APASL, Istanbul, Turkey Day 1

Hepatitis E virus (HEV) infection is increasingly recognized as a clinically significant disease with two distinct presentations—acute self-limiting infection and chronic infection in immunosuppressed patients.

Acute HEV is usually mild and requires only supportive management, including hydration, avoidance of hepatotoxic drugs, and monitoring. However, certain groups need special attention. Pregnant women (especially 2nd–3rd trimester)and patients with pre-existing liver disease are at high risk of acute liver failure (ALF) or ACLF. In such severe cases, ribavirin may be considered, although it is not routinely recommended and is contraindicated in pregnancy.

Chronic HEV is now well established, particularly in solid organ transplant recipients and other immunosuppressed individuals. It should be suspected in patients with persistent elevation of liver enzymes, and diagnosis relies on HEV RNA testing, as serology may be unreliable.

The first step in management is cautious reduction of immunosuppression, which alone can lead to viral clearance in some cases. If viremia persists beyond 3 months, ribavirin monotherapy for ~12 weeks is the treatment of choice, achieving high sustained virological response rates. Treatment should be guided by HEV RNA monitoring, with extension of therapy if viral clearance is incomplete.

Key Message:
HEV is no longer just an acute infection—clinicians must recognize and actively treat chronic HEV, especially in immunosuppressed patients, while reserving antivirals in acute disease for selected severe cases only.

This APASL 2026 topic focuses on how artificial intelligence (AI) is changing cirrhosis care from a late, reactive approach to an early, predictive, and personalized model. In the APASL 2026 program, this lecture is listed under cirrhosis-focused academic content, reflecting the growing role of AI in hepatology.

In diagnosis, AI can combine clinical data, laboratory parameters, imaging, elastography, and endoscopic findingsto detect cirrhosis earlier and identify patients at risk of clinically significant portal hypertension. This is important because many patients remain clinically silent until decompensation occurs. Recent reviews suggest AI-based models may improve diagnostic precision and support earlier recognition of advanced liver disease.

In outcome prediction, AI can analyze multiple variables simultaneously and continuously, often outperforming static conventional scores alone in predicting hepatic decompensation, hospitalization, variceal bleeding, and mortality. This allows clinicians to identify high-risk patients earlier, intensify follow-up, optimize therapy, and improve transplant referral timing.

In patient management, the real value of AI lies in supporting decisions such as surveillance intensity, early intervention, and prioritization of resources. However, AI should be seen as a decision-support tool, not a substitute for hepatology expertise. Current limitations include data heterogeneity, limited external validation, interpretability issues, and challenges in routine clinical integration.

Key message: AI has the potential to make cirrhosis care more accurate, proactive, and individualized, but its future depends on strong validation and careful clinical adoption.

Metabolic dysfunction–associated fatty liver disease (MAFLD) is now understood as a systemic metabolic disorderrather than a purely hepatic condition. Its pathophysiology is best explained by a “multiple-hit” model, where several parallel mechanisms drive disease progression from steatosis to steatohepatitis, fibrosis, and cirrhosis.

The central driver is insulin resistance, which increases lipolysis in adipose tissue, leading to excess free fatty acid (FFA) flux to the liver. This results in hepatic triglyceride accumulation and lipotoxicity, particularly from toxic lipid intermediates rather than simple fat deposition.

A key second component is mitochondrial dysfunction and oxidative stress, which promote hepatocyte injury through reactive oxygen species and impaired β-oxidation. This is accompanied by endoplasmic reticulum stress and activation of inflammatory pathways.

Inflammation plays a pivotal role, with activation of Kupffer cells and recruitment of immune cells driven by cytokines such as TNF-α and IL-6. In parallel, gut–liver axis dysfunction—including increased intestinal permeability and dysbiosis—contributes to endotoxemia and further hepatic inflammation.

Progression to fibrosis is mediated by hepatic stellate cell activation, triggered by chronic inflammation and oxidative stress, leading to extracellular matrix deposition.

Genetic and epigenetic factors (e.g., PNPLA3, TM6SF2 variants) modulate susceptibility and disease severity, explaining inter-individual variability.

Key Message:
MAFLD is a multifactorial, systemic disease driven by insulin resistance, lipotoxicity, inflammation, and gut–liver interactions, with genetics influencing progression—making it an ideal target for multi-pathway therapeutic strategies.

Metabolic dysfunction–associated fatty liver disease (MAFLD) is now recognized as the hepatic manifestation of systemic metabolic syndrome, tightly linked with multiple metabolic complications that drive both liver-related and cardiovascular outcomes.

The strongest association is with type 2 diabetes mellitus (T2DM). MAFLD and T2DM share a bidirectional relationship—insulin resistance promotes hepatic steatosis, while MAFLD itself increases the risk of incident diabetes and worsens glycemic control. Importantly, the presence of T2DM significantly accelerates progression to steatohepatitis, fibrosis, and cirrhosis.

