The concept of recompensation has emerged as an important milestone in cirrhosis management, shifting attention beyond symptom control toward sustained recovery of liver function. At EASL Congress 2026, the EUROTIPS-German Cirrhosis Study Group presented multicenter data demonstrating that recompensation following transjugular intrahepatic portosystemic shunt (TIPS) is achievable and associated with excellent long-term outcomes.

Baveno VII defines recompensation as durable clinical recovery after control or removal of the underlying liver disease cause. This requires sustained absence of decompensating events, withdrawal of therapies previously needed for complications, and stable restoration of liver function. The concept reflects meaningful disease stabilization rather than temporary symptomatic improvement.

The EuroTIPS study focused on patients with decompensated cirrhosis undergoing TIPS for recurrent variceal bleeding or refractory and recurrent ascites. Investigators specifically examined whether portal decompression through TIPS could facilitate recompensation in patients with potentially controllable etiologies such as alcohol-related liver disease, viral hepatitis, and autoimmune hepatitis.

The findings were encouraging. Approximately one-tenth of eligible patients achieved recompensation following TIPS. More importantly, most individuals who reached this state maintained durable clinical stability during follow-up, while only a small minority developed renewed decompensation. These observations suggest that meaningful hepatic recovery can occur after successful portal pressure reduction in appropriately selected patients.

Recompensation carried substantial prognostic significance. Patients who achieved recovery demonstrated markedly superior transplant-free survival compared with those who remained decompensated. The survival benefit persisted throughout long-term follow-up, supporting the view that recompensation reflects genuine disease modification rather than transient clinical improvement.

Clinical recovery was also accompanied by reduced treatment burden. Many recompensated patients were able to discontinue medications previously required for ascites or hepatic encephalopathy management, further supporting the durability of improvement after TIPS.

Investigators identified several factors associated with successful recompensation. Patients generally had better preserved liver function at the time of TIPS placement, and lower MELD scores emerged as an independent predictor of recovery. Alcohol-related liver disease also showed a greater likelihood of recompensation, suggesting that disease etiology remains an important determinant of reversibility.

Although re-decompensation occurred in a minority of cases, outcomes remained favorable overall. The study reinforces the concept that TIPS may offer more than portal decompression alone and supports recompensation as an important therapeutic endpoint in advanced cirrhosis management.

Cirrhosis represents more than progressive fibrosis; it reflects a state of regenerative failure in which the liver gradually loses its ability to repair and restore functional tissue. At EASL Congress 2026, investigators presented early clinical findings evaluating hepatocyte-derived liver progenitor-like cells (HepLPCs) as a regenerative treatment strategy for advanced cirrhosis.

In advanced disease, extensive fibrosis, portal hypertension, and structural distortion create a hostile hepatic environment that limits natural regeneration and increases the risk of decompensation. While liver transplantation remains the definitive treatment, donor shortages and limited accessibility continue to leave many patients without viable options. This has stimulated growing interest in therapies capable of restoring hepatic regeneration rather than solely slowing disease progression.

The presented studies explored the use of HepLPC therapy in patients with cirrhosis through prospective, open-label clinical trials. Cells were administered using image-guided hepatic arterial infusion, a minimally invasive approach designed to deliver regenerative cells directly to the diseased liver while maintaining procedural safety.

A key finding was the favorable early safety profile. Investigators reported few treatment-related adverse events and no significant treatment-related serious adverse events during follow-up. Successful completion of therapy without major procedural complications supported the feasibility of hepatic arterial delivery in carefully selected cirrhotic patients.

Beyond safety, early signals of clinical benefit were observed. Serial assessments demonstrated improvements in global liver function, including trends toward lower Child-Pugh and MELD scores, suggesting potential enhancement of overall hepatic status. Recovery was also reflected in markers of hepatic synthetic function. Progressive increases in albumin, prealbumin, and cholinesterase levels suggested improved protein synthesis, while reductions in blood ammonia supported better detoxification capacity.

Coagulation parameters, which are often impaired in advanced cirrhosis, also showed improvement following therapy, indicating broader recovery of hepatic synthetic pathways involved in hemostatic regulation. In addition, reductions in hepatic venous pressure gradient suggested potential improvement in portal hypertension and the underlying hepatic microenvironment.

Long-term follow-up provided further encouraging observations. Imaging demonstrated reduction of ascites and improvement in portal hypertension–related manifestations, while some patients achieved sustained clinical stability without liver transplantation.

Although these findings remain preliminary and require longer follow-up, HepLPC therapy introduces an important regenerative concept in hepatology. Rather than focusing exclusively on fibrosis suppression, this strategy aims to restore hepatic function and potentially modify the disease trajectory of decompensated cirrhosis.

The gut microbiome continues to emerge as an important contributor to outcomes in cirrhosis. At EASL Congress 2026, investigators presented findings from a multinational cohort study examining whether microbial composition and metabolic pathways could predict short-term hospitalization risk in patients with cirrhosis.

The study evaluated microbiome profiles across international cohorts and demonstrated clear geographic differences in microbial diversity. However, despite these regional variations, a consistent pattern emerged among patients who required hospitalization within 90 days. These individuals generally exhibited lower microbial diversity compared with patients who remained clinically stable, suggesting that reduced microbial richness may reflect increased vulnerability and disease instability.

Interestingly, geographic differences became less pronounced among higher-risk patients. While stable patients showed substantial microbiome variability between countries, hospitalized individuals appeared to converge toward a shared microbial pattern associated with advanced clinical risk. This finding suggests that disease-related microbial changes may outweigh regional influences as cirrhosis progresses.

Beyond microbial composition, investigators identified important alterations in microbial metabolic pathways. Patients who were later hospitalized showed reduced activity in pathways involved in carbohydrate degradation, amino acid metabolism, and short-chain fatty acid fermentation. In contrast, pathways associated with stress adaptation, membrane biosynthesis, lipid metabolism, and nucleotide metabolism were relatively enriched. These findings point toward a microbiome that becomes increasingly stress-adapted and metabolically altered in higher-risk cirrhosis.

Such pathway remodeling may have important biological consequences. Reduced fermentation and diminished production of beneficial microbial metabolites may impair intestinal barrier integrity and microbial homeostasis, while increased reliance on nitrogen- and sulfur-containing substrates could promote accumulation of potentially harmful metabolites. Several specific microbial pathways remained independently associated with hospitalization risk even after adjustment for MELD score, cirrhosis etiology, decompensation status, and commonly used therapies.

Traditional clinical markers continued to retain prognostic value. Higher MELD scores, alcohol-related liver disease, ascites, and lactulose use were associated with greater hospitalization risk, whereas higher serum albumin levels appeared protective. Certain microbial species also showed important associations, with Enterococcus faecium linked to increased risk and beneficial commensals such as Bifidobacterium and Faecalibacterium associated with more favorable outcomes.

