AASLD 2025

Autoimmune hepatitis (AIH) remains difficult to manage when patients fail or cannot tolerate standard therapy with steroids and azathioprine. Many patients require long-term immunosuppression, and flares are common. This has led to interest in targeted immune-modulating therapies that can control disease without the toxicities of current drugs.

1. What is Zetomipzomib?

Zetomipzomib (KZR-616) is a first-in-class selective immunoproteasome inhibitor. Unlike conventional proteasome inhibitors used in oncology, zetomipzomib targets the LMP7 and LMP2 immunoproteasome subunits, which are primarily active in activated T cells, B cells, and antigen-presenting cells.
By selectively inhibiting the immunoproteasome, zetomipzomib:

• Reduces presentation of autoantigens

• Downregulates pathogenic Th1/Th17 responses

• Restores regulatory immune balance
  while minimising broad immunosuppression.

2. The PORTOLA Phase 2a Trial

PORTOLA is the first study to evaluate zetomipzomib in autoimmune hepatitis patients inadequately controlled on standard therapy.
Key features include:

• Open-label, multi-center design

• Subcutaneous weekly dosing

• Inclusion of patients with persistent ALT/AST elevation despite immunosuppression

3. Emerging Clinical Outcomes

Preliminary results presented in 2024–2025 show:

• Meaningful reductions in ALT and AST

• Improvement in IgG levels

• Reduction in steroid requirements in several patients

• Acceptable tolerability, with main adverse effects being mild fatigue, injection-site reactions, and transient GI symptoms
  Importantly, several patients achieved biochemical remission or near-remission while tapering conventional immunosuppressants.

4. Why This Matters for AIH

If larger studies confirm these findings, immunoproteasome inhibition may become:

• A steroid-sparing option

• A therapy for incomplete responders

• A targeted immunologic approach that addresses core AIH pathophysiology

Zetomipzomib represents the first major mechanistically novel drug for AIH in decades and holds promise for patients with difficult-to-treat disease.

Clinically significant hypersplenism—characterised by splenic enlargement with cytopenias (thrombocytopenia, leukopenia, anaemia)—is common in portal hypertension due to cirrhosis. While supportive care (transfusions, TPO agonists, antiviral therapy) may help, emerging interventional therapies are now transforming management.

1. Partial Splenic Embolisation (PSE)

PSE is increasingly used as a minimally invasive option to improve cytopenias by reducing splenic blood flow while preserving some splenic tissue.
Benefits:

• Marked improvement in platelet count and leukocytes

• Helps optimise patients for high-risk procedures, TIPS, or antiviral therapy

• Can delay or avoid splenectomy
  Advances: Modern techniques using smaller embolic particles, antibiotic prophylaxis, and staged embolisation have reduced risks such as post-embolization syndrome and abscess.

2. TIPS + PSE Combination

For patients with severe portal hypertension and hypersplenism, combining PSE with TIPS can improve portal flow, lower variceal risk, and substantially increase platelet counts. This combination is promising in patients awaiting liver transplantation or those needing repeated interventions.

3. Splenic Radiofrequency Ablation (RFA) and Microwave Ablation

Emerging percutaneous technologies allow targeted ablation of splenic tissue under ultrasound or CT guidance.
Advantages: Less pain, reduced risk of infarction, shorter hospital stays compared with PSE. Early studies show a good platelet response.

4. Laparoscopic & Robotic Splenectomy

Still reserved for selected patients (massive splenomegaly, refractory cytopenias, or splenic artery aneurysm). Robotic approaches improve visualisation and decrease blood loss.

5. Novel Pharmacologic and Regenerative Strategies

• TPO receptor agonists (avatrombopag, lusutrombopag) assist with procedure-related thrombocytopenia.

• Research into portal pressure–reducing agents, endothelial modulators, and splenic immune rebalancing is ongoing.

Coagulation in liver disease is complex because the liver controls both clotting and bleeding. Traditionally, patients with cirrhosis were considered “auto-anticoagulated,” but modern understanding shows that they live in a fragile balance—called rebalanced hemostasis—where they can bleed or clot depending on the situation.

1. Why the Liver Matters in Coagulation

The liver produces most clotting factors (II, V, VII, IX, X, XI), natural anticoagulants (protein C, protein S, antithrombin), and fibrinolytic proteins. When the liver is damaged, all these factors decrease, but they fall together, creating a new equilibrium rather than a simple bleeding tendency.

