APASL, Istanbul, Turkey.. Day 4.

MASLD-related hepatocellular carcinoma (HCC) is becoming a major clinical challenge because a meaningful proportion of cases arise without established cirrhosis. This differs from viral hepatitis–related HCC, where surveillance is largely built around cirrhosis-based risk.

Recent multicenter data suggest that non-cirrhotic patients may account for about one-third of MASLD-related HCC cases, often presenting at an older age and with larger tumors, because they are usually outside routine surveillance programs.

The pathogenesis is driven by insulin resistance, lipotoxicity, oxidative stress, chronic inflammation, immune dysfunction, and genetic susceptibility. Metabolic comorbidities such as type 2 diabetes, obesity, hypertension, and dyslipidemia amplify carcinogenic risk, even before cirrhosis develops.

The major clinical problem is risk stratification. Current AASLD guidance does not recommend routine HCC surveillance for non-cirrhotic MASLD, while EASL allows consideration in selected advanced fibrosis patients based on individual risk assessment.

Future strategies must move beyond cirrhosis alone and incorporate fibrosis stage, diabetes, age, sex, platelet count, elastography, genetics, and biomarkers such as AFP-based models, GALAD, and PIVKA-II.

Key Message:
MASLD-HCC without cirrhosis exposes a major gap in current surveillance. The future will require personalized, risk-based screening models to identify high-risk non-cirrhotic MASLD patients before cancer presents at an advanced stage.

Liver transplantation for HCC should stop when the expected benefit becomes biologically and ethically unjustifiable. The goal is not only technical transplantability, but acceptable post-transplant survival with low recurrence risk.

The Milan criteria remain the benchmark because they provide excellent long-term outcomes: single tumor ≤5 cm or up to 3 tumors each ≤3 cm, without vascular invasion or extrahepatic spread. However, modern practice has moved beyond size and number alone. Expanded criteria and downstaging are acceptable when tumor biology is favorable, particularly with low or falling AFP, good response to locoregional therapy, no vascular invasion, and durable disease control. Updated EASL guidance supports considering transplantation after successful downsizing or downstaging in selected patients.

We should stop when there is macrovascular invasion, extrahepatic spread, rapidly progressive disease, poor response to downstaging therapy, very high or rising AFP, infiltrative tumor pattern, or poor liver/functional reserve making transplant futile. In such patients, transplantation risks early recurrence and wastes a scarce graft that could benefit another patient.

The future is biology-based selection, not rigid tumor size alone. AFP models, radiologic response, PET biology, liquid biomarkers, and molecular signatures may better define who deserves transplant and who should receive systemic or palliative therapy instead.

Key Message:
We should stop transplantation in HCC when tumor biology predicts high recurrence and poor survival. The boundary is not simply “beyond Milan,” but beyond acceptable biology, durable control, and fair graft utility.

Immunosuppression after liver transplantation for hepatocellular carcinoma (HCC) requires a careful balance between preventing graft rejection and minimizing tumor recurrence. Excessive immunosuppression, particularly high early exposure to calcineurin inhibitors such as tacrolimus or cyclosporine, has been associated with increased HCC recurrence risk; therefore, many centers favor CNI minimization in HCC recipients.

A major strategy is the use of mTOR inhibitors such as sirolimus or everolimus, which provide immunosuppression and may have anti-proliferative effects. Evidence suggests possible benefit in reducing recurrence or improving survival in selected HCC transplant patients, especially when combined with reduced-dose tacrolimus, though results are not uniform and protocols vary.

Steroids are generally tapered early where feasible, and long-term regimens should be individualized based on rejection risk, renal function, tumor biology, AFP, vascular invasion, and explant pathology. In patients with high recurrence risk, clinicians often aim for the lowest effective immunosuppression while maintaining graft safety.

If HCC recurrence occurs, immunosuppression is usually reduced, steroids are stopped if possible, and mTOR-based therapy may be introduced or intensified. Immune checkpoint inhibitors after transplant remain highly risky because they can trigger severe or fatal graft rejection.

