Risk for Recurrence in Long-Term Follow-Up of Children after Liver Transplantation for Hepatoblastoma or Hepatocellular Carcinoma.

The aim of this study was to assess the long-term results of liver transplantation (LT) in pediatric patients with unresectable hepatoblastoma (HB) or hepatocellular carcinoma (HCC) with special reference to the risk of tumor recurrence. We retrospectively analyzed data from 46 HB and 26 HCC patients who underwent LT between 1990 and 2022. In HCC patients, we compared outcomes depending on donor type. We evaluated the impact of a number of risk factors on recurrence-free survival after LT. Estimated patient survival after 5, 10, and 15 years was 82%, 73%, and 73% in the HB group and 79%, 75%, and 75% in the HCC group, respectively (p = 0.76). In the HCC group, living donor LT (LDLT) and deceased donor LT (DDLT) provided similar patient survival (p = 0.09). Estimated recurrence-free survival in patients who had three or fewer risk factors was significantly better than in patients with more than three risk factors (p = 0.0001). Adequate patient selection is necessary when considering LT for primary liver tumors in children. The presence of more than three risk factors is associated with a very high risk of recurrence and indicates poor prognosis, whereas extrahepatic disease may be considered a contraindication for transplantation.

Identification of Iatrogenic Perforation in Pediatric Gastrointestinal Endoscopy.

OBJECTIVES: Iatrogenic viscus perforation in pediatric gastrointestinal endoscopy (GIE) is a very rare, yet potentially life-threatening event. There are no evidence-based recommendations relating to immediate post-procedure follow-up to identify perforations and allow for timely management. This study aims to characterize the presentation of children with post-GIE perforation to better rationalize post-procedure recommendations. METHODS: Retrospective study based on unrestricted pooled data from centers throughout Europe, North America, and the Middle East affiliated with the Endoscopy Special Interest Groups of European Society for Paediatric Gastroenterology Hepatology and Nutrition and North American Society for Pediatric Gastroenterology Hepatology and Nutrition. Procedural and patient data relating to clinical presentation of the perforation were recorded on standardized REDCap case-report forms. RESULTS: Fifty-nine cases of viscus perforation were recorded [median age 6 years (interquartile range 3-13)]; 29 of 59 (49%) occurred following esophagogastroduodenoscopy, 26 of 59 (44%) following ileocolonoscopy, with 2 of 59 (3%) cases each following balloon enteroscopy and endoscopic retrograde cholangiopancreatography; 28 of 59 (48%) of perforations were identified during the procedure [26/28 (93%) endoscopically, 2/28 (7%) by fluoroscopy], and a further 5 of 59 (9%) identified within 4 hours. Overall 80% of perforations were identified within 12 hours. Among perforations identified subsequent to the procedure 19 of 31 (61%) presented with pain, 16 of 31 (52%) presented with fever, and 10 of 31 (32%) presented with abdominal rigidity or dyspnea; 30 of 59 (51%) were managed surgically, 17 of 59 (29%) managed conservatively, and 9 of 59 (15%) endoscopically; 4 of 59 (7%) patients died, all following esophageal perforation. CONCLUSIONS: Iatrogenic perforation was identified immediately in over half of cases and in 80% of cases within 12 hours. This novel data can be utilized to generate guiding principles of post-procedural follow-up and monitoring. PLAIN LANGUAGE SUMMARY: Bowel perforation following pediatric gastrointestinal endoscopy is very rare with no evidence to base post-procedure follow-up for high-risk procedures. We found that half were identified immediately with the large majority identified within 12 hours, mostly due to pain and fever.

The Impact of Hepatic Artery Thrombosis on the Outcome of Pediatric Living Donor Liver Transplantations.

The aim of our study was to assess risk factors for hepatic artery thrombosis (HAT) and to evaluate the impact of HAT management on long-term outcomes after pediatric living donor liver transplantation (LDLT). We retrospectively analyzed 400 patients who underwent primary LDLT between 1999 and 2020. We compared preoperative data, surgical factors, complications, and patient and graft survivals in patients with HAT (HAT Group) and without HAT (non-HAT Group). A total of 27 patients (6.75%) developed HAT. Acute liver failure, a hepatic artery (HA) anastomosis diameter below 2 mm, and intraoperative HA flow dysfunction were significantly more common in the HAT Group (p < 0.05, p = 0.02026, and p = 0.0019, respectively). In the HAT Group, 21 patients (77.8%) underwent urgent surgical revision. The incidence of biliary stenosis and retransplantation was significantly higher in the HAT Group (p = 0.00002 and p < 0.0001, respectively). Patient and graft survivals were significantly worse in the HAT Group (p < 0.05). The close monitoring of HA flow with Doppler ultrasound during the critical period of 2 to 3 weeks after LDLT and the immediate attempt of surgical revascularization may attenuate the elevated risk of biliary stenosis, graft loss, and the need for retransplantation due to HAT.