2. Bleeding in Liver Disease

Bleeding risks increase during:

• Variceal rupture from portal hypertension

• Procedures (biopsy, paracentesis in select cases)

• Severe thrombocytopenia

• Infection or acute kidney injury
  Bleeding is often related more to portal hypertension than to low clotting factors.

3. Thrombosis in Liver Disease

Despite abnormal INR, patients with cirrhosis can develop clots, especially:

• Portal vein thrombosis

• Deep vein thrombosis and pulmonary embolism
  Inflammation, decreased anticoagulant proteins, and sluggish portal flow promote thrombosis.

4. Why INR Is Not Reliable

INR only measures procoagulant pathways and does not reflect anticoagulant protein levels. Thus, INR is not a good measure of bleeding risk in cirrhosis.

5. Clinical Principles

• Avoid routine correction of INR before procedures.

• Platelet transfusion or TPO agonists may help if platelets <50,000 in high-risk procedures.

• Anticoagulation is safe and often necessary for portal vein thrombosis.

6. Key Concept

Cirrhosis leads to a delicate hemostatic balance. Small triggers—like infection, bleeding, or thrombosis—can tip the system toward either uncontrolled bleeding or excessive clotting.

1. Obesity Before Transplant

Obesity is now one of the most common conditions in liver transplant candidates, especially with the rise of MASLD. Severe obesity increases the risk of wound complications, infections, cardiopulmonary problems, and early graft dysfunction. A key focus is pre-transplant weight optimisation, which may include:

• Lifestyle and nutritional interventions

• Endoscopic bariatric therapies (intragastric balloons, endoscopic sleeve gastroplasty)

• Select bariatric surgery strategies in specialised centres
  The goal is not perfection but improving metabolic fitness to reduce perioperative risk.

2. Frailty and the Role of Prehabilitation

Frailty—low physiologic reserve—is strongly linked to mortality both before and after transplant. It can exist even in young patients with cirrhosis. “Prehab” programs help build strength and endurance through:

• Supervised exercise

• Nutritional therapy (protein-rich diet, supplementation)

• Cognitive and functional training
  Prehab improves wait-list survival and shortens post-transplant recovery.

3. Advanced Age

More older adults (≥70 years) are being considered for transplant. Chronologic age alone is no longer a contraindication. Selection now focuses on:

• Physiologic age

• Cardiovascular fitness

• Absence of severe frailty
  With proper evaluation, older recipients can achieve outcomes similar to younger patients.

4. Complex Surgical Anatomy

Prior abdominal surgeries, portal vein thrombosis, congenital anomalies, and difficult biliary anatomy complicate transplantation. Modern imaging, 3D reconstruction, and meticulous surgical planning allow safe transplantation even in challenging cases.

Acute-on-chronic liver failure (ACLF) is recognised worldwide as acute decompensation in a patient with chronic liver disease, complicated by organ failures and high 28- to 90-day mortality—but East and West define and manage it differently.

1. Definitions: APASL vs AASLD/CLIF (West)

• APASL (Asia–Pacific)

  • ACLF = acute hepatic insult (e.g., flare of HBV, acute alcoholic hepatitis, drug-induced injury, infection) in a patient with chronic liver disease or compensated cirrhosis, leading to jaundice (bilirubin ≥5 mg/dL) and coagulopathy (INR ≥1.5), complicated within 4 weeks by ascites and/or encephalopathy.

  • Focus is liver failure first, then extrahepatic organ dysfunction.

• AASLD/CLIF (Western, EASL-CLIF)

  • ACLF is defined in decompensated cirrhosis based on organ failures using the CLIF-SOFA/CLIF-OF score (liver, kidney, brain, coagulation, circulation, respiration) and associated 28-day mortality.

  • Here, ACLF is a multiorgan failure syndrome in cirrhosis, often triggered by infection, active alcohol use, or bleeding.

2. Management: East vs West

• Western (AASLD / EASL-CLIF)

  • Early ICU-level care, aggressive sepsis control, vasopressors, RRT.

  • Strong emphasis on early transplant evaluation; “transplant or die” paradigm in high-grade ACLF.

• Eastern (APASL)

  • Greater emphasis on aggressive medical management and liver regeneration: antivirals for HBV flares, albumin infusions, plasma exchange, stem-cell/regenerative approaches in some centres.

  • Transplantation is important but often limited by access; thus, bridge and rescue therapies receive more focus.

3. Why This Contrast Matters

Understanding both frameworks helps you:

• Recognise ACLF earlier across different etiologies (especially HBV in Asia vs alcohol/MASLD in the West).