Key Message:
Post-transplant immunosuppression in HCC should be oncologically aware: avoid excessive CNI exposure, consider mTOR-based CNI minimization in selected patients, and tailor therapy according to recurrence risk and graft safety.

Artificial and bioartificial liver devices are designed to support patients with acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) as a bridge to recovery or transplantation. They aim to remove toxins, reduce inflammation, and temporarily replace selected liver functions while the native liver regenerates or a graft becomes available.

Artificial liver support systems are non-cell-based devices. Examples include MARS, Prometheus, SPAD, ADVOS, and newer systems such as DIALIVE. These mainly remove albumin-bound and water-soluble toxins, including bilirubin, bile acids, ammonia-related metabolites, and inflammatory mediators. They may improve biochemical parameters and encephalopathy, but survival benefit has been inconsistent across trials.

Bioartificial liver devices incorporate functional hepatocytes within bioreactors, aiming to provide not only detoxification but also partial metabolic and synthetic liver functions. However, challenges include cell source, viability, immune compatibility, cost, infection risk, and scalability.

The most realistic current role of these devices is in carefully selected ICU patients with potentially reversible liver failure or those awaiting transplantation. Emerging devices like DIALIVE are being studied in ACLF, where modulation of systemic inflammation and albumin dysfunction may be especially relevant.

Key Message:
Artificial and bioartificial liver devices are promising bridging technologies, but they are not yet substitutes for liver transplantation. Their future depends on proving survival benefit, patient selection, and integration with ICU and transplant pathways.

Regenerative biotechnology is opening a new frontier in liver disease by aiming not only to slow injury but to restore hepatic structure and function. This field includes stem-cell therapies, organoids, tissue engineering, extracellular vesicles, gene editing, and mRNA-based platforms.

In liver disease, regenerative strategies may help in acute liver failure, ACLF, cirrhosis, inherited metabolic liver diseases, and post-transplant graft dysfunction. The goal is to enhance hepatocyte regeneration, reduce inflammation, reverse fibrosis, and provide temporary or durable functional support.

mRNA technology is especially exciting because it allows transient, programmable protein expression without permanent genomic integration. In hepatology, mRNA platforms could be used to deliver regenerative factors, correct deficient proteins in metabolic liver diseases, modulate immune responses, or promote controlled tissue repair. Unlike gene editing, mRNA is reversible and dose-adjustable, which may improve safety.

Another promising area is combining mRNA with lipid nanoparticles, which naturally target the liver after systemic delivery. This makes the liver an attractive organ for mRNA-based therapeutics.

However, key challenges remain: targeted delivery to specific liver cells, immune activation, durability of effect, dosing frequency, manufacturing scale, and long-term safety.

Key Message:
Regenerative biotechnologies and mRNA therapies may transform liver care from replacement-based therapy to repair-based medicine. Their future lies in safe, targeted, and controllable approaches that stimulate regeneration, correct metabolic defects, and reduce fibrosis without causing uncontrolled immune activation or tumor risk.

Diagnosis of alcohol-associated liver disease (ALD) is often difficult because patients may underreport alcohol intake and routine markers such as AST/ALT ratio, GGT, and MCV lack specificity. Newer biomarkers are improving diagnostic confidence by detecting both recent alcohol exposure and alcohol-related liver injury.

The most useful alcohol-use biomarker is phosphatidylethanol (PEth), a direct alcohol metabolite formed in red blood cell membranes. It has high sensitivity and specificity for recent alcohol consumption and is increasingly used in transplant evaluation and relapse monitoring. Other direct markers include ethyl glucuronide (EtG) and ethyl sulfate (EtS) in urine, blood, or hair, which help detect recent or longer-term alcohol exposure.

For liver injury severity, emerging markers include cytokeratin-18 fragments, reflecting hepatocyte apoptosis and necrosis, and inflammatory markers such as IL-6, TNF-α, and lipopolysaccharide-related signatures, which reflect gut–liver axis activation. In severe alcohol-associated hepatitis, prognostic biomarkers are being explored to improve selection for corticosteroids, ICU care, and transplantation.

