∆4-3-oxo-5ß-reductase deficiency: favorable outcome in 16 patients treated with cholic acid.

BACKGROUND: Oral cholic acid therapy is an effective therapy in children with primary bile acid synthesis deficiencies. Most reported patients with this treatment have 3ß-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ4-3-oxosteroid 5ß-reductase (Δ4-3-oxo-R) deficiency. METHODS: Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed. RESULTS: First symptoms were reported early in life (median 2 months of age), with 14 and 3 patients having cholestatic jaundice and severe bleeding respectively. Fifteen patients received ursodeoxycholic acid before diagnosis, with partial improvement in 8 patients. Four patients had liver failure at the time of cholic acid initiation. All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment. After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver. Median daily cholic acid dose at last follow-up was 8.3 mg/kg of body weight. All patients, but one, had normal physical examination and all had normal serum liver tests. Fibrosis, evaluated using liver biopsy (n = 4) or liver elastography (n = 9), had stabilized or improved. Cholic acid therapy enabled a 12-fold decrease of 3-oxo-∆4 derivatives in urine. Patients had normal growth and quality of life. The treatment was well tolerated without serious adverse events and signs of hepatotoxicity. CONCLUSIONS: Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency.

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.

Cell-based BSEP trans-inhibition: A novel, non-invasive test for diagnosis of antibody-induced BSEP deficiency.

Background & Aims: Antibody-induced bile salt export pump deficiency (AIBD) is an acquired form of intrahepatic cholestasis, which may develop following orthotopic liver transplantation (OLT) for progressive familial intrahepatic cholestasis type 2 (PFIC-2). Approximately 8-33% of patients with PFIC-2 who underwent a transplant develop bile salt export pump (BSEP) antibodies, which trans-inhibit this bile salt transporter from the extracellular, biliary side. AIBD is diagnosed by demonstration of BSEP-reactive and BSEP-inhibitory antibodies in patient serum. We developed a cell-based test directly measuring BSEP trans-inhibition by antibodies in serum samples to confirm AIBD diagnosis. Methods: Sera from healthy controls and cholestatic non-AIBD or AIBD cases were tested (1) for anticanalicular reactivity by immunofluorescence staining of human liver cryosections, (2) for anti-BSEP reactivity by immunofluorescence staining of human embryonic kidney 293 (HEK293) cells expressing BSEP-enhanced yellow fluorescent protein (EYFP) and immunodetection of BSEP-EYFP on Western blot, and (3) for BSEP trans-inhibition using HEK293 cells stably expressing Na+/taurocholate cotransporting polypeptide (NTCP)-mCherry and BSEP-EYFP. The trans-inhibition test uses [3H]-taurocholate as substrate and is divided into an uptake phase dominated by NTCP followed by BSEP-mediated export. For functional analysis, sera were bile salt depleted. Results: We found BSEP trans-inhibition by seven sera containing anti-BSEP antibodies, but not by five cholestatic or nine control sera, all lacking BSEP reactivity. Prospective screening of a patient with PFIC-2 post OLT showed seroconversion to AIBD, and the novel test method allowed monitoring of treatment response. Notably, we identified a patient with PFIC-2 post OLT with anti-BSEP antibodies yet without BSEP trans-inhibition activity, in line with asymptomatic presentation at serum sampling. Conclusions: Our cell-based assay is the first direct functional test for AIBD and allows confirmation of diagnosis as well as monitoring under therapy. We propose an updated workflow for AIBD diagnosis including this functional assay. Impact and Implications: Antibody-induced BSEP deficiency (AIBD) is a potentially serious complication that may affect patients with PFIC-2 after liver transplantation. To improve its early diagnosis and thus immediate treatment, we developed a novel functional assay to confirm AIBD diagnosis using a patient's serum and propose an updated diagnostic algorithm for AIBD.

Long-term outcome after combined or sequential liver and kidney transplantation in children with infantile and juvenile primary hyperoxaluria type 1.

Introduction: Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare. Methods: All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively. Results: Eighteen patients (infantile PH1 n = 10, juvenile PH1 n = 8) underwent transplantation (CLKT n = 17, SLKT n = 1) at a median age of 5.4 years (1.5-11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4-11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4-2.4) vs. 12.8 years (8.4-14.1), P = 0.003). Median follow-up was 11.0 years (6.8-11.6) in patients with infantile PH1 vs. 6.9 years (5.7-9.9) in juvenile PH1 (P = 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8, P = 0.59). Discussion: In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1.