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.

ABO Incompatible Liver Transplantation in Children: A 20 Year Experience from Centres in the TransplantChild European Reference Network.

An increasing number of AB0-incompatible (AB0i) liver transplantations (LT) are being undertaken internationally in recent years due to organ shortages and the need for urgent transplantation. The aim of our study was establish the value of ABOi LT from available retrospective results of AB0i pediatric liver transplantations performed in European reference centers now belonging to the TransplantChild, European Reference Network (ERN). Data from medical records were analyzed, including demographic data, diagnosis, urgency of transplantation, time on the waiting list, PELD/MELD score, desensitization procedures, immunosuppression, selected post-transplant complications, and patient and graft survival. A total of 142 patients (pts) with transplants between 1986 and 2018 in 8 European transplant centers were included in the study. The indications for liver transplantation were: cholestatic diseases in 62 pts, acute liver failure in 42 pts, and other conditions in the remaining 38 pts. Sixty-six patients received grafts from living donors, and seventy-six received grafts from deceased donors. Both patient and graft survival were significantly affected by deceased donor type, urgent transplantation, and the development of vascular complications. In the multivariate analysis, vascular complications had a negative impact on patient and graft survival, while a longer time from the first AB0i LT in the study showed better results, suggesting an international learning experience. In conclusion, we believe that AB0i LT in children is now a safe procedure that may be adopted more readily in children.

Impact of Graft Size Matching on the Early Post-Transplant Complications and Patients Survival in Children after Living Donor Liver Transplantations.

We aimed to assess the impact of the graft-recipient weight ratio (GRWR) on early post-transplant complications and patient survival rates in children after living donor liver transplantation (LDLT). We retrospectively analyzed 321 patients who underwent LDLT from 2004 to 2019. The recipients were categorized into four groups: 37 patients had a GRWR ≤ 1.5% (Group A), 196 patients had a GRWR > 1.5% and ≤3.5% (Group B), 73 patients had a GRWR > 3.5% and <5% (Group C) and 15 patients had a GRWR ≥ 5% (Group D). Incidence of early surgical complications including vascular complications, biliary complications, postoperative bleedings, gastrointestinal perforations and graft loss were comparable among groups with a different GRWR. Delayed abdominal wound closure was more common in patients with a GRWR > 3.5%. Recipients with a GRWR < 5% had a significantly better prognosis concerning patients and graft survival. Using grafts with a GRWR < 5% allows us to expand the donor pool and decrease the risk of mortality while on the waiting list, when patients at the time of transplantation have less advanced liver disease. LDLT with a GRWR ≥ 5% is related to a higher risk of poor outcome, and thus should be an option for treating selected patients when the risk of a delayed transplantation is high and access to deceased donors is limited.

Phase I/II Trial of Liver-derived Mesenchymal Stem Cells in Pediatric Liver-based Metabolic Disorders: A Prospective, Open Label, Multicenter, Partially Randomized, Safety Study of One Cycle of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in Urea Cycle Disorders and Crigler-Najjar Syndrome Patients.

BACKGROUND: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. OBJECTIVE: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. METHODS: Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. RESULTS: The overall safety of HepaStem was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age, and underlying diseases. CONCLUSIONS: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.

Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype.

BACKGROUND & AIMS: Wilson's disease (WD) is an autosomal recessive disorder associated with disease-causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes. METHODS: A total of 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform. RESULTS: ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurological phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset. CONCLUSIONS: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype.

Percutaneous Treatment of Biliary Strictures After Pediatric Liver Transplantation.

BACKGROUND Biliary strictures (BS) are frequent after pediatric liver transplantation (LTx) and in spite of ongoing progress, they remain a significant cause of morbidity. In children, the majority of reconstruction is hepatico-jejunal anastomosis (HJA). The aim of this study was to analyze our experience in percutaneous transhepatic treatment of BS. MATERIAL AND METHODS Between 1998 and 2014, 589 (269 living donor) pediatric LTx were performed in our institution. We retrospectively reviewed clinical data of patients with HJA who developed BS and who underwent percutaneous transhepatic biliary drainage (PTBD). RESULTS Out of 400 patients with HJA, 35 patients developed BS. There were 27 cases (77%) of anastomotic BS (ABS) and 8 cases (23%) of multilevel BS (MBS). Ninety-two PTBD sessions (2.5 per patient) were performed, with successful outcomes in 20 cases (57%). Fifteen patients, after failed PTBD, underwent surgery which was successful in 11 cases. Overall good outcomes were achieved in 31 cases (88.5%). The most common complication of PTBD was cholangitis which occurred in 5.4% of the cases. We did not find any risk factors for PTBD failure, except for treatment occurring before 2007. CONCLUSIONS Percutaneous treatment is effective and safe in BS and is recommended as a first-line approach. The majority of patients in our study required multiple interventions, however, the overall risk of complications was low. Surgery is essential in selected cases and always should be considered if PTBD fails.

