Acute severe non-A-E-hepatitis of unknown origin in children - A 30-year retrospective observational study from north-west Germany.

BACKGROUND & AIMS: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. We aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic. METHODS: We analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to 16 May 2022. We separated cases into a historic cohort (1990-2018) and a COVID-19 era cohort (2019-2022). RESULTS: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were HHV-6 (4), CMV, HSV, EBV(3). Sixty-nine patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. Twenty-five patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died. CONCLUSIONS: Acute non-A-E-hepatitis in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in our current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in our centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases. IMPACT AND IMPLICATIONS: As the current epidemic of severe acute non-A-E-hepatitis cases in children highlights our limited understanding in the field, we aim to describe current cases, characterizing the presentation over time, and defining similarities and discrepancies before and during the COVID-19 pandemic. Our data show a rising incidence of non-A-E-hepatitis cases since the beginning of the COVID-19 pandemic. These cases were not associated with adenoviral infections, suggesting that the recently described accumulation of adenovirus infections in relationship to hepatitis is a new trigger for a known phenomenon, rather than a new disease entity. Therefore, the role of protective isolation and subsequent lack of contact with trivial infections in children during the pandemic should be the subject of further examinations. We expect our data to contribute to a better understanding of severe acute hepatitis in childhood, increased vigilance for this potentially lethal disease beyond the current epidemic, and ultimately improved clinical diagnosis and care.

Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson's disease.

Wilson's disease (WD, MIM#277900) is an autosomal recessive disorder resulting in copper excess caused by biallelic variants in the ATP7B gene (MIM#606882) encoding a copper transporting P-type ATPase. ATP7B variants of unknown significance (VUS) are detected frequently, sometimes impeding a clear diagnosis. Functional analyses can help to classify these variants as benign or pathogenic. Additionally, variants already classified as (likely) pathogenic benefit from functional analyses to understand their pathomechanism, thus contribute to the development of personalized treatment approaches in the future. We described clinical features of six WD patients and functionally characterized five ATP7B missense variants (two VUS, three yet uncharacterized likely pathogenic variants), detected in these patients. We determined the protein level, copper export capacity, and cellular localization in an in vitro model and potential structural consequences using an ATP7B protein model based on AlphaFold. Our analyses give insight into the pathomechanism and allowed reclassification for the two VUS to likely pathogenic and for two of the three likely pathogenic variants to pathogenic.

Biallelic known and novel DCDC2 variants in cholestatic liver disease: Phenotype-genotype observations in four children.

Neonatal sclerosing cholangitis (NSC) is associated with progressing biliary fibrosis that often requires liver transplantation in childhood. Several recent studies have identified variants in DCDC2, encoding doublecortin domain-containing protein 2 (DCDC2), expressed in primary cilia, that accompany syndromic disease and NSC. We report four patients with hepatobiliary disease associated with two novel homozygous or compound heterozygous variants in DCDC2. Three patients with protein-truncating variants in DCDC2, expressing no DCDC2, presented with the originally described severe hepatic phenotype in infancy. One patient with a novel homozygous DCDC2 missense variant shows a markedly milder phenotype only manifest in childhood and with retained DCDC2 expression. Concomitant nephronophthisis is present in three patients and learning disability in two. This report widens the phenotypic spectrum of DCDC2-associated hepatobiliary disease. Testing for DCDC2 expression and DCDC2 variants should be included in the evaluation of cholangiopathy of unknown aetiology in childhood as well as in infancy.

Long-term outcome of primary percutaneous stent angioplasty for pediatric posttransplantation portal vein stenosis.

This study aims to evaluate the long-term efficacy and reintervention rate after primary percutaneous portal vein stent angioplasty for portal vein stenosis (PVS) in pediatric liver transplantation (LT) recipients. From 2004 to 2020, a total of 470 pediatric LTs were performed in our center. All cases were screened for interventional PVS treatment and analyzed retrospectively. We identified 44 patients with 46 percutaneous angioplasties for posttransplantation PVS. The median interval from LT to percutaneous catheter intervention was 5 months (16 days-104 months) with a median follow-up (f/u) period after catheter intervention of 5.7 years (2-156 months). In 40 patients, an endovascular stent was placed as primary (n = 38) or secondary (n = 2) intervention. The median age at stent placement was 23 (6-179) months with a median weight of 10 kg (6-46 kg). Technical success and relief of PVS were achieved in all patients irrespective of age or weight. Adverse events occurred peri-interventionally in two patients and were resolved with standard care. All primary portal vein (PV) stents remained patent until the end of f/u. Reinterventions have been successfully performed in 10 patients for suspected or proven restenosis, resulting in a primary patency rate of 75% and an assisted patency rate of 25%. The median time to reintervention was 6.2 years (range 1-10 years). The need for reintervention was independent of age or weight at both transplantation and initial angioplasty as well as of additional risk factors due to portal hypertension. Percutaneous transhepatic PV stent angioplasty in children is safe and effective in all age groups, with excellent long-term patency. Primary stent angioplasty should be considered as first-line treatment for PVS after pediatric LT.

