Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction and alcohol-related liver disease (MetALD) exist on a continuous spectrum in which fibrosis stage remains the dominant predictor of liver‑related complications. Contemporary non‑invasive risk stratification uses simple serum scores (e.g., Fibrosis‑4 index [FIB‑4]) as a first step, followed by vibration‑controlled transient elastography (VCTE) or liver‑specific blood tests (enhanced liver fibrosis [ELF], procollagen III N‑terminal propeptide [PRO‑C3]) to refine risk and triage referrals. Magnetic resonance elastography (MRE) provides higher accuracy than ultrasound‑based elastography, though limited by its availability. Composite models (Agile 3+/4, steatosis‑associated fibrosis estimator [SAFE]) can reduce indeterminate classifications but may require additional calibration for alcohol exposure for use in MetALD. Prognosis should incorporate dynamic, longitudinal measurement of non‑invasive tests, and integrate extrahepatic risks, particularly cardiovascular and kidney disease. In MetALD, quantitative alcohol assessment can be improved by incorporating objective biomarkers such as phosphatidylethanol (PEth) as part of a triangulation approach that integrates self‑reported alcohol intake, the Alcohol Use Disorders Identification Test‑Consumption (AUDIT‑C), and clinical history.1 Challenges remain, particularly for MetALD, and future research will focus on integrating dynamic biomarkers, predicting treatment response, and utilizing artificial intelligence (AI) for personalized risk and treatment prediction, combining genetic modifiers and polygenic risk scores with clinical and imaging data, with validation across diverse populations.
Accurate classification and risk stratification across metabolic dysfunction-associated steatotic liver disease (MASLD), MetALD, and alcohol-associated liver disease (ALD) depend critically on the assessment of alcohol exposure. However, current clinical practice relies largely on self-reported alcohol intake, which may underestimate drinking quantity, pattern, and prior heavy exposure and consequently lead to subtype misclassification. This review focuses on an alcohol-aware approach to steatotic liver disease (SLD) phenotyping and clinical management. We discuss the complementary role of structured alcohol assessment and objective biomarkers, particularly phosphatidylethanol (PEth), while emphasizing biological, analytical, and host factors that limit interpretation of a single biomarker value. We further examine how active or recent alcohol exposure modifies the interpretation of commonly used risk-stratification tools, particularly FIB-4 and liver stiffness measurement, and when repeat assessment after alcohol reduction or abstinence may be appropriate. Finally, we propose practical subtype-specific care pathways integrating alcohol exposure, non-invasive fibrosis assessment, and longitudinal reassessment across MASLD, MetALD, and ALD. An alcohol-aware approach may reduce subtype misclassification and enable more appropriate referral, monitoring, and therapeutic decision-making across the SLD spectrum.
Background/Aims:Wilson's disease (WD) is an inherited and treatable disorder of copper metabolism with hepatic or neurological manifestations. It continues to pose challenges in clinical management, and long-term outcome data remain limited. This study investigated hepatic involvement and clinical outcomes in cohorts from Taiwan. Methods:Longitudinal data from 146 patients with WD, retrieved from the medical database of a tertiary referral center, were analyzed (mean age at diagnosis 20.7 ± 12.4 years; mean follow-up 16.8 ± 10.8 years; maximum 51.8 years). All patients received standard treatment and care. Results:Nine patients (6.2%) underwent liver transplantation, 6 patients (4.1%) died, and 3 patients (2.1%) developed hepatocellular carcinoma (HCC). Thrombocytopenia <100 K/μL at diagnosis was associated with reduced survival (P=0.0001). Univariate Cox regression identified thrombocytopenia at diagnosis as a strong predictor of liver transplantation or death (P = 0.0001; hazard ratio (HR): 8.41; 95% CI: 2.97-23.78). Consistently, thrombocytopenia <100 K/μL was associated with reduced survival (P < 0.0001) in an external cohort of 155 patients. In the original cohort, the estimated annual HCC risk was 0.12% (95% CI: 0.03-0.36), increasing to 0.86% (95% CI: 0.18-2.5) in those with thrombocytopenia at diagnosis (P=0.029). An exploratory Firth penalized logistic regression showed that older age at diagnosis was associated with higher odds of developing HCC (odds ratio: 1.096; 95% CI: 1.009-1.191; P = 0.031). Conclusion:WD patients have a high rate of liver fibrosis, regardless of whether they present with neurological and hepatic symptoms, and are at risk of developing HCC, warranting lifelong hepatic surveillance.
