UK guideline on the transition and management of childhood liver diseases in adulthood.

INTRODUCTION: Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS: To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS: A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS: These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.

Self-management skills in a UK sample of young people with chronic liver disease.

BACKGROUND: We aimed to assess self-management skills and adherence behaviors in young people post-liver transplant and compare these with those of young people with autoimmune liver disease and other forms of chronic liver disease. METHOD: As part of our specialist multidisciplinary clinic, n = 156 young people (aged 16-25 years) completed the Liver Self-Management Questionnaire (an adaptation of the Developmentally Based Skills Checklist for adolescents post-liver transplant and modified for us across liver disease type and within the United Kingdom). Those taking medication (n = 128) also completed a service-designed questionnaire regarding adherence. The statistical significance of group differences was assessed with non-parametric analyses. RESULTS: Young people post-liver transplant were less likely to report managing their condition independently than those with autoimmune liver disease or those with other forms of chronic liver disease. They also reported higher adherence (93%) compared to those with autoimmune liver disease (77%) and those with other forms of chronic liver disease (85%). However, the vast majority of self-management and adherence behaviors were comparable between young people post-transplant and those with autoimmune liver disease/other forms of chronic liver disease. CONCLUSION: Our data are in line with existing data from US samples and also extend these findings to include those with other forms of chronic liver disease. These data highlight the importance of individualized care for young adults, regardless of condition type or healthcare setting, and of clinicians managing their expectations regarding what is considered appropriate condition management in early adulthood.

Biliary Atresia in Adolescence and Adult Life: Medical, Surgical and Psychological Aspects.

Prior to 1955, when Morio Kasai first performed the hepatic portoenterostomy procedure which now bears his name, Biliary atresia (BA) was a uniformly fatal disease. Both the Kasai procedure and liver transplantation have markedly improved the outlook for infants with this condition. Although long-term survival with native liver occurs in the minority, survival rates post liver transplantation are high. Most young people born with BA will now survive into adulthood but their ongoing requirements for health care will necessitate their transition from a family-centred paediatric service to a patient-centred adult service. Despite a rapid growth in transition services over recent years and progress in transitional care, transition from paediatric to adult services is still a risk for poor clinical and psychosocial outcomes and increased health care costs. Adult hepatologists should be aware of the clinical management and complications of biliary atresia and the long-term consequences of liver transplantation in childhood. Survivors of childhood illness require a different approach to that for young adults presenting after 18 years of age with careful consideration of their emotional, social, and sexual health. They need to understand the risks of non-adherence, both for clinic appointments and medication, as well as the implications for graft loss. Developing adequate transitional care for these young people is based on effective collaboration at the paediatric-adult interface and is a major challenge for paediatric and adult providers alike in the 21st century. This entails education for patients and adult physicians in order to familiarise them with the long-term complications, in particular for those surviving with their native liver and the timing of consideration of liver transplantation if required. This article focusses on the outcome for children with biliary atresia who survive into adolescence and adult life with considerations on their current management and prognosis.

Hepatic Dry Copper Weight in Pediatric Autoimmune Liver Disease.

OBJECTIVES: Elevated hepatic dry copper weight is recognized in adults with autoimmune liver disease (AILD) and chronic cholestasis. We aim to review hepatic dry copper weight in pediatric AILD. METHODS: Retrospective review of pediatric AILD managed at our institution from 1999 to 2018, and 104 patients with hepatic dry copper weight assessment were included. RESULTS: Median age at presentation was 13.4 years (interquartile range, IQR, 11.7-14.9), 60% female, 54% autoimmune hepatitis, 42% autoimmune sclerosing cholangitis, and 4% primary sclerosing cholangitis. Histological features of advanced liver fibrosis in 68%. Median hepatic dry copper weight was 51.1 µg/g dry weight (IQR, 28.0-103.8). Elevated hepatic dry copper weight (>50 µg/g dry weight) was present in 51%, and was not associated with AILD subtype ( P = 0.83), age at presentation ( P = 0.68), or advanced fibrosis ( P = 0.53). Liver transplantation (LT) was performed in 10%, who had higher hepatic dry copper weight (148.5 µg/g dry weight [IQR, 39.5-257.3] vs 47.5 [IQR, 27.8-91.5], P = 0.04); however this was not associated with LT on multivariate analysis (hazard ratio 1.002, 95% CI 0.999-1.005, P = 0.23). In 8 (7.7%) patients ATP7B was sequenced and potentially disease causing variants were identified in 2 patients, both who required LT. CONCLUSIONS: Elevations in hepatic dry copper weight are common in pediatric AILD. Unlike in adults, it is not associated with AILD subtypes with cholestasis. Higher dry copper weight was detected in patients who required LT. While further work is needed to identify the significance of copper deposition in pediatric AILD, we recommend close monitoring of patients with elevated levels for progressive liver disease.