• Adapt management to resource-limited settings, where a transplant may not be immediately available.

Together, APASL and AASLD perspectives are converging toward a more unified, phenotype-based, transplant-aware, but regeneration-friendly approach to ACLF.

By 2025, systemic therapy for HCC will have clearly moved from single-agent TKIs to immunotherapy-anchored and combination strategies, with an eye toward cure in selected patients.

1. Frontline: IO-Based Standards and New Contenders

Two immune-based regimens dominate first-line treatment:

• Atezolizumab + bevacizumab (IMbrave150) remains a key backbone, with durable survival and real-world confirmation of benefit.

• Durvalumab + tremelimumab (STRIDE, HIMALAYA) provides an all-IO alternative, now with 4–5-year OS data showing ~20–25% patients alive at long-term follow-up, roughly doubling survival versus sorafenib.

New PD-1 backbones are emerging: Tislelizumab proved non-inferior to sorafenib with better responses and quality of life, offering a simpler IO monotherapy option where combinations are not feasible.

The Camrelizumab + Rivoceranib combo showed the longest OS to date in a phase 3 HCC trial (median OS ~23.8 vs 15.2 months vs sorafenib), but repeated FDA complete response letters underline the tension between strong clinical signals and regulatory scrutiny of trial conduct and data quality.

2. Earlier Disease: Neoadjuvant / Adjuvant and Downstaging

The IMbrave050 adjuvant trial initially suggested improved recurrence-free survival with atezo–bev after resection/ablation, but updated analyses failed to confirm a clear benefit, so adjuvant IO remains investigational and controversial.

Conversely, small series report successful downstaging with atezo–bev to resection or liver transplant, hinting that systemic IO may convert advanced disease into curative candidates in carefully selected patients.

3. Beyond Checkpoint Inhibitors: Next-Wave Technologies

ASCO 2024–2025 updates highlight CAR-T cells, bispecific antibodies, and oncolytic viruses targeting glypican-3 and other HCC antigens, as well as trials layering anti-PD-1/PD-L1 onto second-line TKIs.

Parallel efforts use AI-based models to refine patient selection, integrate radiomics and genomics, and predict benefit or toxicity from IO-based regimens.

This session highlights the ongoing challenge of interpreting liver biopsies in the era of MASLD, MASH, and MetALD, where overlapping features make diagnosis complex. Pathologists and hepatologists often “speak different languages,” and meaningful diagnosis requires tight clinicopathologic correlation.

1. Distinguishing MASLD, MASH, and MetALD on Biopsy

Although pathologists can reliably identify steatosis, ballooning, lobular inflammation, and fibrosis, biopsy alone often cannot separate pure MASLD from MetALD, because both metabolic injury and moderate alcohol use produce similar histologic patterns. Features sometimes associated with alcohol—such as Mallory–Denk bodies, neutrophil-rich inflammation, or sclerosing hyaline necrosis—are not specific. Therefore, clinical history (alcohol biomarkers, PEth, CDT), metabolic risk factors, and imaging must complement pathology.

2. Alcohol-Related vs Metabolic Injury

In MetALD, pathologists see “dual hits”: steatohepatitis from metabolic dysfunction plus alcohol-associated injury. The biopsy may show more pronounced neutrophils, canalicular cholestasis, or perivenular fibrosis, but definitive attribution to alcohol is rarely possible without clinical data.

3. Mimickers: Wilson Disease, AAT Deficiency, and DILI

Other conditions—Wilson disease, alpha-1 antitrypsin deficiency, drug-induced steatohepatitis (eg, methotrexate, amiodarone, tamoxifen)—may mimic MASH but have key clues:

• Wilson disease: glycogenated nuclei, copper-associated protein.

• AAT deficiency: PAS-D–positive globules.

• DILI: mixed patterns, eosinophils, zone-specific injury.

4. Utility and Limitations of Biopsy

Biopsy remains the gold standard for grading steatosis, ballooning, and fibrosis, but cannot determine aetiology alone. The session emphasises using pathology reports as part of a diagnostic puzzle, not in isolation.

Liver transplantation is entering a new era where artificial intelligence (AI) and advanced technologies are improving every step of care—from donor selection to post-transplant follow-up. Inspired by the pioneering vision of Thomas E. Starzl, modern transplant programs now use digital tools to make transplant surgery safer, more precise, and more widely accessible.

