Society: AASLD

Background The prevalence of chronic liver disease is increasing but it remains underdiagnosed, with frequent late presentation. Development in early adulthood is likely to associate with higher lifetime cirrhosis risk but early identification of asymptomatic patients can prove challenging. We have developed a novel case finding database¹ that can rapidly search all blood test results in Somerset, UK (pop. 560,000) to identify young patients with persistently abnormal liver biochemistry. In this study we tested the hypotheses that a) prevalence of liver disease is increasing in young adults, b) these people are under investigated, c) our case finding database can identify them prior to the development of advanced fibrosis, allowing opportunity for treatment.

Methods Data within our case finding system was used to analyse results from patients born between 1/1/1980 – 31/12/1989 [blood results from 2005-2020 were available which covered age range 25-29: males 21,246, females 35,523]. The prevalence of abnormal ALTs and adequacy of subsequent investigation (with a non-invasive liver screen) was assessed. Where possible the system calculated a FIB-4 score.

Results For patients aged 25-29 the number of ALTs requested has increased over time. Comparing patients born in 1989 to those in 1980 there has been an 83% increase in tests, and a 63% increase in the number of abnormal results. The relationship was linear (for tests, R²=0.9749; p<10^-6; for abnormal R² = 0.8518; p=0.004). The number of patients with >2 abnormal results also increased (Fig 1; p=0.0005). However, there was no significant change in mean ALT (p=0.42) or proportion of tests which were abnormal (p=0.32) suggesting a true increase in disease prevalence.

Rates of follow up investigations for patients with persistently abnormal ALT (>40 for at least 90 days until last result) are shown in Table 1. For men and women respectively only 41% and 47% had sufficient viral serology and only 26% and 28% had an AST (allowing estimate of fibrosis). There were significantly more men than women (477 vs 176) because the laboratory definition of abnormal was used. Of those for whom calculation of FIB-4 was possible the result was low – mean 0.72 + 0.053 (men), 0.79 + 0.094 (women), excluding significant fibrosis in 94% and 87% respectively.

Conclusion The prevalence of liver disease in young adults in the UK is rising but is frequently under investigated. These patients mostly have early disease (as defined by FIB-4) and thus there is significant benefit of targeting them for treatment. We have demonstrated that our case finding database can identify these cohorts of patients in seconds, allowing subsequent follow up and treatment to reduce the future risk of cirrhosis.

1) Wesley E et al. A cumulative liver damage index (CLDI) identifies patients at risk of significant liver disease. Gut 2022:71:A4

Background: TAF, a novel prodrug of tenofovir, has demonstrated noninferior efficacy with superior bone and renal safety compared to tenofovir disoproxil fumarate and is approved for treatment in adults with CHB. TAF has shown superior efficacy and comparable safety to placebo (PBO) at Week 24 in a multicenter, randomized, double-blind (DB), placebo-controlled trial in children 6 years and older weighing ≥25 kg. Here we report efficacy and safety findings at Week 48.

Methods: Pediatric patients 12 to <18 y weighing ≥35 kg (Cohort 1) and 6 to <12 y weighing ≥25 kg (Cohort 2, Group 1), with HBV DNA ≥2 × 10⁴ IU/mL, ALT ≥1.5 × ULN, and creatinine clearance (eGFR; Schwartz method) ≥80 mL/min were enrolled in this ongoing trial (NCT02932150) and randomized (2:1) to TAF 25 mg or PBO daily for 24 weeks (primary endpoint: % with HBV DNA <20 IU/mL), after which all patients received open-label (OL) TAF for up to Week 240 (ie, TAF vs PBO→TAF). At Week 48, efficacy was assessed based on the proportion with HBV DNA <20 IU/mL, serological, and biochemical responses. Safety assessments included serious adverse events (SAEs) and all adverse events (AEs), bone mineral density (BMD; spine and whole body [minus head]), and resistance surveillance.