Novel molecular markers such as microRNAs, extracellular vesicles, metabolomic signatures, and cell-free DNA methylation/fragmentation patterns may help distinguish ALD from MASLD and assess fibrosis earlier than conventional tools. A recent cfDNA-based approach has shown potential for detecting liver fibrosis non-invasively, although further validation is needed.

Key Message:
New ALD biomarkers are moving diagnosis from indirect suspicion to objective confirmation of alcohol exposure, liver injury, inflammation, and fibrosis, with PEth currently the most clinically useful marker and molecular biomarkers representing the future.

Hepatitis C treatment has been revolutionized by direct-acting antivirals (DAAs), making HCV one of the few chronic viral infections that can be reliably cured. Current oral DAA regimens achieve >95% sustained virological response (SVR) in most patients, usually with 8–12 weeks of therapy, excellent tolerability, and minimal monitoring.

The major advance is the availability of pangenotypic regimens, mainly sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, which simplify treatment by covering all major HCV genotypes. This has enabled “test-and-treat” and simplified care models, including treatment in primary care, prisons, addiction clinics, and community programs. AASLD-IDSA guidance now emphasizes simplified treatment pathways and point-of-care algorithms to improve linkage to care.

DAAs are effective in most difficult groups, including compensated cirrhosis, chronic kidney disease, HIV coinfection, and post-transplant patients. Retreatment options, such as sofosbuvir/velpatasvir/voxilaprevir, are available for DAA failures. Acute HCV is now treated with the same approach as chronic HCV, without waiting for spontaneous clearance.

The remaining challenge is not drug efficacy but diagnosis, access, affordability, and reinfection prevention. There is still no effective vaccine, so elimination depends on screening, harm reduction, treatment scale-up, and post-SVR surveillance in patients with advanced fibrosis.

Key Message:
HCV has become a curable infection, but global success now depends on moving from excellent drugs to universal diagnosis, simplified treatment access, and prevention of reinfection.

Portal hypertension results from a combination of increased intrahepatic vascular resistance and splanchnic vasodilation. Modern therapy is increasingly grounded in understanding these molecular mechanisms rather than treating complications alone.

The primary driver is sinusoidal endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailabilityand increased vasoconstrictors such as endothelin-1. This leads to increased intrahepatic resistance. At the same time, activation of pathways like Rho-kinase enhances vascular tone and contraction of hepatic stellate cells.

Another key component is fibrosis and extracellular matrix deposition, which structurally distort hepatic architecture. Activated stellate cells contribute to both mechanical resistance and dynamic vasoconstriction through mediators like TGF-β.

Systemically, portal hypertension is amplified by splanchnic vasodilation, driven by excess NO and inflammatory mediators, leading to increased portal inflow and hyperdynamic circulation.

Therapies target these pathways:

• Non-selective beta-blockers (e.g., carvedilol): reduce portal inflow and intrahepatic resistance

• Statins: improve endothelial function and NO production

• Rho-kinase inhibitors (emerging): reduce intrahepatic vascular tone

• FXR agonists and antifibrotic agents: target fibrosis and bile acid signaling

• Gut–liver axis therapies: reduce inflammation and endotoxemia

Key Message:
Portal hypertension therapy is evolving toward mechanism-based treatment, targeting endothelial dysfunction, fibrosis, and splanchnic circulation—offering the potential to prevent disease progression, not just manage complications.

Portal-hypertensive gastroenteropathy (PHG) and Gastric Antral Vascular Ectasia (GAVE) are important but distinct causes of chronic gastrointestinal bleeding and anemia in patients with liver disease.

PHG occurs due to portal hypertension, leading to mucosal congestion and vascular ectasia. Endoscopy shows a characteristic mosaic or “snake-skin” pattern, often in the gastric body and fundus. It is typically associated with cirrhosis and elevated portal pressure.

In contrast, GAVE is not directly related to portal hypertension and may occur with cirrhosis, autoimmune disease, or even without liver disease. Endoscopically, it appears as longitudinal red stripes in the antrum (“watermelon stomach”) or diffuse punctate lesions.