1. AI in Donor–Recipient Matching

AI algorithms can analyse large datasets—donor characteristics, imaging, labs, waiting-list profiles—to predict which donor liver will work best for each patient. These models help optimise organ allocation, reduce wait-list mortality, and identify high-risk grafts more accurately than traditional scoring systems.

2. Machine Perfusion Technologies

Normothermic and hypothermic machine perfusion keep livers functioning outside the body, allowing doctors to assess organ quality, repair marginal grafts, and safely use livers that were previously discarded. AI-driven monitoring systems can analyse bile production, lactate clearance, and perfusion signals in real time to predict transplant success.

3. Operative and Technical Innovations

3D imaging, virtual-reality planning, and robotic assistance are being integrated into complex transplant procedures. These technologies support safer living donor transplantation and improve surgical precision.

4. Predictive Analytics After Transplant

AI models now help predict complications such as rejection, infection, biliary strictures, and renal dysfunction. Wearable monitoring devices and digital platforms allow remote follow-up, reducing hospital visits and catching complications earlier.

5. Training and Equity

Simulation platforms using VR/AI are transforming surgical training and making advanced transplant education available worldwide, supporting global equity in transplant services.

1. MetALD (Metabolic Dysfunction–Associated Alcohol-Related Liver Disease)

AASLD/EASL MetALD Working Group Consensus Endpoints (2024–2025):

Primary Endpoints

• Histologic improvement: ≥1-stage fibrosis improvement without worsening of steatohepatitis

• Resolution of steatohepatitis (if steatohepatitis is present at baseline)

• Sustained reduction in alcohol intake (biomarker-confirmed, e.g., PEth)

• Composite liver-related clinical outcomes (decompensation, transplant, HCC)

Secondary Endpoints

• Non-invasive fibrosis improvement (VCTE, MRE, ELF, PRO-C3)

• Improvement in metabolic markers (HbA1c, TG, LDL, BMI, waist circumference)

• Reduction in alcohol-use biomarkers (PEth, CDT)

• Patient-reported outcomes (quality of life, fatigue scores)

2. Alcohol-Associated Liver Disease (ALD)

Primary Endpoints

• 90-day survival (especially in severe AH trials)

• Reduction in MELD or Lille scores

• Resolution of alcoholic hepatitis biomarkers (bilirubin, INR, creatinine)

Secondary Endpoints

• Prevention of progression to cirrhosis

• Reduction in hepatic decompensation events

• Abstinence endpoints (biomarker or self-report)

• Improvement in portal pressure (HVPG)

3. MASLD / MASH

Primary Endpoints (FDA/EMA-accepted)

• MASH resolution without worsening fibrosis

• ≥1-stage fibrosis improvement without worsening MASH

Secondary Endpoints

• MRI-PDFF fat reduction ≥30%

• Non-invasive fibrosis improvement (VCTE, MRE, ELF, PRO-C3)

• Metabolic outcomes (weight loss, HbA1c)

• Cardiometabolic endpoints (lipids, blood pressure)

• Patient-reported quality-of-life outcomes

Immune-mediated liver injury from checkpoint inhibitors (ILICI) is a growing challenge as immunotherapy use expands. Most patients respond to first-line corticosteroids, but 10–20% develop steroid-refractory or steroid-resistant hepatitis, requiring hepatology input and second-line therapy.

Refractory ILICI reflects deeper immune activation with T-cell infiltration, PD-1/PD-L1 pathway disruption, and cytokine-driven hepatocyte injury. Management is guided by experience from other immune-mediated toxicities such as colitis, pneumonitis, and myocarditis.

Second-line options include:

• Mycophenolate mofetil (MMF) – most widely used; suppresses T- and B-cell proliferation.

• Tacrolimus – calcineurin inhibition to reduce activated T-cell response.

• Azathioprine – alternative when MMF is not tolerated.

• Budesonide – useful in mild, localised immune hepatitis with fewer systemic effects.

Third-line or rescue options (case-based evidence):

• Anti–TNF agents (infliximab) – effective in refractory colitis; cautiously used in ILICI due to theoretical hepatotoxicity, but successful cases exist.

• Vedolizumab – gut-selective, used when liver injury coexists with severe colitis.

• Tocilizumab (IL-6 blockade) and abatacept (CTLA-4 fusion protein) – used in steroid-resistant myocarditis and being explored in severe ILICI.

• Plasma exchange – occasionally used in fulminant cases to rapidly remove cytokines.

Early identification, close monitoring, and a multidisciplinary approach with oncology and rheumatology are essential. Rechallenge with immunotherapy requires individualised risk assessment.