Results: 88 patients were randomized and treated (Cohort 1: TAF 47, PBO 23; Cohort 2 group 1: TAF 12, PBO 6). Overall mean (range) age and mean (SD) weight were 14 (7-17) years and 50.9 (12.9) kg, respectively; 58% were male, 66% Asian, 68% had HBV DNA ≥8 log₁₀ IU/mL and mean (SD) ALT 107 (118) U/L. 99% were HBeAg-positive, with genotype D (44%) being most common. Week 48 efficacy results were similar for TAF vs PBO→TAF by missing = failure analysis (Table). The proportion with HBV DNA <20 IU/mL in the TAF group increased from Week 24 to Week 48, 11/59 (19%) vs 22/59 (37%), respectively. A lower response rate with TAF treatment was observed in patients with genotype D; however, with longer-term treatment, an improved response was seen relative to Week 24 (17% vs 0%). Viral resistance was not detected through Week 48. Most AEs during the OL phase were mild-moderate; no patient had a Grade 3/4 AE or SAE related to study treatment, and none discontinued OL treatment due to an AE. At Week 48, the median change from baseline in eGFR mL/min/1.73m² for TAF vs PBO→TAF was similar (Table), and no patient had eGFR <90 mL/min/1.73m² through Week 48. BMD increased from baseline to Week 48, and mean % change was similar in both groups (Table).

Conclusion: Increasing rates of viral suppression were seen in pediatric CHB patients who completed 48 weeks of TAF treatment, while the safety profile remained favorable. Patients switching from PBO →TAF at Week 24 had similar safety and efficacy results relative to the TAF group during the DB phase.

Background: Primary sclerosing cholangitis (PSC) is a progressive choleostatic disease and up to 80% of patients also have ulcerative colitis (PSC-UC). This presents a clinical challenge owing to difficulty in diagnosis and increased risk for developing cancer. While several multifactorial processes including inflammation and microbial dysbiosis have been associated with PSC-UC pathogenesis, the precise molecular factors that regulate the phenotype of this disease subtype remain unknown.

Methods: Here, we applied methyl-capture sequencing and mRNA sequencing to colonic mucosal biopsies to identify transcriptomic and epigenetic alterations differentiating UC from PSC-UC. Samples were taken from 3 groups of treatment-naïve children at diagnosis who participated in the DOCHAS study (GEN-193/11) - UC (n=10), PSC-UC (n=10) and healthy controls(n=10).

Results: Differential gene expression between UC and PSC-UC identified disease-associated genes that were either up- or down-regulated in UC or PSC relative to controls. Furthermore, the expression of these genes was intricately regulated by master transcriptional regulators (pro-caspases, IL7RA) and transcription factors (AR, p53, JUND, CEBPA). Importantly, gene expression comparison between UC vs PSC-UC revealed 4 up-regulated genes in PSC-UC (RAB31, TENM3, KLHL17 and COL7A1). Notably, RAB31 and TENM3 are also significantly up-regulated in gastrointestinal (GI) cancers. We also identified 4 down-regulated genes in PSC-UC (H3C15, SLC37A2, SLC14A2 and IL20RA).
Differential methylation analysis between healthy control biopsies vs PSC-UC and UC demonstrated >1000 differentially methylated regions (DMRs, 5Kb), with the majority of these sites displaying hypermethylation. Interestingly, PSC-UC vs UC analysis identified 53 regions and 59 DMRs that are hyper- and hypomethylated respectively in PSC-UC, with a large proportion of these DMRs located in gene promoters and putative enhancer regions and notably impacted gene expression of differentially expressed genes identified from the mRNAseq analysis.

Conclusion: Taken together, our study for the first time identifies distinct gene expression and DNA methylation alterations that differentiate UC from PSC-UC at diagnosis in treatment-naïve paediatric patients, some of which are associated with GI cancers. Their potential utility as predictive biomarkers of PSC development in UC or dysplasia risk in PSC-UC warrants further validation through larger patient cohorts.