Early Onset of Wilson Disease: Diagnostic Challenges.

OBJECTIVES: The aim of the study was to analyze the clinical presentations, diagnosis, and treatment of patients ages ≤5 years with early onset Wilson disease (WD). METHODS: Data from 143 pediatric patients with WD treated at our center between January 1996 and November 2015 were retrospectively analyzed. RESULTS: A review of the 143 pediatric patients with WD identified 21 (10 girls, 11 boys) with first symptoms or abnormal liver function test results at age ≤5 years. The diagnosis of WD was confirmed in 8 patients younger than 5 years. At baseline the mean serum alanine aminotransferase level was 222 U/L and the mean serum aspartate aminotransferase level was 130 U/L. The mean serum ceruloplasmin concentration in 16 tested patients was <20 mg/dL. Of the 15 patients who underwent urinary copper excretion testing, 8 had levels between 40 and 100 µg/day, with only 4 having levels >100 µg/day. Liver copper quantification was >250 µg/g dry weight in 16 patients. The most common mutation was p.H1069Q, with compound heterozygosity in 5 patients and homozygosity in 9. Sixteen patients were treated with zinc salts and 5 with D-penicillamine. Both treatments were effective, with no serious side effects observed after 3 to 24 months. CONCLUSIONS: WD can present as early as 2 years of age. Because biochemical tests may be less sensitive in very young children, diagnoses may require a combination of tests. If molecular tests are inconclusive, liver copper content should be measured.

Clinical presentations of Wilson disease among Polish children.

INTRODUCTION: Wilson disease (WD) may present from early childhood up to the eighth decade, presenting with variable hepatic and neuropsychiatric symptoms. Establishing the diagnosis is straightforward if the major clinical and laboratory features are present. However, clinical phenotypes are highly varied and early, proper diagnosis can be challenging. AIM: The aim of our study was to analyze clinical presentations and diagnostic tests of Polish pediatric patients with WD. METHODS: We retrospectively analyzed medical history of 156 patients with confirmed diagnosis of WD treated at our Institute from 1996 till March 2016. RESULTS: The mean age at onset of symptoms was 10.15±4.23 years of age. Hepatic presentation was the most common one (94.23%) with either liver failure (16.03%) or more frequently increased transaminases (78.2%). In 90.26% cases ceruloplasmin serum concentration was ≤0,2 g/l, in 51.93% patients basal urinary copper excretion was >100 µg/24 h. Mutation analysis was performed in 155 (99.36%) cases. The most common mutation was p.H1069Q. CONCLUSIONS: Wilson disease can present with only significantly increased transaminases activity and hepatomegaly or liver failure, but neurological symptoms are very rare in children. Diagnostic approach is challenging due to wide spectrum of clinical presentations in a high variable degree of severity. Genetic screening is supportive, ceruloplasmin and urinary copper excretion are valuable tests in the majority of patients but do not allow to exclude WD.

The limited prognostic value of liver histology in children with biliary atresia.

UNLABELLED: Background and rationale for the study. The aim of the study was to determine the prognostic value of histopathological findings with special care to the severity of liver fibrosis at the moment of hepatoportoenterostomy (HPE) in children with biliary atresia (BA). We performed analysis of 142 wedge liver biopsies taken at the time of HPE. All patients were operated by the same surgical team between 1995 and 2007. According to the outcome 6 months after HPE patients were divided into prognostic groups: group 1-bilirubin level < 2 mg% (n = 65), group 2-bilirubin level > 2 mg% (n = 77). Liver biopsies were re-evaluated according to the extended histopathological protocol and then were compared between the prognostic groups. Survival with native liver (SNL) estimates were performed in regard to severity of liver fibrosis. RESULTS: Survival with native liver estimates after 2, 5 and 10 years in patients after successful operation were 96%, 91%, 75% vs. 30%, 11%, and 5% if operation failed (p < 0.001). There was no difference between groups in the following variables: fibrosis (p = 0.69), portal inflammation (p = 0.99), lobular inflammation (p = 0.95), cholangiolitis (p = 0.23), accumulation of bile pigments (zone 1:p = 0.49; zone 2:p = 0.51; zone 3:p = 0.48), bile plugs in canaliculi (p = 0.12), bile plugs in ducts (p = 0.32), bilirubinostasis in hepatocytes (p = 0.45), bile ductular proliferation (p = 0.59), ductal plate malformation (p = 0.12), focal necrosis (p = 0.44), giant cell transformation (p = 0.45), haematopoesis (p = 0.52), ductopenia (p = 0.46), microabscesses (p = 0.49), ballooning of hepatocytes (p = 0.08). The actuarial 5/10-year SNL was not dependent on severity of liver fibrosis (log-rank test p = 0.84). The severity of fibrosis corresponded neither with the age at HPE nor with the laboratory findings before operation but increased the risk of portal hypertension. CONCLUSION: Liver histology at the time of HPE is of limited value in prognosis making in BA.