Diagnosis is primarily endoscopic, with clinical correlation. Differentiation is crucial because management differs significantly.

Management of PHG:

• Non-selective beta-blockers (NSBBs) are first-line to reduce portal pressure

• Iron supplementation for chronic blood loss

• Endoscopic therapy rarely needed; TIPS considered in refractory cases

Management of GAVE:

• Primary treatment is endoscopic therapy, especially argon plasma coagulation (APC)

• Other options include radiofrequency ablation or band ligation

• Medical therapy (e.g., hormones, thalidomide) has limited role

Key Message:
PHG and GAVE may appear similar clinically but are fundamentally different—PHG is portal pressure–driven and treated medically, whereas GAVE is a mucosal vascular disorder requiring endoscopic therapy. Accurate diagnosis is essential to guide appropriate management.

Fecal microbiota transplantation (FMT) is an emerging therapy targeting gut dysbiosis, a central driver of complications in cirrhosis via the gut–liver axis. Cirrhotic patients exhibit reduced microbial diversity, overgrowth of pathogenic bacteria, and increased intestinal permeability, leading to bacterial translocation, systemic inflammation, and ammonia production.

The strongest evidence for FMT is in hepatic encephalopathy (HE). Clinical studies have shown that FMT can reduce HE recurrence, improve cognitive function, and decrease hospitalizations, likely by restoring a healthier microbiome and reducing ammonia-producing bacteria. It may also enhance response to standard therapies like lactulose and rifaximin.

FMT is also being explored in other cirrhosis-related conditions:

• Recurrent infections (including multidrug-resistant organisms)

• Acute-on-chronic liver failure (ACLF)

• Spontaneous bacterial peritonitis (SBP) prevention

• Modulation of systemic inflammation

Routes of administration include oral capsules, nasoenteric tubes, and colonoscopy, with donor selection and screening being critical for safety.

However, FMT remains investigational in cirrhosis. Concerns include risk of infection transmission, sepsis, and variability in response, particularly in immunocompromised patients.

Key Message:
FMT represents a promising microbiome-based therapy in cirrhosis—especially for recurrent HE—but requires careful patient selection, strict safety protocols, and further large-scale trials before routine clinical use.

Fecal microbiota transplantation (FMT) is emerging as a promising therapy in liver diseases by targeting the gut–liver axis. Many liver disorders are associated with gut dysbiosis, increased intestinal permeability, bacterial translocation, systemic inflammation, and altered bile acid metabolism.

The strongest clinical evidence is in cirrhosis with recurrent hepatic encephalopathy (HE). Randomized studies suggest that FMT can improve microbial diversity, reduce HE recurrence, improve cognition, and decrease hospitalizations, with acceptable safety in carefully selected patients.

FMT is also being explored in alcohol-associated hepatitis, ACLF, MASLD, chronic hepatitis, and liver cancer, but evidence is still early and heterogeneous. In alcohol-associated hepatitis and ACLF, FMT may reduce inflammation and improve clinical severity, but larger controlled trials are needed before routine use.

Recent expert consensus highlights the need for standardization of donor selection, screening, route of delivery, dose, frequency, contraindications, and safety monitoring before FMT can be widely adopted in chronic liver disease.

Key Message:
FMT represents a new microbiome-based treatment strategy in hepatology. Its most mature application is recurrent HE in cirrhosis, while its role in MASLD, alcohol-associated liver disease, ACLF, and liver cancer remains investigational. Future progress depends on rigorous trials, standardized protocols, and careful safety surveillance.

Endoscopic ultrasound (EUS) has evolved from a diagnostic tool to a versatile platform for minimally invasive therapeutic interventions in hepatology and pancreatobiliary diseases. Its strength lies in real-time imaging with precise needle or device guidance, enabling targeted therapy with reduced invasiveness.

In hepatology, EUS-guided therapies are increasingly used in portal hypertension. Techniques such as EUS-guided coil and glue injection allow precise treatment of gastric varices, improving efficacy and reducing embolic complications compared to conventional endoscopic methods.