Importantly, predictive models integrating microbiome and clinical data outperformed models based on clinical variables alone. These findings suggest that microbial profiling may become a valuable adjunct to conventional prognostic tools, potentially supporting earlier identification of high-risk patients and more personalized management strategies in cirrhosis.

Alcohol use disorder remains a major contributor to cirrhosis progression, hepatic decompensation, and reduced transplant eligibility. While alcohol abstinence continues to be the foundation of treatment, maintaining long-term abstinence is often difficult, and currently available pharmacologic therapies may have limitations in patients with advanced liver disease. At EASL Congress 2026, investigators presented real-world evidence suggesting that GLP-1 receptor agonists may offer benefits extending beyond metabolic control in patients with alcohol-related liver disease.

GLP-1 receptor agonists, commonly prescribed for type 2 diabetes and obesity, have attracted attention because of their potential influence on alcohol-related behaviors and liver injury. Their proposed mechanisms include modulation of brain reward pathways involved in alcohol craving, particularly within dopaminergic circuits, alongside metabolic and anti-inflammatory effects. These agents may reduce insulin resistance, decrease hepatic steatosis, promote weight loss, and suppress inflammatory and fibrogenic pathways, providing a biologically plausible role in alcohol-related liver disease.

The study utilized data from the TriNetX network, including 111 healthcare organizations across the United States. Investigators evaluated patients with alcohol-related liver disease and type 2 diabetes over a five-year period. After extensive matching for demographic, metabolic, laboratory, and treatment-related variables, two comparable cohorts of approximately 9,000 patients each were analyzed—one receiving GLP-1 receptor agonists and one without GLP-1 therapy.

Results demonstrated significant associations between GLP-1 therapy and improved alcohol-related outcomes. Patients receiving treatment experienced fewer alcohol intoxication events and reduced alcohol withdrawal episodes over follow-up. Liver-related outcomes were also favorable, with lower rates of alcohol-associated hepatitis, cirrhosis progression, hepatic decompensation, and overall hospitalization compared with matched controls. Event curves remained consistently separated over time, suggesting sustained benefit.

Investigators also explored additional endpoints, including alcohol remission, transplant-related outcomes, and biomarkers of alcohol use. Although several trends favored GLP-1 therapy, these findings did not consistently achieve statistical significance, partly because objective alcohol biomarkers such as phosphatidylethanol were infrequently available.

Despite encouraging findings, important limitations remain. The study was retrospective and observational, relied on coding data, and could not confirm long-term treatment adherence or establish direct causality.

Overall, this large U.S. cohort suggests that GLP-1 receptor agonists may have a promising adjunctive role in alcohol-related liver disease and cirrhosis. However, prospective randomized studies remain necessary before defining their place alongside established therapies for alcohol use disorder.

Understanding the true burden of steatotic liver disease remains an important public health challenge. At EASL Congress 2026, findings from the multinational LiverScreen study provided valuable insight into the prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD) across Europe.

The LiverScreen project involved more than 30,000 individuals over 40 years of age from nine European countries and used liver stiffness measurement and ALT testing as initial screening tools. Participants with abnormal findings underwent further hepatology evaluation, including repeat elastography, imaging, laboratory assessment, and liver biopsy when appropriate. Classification followed the updated steatotic liver disease nomenclature.

The study demonstrated that MASLD is by far the most common form of steatotic liver disease in the general population. However, an important clinical paradox emerged. Although MASLD accounted for most detected cases, disease severity increased progressively from MASLD to MetALD and ALD. Patients with alcohol-related phenotypes showed substantially higher rates of elevated liver stiffness and advanced fibrosis, indicating greater risk of clinically significant liver disease.

Several factors independently increased the likelihood of liver stiffness elevation. Type 2 diabetes, obesity, multiple cardiometabolic risk factors, and excess alcohol consumption all contributed to worsening liver disease severity. Importantly, investigators observed a synergistic relationship between alcohol exposure and diabetes or glucose intolerance, suggesting that metabolic dysfunction and alcohol together may accelerate hepatic injury more aggressively than either factor alone.

The study also highlighted a major challenge in population-based liver disease research: underreporting of alcohol intake. In a Danish sub-cohort, phosphatidylethanol (PEth), an objective alcohol biomarker, revealed substantial discrepancies between self-reported alcohol use and biological assessment. Many participants initially classified as MASLD or MetALD would have met criteria for more alcohol-related disease categories when PEth results were considered. These findings suggest that the true burden of MetALD and ALD may be considerably underestimated.

Among patients undergoing specialist evaluation and biopsy, advanced fibrosis was more frequent in MetALD and ALD than in MASLD, further reinforcing the greater severity associated with alcohol-related disease phenotypes.

Overall, the LiverScreen study emphasizes that prevalence alone does not reflect disease impact. While MASLD remains the dominant phenotype across Europe, alcohol-related liver disease carries disproportionate severity and may be more common than currently recognized when objective alcohol assessment is incorporated.

Overlap and variant syndromes in autoimmune liver disease remain among the most challenging areas in hepatology because patients often present with findings that do not fit neatly into a single diagnosis. At EASL Congress 2026, experts emphasized that conditions such as MASLD-AIH, PSC-AIH, and PBC-AIH require careful interpretation of biochemical, serological, histological, and radiological findings rather than reliance on a single marker or scoring system.

One major challenge involves distinguishing autoimmune hepatitis (AIH) from metabolic dysfunction-associated steatotic liver disease (MASLD). Patients with obesity, diabetes, hepatic steatosis, positive autoantibodies, and elevated liver enzymes frequently create diagnostic uncertainty. Importantly, the presence of ANA, SMA, or mildly elevated IgG does not automatically confirm AIH, as these abnormalities may also occur in MASLD. Features raising suspicion for AIH include markedly elevated ALT levels, significant autoantibody titers, IgG elevation, and liver injury disproportionate to expected metabolic disease activity. In such situations, liver biopsy becomes essential. Histological evaluation, particularly the presence and severity of interface hepatitis and lymphoplasmacytic infiltration, helps distinguish true autoimmune disease from steatohepatitis with incidental immune findings.

The session also explored the evolving relationship between AIH and primary sclerosing cholangitis (PSC). In younger patients, AIH may initially dominate the clinical picture and respond to immunosuppression, while cholestatic features later emerge, suggesting progression toward PSC. Rising alkaline phosphatase levels, positive ANCA, inflammatory bowel disease, or ductular changes should prompt cholangiographic evaluation. MRCP was highlighted as the key diagnostic investigation because liver biopsy may fail to identify large-duct PSC.

PBC-AIH was discussed as a variant syndrome rather than a true overlap syndrome in most patients. Persistent or disproportionate transaminase elevation, elevated IgG, and inadequate explanation by cholestatic disease alone should prompt reconsideration of the diagnosis. Reassessment following UDCA therapy and careful histological evaluation remain central to management decisions.

