APASL, Istanbul, Turkey. Day- 2

A growing number of genetic and metabolic liver diseases are now recognized to present in adulthood, often with subtle or atypical features. These conditions are frequently underdiagnosed or misclassified as common liver diseases such as MAFLD or cryptogenic cirrhosis.

Key disorders include Hemochromatosis, presenting with elevated ferritin, liver disease, diabetes, and cardiomyopathy; Wilson disease, which may present with liver disease, neuropsychiatric symptoms, or unexplained transaminitis even in adults; and Alpha-1 antitrypsin deficiency, associated with cirrhosis and emphysema.

Metabolic conditions such as Glycogen storage diseases and Lysosomal storage disorders can also present later in life with hepatomegaly, abnormal liver enzymes, or fibrosis.

A key clinical challenge is overlap with common liver diseases, particularly MAFLD and alcohol-related liver disease. Red flags include family history, early-onset cirrhosis, unexplained liver dysfunction, multi-system involvement, and disproportionate disease severity.

Diagnosis relies on a combination of biochemical markers (iron studies, ceruloplasmin, A1AT levels), imaging, and genetic testing. Early identification is crucial, as many of these conditions have disease-specific therapies (e.g., phlebotomy for hemochromatosis, chelation for Wilson disease).

Key Message:
Adult-onset genetic and metabolic liver diseases are often missed—a high index of suspicion and targeted testing are essential, as early diagnosis can significantly alter prognosis and management.

Drug development in liver disease is rapidly evolving but remains challenging due to disease heterogeneity, slow progression, and lack of validated endpoints. Conditions such as MAFLD/MASH, fibrosis, and cirrhosis require long timelines to demonstrate meaningful clinical outcomes, making traditional trial designs difficult.

A major focus is the use of non-invasive biomarkers and surrogate endpoints to accelerate trials. Tools such as elastography, serum fibrosis markers, imaging (MRI-PDFF), and emerging molecular biomarkers are increasingly used to assess treatment response without biopsy. Regulatory agencies are gradually accepting these as intermediate endpoints, particularly in early-phase trials.

Another key advancement is adaptive and platform trial designs, which allow multiple therapies to be evaluated simultaneously and modified based on interim results. This improves efficiency and reduces cost.

Patient stratification is critical. Incorporating genetics, metabolic profile, disease stage, and comorbidities helps identify subgroups most likely to benefit, enabling precision medicine approaches.

The development pipeline is also shifting toward combination therapies, targeting multiple pathways such as inflammation, fibrosis, and metabolism—especially relevant in MAFLD/MASH.

Collaboration between academia, industry, and regulatory bodies is essential to standardize endpoints, validate biomarkers, and streamline approval pathways.

Key Message:
Facilitating liver drug development requires a shift toward non-invasive endpoints, innovative trial designs, and precision medicine, enabling faster, more efficient translation of therapies from bench to bedside.

Endohepatology integrates advanced endoscopic ultrasound (EUS) techniques into hepatology, enabling minimally invasive, real-time assessment of liver disease. In the non-interventional domain, EUS serves as a powerful diagnostic adjunct rather than a therapeutic tool.

A key application is EUS-based liver imaging, which provides high-resolution visualization of liver parenchyma, surface nodularity, and focal lesions—often detecting abnormalities missed on conventional imaging. It is particularly useful in evaluating small lesions, early cirrhosis, and vascular structures.

EUS elastography allows assessment of liver stiffness, offering a surrogate for fibrosis staging. Compared to transabdominal elastography, EUS may provide more precise, segmental evaluation, especially in obese patients or those with poor acoustic windows.

Another important role is in portal hypertension assessment. EUS can visualize portal vein, collateral circulation, and varices, helping in risk stratification. Emerging techniques enable indirect estimation of portal pressure dynamics.

EUS also facilitates guided sampling, including fine-needle aspiration (FNA) of focal liver lesions and lymph nodes for diagnostic clarification—though this borders on minimally invasive intervention.

The major advantages include high sensitivity, ability to combine imaging and tissue assessment, and utility in difficult-to-image patients. Limitations include availability, operator dependence, need for sedation, and cost.

Key Message:
Non-interventional endohepatology expands diagnostic capability by providing high-resolution, real-time liver assessment, improving early detection and characterization of liver disease while complementing conventional imaging modalities.

Incidental liver lesions are increasingly detected due to widespread use of imaging such as ultrasound, CT, and MRI. The key clinical challenge is to differentiate benign from malignant lesions while avoiding unnecessary investigations.

Most incidental lesions in the general population are benign, especially in patients without chronic liver disease. Common benign entities include Hepatic hemangioma, Focal nodular hyperplasia, and Hepatic adenoma. These often have characteristic imaging features and usually do not require intervention unless symptomatic or complicated.

