Ken Liu

Background: Alcohol‐related hepatitis (AH) is an acute form of liver disease with a high short‐term mortality. A variety of treatments have been explored in randomised studies. Recent consensus on study outcomes has identified 90‐day survival as the primary outcome metric. Aims: This systematic review and network meta‐analysis is to update understanding of the comparative efficacy of treatments for AH, based on 90‐day survival, to inform future Phase III studies. Methods: PubMed, Ovid‐Medline and Embase were searched for randomised studies of treatments of AH. The risk of bias in included papers was measured using the Cochrane risk of bias 2 tool. Data were synthesised with network meta‐analysis to estimate risk ratio (RR) of survival at 90 days after randomisation. Heterogeneity was assessed with the magnitude of the between‐study variance (tau ² ). Results: Thirty five studies including 5045 participants were identified that examined 24 treatments for AH. Twenty‐three studies were considered to be at low risk of bias. In network meta‐analysis considering placebo as the reference treatment, only granulocyte colony stimulating factor (GCSF) showed a statistically significant benefit on 90‐day mortality (RR 0.49, 95% CI 0.28–0.84; p = 0.009). In subgroup analysis of studies at low risk of bias, no treatments showed a significant effect on mortality at 90 days. Conclusions: Individual studies are small and heterogeneity is marked; however, some agents show promise to improve survival at 90 days in people with AH. This information should inform adequately powered studies to explore potential treatments for AH.

Background: The risks of recurrent hepatocellular carcinoma (HCC) and HCC‐specific mortality post‐liver transplant (LT) are influenced by the number and size of viable tumours. This study assesses HCC‐specific mortality post‐transplant for patients in two groups—those with no viable disease versus single viable tumour ≤ 3 cm, as assessed on most recent imaging prior to transplantation. Methods: This retrospective cohort study included adult patients transplanted for the indication of HCC between 1998 and 2018 at two Australian centres. Competing risks regression assessed 5‐year HCC‐specific mortality, with the competing risk of non‐HCC‐specific mortality. Results: There was a significantly lower 5‐year HCC‐specific mortality post‐transplant for those with no viable disease ( n = 152) versus single viable tumour ≤ 3 cm ( n = 145) (4.0% vs. 10.5%, SHR 2.72, 95% CI: 1.06–6.98, p = 0.038) on univariable analysis. On multivariable competing risks analysis, the modified Response Evaluation Criteria In Solid Tumour (mRECIST) criteria and higher AFP level at transplant were significant predictors of 5‐year HCC specific mortality, with progressive disease (aSHR 16.33, 95% CI: 2.35–113.6, p = 0.005) and stable disease (aSHR 10.26, 95% CI: 1.81–58.2, p = 0.0012) having a higher risk than complete response; whilst the significance of no viable disease versus single viable tumour ≤ 3 cm was not significant on multivariable analysis. Conclusions: There was a significantly lower 5‐year HCC‐specific mortality for those with imaging showing no viable disease versus single viable tumour ≤ 3 cm, prior to transplantation. Lower HCC‐specific mortality was demonstrated for those with a lower AFP level and those in radiological complete response at time of transplant.

Background: Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma (KS)‐associated herpesvirus, can cause severe disease in liver transplant (LT) recipients, be donor‐derived, and present variably. We describe HHV8 disease post‐LT. Methods: HHV8 disease was identified post‐LT in New South Wales (NSW), 2017–2024, and from systematic review. Reports were compared by suspected donor‐derived infection (DDI) and disease manifestation, using chi‐square and t ‐tests. Survival was investigated with Cox proportional hazards. Results: Of 188 records, 79 publications (131 cases) were included, plus four NSW cases ( n = 135). Median onset was 7 months posttransplant (IQR: 5–13), with 33% suspected DDI. After median 12 months of follow‐up, 68/125 had disease remission/regression; 59/135 died (49 HHV8‐related). In NSW, Case 1 was proven DDI: visceral KS, 6 months post‐LT; complete remission occurred with immunosuppression modification and chemotherapy. Case 2 was probable DDI: KS, multicentric Castleman's disease, and hemophagocytic lymphohistiocytosis, 3 months post‐LT; the patient died despite immunosuppression modification, hydrocortisone and rituximab. Case 3 was possible DDI: KS‐herpesvirus‐induced cytokine syndrome, 6 months post‐LT; died despite immunosuppression modification and ganciclovir. Case 4 was unlikely DDI: visceral KS, 5 months post‐LT; complete remission occurred with surgery and immunosuppression modification. Survival was worse with visceral KS and non‐KS disease (aHR 5.83 and 4.32, p = 0.002). Reduced immunosuppression, mTORi, and chemotherapy improved survival (aHRs 0.53, 0.36, 0.43; p = 0.006, 0.044, and 0.030). Treatment effects diverged by KS and non‐KS disease. Donor screening identified more KICS and DDI, with improved non‐KS disease survival. Conclusion: Post‐LT HHV8 disease is heterogeneous, with high mortality. Targeted treatments and possibly donor screening improve survival. image

Postliver transplant ascites occurs in 5%–7% of recipients. This report describes splenic artery steal syndrome, causing refractory post-transplant ascites and ischemic biliopathy requiring splenectomy. A 65-year-old man with alcohol-related cirrhosis underwent orthotopic liver transplantation (Model for End-Stage Liver Disease 12) with pretransplant splenomegaly and splenic-artery dilatation. Postoperatively, computed tomography demonstrated persistent ascites, splenic-to-hepatic artery ratio of 2.5, and reduced hepatic arterial perfusion. Endoscopic retrograde cholangiopancreatography identified an anastomotic stricture with intrahepatic biliopathy. Two splenic artery embolization procedures were unsuccessful. Salvage splenectomy achieved resolution of ascites, cholestasis, and biliopathy. Splenic artery steal syndrome is an under-recognized cause of refractory post-transplant ascites which may benefit from splenectomy after embolization failure.

