APASL, Istanbul, Turkey. Day 3

Downstaging in hepatocellular carcinoma (HCC) aims to convert patients with initially unresectable or transplant-ineligible tumors into candidates for curative therapy, such as liver resection or transplantation. Traditionally, this has been achieved with locoregional therapies such as TACE, radioembolization, or ablation. The major new development is the use of immuno-oncological treatments, especially immune checkpoint inhibitor–based combinations.

Combinations such as atezolizumab–bevacizumab and durvalumab–tremelimumab can produce meaningful tumor responses in advanced or borderline HCC, creating opportunities for conversion surgery or downstaging into transplant criteria. Updated HCC guidance recognizes that patients who achieve successful downsizing or downstaging after treatment may be reconsidered for resection or transplantation.

For surgery, immunotherapy-based downstaging is promising because tumor shrinkage, vascular response, and improved disease control may allow resection in selected patients with preserved liver function. However, careful assessment of residual liver reserve, portal hypertension, and radiological response remains essential.

For transplantation, the situation is more complex. Pre-transplant immune checkpoint inhibitors may help downstage HCC, but they also carry a risk of post-transplant acute rejection, including graft loss. Therefore, transplant use requires strict selection, multidisciplinary discussion, and adequate washout before surgery.

Key Message:
Immuno-oncological therapy is expanding the boundaries of curative HCC treatment by enabling downstaging for surgery and transplantation, but in transplant candidates, the benefit must be balanced against the serious risk of immune-mediated graft rejection.

Klatskin tumor, or perihilar cholangiocarcinoma, remains one of the most technically demanding hepatobiliary cancers. Surgery is the only potentially curative option, but success depends on careful preoperative staging, resectability assessment, and prevention of post-hepatectomy liver failure. Recent EASL guidance emphasizes a pragmatic, multidisciplinary approach for extrahepatic cholangiocarcinoma management.

Modern surgery has moved beyond simple bile duct excision. Most curative operations require major hepatectomy with caudate lobectomy, bile duct resection, lymphadenectomy, and biliary reconstruction, aiming for an R0 margin. Portal vein involvement is no longer an absolute contraindication in expert centers, as portal vein resection and reconstruction can be performed when needed.

A major update is improved preoperative optimization. Selective biliary drainage of the future liver remnant and portal vein embolization (PVE) are increasingly used to reduce postoperative liver failure and expand resectability in patients needing extended hepatectomy.

For borderline cases with inadequate future liver remnant, advanced strategies such as ALPPS or radiofrequency-assisted liver partition are being explored, but these remain highly specialized because morbidity can be significant.

Another evolving area is liver transplantation for carefully selected unresectable perihilar cholangiocarcinoma after strict neoadjuvant protocols, although availability and selection remain major limitations.

Key Message:
Klatskin tumor surgery is now defined by precision selection, liver-remnant optimization, vascular reconstruction when appropriate, and multidisciplinary planning to achieve R0 resection while minimizing liver failure.

Hepatic encephalopathy (HE) care is moving from episodic treatment of confusion to a more proactive, preventive, and multidisciplinary model. HE is no longer viewed only as a neurological complication of cirrhosis, but as a marker of advanced liver dysfunction, sarcopenia, systemic inflammation, gut dysbiosis, and poor prognosis.

The foundation of management remains early identification and correction of precipitants, including infection, gastrointestinal bleeding, constipation, dehydration, electrolyte imbalance, renal dysfunction, sedatives, and excess diuretics. Lactulose remains first-line therapy, titrated to achieve 2–3 soft stools per day. Rifaximin is now well established for prevention of recurrent HE, especially after a second episode or in patients with frequent hospitalization.

Recent advances emphasize the role of nutrition and muscle health. Protein restriction is no longer recommended; patients need adequate protein intake, preferably with late-evening snacks and branched-chain amino acids in selected cases. Treating sarcopenia is important because skeletal muscle contributes to ammonia detoxification.

There is growing interest in microbiome-based therapies, including probiotics, synbiotics, and fecal microbiota transplantation, though routine use still needs stronger evidence. Digital tools and simple cognitive testing may improve detection of minimal HE, which often affects driving, work performance, and quality of life.

Key Message:
Modern HE care requires more than lactulose alone—it needs precipitant control, rifaximin-based recurrence prevention, nutritional optimization, sarcopenia management, microbiome-focused strategies, and early detection of minimal HE to reduce hospitalizations and improve patient outcomes.

Biologic agents are transforming the management of autoimmune liver diseases—particularly autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC)—especially in patients who are refractory or intolerant to standard therapy.

In AIH, conventional treatment with steroids and azathioprine is effective in most patients, but biologics are increasingly used in difficult cases. B-cell–targeted therapy with Rituximab has shown benefit by reducing autoantibody production and modulating immune activity. Agents targeting T-cell co-stimulation, such as Abatacept, are also being explored to restore immune tolerance.