Experience with the mTOR Inhibitor Everolimus in Pediatric Liver Graft Recipients.

INTRODUCTION: Immunosuppression after pediatric liver transplantation remains a major challenge. MTOR inhibitors provide a promising therapeutic approach in combination with reduced CNI after transplantation. However, there are still few data regarding their use in children. PATIENTS: We analyzed 37 patients with a median age of 10 years, who received Everolimus for one or more of the following indications: I = chronic graft dysfunction (n = 22); II = progressive renal impairment (n = 5); III = non-tolerable side effects with previous immunosuppressive medication (n = 6); and IV = malignancies (n = 10). The median follow-up time was 36 months. RESULTS: Patient survival was 97%, and graft survival 84%, respectively. Stabilization of graft function was observed in 59% in subgroup 1, with 18.2% ultimately requiring retransplantation. No patient in subgroup IV developed recurrence of his primary tumor or PTLD by the endpoint of the study. Side effects were observed in 67.5% of the study patients, with infections being the most frequent (n = 20; 54.1%). There were no relevant effects on growth and development. CONCLUSION: Everolimus seems to be a treatment option in selected pediatric liver graft recipients for whom other regimens are not suitable. Overall, the efficacy was good and the side effect profile appeared to be acceptable.

Long-term Outcome of Pediatric Liver Transplant Recipients Who Have Reached Adulthood: A Single-center Experience.

BACKGROUND: As long-term survival of pediatric liver transplant recipients increases, the assessment of physical, psychological, and social well-being becomes more important. METHODS: In this retrospective analysis, 120 young adult patients (age ≥18 y) who underwent liver transplantation in childhood were studied. Patients with ideal outcome were defined as patients with perfect graft function, with no complications from the immunosuppressive medication, no late retransplantation, and no steroid treatment. Also, the patients' drug adherence and their psychosocial situation were assessed. RESULTS: After a median follow-up of 19 y, only 16.7% of the patients (mean age: 26.5 y) were considered patients with ideal outcome. The main reasons precluding ideal outcome were chronic kidney disease (38.3%), elevated liver enzymes (33.3%), and arterial hypertension (31.7%). Ideal outcome decreased over time from 54% to 42%, 26%, and 8% at 10-, 15-, 20-, and 25-y follow-up, respectively. Reduced drug adherence was noted in 24.8% of patients and associated with a significantly higher prevalence of donor-specific antibodies class II ( P = 0.015), elevated transaminases ( P = 0.010), and chronic rejection ( P < 0.001). Also, 15% of patients had a psychiatric disease, mainly depression. CONCLUSIONS: The morbidity of young adults who underwent liver transplantation as children was high and increased over time. The majority developed complications from immunosuppression or chronic graft dysfunction. More than 1 in 7 patients had a psychiatric disease and 1 in 4 was not perfectly drug adherent. Therefore, immunosuppressive treatment and psychological care should be optimized for these particularly vulnerable patients.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Protocol Biopsies in Pediatric Liver Transplantation Recipients Improve Graft Histology and Personalize Immunosuppression.

OBJECTIVES: Protocol liver biopsies (PLBs) are part of the follow-up program at many pediatric liver transplant centers, but the impact on clinical decision-making and allograft histology following adjustments of immunosuppression (IS) after PLB has not been thoroughly analyzed. METHODS: Following our previous single-center cohort study, we have now evaluated histological findings of 178 PLBs of 118 pediatric patients transplanted at our center between 1998 and 2017. In particular, we focused on the changes in allograft histology in the follow-up biopsy of a subgroup of 22 patients, in which the histologic findings led to an adjustment of immunosuppressive therapy. All biopsies of this sub-study group were reevaluated by an experienced pathologist. RESULTS: The overall frequency and severity of fibrosis increased over time after orthotopic liver transplantation. Patients with donor-specific antibodies (DSAs) had a higher prevalence of fibrosis than DSA-negative patients. Graft inflammation decreased significantly after intensifying IS, but renal function needs to be monitored. A significant increase in fibrosis was detected in children with reduced IS. CONCLUSION: The adjustment of IS following PLBs has a significant impact on allograft histology. Since chronic inflammatory changes may lead to graft failure, adjustment of IS seems to be of major importance for the long-term outcome.

Liver cirrhosis in children - the role of imaging in the diagnostic pathway.

