high aspartate transaminase levels. A possible protective effect from INSTIs deserves further investigation. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction‐associated steatotic liver disease (MASLD), is a silent killer that often progresses to metabolic dysfunction‐associated steatohepatitis (MASH). To date, there are no pharmacological treatments for MASLD. While obesity is a major cause of the development and progression of MASLD, the underlying mechanisms remain unclear. We hypothesize that ferroptosis, a recently discovered nonapoptotic iron‐dependent form of cell death, is activated during the progression of MASLD and may be a potential target for treating MASLD. Using a murine model of Western diet‐induced obesity, C57BL/6J male mice were exposed to a long‐term (36 weeks) Western diet. Controls were maintained with a standard chow diet. Western diet‐induced obesity was confirmed by increased body mass index (BMI). Histopathological analysis demonstrated the progression of MASLD to MASH in the obese group, which was accompanied by significant hepatic iron deposition, oxidative damage, and lipid peroxidation. Hepatic ferroptosis was further confirmed by decreased protein expression of glutathione peroxidase 4 (GPX4) and increased acyl‐CoA synthetase long‐chain family member 4 (ACSL4), markers of ferroptosis. These findings suggest that ferroptosis is a potential mechanism involved in the pathogenesis of MASLD in male mice. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common liver disease worldwide, affecting 30% of the population in Western countries. MASLD is considered the hepatic manifestation of the metabolic syndrome, pathophysiologically underpinned by insulin resistance and frequently co‐exists with hypertension, central obesity and dyslipidaemia. Currently, safe and effective pharmacotherapies for MASLD are limited, making weight loss with lifestyle changes the mainstay therapy. A Mediterranean diet (MedDiet) has emerged as an effective dietary pattern for preventing and managing MASLD, but most studies have been conducted in Mediterranean countries, necessitating further investigation into its benefits in Western populations. Additionally, the effect of holistic multimodal lifestyle interventions, including physical activity combined with the MedDiet, is not well established. Finally, MASLD's widespread prevalence and rapid growth require improved accessibility to interventions. Digital health delivery platforms, designed for remote access, could be a promising approach to providing timely support to individuals with MASLD. This narrative review summarises the current evidence related to the effects of the MedDiet in Western, multicultural populations with MASLD. This includes a detailed description of the composition, prescription and adherence to dietary interventions in terms of how they have been designed and applied. The evidence related to the role of physical activity or exercise interventions prescribed in combination with the MedDiet for MASLD will also be reviewed. Finally, recommendations for the design and delivery of dietary and physical activity or exercise interventions to inform the design of future randomised controlled trials to facilitate the optimal management of MASLD are outlined. [ABSTRACT FROM AUTHOR]

Background and Aims: Individuals with genetic polymorphisms in UGT1A1 exhibit bilirubin levels that belie their risk of liver disease (Gilbert's syndrome) but it is not known if this phenomenon extends to other common liver blood tests (LBTs). Methods: A genome‐wide association analysis of 10 LBTs was conducted using the UK biobank. Polygenic scores (PGS) were created from discordant loci (e.g. loci associated with the LBT but not associated with cirrhosis morbidity risk). Participants were assigned to a low, intermediate or high PGS for each LBT. A high PGS approximates Gilbert's syndrome (i.e. elevated LBT without an analogous increase in disease risk). The prognostic significance of an 'elevated' LBT—and how this differs by PGS—was assessed through competing risk survival analysis. Results: This study included 157 005 and 166 871 participants for the discovery and validation phases, respectively. Elevated LBTs were more prevalent in the high versus low PGS group, yet the 10‐year risk of cirrhosis morbidity was comparable. For example, in the low PGS group, 4.3% had an elevated gamma‐glutamyltransferase (GGT) and the 10‐year risk of cirrhosis morbidity was.45%. Conversely, in the high PGS group, 21.2% had an elevated GGT and the 10‐year risk was.38%. Accordingly, the 10‐year risk of cirrhosis morbidity for individuals with an elevated GGT was markedly different in the low vs. high group (4.2% vs. 1.2%; p <.001). Similar results were apparent for Fibrosis‐4 index, total bilirubin, and platelet count. Conclusion: Variability in LBTs is influenced by genetic polymorphisms that have a neutral effect on disease risk. These findings have implications for interpreting elevated LBTs in clinical practice. [ABSTRACT FROM AUTHOR]