Background: Alpha‐fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC). Given the wide variation in AFP values, conventional linear regression methods may provide an incomplete understanding of complex predictor relationships. Therefore, we utilized quantile regression to examine the association of clinical factors with AFP distribution. Methods: In this multicenter study, we analyzed retrospective data from an adult HCC cohort, collected across nine tertiary healthcare institutions from 2003 to 2021. Quantile regression, which can model covariate effects at different specified points of the outcome distribution, was used to account for heterogeneity across the AFP value range, assessing the effects of predictors associated with AFP levels at the 0.10, 0.50, and 0.90 quantiles. Logistic regression was performed with AFP < 20 ng/mL and ≥ 20 ng/mL groups. Results: The cohort included 2298 individuals with HCC, with median AFP of 13.70 ng/mL. Multivariable quantile regression determined that factors such as Asian ethnicity, elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), Barcelona Clinic Liver Cancer (BCLC) stage, hepatitis B (HBV), and hepatitis C (HCV) were associated with higher AFP, while male sex, older age, higher BMI, and elevated creatinine were associated with lower AFP levels. Compared to metabolic dysfunction‐associated steatotic liver disease, HBV (β = 0.44 at Q50) and HCV (β = 0.30 at Q10; β = 0.40 at Q50) were associated with higher AFP. Conclusion: There is substantial heterogeneity in how clinical factors influence AFP levels across its distribution. These data may stimulate the development of more granular cut‐points for AFP that differ according to disease stage and etiology.

Introduction: For many patients, liver transplantation (LT) is not feasible due to a shortfall of suitable organs. In Australia, almost all grafts come from deceased donors, a pool not easily expanded, and many potentially useable grafts are declined for viability concerns. Despite this, referral utilisation is incompletely understood. The objective of this paper was to characterise deceased donor liver utilisation and referral patterns at a major Australian LT unit. Methods: All deceased donor referrals made to the Australian National Liver Transplantation Unit (ANLTU) from 2014 to 2024 were included. The primary endpoint was the utilisation rate of referrals made to the ANLTU. Secondary endpoints included the effect of referring hospital location on utilisation, reason for decline and donor characteristics. Results: A total of 1649 referrals were included. During the study period, out‐of‐network referral volume increased significantly, from 23 to 77 annually ( p = 0.044). Overall, utilisation fell from 61.3% to 43.2% ( p = 0.045), due to falling utilisation of out‐of‐network referrals. In‐network donation after neurological determination of death (DNDD) and circulatory determination of death (DCDD) referral utilisation was stable at 65.3% ( p = 0.979) and 30.0% ( p = 0.621), respectively. In‐network referrals were increasingly declined due to an absence of a suitable potential recipient ( p = 0.003) and out‐of‐network due to the graft being unsuitable for the urgently listed patient ( p = 0.038). Conclusion: Utilisation of in‐network referrals has remained unchanged since 2014. Out‐of‐network referral volume is increasing, with reduced utilisation of grafts amongst this cohort. Techniques to improve organ utilisation will be critical to expand access to LT in Australia.

Background: Despite advancements in the detection and treatment of hepatocellular carcinoma (HCC), the overall survival remains poor. Traditional survival analyses, such as the Cox model, are limited in capturing the dynamic progression across different clinical states. Our paper proposes the utilization of a continuous‐time multi‐state Markov model to inform risk stratification and management strategies for HCC by accounting for transitions between disease states. Methods: This cohort study included 934 adult patients (25.0% female) with HCC who underwent curative treatment, defined as liver transplantation, resection or ablation, across eight tertiary centres in Australia, China, Japan, Singapore, South Korea and the United States. The primary objective was to assess the risk of HCC recurrence and survival following curative treatment. Results: The median (IQR) age of the cohort was 65 (IQR 58–74), and 72% had known cirrhosis. Distinct clinical trajectories were identified: recurrence, death without recurrence and death after recurrence. The median (IQR) time from curative treatment to recurrence, from recurrence to death, and from curative treatment to death without recurrence was 15.40 months (4.78–26.01), 51.27 months (20.04–82.50), and 23.13 months (9.26–37.01), respectively. Analyses revealed that advancing age and HCV were associated with recurrence risk, while liver transplantation was protective against recurrence. Ablation, non‐curative locoregional therapy, and systemic therapies were associated with higher risks of recurrence and post‐recurrence death. Alpha‐fetoprotein, tumour size, INR, bilirubin and advanced BCLC stage were key predictors of recurrence and mortality. Conclusion: By modelling disease as a sequence of interlinked transitions, we provide updated estimates for the time spent within each transition state and predictors for disease progression within a dynamic framework.