MAFLD is also closely associated with obesity, particularly visceral adiposity, which increases free fatty acid flux to the liver and promotes lipotoxicity. In addition, dyslipidemia—characterized by elevated triglycerides, low HDL, and atherogenic LDL particles—is common and contributes to both liver disease progression and cardiovascular risk.

The most critical clinical implication is the strong link with cardiovascular disease (CVD), which remains the leading cause of mortality in MAFLD patients. Endothelial dysfunction, chronic inflammation, and a pro-atherogenic state all contribute to this risk.

Other important associations include chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), and obstructive sleep apnea (OSA), reflecting the systemic nature of MAFLD.

Key Message:
MAFLD is not just a liver disease—it is a multisystem metabolic disorder. Effective management requires a holistic approach, targeting metabolic risk factors (diabetes, obesity, dyslipidemia) to improve both hepatic outcomes and overall survival, especially by reducing cardiovascular risk.

Hepatic stellate cells (HSCs) are central regulators of liver homeostasis and fibrosis, acting as the key effector cells in chronic liver disease progression.

In the healthy liver, HSCs exist in a quiescent state, located in the space of Disse, where they function primarily as vitamin A–storing cells and help maintain extracellular matrix (ECM) balance. They also contribute to normal sinusoidal architecture and hepatic microcirculation.

In liver injury, HSCs undergo a critical transformation into an activated, myofibroblast-like phenotype. This activation is triggered by signals from injured hepatocytes, Kupffer cells, and inflammatory mediators such as TGF-β, PDGF, and reactive oxygen species. Once activated, HSCs proliferate, lose vitamin A stores, and produce large amounts of collagen and extracellular matrix, leading to fibrosis.

HSC activation is not a single-step process but involves initiation, perpetuation, and resolution phases. Persistent activation drives progressive fibrosis and ultimately cirrhosis, while resolution may occur through HSC apoptosis, senescence, or reversion to an inactive phenotype.

Beyond fibrosis, HSCs also play roles in immune modulation, angiogenesis, and portal hypertension, making them central to multiple aspects of chronic liver disease.

Key Message:
Hepatic stellate cells are the master regulators of liver fibrosis—understanding their activation and reversibility provides a critical therapeutic target for antifibrotic strategies in diseases such as MAFLD, viral hepatitis, and alcoholic liver disease.

Extracellular vesicles (EVs) are emerging as key mediators of intercellular communication in the liver, playing critical roles in both physiological homeostasis and disease progression. EVs include exosomes, microvesicles, and apoptotic bodies, released by hepatocytes, Kupffer cells, hepatic stellate cells, and cholangiocytes.

In the healthy liver, EVs help maintain homeostasis by facilitating communication between liver cells, regulating metabolism, immune tolerance, and tissue repair. They carry bioactive cargo such as proteins, lipids, mRNA, and microRNA, allowing precise signaling across the hepatic microenvironment.

In liver disease, EVs become pathogenic mediators. Injured hepatocytes release EVs enriched with inflammatory signals that activate Kupffer cells and hepatic stellate cells, promoting inflammation and fibrosis. In MAFLD and alcoholic liver disease, EVs contribute to lipotoxicity, oxidative stress, and immune activation, accelerating progression to steatohepatitis and fibrosis.

EVs also play a role in viral hepatitis, where they can modulate immune responses and even facilitate viral persistence. In hepatocellular carcinoma (HCC), tumor-derived EVs promote angiogenesis, immune evasion, and metastasis, highlighting their role in cancer biology.

Clinically, EVs are gaining attention as non-invasive biomarkers, as they can be detected in blood and reflect disease activity. They also represent potential therapeutic targets and drug delivery vehicles.

Key Message:
Liver extracellular vesicles are not just bystanders—they are active drivers of liver disease and promising tools for diagnosis, prognosis, and targeted therapy in hepatology.

Liver macrophages are central to maintaining hepatic homeostasis, immune surveillance, and tissue repair, while also driving inflammation and fibrosis in chronic liver disease. They exist as two major populations: resident Kupffer cellsand monocyte-derived macrophages recruited during injury.

In the healthy liver, Kupffer cells reside within the sinusoids and maintain immune tolerance despite constant exposure to gut-derived antigens. They clear pathogens, apoptotic cells, and debris, and regulate inflammation through anti-inflammatory cytokines such as IL-10, thereby preserving hepatic balance.

During liver injury, macrophage dynamics change dramatically. Damage-associated signals and gut-derived endotoxins activate Kupffer cells and recruit circulating monocytes, which differentiate into inflammatory macrophages. These cells release cytokines such as TNF-α, IL-1β, and IL-6, amplifying inflammation and contributing to hepatocyte injury.

Macrophages also play a pivotal role in fibrosis by interacting with hepatic stellate cells. Pro-inflammatory macrophages promote stellate cell activation via mediators like TGF-β, leading to extracellular matrix deposition. Conversely, during resolution, a shift toward anti-inflammatory (pro-resolving) macrophages facilitates fibrosis regression by promoting matrix degradation and tissue repair.