Hepatocellular carcinoma (HCC) exhibits substantial molecular and morphological heterogeneity. The recently updated 6th edition of the World Health Organization Classification of Digestive Tumours recognizes nine specific HCC subtypes, each characterized by distinct morphomolecular and clinical profiles. Although these subtypes account for approximately 35% of all HCC cases, the remaining 65% are classified as conventional HCCs. These subtypes are categorized based on their prognostic implications: the unfavorable prognosis group comprises macrotrabecular-massive, sarcomatoid, and neutrophil-rich HCCs; the comparable prognosis group includes steatohepatitic, fibrolamellar, and chromophobe HCCs; and the favorable prognosis group consists of lymphocyte-rich and clear cell HCCs. By contrast, scirrhous HCC is associated with various clinical outcomes. Furthermore, this classification includes two newly recognized patterns: vessels encapsulating tumor clusters and CTNNB1-mutated HCC. The imaging features of HCC are significantly correlated with its molecular-pathological characteristics. In particular, aggressive subtypes frequently present with specific imaging hallmarks such as rim arterial phase hyperenhancement, diffuse arterial phase hypo-enhancement, and intratumoral necrosis on T2-weighted imaging, which serve as critical noninvasive predictors of clinical outcomes. However, a definitive diagnosis of specific subtypes based solely on imaging remains challenging. This review provides a comprehensive overview of the molecular, pathological, and radiological characteristics of HCC subtypes and patterns, emphasizing that a detailed understanding of these features is essential for informed therapeutic decision-making and accurate prognostic assessment.
Steatotic liver disease (SLD) is a leading cause of chronic liver disease worldwide impacting more than 30% of the adult population. With the rise of obesity, metabolic syndrome and alcohol use disorder, the prevalence of the two main subtypes of SLD- metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD)- continues to increase. There has concurrently been an acknowledgement of a third subtype of SLD- MetALD- wherein an individual has both components of metabolic dysfunction and regular alcohol intake. The public health significance of the SLD epidemic is substantial given risk for progression to cirrhosis, end-stage liver disease and development of hepatocellular carcinoma (HCC). Individuals with stage two fibrosis or above and those with active inflammation with hepatocyte injury are at highest risk for adverse liver-related outcomes and overall mortality. Current screening and risk stratification recommendations highlight the importance of identifying individuals at highest risk of clinical outcomes using non-invasive testing (NIT) as these individuals would benefit from liver-directed pharmacotherapy. Importantly, the performance of NITs can vary substantially based on NIT selected, cut-points applied and patient population evaluated. The evidence base for NIT performance is strongest in MASLD with comparatively limited data in ALD and emerging data in MetALD. This review discusses NIT diagnostic performance in SLD and their role in chronic disease management.
Background/Aims:Oral anticoagulants may reduce risk of hepatic decompensation in patients with compensated cirrhosis, but well-powered randomized trials are missing. We aimed to estimate the effect of oral anticoagulants on risk of hepatic decompensation and major bleeding in patients with compensated cirrhosis and atrial fibrillation. Methods:Observational data from Swedish healthcare registers 2011-2022 were used to emulate a target trial of oral anticoagulants in patients with compensated cirrhosis and newly diagnosed atrial fibrillation. Inverse-probability weighted marginal structural models were used to compare 5-year risks of hepatic decompensation and non-portal hypertension-related major bleeding in initiators versus non-initiators of oral anticoagulants. Results:The study included 1,160 patients (715 men [61.6%]; median [p25-p75] age of 73 years [67-79]). The 5-year risk of hepatic decompensation was 10.4% (33/383) in initiators and 16.6% (112/777) in non-initiators (risk ratio [RR]=0.62, 95% confidence interval [CI]=0.33-0.92), corresponding to a number needed to treat of 17 (95%CI=9-112). The risk reduction was primarily driven by a reduced risk of ascites (RR=0.58, 95%CI=0.26-0.90). The risk of major bleeding was 19.0% (63/383) in initiators and 19.8% (149/777) in non-initiators (RR=0.96, 95%CI=0.64-1.28). Risks were similar between treatment groups regarding fatal, intracranial, gastrointestinal, and other bleedings. Conclusions:In this nationwide observational study, patients with compensated cirrhosis and atrial fibrillation who initiated oral anticoagulants had lower risk of hepatic decompensation, and similar risk of major bleeding compared to non-initiators. The results suggest oral anticoagulants are safe in patients with compensated cirrhosis and may improve prognosis. Randomized trials are warranted to confirm these results.