A unifying message emerged throughout the discussion: diagnostic discordance should trigger further investigation. When laboratory findings, imaging, clinical behavior, or histology do not align with the expected disease pattern, clinicians should reconsider the diagnosis. Liver biopsy remains central in many cases, while MRCP is essential when PSC is suspected. Recognizing evolving disease phenotypes and diagnostic inconsistencies is critical for accurate diagnosis and individualized management.

Left-sided portal hypertension is a distinct and often underrecognized form of portal hypertension caused by splenic vein obstruction rather than primary liver disease. Presented at EASL Congress 2026, this session highlighted how the condition differs fundamentally from classical portal hypertension associated with cirrhosis and why recognizing its unique features is essential for accurate diagnosis and management.

Unlike cirrhotic portal hypertension, patients with left-sided portal hypertension usually maintain preserved liver function and rarely develop ascites. The condition is primarily characterized by splenomegaly, thrombocytopenia, and the development of gastric varices, particularly involving the gastric fundus. These clinical features create a disease pattern that is hemodynamically and clinically distinct from conventional portal hypertensive syndromes.

The underlying mechanism begins with obstruction or thrombosis of the splenic vein, which disrupts normal venous drainage from the spleen. This results in the formation of collateral pathways that redirect blood flow, predominantly toward the gastric fundus, leading to isolated gastric varices. An important distinguishing feature is that blood flow in the left gastric vein remains hepatopetal, contrasting with the altered hemodynamics commonly seen in cirrhotic portal hypertension.

Endoscopy plays a valuable role in diagnosis. Isolated fundal gastric varices are the most common finding, although diffuse reticular variceal patterns may also occur. Recognition of these patterns, particularly in the absence of significant liver disease, should raise suspicion for left-sided portal hypertension. Associated findings such as splenic vein abnormalities and splenomegaly further strengthen the diagnosis.

Pancreatic disease remains the leading cause of this condition. Both acute and chronic pancreatitis frequently lead to splenic vein thrombosis, while pancreatic tumors, pseudocysts, and post-surgical pancreatic changes represent additional etiologies. Less commonly, hypercoagulable states may contribute, and thrombophilia evaluation may be appropriate when clinical findings suggest an underlying systemic predisposition.

Although progression to clinically significant variceal bleeding is relatively uncommon, delayed diagnosis remains an important challenge because splenic vein pathology may be overlooked on routine imaging. Careful evaluation of thrombocytopenia, splenomegaly, and gastric varices is therefore critical.

Overall, left-sided portal hypertension should be viewed as a unique vascular disorder rather than a variant of cirrhotic portal hypertension. Early recognition of its characteristic clinical, endoscopic, and radiological features is essential to prevent complications and guide appropriate management.

The updated EASL 2025 treatment recommendations for HBeAg-negative chronic hepatitis B aim to simplify treatment decisions and improve identification of patients who may benefit from antiviral therapy. Presented at EASL Congress 2026, these revised indications move beyond older frameworks by incorporating non-invasive assessment of liver disease severity and reducing the number of patients categorized within the clinically uncertain “grey zone.”

To evaluate the real-world impact of these changes, investigators studied a cohort of 1,501 treatment-naïve patients with HBeAg-negative chronic hepatitis B. Patients previously classified as inactive infection or placed within the grey-zone category under earlier guidelines were reassessed using both the 2017 and 2025 EASL recommendations. Follow-up incorporated liver stiffness measurements and histological evaluation to better characterize disease activity and treatment eligibility.

A major finding was the significant reduction in grey-zone classification under the updated criteria. While the classification of inactive HBV infection remained largely stable, nearly half of the patients previously lacking a clear treatment indication were reclassified as having definite eligibility for therapy. This shift represents an important advance because grey-zone patients have historically posed challenges in clinical decision-making and often required prolonged observation before treatment decisions could be made.

The revised recommendations also expanded identification of patients requiring antiviral treatment. Using the EASL 2025 criteria, over one-third of patients fulfilled treatment indications. Detectable HBV DNA combined with increased liver stiffness emerged as the most frequent reason for treatment eligibility, underscoring the growing role of non-invasive fibrosis assessment in routine hepatology practice. Additional patients qualified based on elevated HBV DNA together with abnormal ALT levels.

Importantly, the updated recommendations showed stronger alignment with real-world physician behavior. Patients meeting the new criteria were considerably more likely to receive antiviral therapy during follow-up than those without treatment indications, and this pattern remained consistent over time. This suggests that the revised algorithm more accurately reflects how clinicians already approach treatment decisions in practice.

Overall, the EASL 2025 treatment framework offers clearer clinical stratification for HBeAg-negative chronic hepatitis B. By simplifying thresholds and incorporating liver stiffness assessment, the new guidance reduces diagnostic uncertainty, limits grey-zone classification, and supports earlier and more precise antiviral treatment decisions in everyday clinical care.

Achieving sustained virological response (SVR) remains a major therapeutic goal in chronic hepatitis D, and new real-world evidence presented at EASL Congress 2026 provides important insights into treatment outcomes with bulevirtide. Findings from the French ANRS HEP-Delta cohort suggest that the duration of HDV RNA suppression during therapy may play a crucial role in predicting long-term viral control after treatment discontinuation.

The study explored whether maintaining undetectable HDV RNA for at least 96 weeks before stopping therapy could predict sustained response in routine clinical practice. Investigators analyzed data from 364 patients treated with bulevirtide, either as monotherapy or in combination with interferon. The cohort reflected real-world practice, including patients with varied backgrounds and a substantial burden of cirrhosis.

A key observation was the strong association between prolonged HDV RNA negativity and post-treatment viral control. Patients who maintained undetectable HDV RNA for longer durations, particularly beyond 96 weeks, experienced significantly higher rates of sustained virological response after stopping bulevirtide. These findings support the concept that extended viral suppression may serve as an important marker of durable treatment success.

The study also highlighted the influence of treatment strategy. Patients receiving early combination therapy with bulevirtide and interferon achieved higher rates of undetectable HDV RNA at the end of treatment compared with those receiving bulevirtide alone. Although treatment durations were similar, interferon appeared to enhance virological suppression and increase the likelihood of achieving end-of-treatment viral negativity.

Another important issue discussed was the role of assay sensitivity in monitoring treatment response. Comparisons between different HDV RNA assays revealed that some samples classified as negative by one platform remained detectable on another, suggesting that assay selection can influence interpretation of virological response and potentially affect treatment decisions.

Further analysis identified lower baseline HDV RNA levels and longer periods of viral suppression as independent predictors of undetectable HDV RNA at treatment completion. However, among patients receiving combination therapy, additional factors such as cirrhosis status and intermittent viral positivity also influenced outcomes.

Overall, the French HEP-Delta experience reinforces the importance of prolonged HDV suppression during bulevirtide therapy. Maintaining HDV RNA negativity for more than 96 weeks emerged as a strong indicator of sustained response following treatment discontinuation, supporting its potential role as a practical marker for long-term treatment success in chronic hepatitis D.