Liver cirrhosis in children is a rare disease with multifactorial causes that are distinct from those in adults. Underlying reasons include cholestatic, viral, autoimmune, hereditary, metabolic and cardiac disorders. Early detection of fibrosis is important as clinical stabilization or even reversal of fibrosis can be achieved in some disorders with adequate treatment. This article focuses on the longitudinal evaluation of children with chronic liver disease with noninvasive imaging tools, which play an important role in detecting cirrhosis, defining underlying causes, grading fibrosis and monitoring patients during follow-up. Ultrasound is the primary imaging modality and it is used in a multiparametric fashion. Magnetic resonance imaging and computed tomography are usually applied second line for refined tissue characterization, clarification of nodular lesions and full delineation of abdominal vessels, including portosystemic communications.

Prognosis of Children Undergoing Liver Transplantation: A 30-Year European Study.

OBJECTIVES: The European Liver Transplant Registry has been collecting data on virtually all pediatric liver transplant (PLT) procedures in Europe since 1968. We analyzed patient outcome over time and identified parameters associated with long-term patient outcome. METHODS: Participating centers and European organ-sharing organizations provided retrospective data to the European Liver Transplant Registry. To identify trends, data were grouped into consecutive time spans: era A: before 2000, era B: 2000 to 2009, and the current era, era C: since 2010. RESULTS: From June 1968 until December 2017, 16 641 PLT were performed on 14 515 children by 133 centers. The children <7 years of age represented 58% in era A, and 66% in the current era (P <.01). The main indications for PLT were congenital biliary diseases (44%) and metabolic diseases (18%). Patient survival at 5 years is currently 86% overall and 97% in children who survive the first year after PLT. The survival rate has improved from 74% in era A to 83% in era B and 85% in era C (P <.0001). Low-volume centers (<5 PLT/year) represented 75% of centers but performed only 19% of PLT and were associated with a decreased survival rate. In the current era, however, survival rates has become irrespective of volume. Infection is the leading cause of death (4.1%), followed by primary nonfunction of the graft (1.4%). CONCLUSIONS: PLT has become a highly successful medical treatment that should be considered for all children with end-stage liver disease. The main challenge for further improving the prognosis remains the early postoperative period.

Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations.

Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-ß signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases.

Psychosocial situation, adherence, and utilization of video consultation in young adult long-term pediatric liver transplant recipients during COVID-19 pandemic.

BACKGROUND: Young adults who underwent liver transplantation in childhood (YALTs) are highly vulnerable to non-adherent behavior and psychosocial problems. During the COVID-19 pandemic, special efforts may be necessary to maintain contact with these patients and offer support. This can be achieved through the use of telemedicine. The study's objective was to assess adherence and the psychosocial situation of YALTs during the COVID-19 pandemic in Germany and to evaluate the utilization of video consultations. METHODS: In May 2020, a questionnaire was sent to YALTs treated at the Hamburg University Transplant Center, accompanied by the offer of video appointments with the attending physician. The questionnaire included the Generalized Anxiety Disorder Scale 7, the Patient Health Questionnaire 2, and questions compiled by the authors. RESULTS: Of 98 YALTs, 12% used the video consultation, while 65% had an in-person appointment. The 56 patients who completed the questionnaire did not report reduced medication adherence during the pandemic, but 40% missed follow-up visits with their primary care physician or check-up laboratory tests. About 70% of YALTs were afraid to visit their physician and the transplant center, and 34% were afraid of a SARS-CoV-2 infection. Mental health and well-being were unimpaired. CONCLUSIONS: During the COVID-19 pandemic, YALTs in our study did not show an increased need for psychosocial support, but a majority were afraid to attend medical appointments, and 40% reported lower appointment adherence. Acceptance of video consultations was lower than expected. The reasons for this need to be further investigated in order to optimize care.

Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation.