Another major advance is EUS-guided portal pressure gradient (PPG) measurement, offering a direct, minimally invasive alternative to traditional transjugular HVPG measurement. This has potential to improve risk stratification and guide therapy.

EUS also enables EUS-guided liver biopsy, providing high-quality tissue with bilobar sampling, and is particularly useful when percutaneous or transjugular routes are difficult.

Emerging applications include EUS-guided tumor therapies such as local ablation, targeted drug delivery, and injection therapies for hepatocellular carcinoma, although these remain investigational.

Advantages include precision, safety, ability to combine diagnosis and therapy in a single session, and utility in difficult anatomical situations. Limitations include operator dependence, need for expertise, cost, and limited availability.

Key Message:
EUS-guided therapies are redefining minimally invasive hepatology—offering precise, targeted interventions in portal hypertension, liver biopsy, and emerging oncologic applications, with growing clinical impact.

Recurrent variceal bleeding is a high-risk scenario requiring escalation beyond standard secondary prophylaxis (non-selective beta-blockers + endoscopic band ligation). The choice between TIPS, BRTO, or a combination depends on variceal type, portal hemodynamics, and patient profile.

TIPS (Transjugular Intrahepatic Portosystemic Shunt) reduces portal pressure and is the preferred option for recurrent esophageal variceal bleeding or mixed variceal disease. It is particularly useful in patients with poor control despite optimal therapy or with refractory ascites. However, TIPS increases the risk of hepatic encephalopathy and may not be suitable in advanced liver failure.

BRTO (Balloon-Occluded Retrograde Transvenous Obliteration) is especially effective for gastric varices with a large gastrorenal shunt. It works by obliterating the varices and shunt, often improving hepatic encephalopathy and liver function. However, it can increase portal pressure, potentially worsening esophageal varices or ascites.

Combination strategy (TIPS + BRTO) is increasingly used in selected patients:

• When gastric varices coexist with significant portal hypertension

• To balance portal decompression (TIPS) with variceal obliteration (BRTO)

• To reduce rebleeding while minimizing complications

How to choose:

• Esophageal varices → TIPS preferred

• Isolated gastric varices with large shunt → BRTO preferred

• Mixed disease or high-risk anatomy → consider combination

Key Message:
The decision is not “TIPS vs BRTO” but patient-specific therapy—use TIPS for portal decompression, BRTO for targeted gastric variceal control, and combine both in complex cases for optimal outcomes.

The liver is frequently involved in hematologic diseases, either as a target organ or through secondary effects of systemic pathology. This relationship is bidirectional—hematologic disorders can cause liver dysfunction, and liver disease can lead to hematologic abnormalities.

In hemolytic disorders (e.g., sickle cell disease, thalassemia), chronic hemolysis leads to hyperbilirubinemia, gallstones, and hepatic iron overload, especially with repeated transfusions. Iron overload can progress to fibrosis and cirrhosis.

Infiltrative hematologic malignancies such as leukemia and lymphoma may involve the liver, presenting with hepatomegaly, cholestasis, or abnormal liver tests. Imaging and biopsy may be required for diagnosis.

Myeloproliferative disorders are associated with portal vein thrombosis and Budd–Chiari syndrome, leading to non-cirrhotic portal hypertension. These conditions require high clinical suspicion and early anticoagulation.

The liver is also affected in coagulation disorders, where impaired synthesis of clotting factors contributes to bleeding risk. Conversely, liver disease itself can cause complex coagulopathy and thrombocytopenia.

Treatment-related liver injury is another key aspect. Chemotherapy, immunotherapy, and hematopoietic stem cell transplantation can lead to complications such as sinusoidal obstruction syndrome (SOS) and drug-induced liver injury.

Key Message:
Liver involvement in hematologic disorders is common and multifactorial—recognition of the underlying mechanism (hemolysis, infiltration, thrombosis, iron overload, or treatment toxicity) is essential for accurate diagnosis and targeted management.