The management of metabolic dysfunction-associated steatohepatitis (MASH) is evolving rapidly, with increasing emphasis on selecting the right patients, monitoring treatment response, and identifying when therapy should be continued or reconsidered. During EASL Congress 2026, experts discussed a practical approach to initiating, monitoring, and stopping anti-MASH therapy.

A central message was that treatment should primarily target patients with clinically significant fibrosis, particularly those with moderate-to-advanced fibrosis (F2–F3), where the risk of disease progression becomes more substantial. Patients with early-stage disease generally derive limited benefit from pharmacological therapy, while evidence supporting routine treatment in advanced cirrhosis remains insufficient. Accurate fibrosis staging is therefore essential before initiating therapy.

Liver biopsy is no longer routinely required for treatment selection. Instead, non-invasive tests have become central to clinical decision-making. Tools such as FibroScan, magnetic resonance elastography, and ELF scoring help identify suitable treatment candidates while reducing procedural burden. However, interpretation should never rely on a single measurement alone and must be integrated with clinical findings, laboratory parameters, and imaging results.

Excluding advanced cirrhosis remains particularly important because most available evidence for anti-MASH therapy comes from non-cirrhotic populations. Findings such as thrombocytopenia, portal hypertension, markedly elevated liver stiffness, or discordant non-invasive assessments should raise suspicion for advanced disease and prompt further evaluation.

Resmetirom was highlighted as an important therapeutic option. By activating thyroid hormone receptor-β pathways, it promotes hepatic fat clearance and improves metabolic activity within the liver. Current evidence supports its use in patients with MASH and significant fibrosis, while caution is advised in advanced cirrhosis, uncontrolled thyroid disease, alcohol-related liver disease, and patients with significant portal hypertensive complications.

Monitoring treatment response relies largely on non-invasive biomarkers rather than repeat biopsy. Improvements in liver stiffness, ALT levels, or hepatic fat content after approximately one year may indicate meaningful biological response and support continuation of therapy. Temporary liver enzyme elevations during early resmetirom treatment were described as generally self-limited and not necessarily indicative of hepatotoxicity.

Semaglutide was also discussed as an important metabolic strategy, particularly because it addresses obesity, insulin resistance, and diabetes while contributing to weight loss and hepatic improvement. Ultimately, continuation of therapy should be guided by objective evidence of benefit, whereas absence of measurable response may support reconsideration of treatment strategy.

Despite growing recognition of hepatitis delta virus (HDV) as a major cause of severe viral hepatitis, reflex testing remains inconsistently implemented across Europe. At EASL Congress 2026, experts explored the barriers limiting wider adoption and emphasized that successful implementation depends not only on scientific evidence but also on healthcare policy, laboratory infrastructure, and coordinated stakeholder engagement.

A central message from the discussion was that national healthcare policies form the foundation of effective HDV reflex testing programs. Experts from several European countries highlighted that clinical awareness alone is insufficient. Reflex testing must be supported through formal reimbursement systems, regulatory approval, and laboratory coding frameworks before it can become part of routine practice. The experience with hepatitis C reflex testing was frequently referenced as a practical model that could guide HDV implementation.

Professional and scientific societies were also identified as key drivers of change. Consensus recommendations from hepatology, virology, microbiology, and infectious disease groups can help establish HDV reflex testing as a recognized standard of care. Such guidance creates momentum for policymakers and healthcare authorities to update national recommendations and funding pathways.

Laboratory infrastructure remains another important challenge. While many local laboratories may lack HDV RNA testing capability, experts stressed that this should not prevent implementation of double reflex testing. Existing referral systems can allow local centers to perform initial screening and forward positive samples to specialized laboratories for confirmatory molecular testing. Experiences from countries such as Spain and Belgium demonstrated that centralized testing models can work effectively when supported by reliable transport systems and standardized referral pathways.

Beyond reimbursement, several operational barriers continue to slow adoption. Laboratories often face staffing shortages, workflow adjustments, equipment limitations, and resistance to changing established practices. Limited availability of automated anti-HDV diagnostic platforms further restricts broader integration into routine laboratory workflows.

The discussion also addressed concerns regarding duplicate testing when patients move between healthcare systems. However, experts agreed that the risk of occasional retesting is outweighed by the clinical consequences of missed HDV diagnoses.

The session concluded that sustainable implementation requires multidisciplinary leadership involving laboratories, clinicians, policymakers, public health experts, and patient advocates. Epidemiological data and cost-effectiveness analyses will be essential to persuade healthcare systems that broader HDV reflex testing can improve diagnosis, reduce disease progression, and support earlier treatment across Europe.

Pulmonary vascular complications are increasingly recognized in chronic liver disease and portal hypertension, particularly hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). These conditions may occur across compensated and decompensated cirrhosis as well as non-cirrhotic portal hypertension and significantly influence transplant eligibility, perioperative risk, and long-term outcomes. Early recognition is therefore essential, especially in patients undergoing liver transplantation or transjugular intrahepatic portosystemic shunt (TIPS) evaluation.

Screening was emphasized in patients presenting with dyspnea, syncope, hypoxemia, elevated NT-proBNP, unexplained fluid retention, or suspected pulmonary vascular disease despite mild liver dysfunction. Echocardiography was identified as the principal screening modality because it allows simultaneous evaluation of pulmonary pressures, right ventricular structure and function, and intrapulmonary shunting using bubble contrast studies. Pulse oximetry may help identify severe HPS but is insufficient to exclude mild disease, as cirrhotic patients may maintain normal oxygen saturation despite significant gas exchange abnormalities. In more complex cases, arterial blood gas analysis, technetium-labeled perfusion scanning, pulmonary function testing, diffusion capacity assessment, and chest CT imaging may help differentiate isolated HPS from coexisting pulmonary disorders.

For POPH, echocardiography was highlighted as a screening rather than diagnostic tool. Risk stratification relied largely on tricuspid regurgitation velocity and indirect signs of pulmonary hypertension. However, definitive diagnosis required right heart catheterization because elevated pulmonary pressures in cirrhosis may reflect hyperdynamic circulation or fluid overload rather than true pulmonary vascular disease. HPS prevalence was estimated at 10–20% among screened patients, while POPH occurs in approximately 2–6% of cases. Importantly, POPH severity does not necessarily correlate with portal hypertension severity and may occur even in relatively mild liver disease.

Management of POPH requires individualized treatment. Non-selective beta-blockers may worsen hemodynamics in severe POPH with right ventricular dysfunction and therefore require careful risk-benefit assessment. Therapeutic options increasingly include endothelin receptor antagonists and phosphodiesterase-5 inhibitors, both of which have demonstrated improvements in exercise capacity, dyspnea, and pulmonary hemodynamics. In advanced liver disease, PDE5 inhibitors are often preferred because endothelin receptor antagonists undergo hepatic metabolism and may increase hepatotoxicity risk.