Direct‐acting antivirals (DAA) achieve high virological response rates with minimal side effects for many patients. Despite their significant impact on the progression and epidemiology of hepatitis C virus (HCV) associated liver disease, the global annual incidence of chronic infections is expected to remain relatively constant, averaging 1.42 million new cases each year until 2030. Furthermore, by 2030, there will be a 14–17% increase in end‐stage liver disease outcomes such as liver‐related deaths, hepatocellular carcinoma (HCC), and decompensated cirrhosis in adults aged 18 years and over. Although reductions in liver decompensation, HCC occurrence, and mortality have been shown in patients with advanced liver disease who achieved sustained virological response (SVR) with DAA, these benefits may be less significant in those with decompensated liver cirrhosis. This review aims to summarise the impact of the virological response to DAA on liver disease progression and outcomes in patients with advanced chronic liver disease, which appears to be crucial for defining patient‐specific follow‐up. [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post‐LT setting of patients transplanted for metabolic dysfunction‐associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings. Methods: This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1‐year after LT. Results: In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16–46) and 26.0 (IQR: 16.8–41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0–5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post‐LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8–80.4, p =.010) and post‐LT dyslipidaemia (OR: 7.9, 95% CI: 1.3–47.1, p =.024) with LSM (OR: 1.7, 95% CI: 1.1–2.8, p =.030) was independently associated with MASLD. Conclusions: Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis. [ABSTRACT FROM AUTHOR]

Summary: Background: The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction‐associated steatotic liver disease and those with metabolic dysfunction and alcohol‐associated liver disease remain unclear. Aims: To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases. Methods: This observational cohort study included 1866 patients with metabolic dysfunction‐associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol‐associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non‐invasive liver fibrosis scores were assessed using the Cox regression analysis. Results: Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol‐associated liver disease than with metabolic dysfunction‐associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction‐associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor. Conclusions: Although both metabolic steatotic liver disease and metabolic alcohol‐associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction‐associated steatotic liver disease. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: While immune checkpoint inhibitors (ICIs) are revolutionising cancer therapy, checkpoint inhibitor‐induced liver injury is a significant immune‐related side effect of this immunotherapy. This study focuses on the severity classifications and characteristics of patients with checkpoint inhibitor‐induced hepatitis. Methods: A retrospective analysis of patients with severe Checkpoint Inhibitor‐induced hepatitis grade 3 and 4 according to the recommended Common Terminology Criteria for Adverse Events (CTCAE) classification was conducted. Data on clinicobiological characteristics, treatment and outcomes were collected from 3 university hospitals, and causality was assessed by using the updated Roussel Uclaf Causality Assessment Method. The severity of hepatitis was assessed using the Model for End‐stage Liver Disease score, the Drug‐Induced Liver Injury Network, and the Drug‐Induced Liver Injury International Expert Working Group classifications. Results: We retrospectively included 100 patients presenting various hepatitis patterns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of severe cases was observed when using the Drug‐Induced Liver Injury classifications instead of the recommended CCTCAE classification, and this was correlated with outcomes. Conclusions: This retrospective study challenges the efficacy of the CTCAE classification in defining the severity of Checkpoint Inhibitor‐induced hepatitis and suggests that the traditional hepatology‐focused scores may be more relevant. The CTCAE classification is inconsistent and gives equal weight to jaundice and elevated transaminases, which leads to steroid overtreatment and limits the rechallenge of ICIs. [ABSTRACT FROM AUTHOR]

Background: Adenovirus has been implicated as a cause of acute liver failure (ALF) following a global outbreak of adenovirus‐associated ALF in 2021. To understand any association between viral infection and ALF, it is important to know the baseline prevalence of that virus in children undergoing liver transplant for acute and chronic liver disease (CLD). Our objective was to perform retrospective evaluation of prevalence of common hepatotropic viruses among children who underwent liver transplant at our center. Methods: We studied 33 stored frozen hepatic explant samples (originally collected between 2004 and 2021 as part of a liver repository) which fell into three categories: ALF (n = 18), acute on chronic liver failure (ACLF, n = 7), and CLD (n = 8). DNA was extracted from the samples, and viral PCR testing was performed for adenovirus, EBV, CMV, and HHV‐6. Results: Adenovirus was detected in a single case of indeterminate ALF transplanted in 2019. CMV was detected in two cases, and there were no EBV positive specimens in any group. HHV‐6 was more prevalent with 21 of 33 specimens testing positive including ALF, ACLF, and CLD cases. Conclusion: This retrospective study of common childhood virus prevalence in liver explants provides important baseline information for studying potential viral etiologies of ALF. We did not identify any clusters of infections. The most frequently occurring virus and only virus found in all categories was HHV‐6, underscoring the high prevalence in this heterogenous group. Adenovirus was identified in 1 out of 18 of ALF samples, but likely was not a hepatic pathogen. [ABSTRACT FROM AUTHOR]