The 2023 multisociety Delphi consensus redefined the nomenclature for steatotic liver disease (SLD) by replacing nonalcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated steatotic liver disease (MASLD) and introducing metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD). This revised framework is expected to enhance epidemiological surveillance, phenotyping of SLD, and public health interpretation. This review summarizes contemporary literature on the global epidemiology, disease burden, and comparative outcomes of MASLD, MetALD, and ALD. MASLD remains the most prevalent SLD subtype, affecting approximately 30%-40% of adults worldwide, with a rising burden over time. MASLD rapidly increases in regions with lower sociodemographic indices. MetALD affects an estimated 2%-8% of adults and represents an important overlap phenotype, although its prevalence is likely underestimated due to frequent underreporting of alcohol intake. ALD has a lower prevalence but contributes disproportionately to higher liver-related morbidity and mortality and is reported to have a marked regional variation linked to patterns of alcohol consumption. SLD has emerged as a major global epidemic, with MASLD imposing the greatest population burden and MetALD/ALD disproportionately contributing to severe liver-related outcomes. Across SLD phenotypes, cardiovascular disease is a major cause of death in non-cirrhotic disease, while liver-related outcomes show a gradient associated with alcohol exposure. Significant epidemiologic limitations include heterogeneity in the steatosis assessment methods, limited availability of cardiometabolic criteria, and reliance on self-reported alcohol consumption. Mitigating this growing burden of SLD requires public health policies that incorporate metabolic risk prevention, regulation of alcohol consumption, and early risk stratification.
Chronic liver disease is a rapidly growing cause of morbidity and mortality worldwide, and this increase is largely driven by steatotic liver disease (SLD) comprising metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and MASLD and increased alcohol intake (MetALD). Hepatic steatosis and fibrosis are highly heritable and genetic variation has also associated with risk of hepatocellular carcinoma and hepatic decompensation. This review summarizes the state of the art of genetics and genomics in SLD, with particular emphasis on potential clinical utility. Variants in/near genes including PNPLA3, TM6SF2, and HSD17B13 have been associated with cirrhosis and hepatocellular carcinoma (HCC) in both MASLD and ALD, while others such as those in GCKR, TRIB1, and GPAM have been consistently associated with greater risk of hepatic steatosis in MASLD with much weaker effects if any on cirrhosis and hepatocellular carcinoma. While data on MetALD genetics are limited, we believe that the genetic risk factors for liver steatosis, cirrhosis, and HCC will be similar in MetALD compared to MASLD and ALD based on the largely shared genetic risk factors for MASLD and ALD. Finally, we discuss future directions in SLD genetics, notably genetically-defined disease subtypes, gene-environment interactions and its implications for therapy, and utility of genetics in clinical risk stratification. Genetic studies have provided insight into important disease processes in SLD and may have an upcoming role in clinical care.
International and regional clinical practice guidelines (CPGs) for chronic hepatitis B (CHB) have recently been updated to incorporate evolving clinical evidence. This review compares the latest major CPGs regarding natural history classification, treatment initiation, and selection of antiviral agents, specifically focusing on updates from the Korean Association for the Study of the Liver-East Asia Liver Alliance (KASL-EALA), the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the World Health Organization (WHO). While all guidelines recognize the heterogeneous and dynamic nature of CHB, managing patients in the “grey zone” or indeterminate phase remains a major challenge. The KASL–EALA 2026 guideline introduces a novel framework based primarily on hepatitis B virus (HBV) DNA levels—independent of alanine aminotransferase criteria—eliminating the indeterminate category to better align with hepatocellular carcinoma risks and simplify treatment decision-making. In contrast, AASLD 2025, EASL 2025, and WHO 2024 retain conventional immunological phase-based classifications for natural history. For treatment indications, all four guidelines advocate broader access to antiviral therapy despite their divergent structural approaches. AASLD suggests shared decision-making, EASL emphasizes individualized risk assessment, and WHO 2024 abandons the phase-based framework for treatment decisions entirely. Understanding these key similarities and differences will help clinicians optimize patient care and inform future efforts toward global harmonization in CHB management.
