Incidence, management and outcomes in hepatic artery complications after paediatric liver transplantation: protocol of the retrospective, international, multicentre HEPATIC Registry.

INTRODUCTION: Hepatic 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 ANALYSIS: The 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 DISSEMINATION: All 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 NUMBER: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.

Diminished measles immunity after paediatric liver transplantation-A retrospective, single-centre, cross-sectional analysis.

Liver transplantation in childhood has an excellent long-term outcome, but is associated with a long-term risk of infection. Measles is a vaccine-preventable infection, with case series describing severe courses with graft rejection, mechanical ventilation and even death in liver transplant recipients. Since about 30% of liver transplanted children receive liver transplants in their first year of life, not all have reached the recommended age for live vaccinations. On the contrary, live vaccines are contraindicated after transplantation. In addition, vaccination response is poorer in individuals with liver disease compared to healthy children. This retrospective, single-centre, cross-sectional study examines measles immunity in paediatric liver transplant recipients before and after transplantation. Vaccination records of 239 patients, followed up at Hannover Medical School between January 2021 and December 2022 were analysed. Twenty eight children were excluded due to stem cell transplantation, regular immunoglobulin substitution or measles vaccination after transplantation. More than 55% of all 211 children analysed and 75% of all those vaccinated at least once are measles seropositive after transplantation-48% after one and 84% after two vaccinations-which is less than in healthy individuals. Interestingly, 26% of unvaccinated children also showed measles antibodies and about 5-15% of vaccinated patients who were seronegative at the time of transplantation were seropositive afterwards, both possibly through infection. In multivariable Cox proportional hazards regression, the number of vaccinations (HR 4.30 [95% CI 2.09-8.83], p<0.001), seropositivity before transplantation (HR 2.38 [95% CI 1.07-5.30], p = 0.034) and higher age at time of first vaccination (HR 11.5 [95% CI 6.92-19.1], p<0.001) are independently associated with measles immunity after transplantation. In contrast, older age at testing is inversely associated (HR 0.09 [95% CI 0.06-0.15], p<0.001), indicating a loss of immunity. Vaccination in the first year of life does not pose a risk of non-immunity. The underlying liver disease influences the level of measles titres of twice-vaccinated patients; those with acute liver failure being the lowest compared to children with metabolic disease. In summary, vaccine response is poorer in children with liver disease. Liver transplant candidates should be vaccinated before transplantation even if this is earlier in the first year of life. Checking measles IgG and re-vaccinating seronegative patients may help to achieve immunity after transplantation.

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Mild Crigler-Najjar Syndrome with Progressive Liver Disease-A Multicenter Retrospective Cohort Study.

Crigler-Najjar Syndrome (CNS) with residual activity of UDP-glucuronosyltransferase 1A1 (UGT1A1) and no need for daily phototherapy is called mild Crigler-Najjar Syndrome. Most of these patients need medical treatment for enzyme induction (phenobarbital) to lower blood levels of unconjugated bilirubin (UCB). Apart from this, no long-term problems have been described so far. The phenotype of patients with the homozygous pathogenic variant c.115C>G p.(His39Asp) in UGT1A1 is described as variable. Clinical observations of our patients led to the assumption that patients with variant c.115C>G have a mild CNS phenotype while having a high risk of developing progressive liver disease. For mild CNS disease, progressive liver disease has not been described so far. Therefore, we conducted a retrospective multicenter analysis of 14 patients with this particular variant, aiming for better characterization of this variant. We could confirm that patients with variant c.115C>G have a high risk of progressive liver disease (seven of fourteen), which increases with age despite having a very mild CNS phenotype. Earlier predictors and causes for an unfavorable disease course are not detectable, but close follow-up could identify patients with progressive liver disease at the beginning. In conclusion, these patients need close and specialized follow-up. Our study questions whether fibrosis in the CNS is really driven by high amounts of UCB or phototherapy.