Liver transplantation remains the definitive treatment for HPS, with most patients improving within 6–12 months after transplant. POPH management is more complex and depends on achieving acceptable hemodynamic targets before transplantation. Modern pulmonary vasodilator therapy has improved transplant eligibility, although pulmonary vascular abnormalities may persist or transiently worsen after transplantation, emphasizing the need for careful long-term monitoring.

The role of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their combination with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in metabolic dysfunction-associated steatohepatitis (MASH) remains an area of active investigation. The COMBAT_T2_NASH trial evaluated whether combined therapy with empagliflozin and low-dose semaglutide could improve histologic and metabolic outcomes in patients with biopsy-confirmed MASH and type 2 diabetes.

This randomized, placebo-controlled, double-blind Phase 4 study enrolled 61 patients with MASH and fibrosis stages F1–F3. Participants were assigned to receive empagliflozin plus semaglutide combination therapy (COMBI), empagliflozin alone (EMPA), or placebo for 48 weeks. The primary endpoint was MASH resolution without fibrosis progression, while secondary endpoints included changes in NAFLD activity score (NAS), hepatic steatosis, inflammatory activity, body weight, glycemic control, liver enzymes, and biomarkers of liver injury. The study population had a mean age of 56 years, mean body mass index of 33 kg/m², and average HbA1c of 7.4%, with paired liver biopsy data available for most participants at treatment completion.

Combination therapy demonstrated clear metabolic benefits. Patients receiving empagliflozin plus semaglutide achieved substantial reductions in body weight and glycemic parameters, with a mean weight loss of 8.6 kg and significant improvement in HbA1c compared with placebo. In contrast, empagliflozin monotherapy produced only modest changes. These findings suggest a stronger metabolic effect with combined treatment, likely driven by semaglutide-associated weight and glucose reduction.

Histologic outcomes also favored combination therapy. The proportion of patients achieving MASH resolution without fibrosis progression was numerically higher in the combination group, whereas empagliflozin alone did not demonstrate meaningful benefit. Combination treatment significantly improved the NAFLD activity score with reductions in hepatic steatosis and inflammatory activity, while fibrosis remained generally stable across groups. Biomarker analysis further supported these findings, as patients receiving combined therapy showed significant reductions in liver enzymes and cytokeratin-18 fragments M30 and M65, reflecting improvement in hepatocellular injury and liver inflammation. These biomarker improvements were not observed with empagliflozin monotherapy.

Overall, the COMBAT_T2_NASH trial demonstrated that combined empagliflozin and low-dose semaglutide therapy produced greater improvements in MASH-related steatosis, inflammation, body weight, and glycemic control than placebo after 48 weeks. The findings support the potential role of combination metabolic therapy in patients with MASH and type 2 diabetes, particularly when metabolic and hepatic targets require simultaneous treatment.

Liver biopsy remains the gold standard for fibrosis assessment in metabolic dysfunction-associated steatotic liver disease (MASLD), but its invasiveness, sampling variability, and inconsistent interpretation have encouraged the development of non-invasive alternatives. Liver stiffness measurement (LSM) using vibration-controlled transient elastography and the enhanced liver fibrosis (ELF) score have emerged as promising tools for identifying patients at high risk for cirrhosis progression and major adverse liver outcomes. This study evaluated the accuracy of proposed high-risk thresholds of LSM 10–20 kPa and ELF 9–10.8 using biopsy-confirmed fibrosis as the reference standard.

The analysis included baseline and screening data from 12 multicenter MASH clinical trials involving 4,188 patients with available liver biopsy, LSM, and ELF measurements. Participants were stratified according to fibrosis stage into F0–F2 and F3/F4 groups to determine whether the proposed non-invasive thresholds accurately identified advanced disease. The study population included patients across the fibrosis spectrum, with 8.0% having F0 fibrosis, 17.3% F1, 25.6% F2, 23.7% F3, and 25.5% F4 fibrosis.

Although the proportion of patients meeting LSM and ELF criteria increased with fibrosis severity, important limitations became evident. Notably, many patients with little or no fibrosis also fulfilled the proposed high-risk thresholds. The criteria were met by 18.0% of F0 patients and 23.2% of F1 patients, compared with 41.7% of F3 and 34.7% of F4 patients. Among the 1,373 individuals meeting both LSM and ELF criteria, only 57% actually had advanced fibrosis, while 43% had fibrosis stages F0–F2. Importantly, 10% had no fibrosis and nearly one-third demonstrated only mild fibrosis, suggesting that these thresholds may overestimate advanced disease risk.

Further analysis highlighted the influence of metabolic factors on non-invasive biomarker performance. Patients with F0–F1 fibrosis who met the LSM and ELF criteria were generally older, more frequently diabetic, and demonstrated higher AST, AST/ALT ratio, HbA1C, and FIB-4 values. These findings suggest that metabolic and clinical variables may influence LSM and ELF measurements independently of fibrosis severity.

Overall, the study indicates that while LSM and ELF retain important prognostic value, the currently proposed thresholds may lack sufficient specificity for identifying truly high-risk MASLD. More stringent non-invasive criteria may therefore be necessary to improve risk stratification and more accurately identify patients at greatest risk for cirrhosis progression and adverse liver outcomes.

Pemvidutide, a balanced 1:1 glucagon/GLP-1 dual receptor agonist, is being developed as a therapeutic option for metabolic dysfunction-associated steatohepatitis (MASH). The Phase 2b IMPACT trial evaluated its long-term efficacy and safety in patients with biopsy-confirmed MASH and fibrosis stages F2 or F3. Earlier 24-week findings had already demonstrated histologic improvement and MASH resolution, while the current 48-week analysis focused on non-invasive liver markers, fibrosis progression, weight loss, and treatment tolerability.

The randomized, double-blind, placebo-controlled trial enrolled 212 patients who received once-weekly subcutaneous pemvidutide 1.2 mg, pemvidutide 1.8 mg, or placebo in a 1:2:2 allocation without dose titration. Participants had a mean age of 53 years and a mean body mass index of 39 kg/m², with women accounting for 58% of the cohort and type 2 diabetes present in 43%. Week 48 evaluation included measurements of liver fat content, inflammatory markers such as corrected T1 (cT1) and alanine aminotransferase (ALT), fibrosis biomarkers including enhanced liver fibrosis (ELF) score and liver stiffness measurement (LSM), along with body weight assessment.

Pemvidutide demonstrated substantial and dose-dependent improvements across multiple liver-related parameters. Liver fat content showed marked reductions, decreasing by 45.2% in the 1.2 mg group and 54.7% in the 1.8 mg group compared with 8.2% in the placebo arm. Hepatic inflammation also improved significantly, reflected by reductions in cT1 relaxation time and ALT levels. These findings suggest sustained anti-inflammatory activity alongside improvement in steatotic liver disease.