Acute-on-chronic liver failure (ACLF) is a syndrome of acute deterioration in patients with chronic liver disease, associated with high short-term mortality. However, its definition differs significantly between Eastern and Western hepatology groups, reflecting variations in etiology, patient profile, and clinical priorities.

In the East (APASL definition), ACLF is defined as an acute hepatic insult (commonly viral hepatitis, especially HBV) leading to jaundice (bilirubin ≥5 mg/dL) and coagulopathy (INR ≥1.5), complicated within 4 weeks by ascites and/or encephalopathy. The focus is primarily on liver failure itself, and patients may not have established cirrhosis.

In the West (EASL-CLIF definition), ACLF occurs in patients with cirrhosis and is characterized by acute decompensation with one or more organ failures (liver, kidney, brain, circulation, respiration), assessed using the CLIF-SOFA score. The emphasis is on multi-organ failure and systemic inflammation, with alcohol and bacterial infections being common triggers.

A third perspective, from North America (NACSELD), focuses mainly on extrahepatic organ failures in infected cirrhotic patients.

Key Differences:

• East: Liver-centric, may occur without cirrhosis, often viral triggers

• West: Cirrhosis-based, multi-organ failure, often infection/alcohol-related

Key Message:
ACLF is not a single entity but a spectrum with regional variations—the East focuses on acute hepatic failure, while the West emphasizes systemic inflammation and multi-organ failure, highlighting the need for a unified global definition.

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a serious complication—most commonly after hematopoietic stem cell transplantation (HSCT) or high-dose chemotherapy—characterized by sinusoidal endothelial injury, hepatic congestion, and portal hypertension.

Early recognition is critical, based on clinical features such as painful hepatomegaly, weight gain, ascites, and rising bilirubin. Once established, management is primarily supportive plus disease-specific therapy.

The cornerstone of treatment is Defibrotide, which has endothelial-protective, anti-thrombotic, and anti-inflammatory effects. It improves sinusoidal blood flow and is the only approved therapy with evidence of survival benefit, especially when started early.

Supportive care includes:

• Careful fluid balance (avoid both overload and hypovolemia)

• Diuretics for ascites and weight gain

• Management of renal dysfunction and electrolyte imbalance

• Avoidance of hepatotoxic drugs

• Early ICU support in severe cases

In advanced disease with multi-organ failure, management becomes challenging, and outcomes are poor.

Preventive strategies are equally important in high-risk patients, including risk stratification, minimizing hepatotoxic conditioning regimens, and prophylactic defibrotide in selected cases.

Key Message:
VOD/SOS is a time-sensitive vascular liver injury—early diagnosis and prompt initiation of defibrotide, along with meticulous supportive care, are essential to improve survival.

Magnetic Resonance Proton Density Fat Fraction (MR-PDFF) is now the reference non-invasive imaging method for quantifying hepatic steatosis. It provides a precise, reproducible, and whole-liver assessment of fat content, overcoming the sampling limitations of biopsy and the variability of ultrasound.

MR-PDFF measures the proportion of mobile protons bound to fat relative to total liver protons, expressed as a percentage. It corrects for confounders such as T1 bias, T2 decay, iron overload, and field inhomogeneity, making it highly accurate across a wide range of clinical settings.

Clinically, MR-PDFF can detect even mild steatosis (>5%), unlike CT or ultrasound, which are less sensitive at lower fat levels. It enables quantitative staging and is particularly valuable for:

• Baseline assessment of MAFLD/MASH

• Monitoring response to therapy in clinical trials

• Longitudinal follow-up of disease progression or regression

A key advantage is its ability to assess fat distribution across the entire liver, reducing sampling error. It is also increasingly used as a surrogate endpoint in drug development, due to its sensitivity to change.

Limitations include cost, availability, and inability to directly assess inflammation or fibrosis, which require complementary techniques such as elastography.

Key Message:
MR-PDFF is the gold standard non-invasive tool for quantifying liver fat, offering accurate, reproducible, and sensitive assessment—making it essential for both clinical practice and research in steatotic liver disease.