Gene Therapy in Patients with the Crigler-Najjar Syndrome.

BACKGROUND: Patients with the Crigler-Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation. METHODS: We report the results of the dose-escalation portion of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 µmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy. RESULTS: No serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 µmol per liter. The patients who received the higher dose had bilirubin levels below 300 µmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 µmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 µmol per liter). CONCLUSIONS: No serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).

Patient-reported quality of care in primary sclerosing cholangitis.

BACKGROUND: Management and follow-up strategies for primary sclerosing cholangitis (PSC) vary. The aim of the present study was to assess patient-reported quality of care to identify the most important areas for improvement. METHODS: Data were collected via an online survey hosted on the EU Survey platform in 11 languages between October 2021 and January 2022. Questions were asked about the disease, symptoms, treatment, investigations and quality of care. RESULTS: In total, 798 nontransplanted people with PSC from 33 countries responded. Eighty-six per cent of respondents reported having had at least one symptom. Twenty-four per cent had never undergone an elastography, and 8% had not had a colonoscopy. Nearly half (49%) had never undergone a bone density scan. Ursodeoxycholic acid (UDCA) was used in 90-93% in France, Netherlands and Germany, and 49-50% in the United Kingdom and Sweden. Itch was common (60%), and 50% of those had received any medication. Antihistamines were taken by 27%, cholestyramine by 21%, rifampicin by 13% and bezafibrate by 6.5%. Forty-one per cent had been offered participation in a clinical trial or research. The majority (91%) reported that they were confident with their care although half of the individuals reported the need for more information on disease prognosis and diet. CONCLUSION: Symptom burden in PSC is high, and the most important areas of improvement are disease monitoring with more widespread use of elastography, bone density scan and appropriate treatment for itch. Personalised prognostic information should be offered to all individuals with PSC and include information on how they can improve their health.

The Impact of Thrombophilic Factors on Disease Progression in Children with Biliary Atresia-A Single-Centre Cohort Study.

Epidemiological evidence suggests that thrombophilic factors, including male sex, non-O blood type, MTHFRnt677TT mutation, factor V Leiden G1691A mutation, and prothrombin G20210A polymorphism, may contribute to the progression of fibrosis and occurrence of portal vein thrombosis in liver disease. We retrospectively investigated the effect of potentially thrombophilic factors on native liver survival as a patient-relevant endpoint of disease progression in a cohort of 142 children being followed up for biliary atresia at Hannover Medical School from April 2017 to October 2019. No significant association could be determined. There was no evidence for relevant differences in native liver survival for the Factor V Leiden G1691A mutation (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.38-1.98, p = 0.73), prothrombin G20210A polymorphism (HR = 0.96, 95%CI 0.24-3.65, p = 0.96), non-O blood type (HR = 0.79, 95%CI 0.51-1.21, p = 0.28) or MTHFRnt677TT mutation (HR = 1.24, 95%CI 0.60-2.56, p = 0.56). A certain, albeit not strong, evidence of reduced native liver survival in male patients after Kasai hepatoportoenterostomy, particularly during the first 2000 days (42%; HR = 1.41, 95%CI 0.92-2.18, p = 0.11) was found. All children with pre-transplant portal vein thrombosis (n = 7) had non-O blood types. Larger multi-centre studies are necessary to show if the male sex or other thrombophilic factors could be potentially associated with reduced native liver survival.

Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Long-Term Outcome Following Liver Transplantation for Primary Hepatic Tumors-A Single Centre Observational Study over 40 Years.