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.

KIF12 Variants and Disturbed Hepatocyte Polarity in Children with a Phenotypic Spectrum of Cholestatic Liver Disease.

KIF12 has been identified as a cholestasis-associated candidate gene. We describe 6 cases from 4 unrelated families with diverse cholestatic phenotypes carrying 2 different homozygous KIF12 truncating variants. Immunofluorescence investigations of paraffin-embedded liver sections suggest that KIF12-associated impaired functional cell polarity may be the underlying cause.

Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review.

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS: We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS: Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION: The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.

[Solid Pseudopapillary Neoplasm of the Pancreas in Children and Adolescents - Tailored Diagnostic and Operative Concepts in Four Patients]. / Solide pseudopapilläre Pankreasneoplasie bei Kindern und Jugendlichen.

BACKGROUND: Pancreatic tumors in children and adolescents are rare entities that can stay asymptomatic for long periods. They often become apparent as incidental findings or due to clinical symptoms, like abdominal pain. Solid pseudopapillary neoplasms of the pancreas (SPN) are rare representatives of this group, being low-grade malignant processes and requiring radical surgical treatment. We present four cases of SPN with different diagnostic and therapeutic approaches. METHODS: A retrospective analysis of four cases of SPN treated between 2015 and 2020 was performed. RESULTS: Four female patients (11-17 years) were found to have SPN during diagnostic procedures. Three of them were located in the pancreatic head. Histological confirmation was obtained with endosonographic-, CT-guided and open biopsy, respectively. R0 resection was achieved by a pylorus preserving, partial duodenopancreatectomy according to Traverso-Longmire. In one patient the tumor was located in the pancreatic tail with tumor adherence to the splenic vessels. A CT guided biopsy confirmed an SPN. A distal pancreatectomy and splenectomy was performed. Follow-up (6 months - 6 years) revealed no evidence of tumor recurrence, metastasis, or pancreoprive diabetes. CONCLUSION: For the treatment plan preoperative histological confirmation of SPN is necessary. Based on the tailored diagnostic and operative concepts, treatment at a center with a specialized pediatric surgery, pediatric oncology, pediatric gastroenterology, pediatric radiology and pathology is mandatory.

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.

Survival Benefits Following Liver Transplantation: A Matched-pair Analysis in Pediatric Patients With Cystic Fibrosis.

OBJECTIVES: Cystic fibrosis-related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients. The aim of this study was to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison. METHODS: Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx, and details of surgical procedures. RESULTS: At our institution, 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of posttransplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. Five patients died after LTx, none because of primary hepatic dysfunction (1 because of posttransplant proliferative disorder, 4 because of infection). Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function, and life expectancy of CFLD patients with LTx are comparable with matched CF peers without CFLD. CONCLUSIONS: Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy, and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.

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.

MTF1 binds to metal-responsive element e within the ATP7B promoter and is a strong candidate in regulating the ATP7B expression.

Wilson's disease is an autosomal recessive disorder resulting from copper excess. Some patients with clinical Wilson's disease symptoms exhibit no or only heterozygous pathogenic variants in the coding region of the disease-causing ATP7B gene. Therefore, the ATP7B promoter region is of special interest. Metal-responsive elements (MREs) located in the ATP7B promoter are promising motifs in modulating the ATP7B expression. We studied protein interaction of MREe, MREc, and MREd by electrophoretic mobility shift assays and revealed specific interactions for all MREs. We further narrowed down the specific binding site. Proteins potentially binding to the three MREs were identified by MatInspector analyses. Metal regulatory transcription factor 1 (MTF1) could be validated to bind to MREe by electrophoretic mobility shift assays. ATP7B promoter-driven reporter gene expression was significantly increased because of this interaction. MTF1 is a strong candidate in regulating the ATP7B expression through MREe binding.

Hepatitis-associated Aplastic Anaemia in Children.

