Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and ...HCV-related liver disease has advanced considerably thanks to development and improvements in therapy. Direct-acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype-specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age-specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource-limited settings.
Growth failure persists after pediatric liver transplantation and impairs pediatric development and quality of life. Steroid dose minimization attempts to prevent growth impairment, yet long‐term ...assessment in pediatric liver recipients is lacking. We identified risk factors for impaired linear growth after pediatric liver transplantation, with a special focus on low‐dose steroid therapy. This is a single‐center retrospective analysis of height development in pediatric liver recipients up to 5 years after transplantation. Risk factors for impaired linear growth (height Z‐scores≤‐2) at transplantation, after two (n = 347) and five years (n = 210) were identified by univariate and multivariate logistic regression. At transplantation, growth retardation was found in 52.2%, predominantly younger children. Height Z‐scores improved from −2.23 to −1.40 (SE 0.11; 95%CI 0.74–1.16; p < .001) two years and −1.19 (SE 0.07;0.08–0.34; p = .017) five years post‐transplant. Multivariate analysis showed previous growth impairment (OR=1.484; 95%‐CI=1.107–1.988; p = .004), graft loss (49.006;2.232–1076; p = .006), and prolonged cold ischemic time (1.034;1.007–1.061; p = .011) as main long‐term risk factors; steroid use was a significant predictor of 2‐year but not 5‐year growth impairment. In univariate analysis, impaired growth after 2 and 5 years was associated with continuous low‐dose (2.5 mg/m2BSA) steroid therapy (OR=3.323;1.578–6.996; p < .001/OR=8.352;1.089–64.07; p = .006)and graft loss (OR=2.513;1.395–4.525; p = .003/OR=3.378;1.815–7.576; p < .001). Furthermore, indication and era of transplantation affected growth. Our results show significant catch‐up growth after pediatric liver transplantation, yet growth failure strongly affects particularly young liver recipients. The main influenceable long‐term risk factor is pre‐existing growth failure, emphasizing the importance of early aggressive nutritional therapy. Moreover, low‐dose steroid therapy might impair growth and should therefore be critically questioned in long‐term immunosuppression.
Cardiovascular (CV) events account for 8%‐13% of deaths after liver transplantation (LT) in adulthood. Although CV risk factors (RFs) are present, little is known about the prevalence of subclinical ...CV target organ damage (TOD) in children after LT. The aim of this prospective observational study was to assess the prevalence of subclinical CV TOD in children after LT and to identify RFs contributing to CV damage as potential targets for clinical intervention. In this study, 104 children after LT (54% female, 46% male; aged 11.5 ± 3.8 years) underwent cross‐sectional assessment of subclinical TOD by carotid‐femoral pulse wave velocity (PWV), carotid intima‐media thickness (IMT), and left ventricular mass index (LVMI). Results were correlated with the presence of CV RFs (obesity, hypertension, dyslipidemia, renal impairment, anemia, and microinflammation). Of the patients, 22% were exposed to 2 CV RFs, and 36% displayed 3 or more CV RFs. Pathological results for PWV, IMT, and LVMI were found in 21.9%, 57.0%, and 11.1% of patients, respectively. In the multivariate analysis, diastolic blood pressure (P = 0.01) and estimated glomerular filtration rate (eGFR; P = 0.03) were independently associated with PWV, eGFR (P = 0.005), and age at LT (P = 0.048) with IMT and body mass index with LVMI (P = 0.004). In conclusion, patients after pediatric LT carry a substantial burden of subclinical CV TOD. Identification of modifiable CV RFs opens opportunities for targeted intervention in order to reduce CV morbidity and mortality in the future.
Objective
The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic ...and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH.
Design
pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers (
n
= 285).
Results
IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31–73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6–20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21–34% higher accuracy than conventional autoantibodies, was positive in 43–75% of children with AIH and normal IgG and independent from treatment response.
Conclusion
Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity.
Graphical Abstract
The long-term psychosocial outcome of young adults after paediatric liver transplantation (LT) was investigated with the focus on day-to-day living. We aimed to capture patients' subjective ...perceptions of well-being and autonomy based on key physical outcome parameters.
All patients following paediatric LT at Hannover Medical School born before 2002 with a post-transplant follow-up of at least four years were included in this study. This retrospective observational study compared psychosocial parameters obtained from a self-designed 77-item questionnaire with standard clinical outcome variables.
Eighty-two patients (male: 57%) aged 13-41 years were included in the survey within a three-month period (response rate: 41%). With an adherence rate of 33%, all but two patients were immunosuppressed. In total, 53 patients had transitioned to adult care largely without problems. Eighty-three percent (n = 68) evaluated their current health status as "(very) good". Sixty-seven patients (82%) did not experience health-related anxiety in daily life.
Our results demonstrate psychological stability and high self-esteem of young patients, as well as good integration into society and a high degree of normality during daily life after LT. Adherence rates are lower than anticipated and do not correlate with patients' understanding of their medical condition.
An association of human leukocyte antigen (HLA) class II alleles with autoimmune conditions is increasingly being used for diagnostic purposes. The aim of our study was to examine whether HLA class ...II alleles in pediatric-onset autoimmune liver disease (pAILD) may serve as diagnostic markers and if they correlate with clinical outcome parameters. HLA-DRB1 alleles of 76 children with pAILD (autoimmune hepatitis AIH, autoimmune sclerosing cholangitis AISC, primary sclerosing cholangitis PSC) and of 50 healthy blood donors as control group were analyzed retrospectively. Diagnosis of these patients was confirmed by the autoimmune hepatitis score including liver histology, which has been re-evaluated by a blinded liver pathologist, and by bile duct imaging, as appropriate. Our results showed significant association of HLA-DRB1*03 with AIH1 and AISC with 82 % specificity for AIH. For pAILD (excluding AIH2), HLA-DRB1*03 homozygosity had specificity of 98 %, whereas sensitivity is low. Remission in HLA-DRB1*03-positive patients appears to be less likely. HLA-DRB1*13 is significantly associated with PSC and also with AIH1.
Conclusion
: HLA-DRB1 alleles provide supportive information for diagnostic workup in patients with liver disease, but they were not suitable for differentiation within pAILD. Their prognostic value could be helpful but needs to be evaluated further.
What is Known:
• HLA-DRB1*03 is NOT associated with pediatric AIH in a previous national study.
• In other studies, HLA-DRB1*03 is associated with AIH1.
• HLA-DRB1*13 is associated with PSC.
• HLA-DRB1*04 is described as protective for AILD.
What is New:
• HLA-DRB1 four-digit typing for all alleles and for all subgroups of pAILD combined with re-assessment of liver histology
• HLA-DRB1*03:01 is associated with pediatric AIH1 and AISC.
• HLA-DRB1*03:01 appears to be a prognostic marker.
• HLA-DRB1*13:01 is associated with pediatric AIH1 in mixed ethnicity cohort.
• HLA-DRB1*04 does not show any protective effect for pAILD.
Genetic variants in the adenosine triphosphate‐binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such ...as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid‐associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4‐associated liver disease into younger age (<18 years) or adult age (≥18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid‐associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504‐514)
IntroductionHepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will ...investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications.Methods and analysisThe HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC.Ethics and disseminationAll participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals.Trial registration numberThe HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.
Bile salt export pump (ABCB11) deficiency Progressive familial intrahepatic cholestasis (PFIC2) is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. ...Surgical biliary diversion or pharmacological ileal bile acid transporter inhibitor (IBATi) approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome.
This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed.
Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis.
Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi.
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