Emerging concepts highlight macrophage plasticity, with dynamic switching between pro-inflammatory and restorative phenotypes depending on the microenvironment.

Key Message:
Liver macrophages are double-edged regulators—essential for defense and repair, yet central drivers of inflammation and fibrosis. Targeting macrophage activation and polarization offers a promising therapeutic strategy in chronic liver diseases such as MAFLD, viral hepatitis, and cirrhosis.

The extracellular matrix (ECM) of the liver is a dynamic scaffold that maintains structural integrity, cell signaling, and microvascular architecture. In the normal liver, the ECM is minimal and well organized, composed of collagens (types I, III, IV), laminin, fibronectin, and proteoglycans, particularly within the space of Disse, allowing efficient exchange between hepatocytes and sinusoidal blood.

In health, ECM turnover is tightly regulated by a balance between matrix synthesis and degradation, primarily controlled by hepatic stellate cells and matrix metalloproteinases (MMPs) with their inhibitors (TIMPs). This balance ensures tissue homeostasis and normal liver function.

In liver injury, this balance is disrupted. Chronic insults such as MAFLD, viral hepatitis, or alcohol lead to activation of hepatic stellate cells into fibrogenic myofibroblasts, resulting in excessive deposition of collagen-rich ECM. This causes sinusoidal capillarization, impaired hepatocyte function, and increased intrahepatic resistance, contributing to portal hypertension.

Progressive ECM accumulation leads to fibrosis and ultimately cirrhosis, characterized by architectural distortion and formation of regenerative nodules. Importantly, ECM is not merely structural—it actively modulates cell behavior, inflammation, and fibrosis progression through signaling pathways.

During disease resolution, ECM remodeling can occur via degradation by MMPs, and fibrosis may partially regress if the injurious stimulus is removed.

Key Message:
The liver ECM is a dynamic and biologically active system—its dysregulation is central to fibrosis and cirrhosis, making it a critical target for antifibrotic therapies in chronic liver disease.

Acute liver failure (ALF) is a rapidly progressive syndrome characterized by coagulopathy (INR ≥1.5) and hepatic encephalopathy in patients without prior cirrhosis. The clinical course is unpredictable, with potential for either spontaneous recovery or rapid deterioration, making timely transplant decision-making critical.

The cornerstone of management is early identification of patients unlikely to survive without transplantation. Prognostic models such as King’s College Criteria (KCC) and dynamic markers like serum lactate, INR trends, and ammonia levels are widely used to guide listing decisions. However, no single model is perfect—continuous reassessment is essential.

Etiology matters. Patients with paracetamol (acetaminophen) toxicity often have better spontaneous recovery rates with optimal medical therapy (including N-acetylcysteine), whereas non-acetaminophen ALF (e.g., viral, autoimmune, indeterminate) more frequently requires transplantation.

The timing of transplant listing is the most crucial determinant of outcome. Delayed referral may result in irreversible multi-organ failure or cerebral edema, precluding transplantation. Conversely, premature listing risks unnecessary transplant in patients who may recover.

Liver transplantation offers a survival benefit of >70–80% in appropriately selected ALF patients, transforming an otherwise fatal condition into a treatable one. Both deceased donor and living donor transplantation play important roles, especially in regions with limited organ availability.

Key Message:
In ALF, success depends on early referral, dynamic prognostic assessment, and optimal timing of transplantation—balancing the window between potential recovery and irreversible deterioration to maximize survival benefit.

Liver transplantation (LT) is a curative option for hepatocellular carcinoma (HCC) as it treats both the tumor and the underlying cirrhotic liver. The key challenge is appropriate patient selection to maximize survival while minimizing post-transplant recurrence.

The benchmark remains the Milan Criteria (single tumor ≤5 cm or up to 3 tumors each ≤3 cm, no vascular invasion or metastasis), achieving 5-year survival >70% with low recurrence rates. Over time, expanded criteria such as the UCSF Criteria and Up-to-7 Criteria have allowed inclusion of selected patients with larger tumor burden while maintaining acceptable outcomes.

Modern selection has evolved beyond size and number alone to include tumor biology. Biomarkers such as alpha-fetoprotein (AFP), radiologic response to therapy, and absence of vascular invasion help identify patients with favorable disease. This has shifted practice toward a “biology-based selection” approach.

Bridging and downstaging therapies—such as transarterial chemoembolization (TACE), radiofrequency ablation, and newer locoregional strategies—play a critical role. Successful downstaging into Milan criteria is now an accepted pathway to transplantation in many centers.

Recent advancements include improved imaging, allocation policies, and living donor liver transplantation (LDLT), particularly relevant in regions with limited deceased donors. Emerging areas include immunotherapy and targeted therapy as neoadjuvant or bridging strategies, though concerns about post-transplant rejection remain.

Key Message:
Liver transplantation for HCC has evolved from strict size-based criteria to a comprehensive model integrating tumor biology, response to therapy, and dynamic assessment, enabling safe expansion of transplant eligibility while preserving excellent outcomes.