The incidence of pediatric liver tumors in general has been rising over the last years and so is the number of children undergoing liver transplantation for this indication. To contribute to the ongoing improvement of pre- and post-transplant care, we aim to describe outcome and risk factors in our patient cohort. We have compared characteristics and outcome for patients transplanted for hepatoblastoma to other liver malignancies in our center between 1983 and 2022 and analysed influential factors on tumor recurrence and mortality using nominal logistic regression analysis. Of 39 children (16 f) who had transplants for liver malignancy, 31 were diagnosed with hepatoblastoma. The proportion of malignant tumors in the transplant cohort rose from 1.9% (1983-1992) to 9.1% in the current decade (p < 0.0001). Hepatoblastoma patients were transplanted at a younger age and were more likely to have tumor extent beyond the liver. Post-transplant bile flow impairment requiring intervention was significantly higher compared to our total cohort (48 vs. 24%, p > 0.0001). Hearing loss was a common side effect of ototoxic chemotherapy in hepatoblastoma patients (48%). The most common maintenance immunosuppression were mTor-inhibitors. Risk factors for tumor recurrence in patients with hepatoblastoma were higher AFP before transplant (AFPpre-LTX), a low ratio of AFPmax to AFPpre-LTX and salvage transplantation. Liver malignancies represent a rising number of indications for liver transplantation in childhood. Primary tumor resection can spare a liver transplant with all its long-term complications, but in case of tumor recurrence, transplantation might have inferior outcome. The rate of acute biopsy-proven rejections and biliary complications in comparison to our total transplant cohort needs further investigations.

Intra-Abdominal Hypertension and Compartment Syndrome after Pediatric Liver Transplantation: Incidence, Risk Factors and Outcome.

In pediatric liver transplantation (pLT), the risk for the manifestation and relevance of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) is high. This observational study aimed to evaluate the incidence, relevance and risk factors for IAH and ACS by monitoring the intra-abdominal pressure (IAP), macro- and microcirculation (near-infrared spectroscopy (NIRS)), clinical and laboratory status and outcomes of 27 patients (16 female) after pLT (median age at pLT 35 months). Of the patients, 85% developed an elevated IAP, most of them mild. However, 17% achieved IAH° 3, 13% achieved IAH° 4 and 63% developed ACS. A multiple linear regression analysis identified aortal hepatic artery anastomosis and cold ischemia time (CIT) as risk factors for increased IAP and longer CIT and staged abdominal wall closure for ACS. ACS patients had significantly longer mechanical ventilation (p = 0.004) and LOS-PICU (p = 0.003). No significant correlation between NIRS or biliary complications and IAH or ACS could be shown. IAH and ACS after pLT were frequent. NIRS or grade of IAH alone should not be used for monitoring. A longer CIT is an important risk factor for higher IAP and ACS. Therefore, approaches such as the ex vivo machine perfusion of donor organs, reducing CIT effects on them, have great potential. Our study provides important basics for studying such approaches.

Telomere length is associated with intima-media thickness in pediatric liver transplant patients: A prospective cohort study.

Leukocyte telomere length (LTL) is a marker for biological age. Pediatric liver transplant recipients show a high rate of subclinical atherosclerosis, indicated by elevated intima-media thickness (IMT). We hypothesized that atherosclerosis is associated with biological age in these patients and investigated the course of LTL over time. We measured LTL from peripheral blood leukocytes by quantitative polymerase chain reaction and IMT from 97 pediatric patients after liver transplantation in a prospective cohort study. Of the patients, 71% (n = 69) had two or more assessments (total, 228 observations; median follow-up, 1.1 years). Lower LTL was associated with higher IMT (ß = -0.701, p = 0.01) and higher aspartate aminotransferase (ß = -0.001, p = 0.02), adjusted for age, sex, and age at transplantation. Of the patients, 45% showed decreasing LTL over time, whereas 55% exhibited stable LTL. Patients with stable LTL showed a decrease in IMT (median, -0.02 mm/year) and a decrease of tacrolimus trough levels (median, -0.08 µg/L/year). LTL is associated with IMT independent of age in pediatric liver transplant patients, suggesting that early aging contributes to the high burden of subclinical cardiovascular damage and may furthermore negatively affect the graft.