Liver disease in adolescents.

In this article, we discuss common liver diseases in the adolescent population. We describe the initial evaluation of an adolescent presenting with new-onset liver enzyme abnormalities, based on the clinical history and physical examination. The management approach to the adolescent with liver disease is exemplified, including monitoring for adherence, risk-taking behaviours and focusing on psychosocial aspects of their care. Finally, we highlight the challenges of caring for the adolescent patient and the importance of addressing not only the liver disease but, more importantly, the holistic approach towards their management.

Acute Hepatitis of Unknown Etiology Among Young Children: Research Agenda by the ESPGHAN Hepatology Committee.

In April 2022, an increased incidence of acute hepatitis cases of unknown etiology among previously healthy children across the United Kingdom was described. Since, more than 270 cases from the United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than 6 years of age. The clinical presentation was nonspecific with diarrhea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea, and malaise. Approximately 5% have required liver transplantation. An infectious etiology has been considered likely given the epidemiological and clinical features of the reported cases. Between 50 and 60% of the children tested were diagnosed with adenovirus infection although a clear etiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed a paper on the current outbreak of acute hepatitis of unknown etiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the article are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised.

Long-Term Growth in Children and Young People with Autoimmune Liver Disease Treated with Daily Steroids.

OBJECTIVES: We aimed to evaluate long-term growth in children and young people with autoimmune liver disease (AILD) treated with daily steroids. METHODS: This is a retrospective observational cohort study of patients diagnosed between 1992 and 2004 before the age of 16 years. Growth measurements (height, weight and body mass index (BMI)) converted to z-scores were recorded, at diagnosis, 1 and 5 years after commencing treatment and at age 18 years and analyzed together with demographics, disease and treatment related characteristics. RESULTS: Seventy-four patients (35 female) were started on treatment at median age of 12.85 (Inter quartile range (IQR) 9.44, 14.14) years for median duration of 12.07 (IQR 8.68, 13.97) years. At all time-points, the mean z-scores for weight, height and BMI were within the normal range, indicating normal nutritional status. There was no difference in change in z-score for weight, height and BMI from diagnosis until age 18 years when comparing gender (male vs female), ethnicity (Caucasian vs non-Caucasian), diagnosis (AIH vs ASC) and presence of IBD (n = 23). Change in z-score was lower for height and weight for the < 12 years group compared to the ≥12 years age group ( P < 0.05 and P < 0.05, respectively). In addition, change in height z-score correlated positively with age at start of steroid treatment (r = 0.321, P < 0.05) and negatively with duration of steroid treatment (r = -0.321, P < 0.05). CONCLUSIONS: Growth of patients with AILD on a daily maintenance dose of steroids remains stable and within normal range during long-term follow up. Small, daily doses are effective in maintaining disease control and minimize the need for high-dose steroid pulses during relapses.

Clinical course of inflammatory bowel disease and impact on liver disease outcomes in patients with autoimmune sclerosing cholangitis.

BACKGROUND & AIMS: Autoimmune sclerosing cholangitis (ASC) is a childhood sclerosing cholangitis frequently associated with inflammatory bowel disease (IBD). We describe the IBD phenotype in ASC patients and associated liver disease outcomes. METHODS: Single center retrospective observational review of ASC patients, with a control population of pediatric IBD. Demographic and clinical parameters were obtained. Clinical endpoints were escalation of IBD therapy (biologic or colectomy) and transplant-free survival. RESULTS: In 93 ASC patients (53.8% female) and median follow up of 172 months: 70% had IBD, 25.8% underwent liver transplant. Median age at liver transplant was 21.7 years, at 131 months from ASC diagnosis. There was no association between presence of IBD and transplant-free survival, whilst those requiring second-line immunomodulators for ASC had poorer long-term liver prognosis. During follow-up 22 (33.8%) ASC-IBD required biologic or colectomy. On multivariate analysis ASC was associated with a lower risk of escalation of IBD therapy (HR 0.14, 95% CI 0.05-0.42; P=.001), including biologic therapy (HR 0.21, 95% CI 0.08-0.55, P=.002), but not colectomy on univariate analysis (HR 1.54, 95% CI 0.43-5.44, P=.51). CONCLUSIONS: IBD is common in ASC and during longterm follow up a third of ASC-IBD required escalation of IBD therapy; however ASC-IBD was lower risk compared to IBD alone. IBD does not appear to impact on transplant-free survival in patients with ASC, however second-line immunomodulators for ASC are associated with poorer IBD and liver outcomes.

Proceedings of ESPGHAN Monothematic Conference 2020: "Acute Liver Failure in Children": Diagnosis and Initial Management.