BACKGROUND: In a previous paper, we reported a high prevalence of donor-specific antibody (DSA) in pediatric patients with chronic rejection and expressed the need for confirmation of these findings in a larger cohort. AIM: To clarify the importance of DSAs on long-term graft survival in a larger cohort of pediatric patients. METHODS: We performed a retrospective analysis of 123 pediatric liver transplantation (LT) recipients who participated in yearly follow-ups including Luminex testing for DSA at our center. The cohort was split into two groups according to the DSA status (DSA-positive n = 54, DSA-negative n = 69). Groups were compared with regard to liver function, biopsy findings, graft survival, need for re-LT and immunosuppressive medication. RESULTS: DSA-positive pediatric patients showed a higher prevalence of chronic rejection (P = 0.01), fibrosis (P < 0.001) and re-transplantation (P = 0.018) than DSA-negative patients. Class II DSAs particularly influenced graft survival. Alleles DQ2, DQ7, DQ8 and DQ9 might serve as indicators for the risk of chronic rejection and/or allograft fibrosis. Mean fluorescence intensity levels and DSA number did not impact graft survival. Previous episodes of chronic rejection might lead to DSA development. CONCLUSION: DSA prevalence significantly affected long-term liver allograft performance and liver allograft survival in our cohort of pediatric LT. Screening for class II DSAs in combination with assessment of protocol liver biopsies for chronic antibody-mediated rejection improved early identification of patients at risk of graft loss.

Presence of donor specific HLA class 2 antibodies (DSA class 2) is associated with development of graft fibrosis more than 10 years after liver transplantation-a retrospective single center study.

Here the impact of donor specific human leukocyte antigen (HLA) class 2 antibodies (DSA cl 2) on long term outcome after liver transplantation (LT) was investigated. Altogether 156 (44 pediatric and 112 adult) LT recipients were included in the study. Graft fibrosis was assessed by liver elastography and biopsy. DSA cl 2 were determined by Luminex technology. 46% of LT recipients were positive for DSA cl 2 after a median follow-up of 15 years. In the multivariate analysis DSA cl 2 were significantly associated with immunosuppressive monotherapy (OR 5.42; 95% CI: 1.02-28.90; p = .048). Compared to DSA cl 2 negative patients, positive recipients had significantly more graft fibrosis based on the liver stiffness (mean 9.4 ± 9.0 kPa vs. 6.5 ± 6.3 kPa; p < .002) and fibrosis stages determined by liver elastography (p = .016) and the performed liver biopsies (p = .002). Also, a significantly higher incidence of chronic rejections (11% vs. 2%; p = .045) and graft losses (6% vs. 0%; p = .043) were found. In the multivariate regression analysis DSA cl 2 were significantly associated with graft fibrosis (OR 4.57; 95% CI 1.59-13.10; p = .005). So, these data suggest that development of DSA cl 2 occurs more often with immunosuppressive monotherapy and may ultimately result in chronic rejection and graft fibrosis.

Short- and long-term results of liver transplantation according to age at transplant: a single-center experience of 351 children.

Pediatric liver transplantation (PLT) has very good results at experienced transplant centers. However, there is still an ongoing discussion about inferior outcomes, especially in young infants. The aim of this retrospective study was to evaluate outcomes of infants compared to older recipients in a single center over 20 years. We conducted a retrospective study of children who received liver transplants at our center between 1991 and 2011. Only patients without other limiting organ involvement were included and compared according to age. The inclusion criteria were fulfilled by 351 patients (173 vs. 178). The most common indication in both groups was biliary atresia (82.1% vs. 49.4%). The 1-, 5-, and 10-year patient survivals were 93.8%/91.8%/91.1% and 93%/90.8%/90.1%, and the graft survivals were 90.4%/83.5%/79.6% and 89.4%/81.8%/77.5%, respectively. Complications such as postoperative bleeding, biliary complications, or perfusion impairment occurred more often in infants. Leading indications for retransplantation (vascular complications/primary nonfunction) and leading causes of death (sepsis/multiorgan failure) were the same in both groups. Significant predictors for patient loss were decade of transplantation, retransplantation, postoperative bleeding, and infections for infants. Predictors for graft loss were bowel perforation, arterial thrombosis, and age >12 months. Children can have excellent results, independent of age at PLT.

Outcome of liver transplantation and prevalence of liver fibrosis in Crigler-Najjar syndrome.