Aims: To explore the associations between cuprotosis‐related genes (CRGs) across different stages of liver disease in metabolic dysfunction‐associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). Materials and Methods: We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD‐related HCC (n = 271) and two MAFLD single‐cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome‐wide association study (GWAS). Results: GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD‐related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction‐associated fatty liver to metabolic‐associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. Conclusions: GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T‐cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis. [ABSTRACT FROM AUTHOR]

Evolutionary medicine emerged in the late twentieth century, integrating principles of natural selection and adaptation with the health sciences. Today, with a rapidly widening gap between the biology of Homo sapiens and its environment, maladaptation or maladaptive disorders can be detected in almost all diseases, including liver dysfunction. However, in hepatology, as in most medical specialties, evolutionary considerations are neglected because the majority of the medical community is not familiar with evolutionary principles. The aim of this brief review is to highlight an evolutionary approach that may facilitate understanding various liver diseases. [ABSTRACT FROM AUTHOR]

Background: Multiple and complicated hepatolithiasis can be associated with decompensated cirrhosis. Endoscopic retrograde cholangiopancreatography is unavailable for multiple and complicated hepatolithiasis, and the mainstay for decompensated cirrhosis is liver transplantation. However, due to the ethical factors and the complexity of operation, liver transplantation cannot be widely operated. This study aimed to evaluate percutaneous transhepatic cholangioscopy in the extraction of stones and the recompensation of cirrhosis in patients with hepatolithiasis associated with decompensated cirrhosis. Methods: Between January 2021 and February 2024, we retrospectively reviewed the clinical data of 21 patients with multiple and complicated hepatolithiasis associated with decompensated cirrhosis. Before PTCS, the 21 patients were all assessed by the Model for End‐stage Liver Disease as having indications for liver transplantation. One‐step PTCS (n = 19) and two‐step PTCS (n = 2) were used to remove the stones. Results: The technical success rate was 100%, and most stones were cleared 90.48% (19/21). After 3 months of PTCS, MELD score of the patients had significantly decreased (10.81 ± 3.31 vs. 17.24 ± 3.40, p < 0.05), and it was lowest at 6 months after the operation (9.94 ± 4.31). After a median follow‐up period of 18 months (up to 40 months), the stone recurrence rate was 28.57% (6/21), 13 patients survived without liver transplantation, three patients underwent liver transplantation and survived, and five patients died of liver failure or cancer (mortality rate 23.81%). Conclusions: PTCS can significantly improve patients' liver function in hepatolithiasis associated with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Cilofexor, an oral farnesoid X receptor agonist, and firsocostat, an oral, liver‐targeted inhibitor of acetyl‐coenzyme A carboxylase, are being investigated in combination with semaglutide for the treatment of metabolic dysfunction‐associated steatohepatitis (previously known as nonalcoholic steatohepatitis; NCT04971785). The pharmacokinetics and safety profiles of cilofexor (100 mg) and firsocostat (20 mg) were separately investigated in two phase 1 studies, each of which included healthy Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study) and non‐Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study). Intensive pharmacokinetic sampling was performed over 96 h following a single‐dose administration of the study drug. Safety was monitored throughout the study. In total, 39 participants completed each study. The plasma exposures of cilofexor and firsocostat (area under the concentration–time curve [AUC] calculated from time 0 to infinity [AUCinf]) in Japanese participants were 1.24‐fold and 1.98‐fold, respectively, of those in non‐Japanese participants. Both study drugs were well tolerated with no clear differences in adverse events or laboratory abnormalities between Japanese and non‐Japanese participants. The approximate 2‐fold exposure difference of firsocostat between Japanese and non‐Japanese participants at the 20 mg dose does not warrant dose reduction given the previously established safety and tolerability of once‐daily doses of firsocostat up to 200 mg. [ABSTRACT FROM AUTHOR]