OBJECTIVES: The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. Herewith we have concentrated on detailing the recent advances in acute liver failure in infants and children. METHODS: The 2020 ESPGHAN monothematic three-day conference on pediatric hepatology disease, entitled "acute liver failure" (ALF), was organized in Athens, Greece. ALF is a devastating disease with high mortality and most cases remain undiagnosed. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with the latest research and developments in early recognition, curative therapies and intensive care management, imaging techniques and treatment paradigms in these age groups. RESULTS: In the first session, the definition, epidemiology, various causes of ALF, in neonates and older children and recurrent ALF (RALF) were discussed. The second session was dedicated to new aspects of ALF management including hepatic encephalopathy (HE), coagulopathy, intensive care interventions, acute on chronic liver failure, and the role of imaging in treatment and prognosis. Oral presentations by experts in various fields are summarized highlighting key learning points. CONCLUSIONS: The current report summarizes the major learning points from this meeting. It also identifies areas where there is gap of knowledge, thereby identifying the research agenda for the near future.

Proceedings of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition Monothematic Conference, 2020: "Acute Liver Failure in Children": Treatment and Directions for Future Research.

OBJECTIVES: The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. METHODS: The 2020 single topic ESPGHAN monothematic 3-day conference on pediatric liver disease, was organized in Athens, Greece and was entitled " Acute Liver Failure" (ALF). ALF is a devastating disease with high mortality and in a considerable fraction of patients, the cause remains unresolved. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with developments in medical therapy and indications for liver transplantation (LT) and to identify areas for future research in clinical and neurocognitive outcomes in ALF. RESULTS: We recently reported the epidemiology, diagnosis, and initial intensive care management issues in separate manuscript. Herewith we report on the medical treatment, clinical lessons arising from pediatric studies, nutritional and renal replacement therapy (RRT), indications and contraindications for LT, neurocognitive outcomes, new techniques used as bridging to LT, and areas for future research. Oral presentations by experts in various fields are summarized highlighting key learning points. CONCLUSIONS: The current report summarizes the current insights in medical treatment of pediatric ALF and the directions for future research.

Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.

Mutations in the transaldolase 1 (TALDO1) gene have been described in a limited number of cases. Several organs can be affected and clinical manifestations are variable, but often include liver dysfunction and/or hepatosplenomegaly. We report 4 patients presenting with liver disease: 2 with early-onset hepatocellular carcinoma (HCC). Patients with cholestasis and mutations in TALDO1 were identified by next-generation sequencing. Clinical, laboratory, and histological data were collected. Four (1 male) patients were identified with variants predicted to be damaging in TALDO1. Three patients were homozygous (two protein truncating/one missense mutations), 1 one was compound heterozygous (two missense mutations). Median age at presentation was 4 months (range, 2-210 days) with jaundice (3), hepatosplenomegaly (3), and pancytopaenia (1). The diagnosis was corroborated by detection of minimal transaldolase enzyme activity in skin fibroblasts in two cases and raised urine polyols in the third. Three patients underwent liver transplantation (LT), 2 of whom had confirmed HCC on explanted liver. One patient suddenly died shortly after LT. The nontransplanted case has a chronic liver disease with multiple dysplastic liver nodules, but normal liver biochemistry and alpha-fetoprotein. Median follow-up was 4 years (range, 1-21). Conclusion: Transaldolase deficiency can include early-onset normal gamma-glutamyltransferase liver disease with multisystem involvement and variable progression. Patients with this disease are at risk of early-onset HCC and may require early LT.

Social and Educational Outcomes in Patients With Biliary Atresia: A Systematic Review.

OBJECTIVES: To systematically review the social outcomes of patients with biliary atresia (BA), including educational, employment and family outcomes. METHODS: We conducted a systematic review of Medline, EMBASE, Global Health, Maternity and Infant Care Database, supplemented by reference searching. National Heart, Lung and Blood Institute scoring was conducted for quality assessment. The PROSPERO registration ID was CRD42020178846. RESULTS: Fifty-one studies were included (41 cohort, 10 cross-sectional), including 4631 participants across 16 countries. Cohorts were BA post-liver transplant (LT) (18 studies), native liver survivors (NLS) (16 studies), mixed (13 studies) and four other cohorts. Outcomes covered; education (n = 35), employment (n = 16), family outcomes (n = 22), and social functioning (n = 22). BA patients had lower school functioning scores than controls, with no difference between NLS versus post-LT. Between 2% and 48% of children required additional educational support. Between 60% and 100% of adult patients with BA were employed. Pregnancies were described in 17 studies, with small samples, and some noted complications. Social functioning scores were similar to healthy controls in 8 of 11 comparisons. CONCLUSIONS: Despite BA being the primary indication for liver transplantation in childhood, social outcomes for children and adolescents are predominantly reported in non-controlled, single-centre survey-based studies. School functioning is lower compared to peer groups, with no evidence of a difference for those having a liver transplant. We recommend routine psychosocial assessment of these patients during follow-up, alongside multi-centre collaborations, to maximise the quality of evidence for future patients.