Amoxicillin/clavulanic acid-induced cholestatic liver injury after pediatric liver transplantation.

BACKGROUND: Amoxicillin/clavulanic acid-induced liver injury is a well recognized complication. Presentation and outcome may vary, which is related to individual liver maturity, genetic predisposition, enzyme heterogeneity, intensity of treatment, and drug interactions. In most cases withdrawing the drug is sufficient treatment; however, cases of progressive liver damage leading to liver transplantation have been reported. CASE REPORT: We present the case of an 8-year-old patient after liver transplantation who developed drug induced liver injury (DILI) after amoxicillin/clavulanic acid treatment for upper respiratory tract infection. Jaundice appeared 2 days after cessation of treatment. Clinical presentation and liver biopsy were consistent with DILI. Because of rapidly increasing bilirubin levels, we used 3 boluses of methylprednisolone and ursodeoxycholic acid. The treatment reversed progression of the cholestasis and full recovery was achieved in 3 months. CONCLUSIONS: In most cases of DILI, withdrawing the toxic drug is sufficient treatment, but we must be aware of a possible fatal outcome in case of progressive cholestasis. Corticosteroids may have beneficial effects in these patients.

Successful sirolimus rescue in tacrolimus-induced thrombotic microangiopathy after living-related liver transplantation.

TMA is a rare complication of tacrolimus. Disruption of endothelial cells, platelet aggregation, and intravascular mechanical fragmentation of red cells are core mechanisms of injury; however, exact pathways of toxicity are not clear. The clinical presentation may vary but TMA is a potentially life-threatening condition usually demanding aggressive treatment. We present the case of TMA in a child after living-related liver transplantation (LRLTx) on tacrolimus-based immunosuppressive regiment successfully converted to sirolimus.

Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3.

Biliary atresia (BA) is a progressive, idiopathic obliteration of the extrahepatic biliary system occurring exclusively in the neonatal period. It is the most common disease leading to liver transplantation in children. The etiology of BA is unknown, although infectious, immune and genetic causes have been suggested. Although the recurrence of BA in families is not common, there are more than 30 multiplex families reported and an underlying genetic susceptibility has been hypothesized. We screened a cohort of 35 BA patients for genomic alterations that might confer susceptibility to BA. DNA was genotyped on the Illumina Human Hap 550 Beadchip platform, which analyzes over 550,000 single nucleotide polymorphisms (SNPs) for genomic deletions and duplications. Areas of increased and decreased copy number were compared to those found in control populations. To identify regions that could serve as susceptibility factors for BA, we searched for regions that were found in BA patients, but not in controls. We identified two unrelated BA patients with overlapping heterozygous deletions of 2q37.3. Patient 1 had a 1.76 Mb (280 SNP), heterozygous deletion containing 30 genes. Patient 2 had a 5.87 Mb (1,346 SNP) heterozygous deletion containing 55 genes. The overlapping 1.76 Mb deletion on chromosome 2q37.3 from 240,936,900 to 242,692,820 constitutes the critical region and the genes within this region could be candidates for susceptibility to BA.

[Living related liver transplantation - analysis of the first 102 cases]. / Transplantacja watroby od zywych dawców rodzinnych - analiza pierwszych 102 przypadków.

THE AIM: of the study was to analyse the first 102 living-related liver transplantations performed in Poland at the Children's Memorial Health Institute. MATERIAL: between November 1999 and January 2007 102 living-related liver transplantations were carried out in 101 patients. In 63 the patients the indication for liver transplantation was biliary atresia, in 7 - intrahepatic cholestasis, in 11 - acute liver failure, in 9 - hepatic tumour, in two - graft insufficiency. The remaining indications included hepatic cirrosis in course of cystic fibrosis, Caroli disease and biliary cysts. There were 61 girls and 40 boys aged from 4 months to 11 years (mean 2.5 years). The body weight ranged from 4.5 to 31 kg (mean 12 kg). RESULTS: eighty seven children are alive (86%). Five died in the early posttranplant period (between 2 and 11 days after operation), 9 died in the later period (from 36 days to 5 years and 10 months after the operation). The most serious, life threatening early and late complications were bacterial infections. The most frequent scheme of immunosuppressive treatment was tacrolimus and corticosteroids (64%) and tacrolimus and mycophenolate mofetil (16%). CONCLUSION: living-related liver transplantation is an effective method of treatment of acute and end-stage liver diseases in children with low body mass.