In PBC, beyond ursodeoxycholic acid, newer biologic and targeted therapies focus on immune and metabolic pathways, including FXR agonists and emerging agents targeting bile duct inflammation. In PSC, where no effective medical therapy exists, biologics targeting inflammatory cytokines and gut–liver axis pathways are under investigation, though results remain limited.

The advantage of biologics lies in their targeted mechanism of action, offering the potential for better efficacy with fewer systemic side effects compared to broad immunosuppression. However, challenges include cost, infection risk, long-term safety, and variable response rates.

Key Message:
Biologic agents represent a shift toward precision immunotherapy in autoimmune liver diseases—offering hope for difficult-to-treat cases, but requiring careful patient selection and monitoring for safety and durability of response.

IgG4-related hepatobiliary disease is part of the systemic spectrum of IgG4-related disease (IgG4-RD), most commonly presenting as IgG4-related sclerosing cholangitis (IgG4-SC) and sometimes with autoimmune pancreatitis. It is crucial to distinguish this condition from malignancy and other cholangiopathies.

Diagnosis is based on a combination of clinical, serological, radiological, and histological features. Patients often present with obstructive jaundice, cholestatic LFTs, and biliary strictures. Imaging may show long, smooth stricturesinvolving intrahepatic and/or extrahepatic ducts, often mimicking primary sclerosing cholangitis or cholangiocarcinoma. Elevated serum IgG4 levels support the diagnosis but are not specific. Histology, when available, shows lymphoplasmacytic infiltrate, storiform fibrosis, and IgG4-positive plasma cells.

A key clinical point is the dramatic response to corticosteroids, which is both diagnostic and therapeutic.

Treatment begins with steroid therapy (prednisolone), leading to rapid improvement in symptoms, liver tests, and imaging. However, relapse is common, particularly after tapering. For recurrent or steroid-dependent disease, immunosuppressive agents (e.g., azathioprine, mycophenolate) or B-cell depletion therapy such as Rituximab may be used.

Long-term follow-up is essential due to the risk of relapse and organ involvement.

Key Message:
IgG4-related hepatobiliary disease is a steroid-responsive, immune-mediated condition that mimics malignancy—early recognition and appropriate immunosuppressive therapy can prevent unnecessary interventions and ensure excellent outcomes.

Alcohol-associated hepatitis (AAH) remains a high-mortality syndrome with limited proven therapies. Current management begins with early diagnosis, alcohol abstinence, nutritional support, infection screening, and management of organ failure. For severe AAH, defined commonly by Maddrey discriminant function ≥32 or high MELD, corticosteroids remain the main pharmacologic option, but benefit is modest and mainly short-term. Response should be assessed using the Lille score, and steroids should be stopped in non-responders.

Therapeutic research is now moving beyond steroids toward mechanism-based treatment. Promising strategies include IL-22 agonists, which may enhance hepatocyte regeneration and reduce inflammation; gut–liver axis therapies, including rifaximin, probiotics, and fecal microbiota transplantation; and regenerative approaches such as G-CSF, although trial results remain inconsistent. Recent reviews emphasize that failed anti-cytokine and anti-apoptotic strategies have highlighted the complexity of AAH biology.

Another major advance is early liver transplantation for highly selected patients with severe AAH who are non-responders to medical therapy. EASL transplant guidance notes that early LT can improve short- and long-term survival in selected severe alcohol-related hepatitis patients.

Key Message:
AAH treatment is evolving from steroids alone toward multimodal care: abstinence support, nutrition, infection control, selective corticosteroid use, emerging immune/regenerative/microbiome therapies, and early transplantation for carefully selected non-responders.

The gut microbiome plays a central role in the pathogenesis and progression of liver cirrhosis through the gut–liver axis. Cirrhosis is associated with gut dysbiosis, characterized by reduced beneficial bacteria and overgrowth of pathogenic organisms.

A key mechanism is increased intestinal permeability (“leaky gut”), allowing translocation of bacterial products such as endotoxins (LPS) into the portal circulation. This triggers hepatic inflammation via activation of Kupffer cells and promotes systemic inflammation, which is a hallmark of decompensated cirrhosis.

Microbiome alterations also contribute to major complications:

• Hepatic encephalopathy (HE): Increased ammonia-producing bacteria and altered nitrogen metabolism

• Spontaneous bacterial peritonitis (SBP): Bacterial translocation into ascitic fluid

• Acute-on-chronic liver failure (ACLF): Exaggerated systemic inflammatory response

Additionally, dysbiosis influences bile acid metabolism, immune regulation, and vascular tone, further worsening portal hypertension and disease progression.