Ileal Bile Acid Transporter Inhibition Reduces Post-Transplant Diarrhea and Growth Failure in FIC1 Disease-A Case Report.

Familial intrahepatic cholestasis 1 (FIC1) disease is a genetic disorder characterized by hepatic and gastrointestinal disease due to ATP8B1 deficiency, often requiring liver transplantation (LT). Extrahepatic symptoms, such as diarrhea, malabsorption, and failure to thrive, do not improve and instead may be aggravated after LT. We describe a patient with FIC1 disease who underwent LT at 2 years, 8 months of age. After LT, the child developed severe refractory diarrhea and failed to thrive. The response to bile acid resins was unsatisfactory, and the parents declined our recommendation for partial external biliary diversion (PEBD). Quality of life was extremely impaired, especially due to severe diarrhea, making school attendance impossible. Attempting to reduce the total bile acids, we initiated off-label use of the ileal bile acid transporter (IBAT) inhibitor Elobixibat (Goofice™), later converted to Odevixibat (Bylvay™). After six months of treatment, the patient showed less stool output, increased weight and height, and improved physical energy levels. The child could now pursue higher undergraduate education. In our patient with FIC1 disease, the use of IBAT inhibitors was effective in treating chronic diarrhea and failure to thrive. This approach is novel; further investigations are needed to clarify the exact mode of action in this condition.

Cold Ischemia Time and Graft Fibrosis Are Associated with Autoantibodies after Pediatric Liver Transplantation: A Retrospective Cohort Study of the European Reference Network TransplantChild.

The reported prevalence of autoantibodies (AAB) (ANA, SMA, LKM, SLA) after pediatric liver transplantation (pLTX) varies considerably from 26-75%, but their clinical impact on outcome is uncertain. We aimed to study the prevalence of AAB after pLTX, their association with donor-, transplant-, and recipient-characteristics, and their relation to outcome. In our multicenter retrospective study, we aimed to clarify conflicting results from earlier studies. Six ERN TransplantChild centers reported data on 242 patients, of whom 61% were AAB positive. Prevalence varied across these centers. Independent of the interval between pLTX and AAB analysis, a one-hour increase in CIT resulted in an odds ratio (OR) of 1.37 (95% CI 1.11-1.69) for SMA positivity and an OR of 1.42 (95%CI 1.18-1.72) for ANA positivity. Steroid-free immunosuppression (IS) versus steroid-including IS (OR 5.28; 95% CI 1.45-19.28) was a risk factor for SMA positivity. Liver enzymes were not associated with ANA or SMA positivity. We did not observe an association of rejection activity index with ANA or SMA. However, the liver fibrosis score in follow-up biopsies was associated with ANA titer and donor age. In conclusion, this first multicenter study on AAB after pLTX showed high AAB prevalence and varied widely between centers. Longer CIT and prednisolone-free-IS were associated with AAB positivity, whereas AAB were not indicative of rejection, but instead were associated with graft fibrosis. The detection of AAB may be a marker of liver fibrosis and may be taken into consideration when indications for liver biopsy and immunosuppressive regimes, or reduction of immunosuppression in long-term follow-up, are being discussed. Prospective immunological profiling of pLTX patients, including AAB, is important to further improve our understanding of transplant immunology and silent graft fibrosis.

Recipient-Specific Risk Factors Impairing Patient and Graft Outcome after Pediatric Liver Transplantation-Analysis of 858 Transplantations in 38 Years.

