Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records. A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6-24) and 66 months (35-156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Long-term challenges and perspectives of pre-adolescent liver disease.

Chronic liver disease is a growing problem that has substantial effects on public health. Many paediatric liver conditions are precursors of adult chronic liver disease, cirrhosis, and hepatocellular carcinoma. Clinical management of Wilson's disease, autoimmune liver disease, and chronic biliary disorders, such as biliary atresia, which remains the most common paediatric chronic liver disease and indication for liver transplantation, is similar in children and adults. In the past 10 or so years, paediatric hepatology has expanded into neighbouring clinical areas, such as metabolic liver diseases and systemic conditions with liver involvement. We aim to describe some of these disorders, and outline their natural history and possible differences between management in adults and children to stimulate further debate on the optimal transition of care between paediatric and adult specialists.

Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis: Results of a European Survey.

OBJECTIVE: Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to determine the prevalence of 2 common disorders, 3ß-hydroxy-Δ-C27-steroid dehydrogenase (3ß-HSD) and Δ-3-oxosteroid-5ß-reductase (Δ-3-oxoR) deficiencies and to describe current diagnostic and treatment strategies among different European paediatric hepatology centres. METHODS: A total of 52 clinical paediatric centres were approached and 39 centres in 21 countries agreed to participate in the Web-based survey. The survey comprised questions regarding general information, number of cases, diagnostic, and therapeutic management. RESULTS: Seventeen centres located in 11 countries reported patients with inborn errors in primary BA synthesis, 22 centres never had cases diagnosed. In total, we could identify 63 patients; 55 with 3ß-HSD and 8 with Δ-3-oxoR deficiency in 21 countries. The minimum estimated combined prevalence of these diseases was 1.13 cases per 10 million (0.99 and 0.14 for 3ß-HSD and Δ-3-oxoR deficiencies, respectively). The surveyed colleagues indicated their main challenges to be the rarity of diseases and the lack of convenient laboratory facilities nearby. CONCLUSION: We have identified the largest cohort of patients with 3ß-HSD or Δ-3-oxoR deficiency described so far. These diseases are likely underdiagnosed mainly due to unawareness of their existence and the lack of laboratory facilities.

Combined liver and kidney transplantation in children: analysis of renal graft outcome.

BACKGROUND: Combined liver-kidney transplantation (CLKT) is the accepted treatment for patients with both liver failure and progressive renal insufficiency. Long-term outcome data for CLKT in children is sparse and controversy exists as to whether simultaneous CLKT with organs from the same donor confers immunologic and survival benefit to the kidney allograft. We report the long-term renal graft outcomes of 40 patients who had simultaneous CLKT. METHODS: A retrospective analysis of kidney graft survival (time from transplantation to death, return to dialysis or last follow-up event) in all pediatric patients (age < 18 years old) who underwent CLKT from March 1994 to January 2015. A 1:1 ratio of controls (deceased donor kidney recipients from our centre matched for age (±2 years) at transplant, time from transplant (±1 year) and treated with the same immunosuppressive regime) to cases was used to compare outcome. Estimated glomerular filtration rate (e-GFR) was calculated using the Schwartz formula. Survival curves were determined using Kaplan-Meier analysis. RESULTS: The kidney graft survival for CLKT patients was 87.4, 82, and 82 % at 1, 5, and 10 years; kidney graft survival for isolated KT patients were 97.2, 93, and 93 % at 1, 5, and 10 years (p = NS). There were two acute rejection episodes (5 %) in the CLKT group compared to five (12.5 %) episodes in the isolated KT group. There was no statistically significant difference in e-GFR at 1, 5, and 10 years in the two groups but there was a statistically significantly greater decline in e-GFR in the KT group compared to CLKT group from 5-10 years following transplant. CONCLUSIONS: There are fewer acute rejection episodes following CLKT compared to isolated KT, and we noted a higher mean e-GFR at 1, 5, and 10 years with significantly lesser decline in e-GFR from 5 to 10 years in the CLKT group.

Paediatric non-alcoholic fatty liver disease: a practical overview for non-specialists.

Non-alcoholic fatty liver disease (NAFLD) is the most common paediatric liver disease with a prevalence of almost 10%; therefore, the majority of affected patients are under the care of general practitioners and non-specialists. The condition is caused by central obesity with insulin resistance with additional factors influencing inflammatory activity (steatohepatitis). Ongoing inflammation leads to fibrosis and end-stage liver disease, though this will usually occur after children have transitioned into adult care. However, their main morbidity and mortality is from type 2 diabetes and complications of atherosclerosis. The minority of children undergo biopsy but currently there is no other method to accurately assess the stage of disease. Management is focused at weight loss through a combination of diet and exercise. Here, we present a current review of paediatric NAFLD aimed at non-specialists, with practice points for implementation.

Neonatal jaundice.

Neonatal jaundice lasting greater than 2 weeks should be investigated. Pale stools and dark or yellow urine are evidence of liver disease, which should be urgently investigated. The neonatal hepatitis syndrome has many causes, and a structured approach to investigation is mandatory. It should be possible to confirm or exclude biliary atresia within one week, so that definitive surgery is not delayed unnecessarily. Babies with the neonatal hepatitis syndrome should have vigorous fat-soluble vitamin supplementation, including parenteral vitamin K if coagulation is abnormal. The prognosis for infants with idiopathic neonatal hepatitis and multifactorial cholestasis is excellent.

Metabolic liver disease.

Diagnosis of metabolic liver disease requires a high level of diagnostic suspicion. Diet is usually the primary treatment for metabolic liver disease. Where indicated, liver transplantation provides lifelong functional correction of liver-based metabolic defects. Liver cell therapy warrants further study for the future treatment of metabolic liver disease. All families should receive genetic advice and pre-emptive management of future affected siblings.