In contrast, in patients with cirrhosis or chronic liver disease, any new lesion should be considered hepatocellular carcinoma (HCC) until proven otherwise. Multiphasic imaging with CT or MRI is essential, looking for hallmark features such as arterial phase hyperenhancement and venous washout.

The diagnostic approach depends on patient risk profile, lesion size, and imaging characteristics. Small lesions (<1 cm) in low-risk individuals often require no further evaluation or periodic follow-up, whereas indeterminate or suspicious lesions warrant advanced imaging or biopsy.

MRI with liver-specific contrast agents provides the highest diagnostic accuracy, reducing the need for invasive procedures.

Key Message:
Management of incidental liver lesions is risk-stratified—most are benign in low-risk patients, but in cirrhosis, a high index of suspicion for malignancy is essential. Accurate imaging is the cornerstone to avoid over-treatment and ensure early cancer detection.

Interventional endohepatology represents a major advance where endoscopic ultrasound (EUS) is used not just for diagnosis but for therapeutic interventions in liver disease. It offers a minimally invasive, real-time alternative to radiologic or surgical approaches.

A key application is EUS-guided liver biopsy, which allows bilobar sampling with high diagnostic yield and safety, especially useful when percutaneous or transjugular routes are challenging.

In portal hypertension, EUS enables direct visualization and treatment of varices. Techniques such as EUS-guided coil and glue injection are increasingly used for gastric varices, offering precise targeting and reduced risk of embolization compared to conventional methods.

Another emerging area is EUS-guided portal pressure gradient (PPG) measurement, providing a direct and potentially safer method to assess portal hypertension compared to transjugular hepatic venous pressure gradient (HVPG).

EUS is also being explored for intrahepatic therapies, including targeted drug delivery and tumor ablation, particularly in hepatocellular carcinoma (HCC), although these are still evolving.

Advantages include real-time imaging, precision targeting, reduced invasiveness, and the ability to combine diagnosis and therapy in a single session. However, limitations include operator expertise, availability, procedural cost, and need for standardization.

Key Message:
Interventional endohepatology is redefining hepatology practice by enabling precise, minimally invasive therapeutic procedures, particularly in portal hypertension and liver diagnostics, with the potential to complement or replace traditional approaches.

MAFLD is rapidly becoming one of the leading indications for liver transplantation worldwide, driven by rising obesity, diabetes, dyslipidemia, and metabolic syndrome. Unlike viral hepatitis, MAFLD is a multisystem disease, so transplant assessment must go beyond liver severity alone.

A major challenge is cardiovascular risk, which is a leading cause of post-transplant morbidity and mortality. Many MAFLD candidates have silent coronary artery disease, obesity, renal dysfunction, sarcopenia, and frailty, making pre-transplant evaluation more complex.

Post-transplant, recurrence of metabolic dysfunction is common. Weight gain, diabetes, hypertension, and dyslipidemia may worsen due to immunosuppressive drugs, especially steroids and calcineurin inhibitors. This can lead to recurrent graft steatosis, fibrosis progression, cardiovascular events, and chronic kidney disease.

Management requires a multidisciplinary approach, involving hepatologists, transplant surgeons, cardiologists, endocrinologists, dietitians, and physiotherapists. Careful cardiovascular screening, optimization of diabetes and weight, sarcopenia assessment, and tailored immunosuppression are essential.

Future perspectives include better risk prediction models, use of GLP-1 receptor agonists and metabolic therapies, structured lifestyle programs, and personalized immunosuppression to reduce metabolic complications.

Key Message:
In the MAFLD era, liver transplantation is no longer only about replacing the liver—it requires comprehensive management of the metabolic, cardiovascular, renal, and frailty risks before and after transplantation to improve long-term survival.

Management of chronic hepatitis B (HBV) is evolving from long-term viral suppression toward the goal of a functional cure (HBsAg loss with undetectable HBV DNA).

Current therapy relies on potent nucleos(t)ide analogues such as Tenofovir and Entecavir, which effectively suppress viral replication, improve liver histology, and reduce the risk of cirrhosis and HCC. However, they rarely eliminate cccDNA, requiring long-term or lifelong therapy. Pegylated interferon remains an option in selected patients, offering a finite course with modest rates of HBsAg loss.

Future treatments focus on achieving cure through combination strategies targeting different steps of the viral life cycle and host immunity. These include:

• Direct-acting antivirals: capsid assembly modulators, siRNA, antisense oligonucleotides targeting viral transcripts and cccDNA activity

• Entry inhibitors and agents targeting viral protein production

• Immune modulators: therapeutic vaccines, toll-like receptor agonists, and checkpoint inhibitors to restore antiviral immunity

A key concept is combining viral suppression + immune restoration, similar to strategies used in other chronic viral infections.