Therapeutically, targeting the microbiome has become important. Agents such as Rifaximin reduce bacterial load and improve HE outcomes. Probiotics, prebiotics, and fecal microbiota transplantation (FMT) are being explored, though robust evidence is still evolving.

Key Message:
The microbiome is a key driver of inflammation and complications in cirrhosis. Modulating the gut–liver axis offers promising strategies to prevent decompensation and improve outcomes in advanced liver disease.

Chronic hepatitis B (HBV) is characterized by immune tolerance and T-cell exhaustion, limiting the ability of the host to clear infection. Immune modulators aim to restore antiviral immunity, a key step toward achieving a functional cure (HBsAg loss).

One approach involves Toll-Like Receptor (TLR) agonists, which activate innate immunity. Agents targeting TLR7, TLR8, and TLR9 stimulate interferon production and dendritic cell activation, enhancing antiviral responses. Early studies show transient reductions in HBV DNA and HBsAg, but responses are modest when used alone, highlighting the need for combination strategies.

Another promising class is immune checkpoint inhibitors, which aim to reverse T-cell exhaustion by targeting inhibitory pathways such as PD-1/PD-L1. These agents can potentially reinvigorate HBV-specific T-cell responses, improving viral control. However, their use is limited by concerns of immune-mediated liver flares and hepatotoxicity, especially in patients with underlying liver disease.

Other immune-based strategies include therapeutic vaccines and cytokine-based therapies designed to enhance adaptive immune responses.

The future direction is combination therapy, integrating immune modulators with antivirals (e.g., nucleos(t)ide analogues, siRNA) to reduce antigen load and simultaneously boost immune clearance.

Key Message:
Immune modulators target the core problem in chronic HBV—immune dysfunction. While promising, their success will depend on safe and effective combination strategies that balance immune activation with the risk of liver injury.

The HBV therapeutic landscape is shifting toward functional cure, with novel agents targeting different stages of the viral life cycle. Two key classes are entry inhibitors and gene-silencing therapies.

Entry inhibitors block viral entry into hepatocytes by targeting the NTCP receptor. The prototype, Bulevirtide, prevents new hepatocyte infection and intrahepatic viral spread. While currently established in HDV, its role in HBV is being explored, particularly in combination strategies. Alone, entry inhibition does not eliminate existing intracellular cccDNA but may help limit reinfection and reduce viral persistence.

siRNA and antisense oligonucleotides (ASOs) represent a major advance by targeting HBV RNA transcripts, thereby reducing viral protein production, including HBsAg. Agents such as Vir-2218 and JNJ-3989 have shown significant reductions in HBsAg levels in early trials. This is critical because persistent HBsAg is a major barrier to immune recovery.

These therapies act upstream of viral replication and are often combined with nucleos(t)ide analogues to suppress DNA replication while silencing antigen production. The goal is to restore host immune response, allowing durable viral control.

Challenges include durability of response, delivery systems, off-target effects, and cost, but the concept of combining entry blockade + viral silencing + immune modulation is highly promising.

Key Message:
Entry inhibitors and siRNA/ASO therapies represent a new era in HBV treatment—limiting viral spread and silencing antigen production, paving the way toward functional cure through combination strategies.

Ischemic hepatitis (“shock liver”) is characterized by massive, rapid transaminase elevation due to acute hypoperfusion and hypoxia. It commonly occurs in the ICU setting with septic shock, cardiogenic shock, respiratory failure, or severe hypotension. Management is supportive and cause-directed, as there is no specific liver therapy.

The cornerstone is rapid hemodynamic stabilization. This includes aggressive fluid resuscitation, appropriate use of vasopressors (preferably norepinephrine), and optimization of cardiac output in cardiogenic shock. Simultaneously, ensure adequate oxygen delivery by correcting hypoxia, anemia, and respiratory failure (often requiring ventilatory support).

Early identification and treatment of the underlying cause is critical—prompt antibiotics for sepsis, revascularization for cardiac events, or correction of arrhythmias. Avoid further hepatic insult by withholding hepatotoxic drugs and adjusting medication doses.

Close monitoring is essential:

• Serial LFTs (AST/ALT typically peak and fall rapidly)

• INR and lactate (markers of severity and prognosis)

• Renal function, as AKI commonly coexists

The role of N-acetylcysteine may be considered in selected cases of acute liver injury, although evidence is limited outside acetaminophen toxicity.

Most patients show rapid biochemical recovery within 3–7 days if perfusion is restored. However, prognosis depends largely on the underlying critical illness, not the liver injury itself.

Key Message:
In ischemic hepatitis, the liver is a “victim organ”—early restoration of perfusion and oxygenation is the only effective treatment, with outcomes determined by reversal of the underlying shock state.