Significant benefits were also observed in fibrosis-related outcomes. A larger proportion of patients receiving pemvidutide achieved at least a 30% reduction in liver stiffness compared with placebo. ELF scores improved meaningfully in both treatment groups, whereas placebo recipients experienced worsening values. Combined improvement in ELF and LSM occurred more frequently among patients treated with pemvidutide, supporting a favorable effect on fibrosis progression.

Beyond liver-specific outcomes, pemvidutide produced clinically meaningful weight reduction and improved cardiometabolic parameters, including reductions in triglycerides, total cholesterol, and LDL cholesterol. Mean weight loss reached 4.5% with the 1.2 mg dose and 7.5% with the 1.8 mg dose, while placebo produced minimal change. Treatment was generally well tolerated with very low discontinuation rates. Overall, the IMPACT trial supports pemvidutide as a promising therapeutic candidate for MASH with sustained benefits in inflammation, fibrosis markers, metabolic health, and body weight.

Chronic liver disease is characterized by persistent inflammation, fibrosis, and progression to cirrhosis, with fibrosis severity closely linked to hepatic dysfunction, decompensation, and mortality. Despite the growing global burden of liver fibrosis, effective antifibrotic therapies remain limited. Increasing evidence suggests that macrophage heterogeneity plays a critical role in fibrogenesis and may provide important therapeutic targets. This study explored macrophage diversity in chronic liver disease and identified oxidised LDL receptor-1 (OLR1) and IL-1–associated macrophage pathways as potential antifibrotic targets.

Fibrosis development is closely linked to activation of hepatic stellate cells, which produce extracellular matrix in response to tissue injury. Interactions between monocyte-derived macrophages and stellate cells have attracted particular interest because scar-associated macrophages may demonstrate both profibrotic and antifibrotic properties. To better characterize these populations, investigators developed a comprehensive single-cell atlas of chronic liver disease by integrating datasets from healthy individuals and patients with cirrhosis. This analysis identified 14 macrophage populations, including two distinct scar-associated macrophage subsets termed SAMac-1 and SAMac-2. Although both expressed CD9 and TREM2, they demonstrated markedly different transcriptional profiles, emphasizing substantial functional heterogeneity.

Further analysis revealed clear biological differences between these macrophage subsets. SAMac-1 displayed a pro-inflammatory phenotype characterized by IL-1β, TGF-β, and TNF-α expression, whereas SAMac-2 demonstrated anti-inflammatory features involving IL-10, MMP9, and GPNMB. IL-1 emerged as a particularly important marker because of its selective expression within myeloid cells, potentially enabling more targeted therapeutic strategies. Protein-level validation using multiplex immunofluorescence confirmed the presence of these distinct macrophage populations within collagen-rich fibrotic regions and demonstrated their expansion across several liver disease etiologies, including MASLD-associated F3 fibrosis. Importantly, IL-1 expression strongly correlated with fibrosis severity and adverse clinical outcomes.

Experimental studies further supported these observations. Murine fibrosis models confirmed expansion of both macrophage populations during fibrosis progression and reduction during fibrosis regression, suggesting a close relationship with disease activity. Therapeutic evaluation using IL-1 silencing in monocyte-derived macrophages demonstrated significant reduction in collagen-1 and collagen-3 expression within hepatic stellate cells. Similar antifibrotic effects were observed in multicellular liver spheroid models without impairing macrophage viability.

These findings highlight substantial macrophage heterogeneity in chronic liver disease and identify IL-1–positive, OLR1-associated macrophage pathways as promising therapeutic targets. Suppression of IL-1 signaling reduced fibrogenic activity across experimental models, supporting the future development of targeted antifibrotic therapies in chronic liver disease.

Adipose triglyceride lipase (ATGL), encoded by PNPLA2, plays a central role in maintaining hepatic lipid homeostasis and regulating fibrogenic pathways in chronic liver disease. As the master regulator of lipolysis, ATGL catalyzes the rate-limiting first step in triglyceride breakdown, generating glycerol and free fatty acids essential for energy metabolism and cellular signaling. Because ATGL is widely expressed across liver cell populations, disruption of its activity may significantly impair lipid balance and contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis.

Both excessive and impaired lipolysis may adversely affect liver health. Excessive lipolysis promotes generation of lipotoxic lipid species, leading to oxidative stress, inflammation, and hepatocyte injury, whereas insufficient lipolysis results in intrahepatic lipid accumulation and steatotic liver disease. In MASH-driven fibrosis, disturbed lipid metabolism creates a pro-inflammatory hepatic microenvironment characterized by stressed hepatocytes, lipid-associated macrophages, scar-associated macrophages, and activated hepatic stellate cells, ultimately promoting extracellular matrix deposition, fibrotic scarring, and portal hypertension.

To better understand the role of ATGL, investigators developed a hepatocyte- and cholangiocyte-specific ATGL knockout mouse model using the LOXP-CRE system and induced fibrosis through a high-fat choline-deficient diet. Detailed phenotypic assessment included serum biochemistry, histology, portal pressure measurements, flow cytometry, and single-cell RNA sequencing. Loss of hepatocyte ATGL resulted in marked intrahepatic lipid droplet accumulation, increased liver-to-body weight ratio, and reduced circulating free fatty acid levels, reflecting impaired lipid mobilization.

ATGL deficiency significantly worsened liver injury and fibrosis. Knockout mice demonstrated elevated serum AST, greater collagen deposition, higher portal pressure, and increased spleen-to-body weight ratios, indicating worsening hemodynamic changes associated with advanced fibrosis. Single-cell transcriptomic analysis further revealed expansion of a distinct stressed hepatocyte population characterized by loss of zonation identity, increased endoplasmic reticulum and oxidative stress, and impaired oxidative phosphorylation and fatty acid metabolism. Enhanced epithelial-mesenchymal transition signaling suggested a direct contribution to fibrogenesis.

Loss of hepatocyte ATGL also altered cellular communication within the liver microenvironment. Increased collagen signaling from hepatic stellate cells and activation of immune recruitment and tissue remodeling pathways supported enhanced fibrogenic crosstalk. In parallel, lipid-associated macrophages demonstrated substantial metabolic reprogramming with impaired fatty acid metabolism despite preserved ATGL expression. These findings identify hepatocyte ATGL as a critical regulator of hepatic lipid balance and a promising therapeutic target in progressive MASH-related fibrosis.

Liver disease is increasingly recognized as an important complication in patients with type 2 diabetes mellitus, with cirrhosis affecting a significant proportion of this population. Although international guidelines recommend screening for liver disease in individuals with type 2 diabetes, uncertainty remains regarding whether systematic screening improves clinical outcomes and represents a cost-effective strategy. The REFLEX trial was designed to address this question by evaluating vibration-controlled transient elastography (VCTE) screening within primary care settings.