(1) Background and Aim: Despite excellent long-term results in pediatric liver transplantation (pLTx), mortality and graft loss still are to be diminished. We aim to describe time-dependent changes and long-term outcome of a large single-center pLTx cohort and to identify independent recipient-related risk factors impairing patient and graft survival. (2) Methods: This is a retrospective single-center study analyzing all pediatric liver transplants from 1983-2020. Risk factors for mortality and graft loss were identified by univariable and multi-linear regression analysis. (3) Results: We analyzed 858 liver transplantations in 705 pediatric patients. Five-year patient/graft survival increased from 60.9%/48.0% (1983-1992) to 97.5%/86.5% (OR = 12.5; p < 0.0001/OR = 6.5; p < 0.0001) (2014-2020). Indications changed significantly over time, with a higher proportion of patients being transplanted for malignancies and metabolic disease and indications of PFIC and α1AT-deficiency declining. The era of transplantation (log7.378/9.657; p < 0.0001) and indication of acute liver failure (log = 1.944/2.667; HR = 2.015/1.772; p = 0.0114/0.002) impairs patient/graft survival significantly in the multivariate analysis. Furthermore, patient survival is worsened by re-transplantation (log = 1.755; HR = 1.744; p = 0.0176) and prolonged waiting times in high-urgency status (log = 2.588; HR = 1.073; p = 0.0026), whereas the indication of biliary atresia improved outcome (log = 1.502; HR = 0.575; p = 0.0315). Graft survival was additionally impaired by pre-existing portal vein thrombosis (log = 1.482; HR = 2.016; p = 0.0330). (4) Conclusions: Despite more complex indications, patient and graft survival after pLTx continue to improve.. Acute liver failure remains the indication with poorest outcome, and listing for high urgency liver transplantation should be considered carefully and early to keep waiting time on HU list short. Furthermore, pre-transplant portal vein thrombosis should be prevented whenever possible to improve graft survival.

Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review.

Autoimmune Hepatitis (AIH) is a heterogenous, mostly chronic liver disease that affects people of all age groups, women more often than men. The aim of therapy is to prevent cirrhosis, as it mainly accounts for liver-related mortality in patients with AIH. Rates of remission are high in patients with AIH, but life-long immunosuppressive therapy is required. AIH is hypothesized to originate from immunologic reactivity targeted against mostly unknown self-antigens, potentially triggered by viral infections among other factors. While AIH does not follow a Mendelian inheritance pattern, part of the risk of developing AIH or worse disease course, is attributed to specific genetic risk factors. Major associations for the risk of development of AIH were found for HLA-DRB1*03:01 and HLA-DRB1*04:01 in adult AIH in the only genome-wide association study on AIH. However, other potential risk loci in SH2B3, CARD10 and KIR genes were described. This review covers the current knowledge on genetic risk factors in adult and pediatric AIH.

Current Evidence on the Clinical Relevance of Donor-specific Antibodies in Paediatric Liver Transplantation.

ABSTRACT: The clinical impact of donor-specific antibodies (DSA) occurring before or after liver transplantation (LT) against donor-human leucocyte antigen (HLA) on graft outcome is still unclear. We aim to present the current consensus based on recent paediatric LT case series. Compared to kidney transplantation, the liver seems to be less susceptible to antibody-mediated graft damage, which is likely due to protective Kupffer cell activity. The incidence of DSA after liver transplantation is higher in children than in adults. DSA directed against HLA class II molecules, mainly DQ, occur more often. The presence of such anti-class II DSA (DQ/DR), especially of the complement-binding IgG3 subclass, may be associated with endothelial injury, T-cell-mediated rejection (TCMR), inflammation, and fibrosis. Regular DSA-posttransplant monitoring cannot as yet be recommended in routine practice but may be useful in selected cases.

Low-dose steroids do make a difference: Independent risk factors for impaired linear growth after pediatric liver transplantation.

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/m2 BSA) 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.

Dubin-Johnson Syndrome as Differential Diagnosis for Neonatal Cholestasis.

OBJECTIVES: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS-specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests. METHODS: We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants. RESULTS: Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (P < 0.001), for alanine aminotransferase (ALT) (P = 0.002) and for gamma-glutamyl transferase (GGT) (P < 0.001) compared with BA patients. Other examinations, however, could not clearly discriminate them (e.g.: stool colour, serum bile acids, total serum bilirubin). CONCLUSIONS: DJS is not only a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.