Emerging biomarkers (HBsAg quantification, HBcrAg, HBV RNA) will guide treatment decisions, identify candidates for therapy cessation, and assess cure.

Key Message:
While current therapies provide excellent viral suppression, the future of HBV lies in finite, combination therapies aimed at functional cure, integrating antiviral and immunomodulatory approaches guided by novel biomarkers.

Autoimmune liver diseases—autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC)—are characterized by dysregulated immune responses targeting hepatocytes or bile ducts. While conventional therapies (steroids, azathioprine, UDCA) remain the backbone, a subset of patients are non-responders or intolerant, driving the need for targeted immune modulation.

In AIH, emerging therapies focus on selective immunosuppression with fewer systemic effects. Agents such as mycophenolate mofetil are already used as second-line therapy, while newer strategies target B-cell pathways (e.g., anti-CD20 agents like Rituximab) and T-cell co-stimulation (e.g., Abatacept) to restore immune tolerance.

In PBC, beyond UDCA, newer agents include FXR agonists (e.g., Obeticholic acid) and emerging therapies targeting PPAR pathways and immune-mediated bile duct injury. These not only improve cholestasis but also modulate inflammatory pathways.

In PSC, where effective medical therapy is lacking, immune modulators and antifibrotic agents are under investigation, including biologics targeting inflammatory cytokines and gut–liver axis pathways.

A key direction is precision immunotherapy, tailoring treatment based on immune phenotype and disease activity, aiming to minimize long-term steroid exposure and toxicity.

Key Message:
Emerging immune modulators are shifting autoimmune liver disease management toward targeted, mechanism-based therapy, offering hope for patients with incomplete response to conventional treatment.

Benign liver tumors are increasingly detected incidentally due to widespread imaging. The current approach is shifting from “detect and biopsy” to risk-based diagnosis and conservative management.

The most common benign lesions are hemangioma, focal nodular hyperplasia (FNH), and hepatocellular adenoma (HCA). In low-risk patients, most solid focal liver lesions are benign. Modern guidelines emphasize multiphasic contrast imaging, preferably MRI, for accurate characterization and to avoid unnecessary biopsy. MRI is particularly useful in differentiating FNH from hepatic adenoma, which has major management implications.

For hemangioma and typical FNH, once imaging is characteristic, no treatment or long-term follow-up is usually required. The major change is in hepatic adenoma, where management is now guided by sex, size, subtype, symptoms, and malignant potential. Risk factors include oral contraceptive exposure, anabolic steroids, obesity, metabolic syndrome, glycogen storage disease, and male sex. Lifestyle modification, weight loss, and stopping hormonal/anabolic triggers are key first steps.

Resection is generally considered for men with adenoma, lesions >5 cm, growth despite risk-factor modification, bleeding, or suspected malignant transformation. Molecular classification, especially β-catenin–activated adenoma, is increasingly important because of higher HCC risk.

Key Message:
The modern management of benign liver tumors is imaging-led, risk-stratified, and conservative whenever safe. The central clinical task is to confidently identify harmless lesions while recognizing adenomas with bleeding or malignant potential.

Liver fibrosis is driven by activation of hepatic stellate cells (HSCs), and recent research highlights the THBS2–SPP1 axis as a key molecular pathway regulating this process.

THBS2 (Thrombospondin-2) is an extracellular matrix–associated glycoprotein involved in cell–matrix interactions and tissue remodeling. SPP1 (Secreted Phosphoprotein-1 / Osteopontin) is a multifunctional cytokine-like protein that plays a central role in inflammation, fibrosis, and immune signaling.

During liver injury, hepatocytes and immune cells release signals that upregulate both THBS2 and SPP1. This axis promotes hepatic stellate cell activation, leading to transformation into myofibroblast-like cells. Activated HSCs increase production of collagen and extracellular matrix, driving fibrosis.

Mechanistically, the THBS2–SPP1 interaction enhances pro-fibrogenic signaling pathways, including TGF-β activation, integrin-mediated signaling, and inflammatory cascades, amplifying HSC proliferation, migration, and survival. It also contributes to matrix stiffness and remodeling, further sustaining fibrogenesis.

Importantly, this axis creates a positive feedback loop, where extracellular matrix deposition and inflammatory signaling reinforce continued HSC activation.

From a clinical perspective, both THBS2 and SPP1 are emerging as potential biomarkers of fibrosis severity and therapeutic targets. Inhibition of this pathway could attenuate stellate cell activation and slow fibrosis progression in diseases such as MAFLD, viral hepatitis, and alcoholic liver disease.

Key Message:
The THBS2–SPP1 axis is a novel regulator of stellate cell activation and liver fibrosis, representing a promising target for future antifibrotic therapies and biomarker development.