This parallel‐group, open‐label Phase I study evaluated the effect of mild to moderate hepatic impairment on pharmacokinetics (PK), pharmacodynamics (PD), and safety of a single oral dose of SHR4640. Participants with mild or moderate hepatic impairment were enrolled, with each cohort consisting of eight individuals, alongside eight well‐matched controls with normal hepatic function. The participants were administered 10 mg SHR4640, and blood samples were collected for PK evaluation over 72 h. Additionally, serum uric acid (sUA) levels were measured to assess PD changes. Safety was evaluated through adverse events, laboratory tests, vital signs, and electrocardiograms. The Cmax of SHR4640 decreased by 15.0% in the mild hepatic impairment group (geometric least squares means of the ratios [GMR] = 0.850, 90% CI: 0.701‐1.03) and by 17.5% in the moderate hepatic impairment group (GMR = 0.825, 90% CI: 0.681‐1.00). These reductions were not statistically significant compared to the normal hepatic function group. AUC0‐t and AUC0‐inf were similar across all groups, indicating that overall exposure to the drug was not clinical significantly affected by hepatic impairment. Apparent clearance and volume of distribution of SHR4640 showed no association with the severity of hepatic impairment as measured by the Child–Pugh score. There were no significant differences in the changes in sUA levels from baseline across different levels of hepatic function. SHR4640 is well tolerated in participants with mild or moderate hepatic impairment. Mild and moderate hepatic impairment did not have a clinically relevant impact on PK, PD, and safety of SHR4640. SHR4640 can be used in patients with mild to moderate hepatic impairment without the need for dose adjustment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a deadly cancer that emerges from a continuous progression of liver cells from normal to abnormal, often following infections by hepatitis B/C viruses (HBV/HCV), liver fibrosis, and liver cirrhosis (LC), ultimately culminating in cancer. However, there is currently limited systematic molecular analysis of biomarkers at different stages of HCC progression using multi‐omics approaches. We carried out an innovative pipeline by utilizing targeted proteomics and metabolomics to identify potential biomarkers for early detection of HCC in 316 participants, including healthy adults and patients diagnosed with HBV, HCV, LC, and HCC from three independent cohorts. We first established a detailed database of candidate biomarkers for HCC containing 3059 proteins and 103 metabolites, and identified pivotal candidates implicated in the progressive trajectory of liver cancers. Through our developed DeepPRM, scheduled multiple reaction monitoring (MRM)‐targeted approach, and machine learning‐based computational pipeline, we identified an eight‐biomolecular‐based combination with an accuracy rate of 91.43% for early diagnosis of HCC, and a 12‐biomolecular‐based combination with an accuracy rate of 80.00% for detecting changes in HBV–LC progression. These two biomarker combinations significantly improved accuracy compared to traditional tumor biomarkers. Our extensive analysis provides valuable proteomic and metabolomic data resources that will contribute to a deeper understanding of liver disease progression and enhance the identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

There are three homologous proteins (α, β and γ) in the growth arrest and DNA damage 45 (Gadd45) family. These proteins act as cellular responders to physiological and environmental stimuli. Gadd45β plays a significant role in the pathogenesis of liver diseases. Liver injury and growth stimulation increase expression of Gadd45β, which promotes cell survival, growth and proliferation in normal liver cells. By contrast, Gadd45β plays a role in promoting apoptosis and inhibiting tumour function in hepatocellular carcinoma (HCC). Currently, it is believed that Gadd45β benefits the liver through two different pathways: binding to MAPK kinase 6 (MKK6) to increase PCD induced by p38 (inhibiting tumours) or binding to constitutive androstane receptor (CAR) to jointly activate transcription of liver synthesis metabolism (promoting liver regeneration). This article aims to systematically review the role of Gadd45β in liver diseases, including its regulatory mechanism on expression and involvement in liver cell damage, inflammation, fibrosis and HCC. In conclusion, we explore the potential of targeting Gadd45β as a therapeutic strategy for liver diseases. [ABSTRACT FROM AUTHOR]

Objective: Alcohol‐related liver disease (ALD) has emerged as a significant public health concern, particularly among younger populations. ALD remains the leading cause of alcohol‐attributable deaths. This study aims to forecast ALD mortality trends up to 2030, focusing on individuals under 55 years. Methods: We utilized data from the CDC WONDER database (1999–2022) to examine ALD‐related deaths, identified by ICD‐10 codes (K70.0–K70.9). Crude mortality rates (CMRs) per 100 000 were analyzed and temporal trends were assessed using annual and average annual percent changes (APC/AAPC) with empirical quantile confidence intervals. An Autoregressive Integrated Moving Average (ARIMA) model was employed to project mortality rates until 2030, validated through time series cross‐validation. Results: From 1999 to 2022, there were 181 862 ALD‐related deaths among individuals under 55, with mortality rates increasing from 3.9 per 100 000 in 1999 to 9.7 per 100 000 in 2022 (AAPC 4.66%, 95% CI: 3.90%–5.86%). Projections suggest rates will continue to rise, reaching 14.4 per 100 000 by 2030. From 1999 to 2022, the 25–34 age group experienced the highest increase, with an AAPC of 10.27% (95% CI: 9.19%–11.35%), while the 35–44 and 45–54 age groups showed more moderate increases, with AAPCs of 5.03% and 4.38%, respectively. Projections indicate an AAPC of 3.86% for ages 25–34, 3.90% for ages 35–44, and 6.17% for ages 45–54 by 2030. Conclusion: Forecasts indicate a continued rise in ALD mortality among individuals under 55, necessitating immediate public health strategies to mitigate this trend. [ABSTRACT FROM AUTHOR]