The REFLEX study was a multicentre randomized controlled trial conducted across 26 primary care practices in England. Adults with documented type 2 diabetes but without known liver disease or previous fibrosis assessment were enrolled and randomized equally to either usual care or a VCTE-based screening strategy. The primary objective was to determine whether VCTE screening improved detection of cirrhosis compared with routine care, while secondary objectives included identification of fibrosis, assessment of healthcare costs, long-term liver outcomes, and cost-effectiveness. Additional analyses also evaluated two-step screening approaches using FIB-4 or ELF score before VCTE.

Baseline characteristics were balanced between groups, with most participants being older male White Caucasian individuals. The study demonstrated clear differences between screening strategies. While fibrosis assessment occurred in very few patients receiving usual care, nearly all individuals in the VCTE group completed screening. Importantly, no cirrhosis cases were detected through usual care, whereas VCTE screening identified 12 patients with F4 cirrhosis and prompted referral of 39 individuals to secondary care. Approximately 10% of screened participants demonstrated elevated liver stiffness, and several patients required hepatocellular carcinoma surveillance.

Post hoc analyses revealed important limitations of guideline-recommended two-step screening pathways. When age-adjusted FIB-4 thresholds were used before VCTE, only five of the 12 confirmed cirrhosis cases were identified, while ELF-based pathways detected only six. These findings suggest that reliance on FIB-4 or ELF as initial screening tools may result in substantial underdiagnosis of advanced liver disease.

Economic analyses showed that although VCTE-first strategies involve higher upfront costs than usual care, they remain cost-effective over time. Modeling further suggested that emerging therapies such as semaglutide and resmetirom may enhance the value of early screening by reducing liver-related mortality, particularly when fibrosis is identified before advanced disease develops. Overall, the REFLEX trial supports reconsideration of current MASLD screening pathways and highlights the potential value of VCTE-first approaches in patients with type 2 diabetes.

Hospital readmissions in patients with cirrhosis remain a major global healthcare challenge and are closely linked to poor clinical outcomes. Nearly one-fourth of patients admitted non-electively for cirrhosis are readmitted within 30 days, contributing to increased mortality, healthcare utilization, economic burden, and psychological stress. Long-term prognosis also remains poor, with nearly 80% of patients not surviving beyond one year without liver transplantation. Despite the major clinical impact of readmissions, reliable predictors and effective prevention strategies have remained inadequately defined.

The CLEARED Global Study addressed this gap through a large international multicenter cohort involving more than 8,000 patients hospitalized with cirrhosis or advanced fibrosis across 121 centers on six continents between January 2021 and August 2025. Patients who died or underwent liver transplantation during the index hospitalization were excluded. By including healthcare systems from high-, middle-, and low-income countries, the study was able to evaluate global differences in cirrhosis management and outcomes. The primary objectives were to identify predictors of 30-day readmission, assess associated mortality and transplantation outcomes, evaluate healthcare burden, and examine geographic and socioeconomic disparities.

Several important predictors of readmission were identified, including hepatic encephalopathy, acute kidney injury, hyponatremia, and infections. Ascites, gastrointestinal bleeding, and encephalopathy remained the most common reasons for hospitalization. Patients requiring readmission generally had more severe disease, reflected by higher MELD scores. Importantly, mortality after readmission exceeded 10%, and the relative risk of death was more than twofold higher compared with non-readmitted patients. Readmitted individuals also demonstrated increased rates of liver transplantation, suggesting more advanced disease progression and greater dependence on specialized healthcare services.

One of the most important findings involved global healthcare disparities. High-income countries demonstrated higher readmission rates but lower mortality, likely reflecting better healthcare access, surveillance systems, and continuity of post-discharge care. In contrast, low- and middle-income countries showed lower hospitalization rates but substantially higher mortality, highlighting the consequences of delayed presentation, limited transplant availability, reduced affordability of care, and inadequate healthcare infrastructure.

The CLEARED study therefore identifies 30-day readmission not merely as a marker of disease severity but also as a reflection of healthcare system performance. Strengthening surveillance, improving access to timely liver care, expanding transplantation services, and addressing preventable liver diseases may substantially reduce cirrhosis-related mortality worldwide.

Management of alcohol-related liver disease extends beyond estimating alcohol consumption alone and increasingly requires recognition of alcohol dependence and maladaptive drinking behaviors. Patients may consume alcohol as a coping mechanism for stress, insomnia, anxiety, or depression, and these behavioral patterns may remain unrecognized unless specifically explored during clinical assessment. Understanding alcohol use disorder is therefore essential because it significantly influences long-term disease management, treatment adherence, and transplant outcomes.

Alcohol consumption is dynamic and frequently changes over time, making single clinical encounters insufficient for accurate assessment. Patients may initially minimize alcohol intake due to fear, guilt, or concerns related to transplant evaluation. For this reason, longitudinal assessment combining repeated biomarker testing with ongoing clinical discussion provides a more reliable understanding of drinking behavior. Continued follow-up helps clinicians recognize relapse patterns, behavioral triggers, and treatment engagement, reinforcing the importance of regular reassessment in alcohol-related liver disease.

Phosphatidylethanol (PEth) has emerged not only as a diagnostic biomarker but also as a valuable communication and motivational tool. Open discussion of biomarker results may facilitate honest, nonconfrontational conversations regarding alcohol use. Improvement in PEth levels can reinforce behavioral change, while unexpected elevations may reveal psychosocial stressors or early relapse. This approach strengthens the therapeutic alliance and encourages patients to actively participate in treatment decisions. Biomarkers therefore support both clinical monitoring and patient-centered counseling.

The discussion highlighted the expanding role of hepatologists in recognizing and addressing alcohol dependence. Referral to psychological, psychiatric, or addiction services becomes particularly important when biomarkers indicate persistent or escalating alcohol exposure. Relapse often reflects unresolved emotional or psychiatric distress rather than simple noncompliance, emphasizing the need for comprehensive behavioral support alongside liver disease management.

Alcohol biomarker monitoring also plays an important role after liver transplantation. Relapse commonly occurs months after surgery and may be detected through repeated PEth testing before biochemical deterioration develops. Importantly, biomarkers should function as supportive tools rather than punitive measures, allowing early intervention and counseling. Interpretation, however, remains complex because factors such as bariatric surgery, cirrhosis, hemolysis, altered erythrocyte lifespan, and binge drinking patterns may influence results. Consequently, biomarkers should complement rather than replace careful clinical evaluation.

Modern alcohol-related hepatology increasingly relies on multidisciplinary and personalized care involving hepatologists, addiction specialists, psychologists, transplant teams, and laboratory experts. Long-term therapeutic relationships, nonjudgmental communication, and integrated addiction care remain central to improving transplant outcomes and sustaining long-term disease management.

Alcohol biomarkers are increasingly becoming part of routine hepatology practice, particularly in transplant medicine and in patients with unexplained liver disease. Biomarkers such as phosphatidylethanol (PEth) and ethyl glucuronide provide objective assessment of recent alcohol exposure when clinical history is uncertain. Their use has expanded because alcohol intake is often underreported or difficult to quantify through history alone. Many transplant centers now incorporate these tests during transplant assessment and follow-up of alcohol-related liver disease, while biomarkers also assist in distinguishing metabolic dysfunction-associated steatotic liver disease from mixed metabolic and alcohol-related liver injury.