INTRODUCTION: Crigler-Najjar syndrome (CNS) is a rare inherited disorder that is characterized by high levels of non-hemolytic, unconjugated hyperbilirubinemia leading to brain damage and even death. Liver transplantation (LT) can correct the metabolic defect, but there are little data regarding LT in this patient cohort. The liver parenchyma has been considered to be structurally normal in CNS, but there is growing evidence of clinically silent but histologically significant fibrosis in CNS patients. PATIENTS AND METHODS: We included 13 patients in our retrospective study who underwent LT at our center. Patient survival, graft function, and long-term complications were evaluated over a median follow-up period of 10 years (range: 1-16 years). In addition, the prevalence of histologically relevant fibrosis was characterized. RESULTS: The overall survival among our LT patients was 100%. The graft survival was only 61.5%. During the follow-up period, 5 LT patients had to undergo retransplantation. More than 45% of our patients showed histological signs of fibrosis. CONCLUSION: LT remains the only definite therapeutic option for severe CNS but needs to be considered thoroughly regarding the clinical risk-benefit-ratio and impact on quality of life. Furthermore, hepatic parenchymal injury needs to be considered while evaluating future therapeutic options for CNS.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Infantile Hepatic Hemangioma: Avoiding Unnecessary Invasive Procedures.

Infantile hepatic hemangioma, the most common vascular tumor of the liver in infancy, can occur with acute postnatal liver and congestive heart failure. Nevertheless, its course is often benign, and many children can be diagnosed and treated without surgical intervention. The distinction from malignant diseases is not always easy and it not clear whether invasive procedures for diagnosis and therapy should be performed. Here we report our experiences in our Center for Pediatric Liver Disease and postulate that large studies are needed to avoid unnecessary invasive procedures for these patients in the future.

Impact on the hepatic flow velocity after pediatric combined liver-kidney transplantation compared to isolated pediatric liver transplantation-A matched-pair analysis.

BACKGROUND: Combined liver-kidney transplantation (CLKT) in children is still a rarely performed procedure. Our aim was to analyze the effect of the simultaneous transplantation of the kidney in pediatric CLKT on the liver graft flow velocity, and vascular complications compared to singular liver transplantation (LTX) in children. METHODS: All pediatric CLKT performed at our institution from 1998 to 2016 were matched with singular LTX and retrospectively analyzed. RESULTS: Overall 30 CLKT were performed in 28 children (median age 8 years, range 1-16) and matched with 30 children undergoing singular LTX (median age 7.9 years, range 1-16). No significant differences were found concerning the systolic peak flow velocity of the hepatic artery (HA) or the resistance index (RI). Vascular complications of the hepatic vessels occurred in 16.7% (CLKT) and 6.7% (LTX). The 1-/5- and 10-year patient survival was 93.3%/93.3% and 93.3% (CLKT) and 100%/100% and 92.9% (LTX). 1-/5-and 10-year liver graft survival was 76.7%/73.2% and 73.2% (CLKT) and 84.4%/75.9% and 69.6% (LTX). CONCLUSION: The simultaneous transplantation of the kidney in CLKT had no negative impact on hepatic flow velocity or vascular complications. Frequent Doppler ultrasound examinations, accurate volume management, and avoidance of abdominal pressure might be an explanation for the results and an excellent graft- and patient survival.

Tissue inhibitor of metalloproteinase 1 and AST-to-Platelet Ratio Index as noninvasive biomarkers predict allograft fibrosis after pediatric liver transplantation.

BACKGROUND: Assessing liver fibrosis in patients after liver transplantation is still largely dependent on liver biopsy. Especially in children, noninvasive methods are of utmost importance. We evaluated tissue inhibitor of metalloproteinase 1 (TIMP1) and AST-to-Platelet Ratio Index (APRI) and their potential as serum biomarkers to predict liver allograft fibrosis (LAF) in a pediatric cohort. METHODS: In this retrospective, observational study, we analyzed 91 protocol liver biopsy specimens from 73 children after pediatric liver transplantation (PLT) and compared histological stage of liver fibrosis using LAF Score (LAFSc) and Ishak Score (IshakSc) to TIMP1-serum concentration and APRI using ROC analysis. RESULTS: In our cohort, TIMP1 and APRI reliably predict LAF. Depending on the histological scoring system, cutoff values for TIMP1 were 328 ng/mL (IshakSc ≥ IV) and 351 ng/mL (LAFSc ≥ 5) with AUC of 0.86 and 0.98. The cutoff for APRI was 0.8 with AUC of 0.87 (IshakSc ≥ IV) and 0.94 (LAFSc ≥ 5). Using LAFSc, TIMP1 and APRI showed excellent diagnostic accuracy to detect severe LAF (LAFSc ≥ 5) with PPV of ≥ 90% and NPV of 100%. CONCLUSION: TIMP1 and APRI are accurate biomarkers to predict severe LAF in children. The use of TIMP1 and APRI will not replace but complement liver biopsies after PLT to further improve our understanding of each individual patient.