Epstein-Barr virus status and immunosuppression use in paediatric autoimmune liver disease.

BACKGROUND: Since azathioprine is associated with lymphoproliferative disorders in Epstein-Barr virus (EBV)-naïve patients with inflammatory bowel disease, guidelines advise avoidance. No recommendations exist for autoimmune liver disease (AILD). AIMS: To evaluate EBV status and EBV-related complications in paediatric AILD. METHODS: Single-centre, retrospective, observational study of paediatric AILD. RESULTS: In 245 paediatric patients with AILD, azathioprine was used in 168 (68.6%) and mycophenolate mofetil in 69 (28.2%). EBV status was assessed in 18 (10.7%) prior to azathioprine and 6 (8.7%) MMF. Acute EBV infection was diagnosed in five patients while on immunosuppression, resulting in one transient hepatitis and one persistent hepatitis. There were no cases of lymphoproliferative disorder in native livers. Liver transplantation (LT) was performed in 39 (15.9%) patients, with 8 EBV IgG-negative at LT. Post-LT EBV viraemia developed in 29 (74.4%), first detected at median 26 days (IQR, 13-86). EBV IgG-negative recipients had higher peak viraemia (266 984 IU/mL [IQR, 41108-2429050] v 5333 [IQR, 2036-38770], P = .004) and longer time to peak viraemia (375 days [IQR, 251-884] v 70 [IQR, 21-604], P = .04). Early EBV-associated post-transplant lymphoproliferative disorder (PTLD) was diagnosed in two patients, both EBV-IgG negative with prior azathioprine. CONCLUSIONS: Real-world data demonstrate that EBV serostatus is not routinely checked before immunosuppression for paediatric AILD. Lymphoproliferative disorder was not diagnosed in those with native livers; however, EBV IgG-negative LT recipients receiving EBV IgG-positive donor organs are at risk of early PTLD. Large multicentre studies with longer follow-up are required to further evaluate the risk.

Liver Transplantation for Biliary Atresia in Adulthood: Single-Centre Surgical Experience.

BACKGROUND: Biliary atresia (BA) is the most common indicator for liver transplant (LT) in children, however, approximately 22% will reach adulthood with their native liver, and of these, half will require transplantation later in life. The aim of this study was to analyse the surgical challenges and outcomes of patients with BA undergoing LT in adulthood. METHODS: Patients with BA requiring LT at the age of 16 or older in our unit between 1989 and 2020 were included. Pretransplant, perioperative variables and outcomes were analysed. Pretransplant imaging was reviewed to assess liver appearance, spontaneous visceral portosystemic shunting (SPSS), splenomegaly, splenic artery (SA) size, and aneurysms. RESULTS: Thirty-four patients who underwent LT for BA fulfilled the inclusion criteria, at a median age of 24 years. The main indicators for LT were synthetic failure and recurrent cholangitis. In total, 57.6% had significant enlargement of the SA, 21% had multiple SA aneurysm, and SPSS was present in 72.7% of the patients. Graft and patient survival at 1, 5, and 10 years was 97.1%, 91.2%, 91.2% and 100%, 94%, 94%, respectively Conclusions: Good outcomes after LT for BA in young patients can be achieved with careful donor selection and surgery to minimise the risk of complications. Identification of anatomical variants and shunting are helpful in guiding attitude at the time of transplant.

Inferior outcomes in young adults undergoing liver transplantation - a UK and Ireland cohort study.

Graft loss incidence is reported to be inversely related to recipient age. We used a national cohort of liver transplant (LT) recipients from the United Kingdom and Ireland to compare the age-dependent risk of graft failure in different post-transplantation time-periods ('epochs'). A cohort of first-time LT recipients (1995-2016) were identified (11 006). Cox regression was used to estimate hazard ratios (HR) comparing graft loss between age-groups (18-29, 30-39, 40-49, 50-59 and 60-76 years) and graft loss in different post-transplant epochs: 0-90 days, 90 days-2 years and 2-10 years. The risk of graft failure was highest in those transplanted between age 18 and 29 (adjusted HR 1.25, 95% CI: 1.00-1.57, P = 0.04) and in those aged 30-39 (adjusted HR 1.31, 95% CI: 1.11-1.55, P = 0.02). Graft failure in those under the age of 40 was similar in the first 90 days but worse 2-10 years' post-LT (18-29 years HR 1.36, 95% CI: 0.96-1.93, P < 0.001). Graft failure because of chronic rejection (CR) was more common in recipients aged 18-29 (P < 0.001). Adults transplanted between age 18 and 39 are at risk of late graft loss. CR is a concern for young adults (18-29 years). Our data highlights the need for specialist young adult services within adult healthcare.