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.