Despite growing clinical interest, implementation of alcohol biomarker testing remains uneven across healthcare systems. PEth testing requires mass spectrometry-based analysis, which increases cost and limits availability, particularly in smaller centers. Reimbursement challenges and healthcare infrastructure also influence accessibility. Ethical concerns may arise when patients are expected to pay for tests that influence transplant eligibility, highlighting that implementation depends not only on scientific evidence but also on healthcare policy and institutional resources.

Clinicians emphasized that alcohol biomarker testing should be approached through transparent and nonjudgmental communication. Biomarkers should not be presented as tools to identify dishonesty but rather as components of routine medical evaluation. Open discussion about the clinical importance of alcohol exposure helps maintain trust and improves patient engagement. Written consent is frequently used in transplant settings, particularly when random testing is performed, reinforcing the importance of preserving a supportive therapeutic relationship.

PEth has gained particular value in routine hepatology because repeated testing may offer greater insight into long-term drinking behavior than a single clinical interview. It is especially useful in patients with unexplained liver enzyme abnormalities, uncertain alcohol history, or suspected mixed liver disease. The growing recognition of MetALD has further highlighted the interaction between alcohol use and metabolic liver disease, with alcohol increasingly viewed as a continuous risk factor rather than a fixed diagnostic category. Even moderate alcohol intake may worsen fibrosis progression when combined with obesity, diabetes, and metabolic dysfunction.

Interpretation of PEth values remains complex because results may be influenced by drinking patterns, timing of intake, sex, bariatric surgery, cirrhosis, altered erythrocyte turnover, and binge drinking behavior. Therefore, PEth should always be interpreted alongside clinical history and patient context. In transplant medicine, repeated biomarker monitoring allows early identification of relapse and creates opportunities for psychological and addiction support. As accessibility improves, alcohol biomarkers are expected to become an increasingly important component of precision hepatology.

Pediatric cholestatic liver disorders are predominantly genetic and require early structured evaluation because several conditions demand urgent intervention during infancy. Initial assessment focuses primarily on excluding biliary atresia and treatable metabolic diseases, as delayed diagnosis may significantly worsen outcomes. Direct bilirubin serves as a key early marker, with isolated elevation strongly suggesting significant hepatobiliary disease. Additional biochemical markers, particularly gamma-glutamyl transferase (GGT) and bile acid levels, help classify patients into diagnostic pathways and guide further investigation.

Biochemical profiling plays a major role in differentiating inherited cholestatic disorders. Low-GGT cholestasis commonly suggests progressive familial intrahepatic cholestasis (PFIC), while MDR3 deficiency is more often associated with elevated GGT levels. Importantly, certain bile acid synthesis disorders may present with low serum bile acids despite severe disease, highlighting the need for careful interpretation. Alkaline phosphatase is generally less reliable in pediatric practice because skeletal growth contributes substantially to circulating levels. Therefore, combined interpretation of bilirubin, bile acids, and GGT remains essential for accurate diagnosis.

Genetic testing has become central to pediatric hepatology. Most affected children carry biallelic pathogenic variants, often making interpretation more straightforward than in adults. Targeted gene panels and whole exome sequencing now enable rapid identification of monogenic disorders, allowing earlier diagnosis and initiation of therapy during infancy. Genetic confirmation also supports family counseling and sibling screening, both of which are important components of long-term management.

Liver biopsy continues to play an important diagnostic role when biochemical and imaging findings remain inconclusive. Histopathology may reveal canalicular cholestasis, ductopenia, giant hepatocytes, or bile duct abnormalities that support specific molecular diagnoses. Immunohistochemical staining, including BSEP staining in selected cases, may further strengthen diagnostic confidence. Pediatric inherited cholestatic disorders often demonstrate clearer histological patterns than adult disease, and correlation between histology and genetics substantially improves diagnostic precision.

Syndromic cholestatic disorders remain an important consideration, particularly Alagille syndrome, which may present with cholestasis alongside vascular, skeletal, renal, and characteristic facial abnormalities. Variable clinical severity may delay recognition, especially in milder phenotypes. Interpretation of genetic variants, particularly variants of uncertain significance, remains challenging and requires close correlation with clinical findings, histology, and disease progression. Increasingly, international registries and collaborative networks are improving understanding of genotype-phenotype relationships and supporting both research and patient care. Continued advances in molecular hepatology and multidisciplinary collaboration are expected to further improve outcomes in inherited pediatric cholestatic liver disease.

Genetic cholestatic disorders are increasingly being recognized in adults with previously unexplained cholestatic liver disease, highlighting the growing importance of precision hepatology. Evaluation begins with careful interpretation of bile acids, which remain clinically valuable in unexplained cholestasis. Peak bile acid levels may be more informative than fasting values, particularly in intrahepatic cholestasis of pregnancy, where levels above 100 µmol/L are associated with increased fetal risk after 35 weeks of gestation. Markedly elevated bile acids in the absence of cirrhosis or biliary obstruction may suggest inherited cholestatic disease and support both diagnosis and treatment planning.

An important aspect of evaluation is differentiating hepatocellular injury from cholangiocytic disease. Steatotic and alcohol-related liver disease may show relatively low gamma-glutamyl transferase despite significant hepatocyte injury, while cholangiocyte-predominant disease often requires MRCP, autoimmune assessment, and genetic evaluation. Poor response to conventional therapy should raise suspicion for inherited cholangiopathies such as ABCB4-related disease, and recognition of atypical clinical features can prevent delayed diagnosis.

Adult-onset inherited cholestatic disease is increasingly recognized in hepatology practice. Recurrent gallstones, intrahepatic stones, recurrent cholestatic episodes, and a strong family history may provide important diagnostic clues. Pathogenic variants may even be identified in older adults previously treated as autoimmune cholangiopathies, making family screening an important step once a mutation is confirmed.

Genetic testing is becoming central in unexplained and treatment-resistant cholestatic liver disease. Most centers begin with focused gene panels before progressing to whole exome sequencing when necessary. Interpretation remains challenging because disease expression is often influenced by environmental and metabolic factors such as obesity, alcohol exposure, medications, pregnancy, and inflammatory stress. Even heterozygous variants may become clinically relevant when combined with additional triggers or risk alleles.

Liver biopsy continues to provide valuable diagnostic information by distinguishing canalicular cholestasis from bile duct injury and identifying histological clues such as ductopenia, ductular reaction, and giant hepatocytes. Increasingly, precision hepatology integrates histology, imaging, genetics, and molecular profiling. Emerging technologies and collaborative expert networks are expected to further improve diagnostic accuracy and individualized care in adult cholestatic liver disease.