INTRODUCTION: The growth failure gap is a recognized shortcoming of the pediatric end-stage liver disease (PELD) score and argues that the PELD is a poor predictor of waitlist mortality¹. Sarcopenia was identified as a potential novel and independent predictor of waitlist mortality and outcomes in adults with end-stage liver disease^2-7. Ultrasound (US) has been used to diagnose sarcopenia in geriatric patients^8-9, but no standard exists for the diagnosis of sarcopenia in pediatric patients. The aims of this pilot study are (1) to develop an US method for characterizing muscle quality and quantity in pediatric patients and (2) to examine the correlation of these measures to body mass index (BMI) z-score with the goal of developing a tool for identifying sarcopenia in patients on the liver transplant waitlist.
METHODS: Patients aged 2 months to 18 years with chronic liver disease (CLD) and healthy controls were recruited from March to August 2022 at Children’s Hospital Los Angeles. CLD was defined as history of persistent transaminitis for ≥ 60 days as a result of suspected or known primary hepatic dysfunction. Patients with history of liver transplantation or conditions that may affect the measurement of leg muscles such as neurologic or mechanical abnormalities were excluded. Height, weight and BMI were recorded for all participants. Three US measures for each recti femoris muscle were evaluated in triplicate for each participant; cross-sectional area (CSA), muscle thickness (MT) and echogenic intensity (EI). ImageJ (NIH, Washington DC) was used to calculate the average pixel intensity within the measured CSA for determining EI. US measures were assessed for reliability using intraclass correlation coefficients (ICCs) estimated from two-way mixed effects model for absolute agreement and mean values compared by CLD vs healthy groups using linear regression. Pearson correlation coefficient was used to evaluate the relationship between BMI z-score and each muscle measure.
RESULTS: A total of 119 patients were recruited (n=51, 42.9% CLD; 54.6% male; median age 5 years (IQR 1.7-10.2)). Excellent reliability was demonstrated for CSA (0.994, CI 0.991-0.995), MT (0.971, CI 0.961-0.979) and EI (0.919, CI 0.887-0.942). BMI z-score was correlated with CSA and MT (r=0.30 and 0.34, respectively, all p = <0.001) but not EI (r=0.06, p=0.52). In multivariable linear regression, muscle measurements differed for CLD vs healthy participants for MT and EI after adjusting for sex and age but not for CSA.
CONCLUSION: Ultrasound assessment of rectus femoris muscle is feasible and correlates significantly to BMI z-score. MT and EI significantly differed in CLD vs healthy pediatric patients suggesting this may be a novel tool for assessment of sarcopenia. Correlating muscle measures with waitlist outcomes among persons with CLD is an important future area of research.

Overall patient demographics separated by chronic liver disease and healthy control groups.

Overall patient demographics separated by chronic liver disease and healthy control groups.

Multivariable Linear Regression Model: Chronic Liver Disease vs Healthy Participants

Multivariable Linear Regression Model: Chronic Liver Disease vs Healthy Participants

Background
Biliary atresia (BA) remains the number one indication for pediatric liver transplantation (LT) worldwide, while a less common indication for adult LT. The impact of recent donor allocation changes, the pervasive organ shortage and evolving LT practices on the BA LT population is unknown. Therefore, we performed an updated assessment (Jan 1, 2010, through Dec 31, 2021) of waitlisted and transplanted BA pediatric and adult patients in the US using the UNOS database.

Methods
Intra-group (BA patients <12 years vs. ≥12 years) and inter-group (BA vs. non-BA cholestatic liver disease stratified by age group) comparative analyses were performed. Waitlist outcomes were compared using competing-risk regression analysis, graft survival rates were compared using Kaplan-Meier time-to-event analysis, while Cox proportional hazards modeling provided adjusted estimates.

Results
There were 2,754 BA LT new waitlist additions and 2,206 BA LTs (1,937 <12 years, 269 ≥12 years) (Table 1). Among BA LT recipients, there were 441 (20.0%) living-donor liver transplants (LDLT) and 611 (27.7%) split deceased-donor LTs. The annual frequency of BA LT practice was stable (on average 182 (±16)) while BA LDLT practice increased from 28 in 2010 to 55 in 2021. In intra-group analysis (BA patients only), there were no statistical differences in waitlist mortality or graft survival between age groups. In inter-group (BA vs non-BA cholestatic disease) waitlist mortality analyses, there were no statistically significant differences. The 5-year graft survival among BA patients was 88.3% compared with 79.5% (adjusted p<0.01) in the non-BA patients among older patients, while there was no difference observed in the younger subgroup (Figure 3). LDLT was associated with better graft outcomes compared with split LT (HR:0.28, p<0.01, CI: 0.13-0.57) in BA LT. Finally, low BA LT transplant volume (<3.33 transplants per year) was associated with inferior graft outcomes compared with medium (HR:0.61, CI: 0.44-0.84) and high (HR:0.38, CI: 0.26-0.58) LT volume centers.

Conclusion
There has been a noticeable increase in recent LDLT practice in BA LT. Overall outcomes are excellent, particularly among older BA LT recipients who have superior outcomes to adult non-BA LT recipients. LDLT provided superior outcomes to split grafts in BA LT recipients justifying the increase in LDLT use. BA LT transplant center volume appears important in ensuring optimal graft outcomes and should be considered in future practice guidance.

Keywords
Biliary Atresia (BA); Liver transplantation (LT); Living donor liver transplantation (LDLT); Split liver transplantation (SLT)

Madhukar Patel

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