BACKGROUND: Children with idiopathic acute liver failure (IALF) are at a high risk of developing life-threatening bone marrow failure (BMF). The aim of the study was to describe the development, therapy and prognosis of this hepatitis-associated aplastic anaemia (HAAA) in comparison to isolated acquired aplastic anaemia. RESULTS: We retrospectively found 18 patients (9 female) of HAAA between 1984 and 2017 with an age of 1.4-16.4 years. Fifteen of them fulfilled the SAA criteria, 3 had a bone marrow hypoplasia. Eleven of these children received liver transplantation (LTx) (these were 11 of 42 (26%) children receiving LTx for IALF), 6 patients recovered without LTx. The first signs of BMF, thrombocytopaenia and leucocytopaenia, occurred before LTx in all cases. During the follow-up period 8 patients reached haematological remission, 6 received haematopoietic stem cell transplantation (HSCT). Seven children died in a median of 304 days after the first symptoms mostly because of bleedings and infections. To date, extensive investigations failed to detect a genetically, viral or immunological aetiology. No AA was diagnosed in the 41 patients receiving liver transplants during the same period for ALF of known aetiology. As a comparison group, we collected the data of patients with isolated SAA. 73% achieved a remission after Immunosuppressive therapy (IST) without HSCT, and none of them died during the follow-up period. CONCLUSION: Blood counts should be examined early and regularly (0-22 days after onset) in patients with IALF. Aggressive treatment with LTx, IST and HSCT appears to improve the prognosis.

High Burden of Subclinical Cardiovascular Target Organ Damage After Pediatric Liver Transplantation.

Cardiovascular (CV) events account for 8%-13% of deaths after liver transplantation (LT) in adulthood. Although CV risk factors (RFs) are present, little is known about the prevalence of subclinical CV target organ damage (TOD) in children after LT. The aim of this prospective observational study was to assess the prevalence of subclinical CV TOD in children after LT and to identify RFs contributing to CV damage as potential targets for clinical intervention. In this study, 104 children after LT (54% female, 46% male; aged 11.5 ± 3.8 years) underwent cross-sectional assessment of subclinical TOD by carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (IMT), and left ventricular mass index (LVMI). Results were correlated with the presence of CV RFs (obesity, hypertension, dyslipidemia, renal impairment, anemia, and microinflammation). Of the patients, 22% were exposed to 2 CV RFs, and 36% displayed 3 or more CV RFs. Pathological results for PWV, IMT, and LVMI were found in 21.9%, 57.0%, and 11.1% of patients, respectively. In the multivariate analysis, diastolic blood pressure (P = 0.01) and estimated glomerular filtration rate (eGFR; P = 0.03) were independently associated with PWV, eGFR (P = 0.005), and age at LT (P = 0.048) with IMT and body mass index with LVMI (P = 0.004). In conclusion, patients after pediatric LT carry a substantial burden of subclinical CV TOD. Identification of modifiable CV RFs opens opportunities for targeted intervention in order to reduce CV morbidity and mortality in the future.

Characterization of Glomerular Sox9+ Cells in Anti-Glomerular Basement Membrane Nephritis in the Rat.

Mechanisms of glomerular crescent formation and podocyte repair processes are still unclear. Therefore, we investigated the expression of the transcription factor Sox9 as a potential marker of a subpopulation of parietal epithelial cells (PECs) with potential regenerative properties. Glomerular Sox9 expression was characterized in detail in a rat anti-glomerular basement membrane (GBM) nephritis model using immunofluorescence and confocal laser scanning microscopy. In healthy kidneys Sox9 is expressed in a subpopulation of PECs restricted to approximately 20% to 50% of PEC nuclei and was highly conserved in all investigated species. During rat anti-GBM nephritis the number of glomerular Sox9+ cells increased and was associated with proliferation activity. In nephritic glomeruli Sox9 expression was not restricted to Bowman's capsule lining but was also found on cells of the glomerular tuft. Nearly all Sox9+ cells also expressed the PEC marker Pax8, whereas endothelial cells, mesangial cells, macrophages, and T lymphocytes lacked Sox9 expression. At the margins of crescents Sox9+/Pax8+ cells additionally expressed podocyte markers. In contrast, in sclerotic lesions a minority of Sox9+/Pax8+ cells expressed the myofibroblast marker α-smooth muscle actin. In glomerular Sox9+ cells Jagged 1 was up-regulated. During anti-GBM nephritis Sox9+ PECs proliferate and migrate onto the glomerular tuft. Future studies are needed to confirm the origin of Sox9+ cells from PECs and differentiation in both podocytes and/or myofibroblasts.

Impact of Immunosuppression on Executive Functioning After Pediatric Liver Transplantation: An Observational Cohort Study.

OBJECTIVES: Children after liver transplantation show increased rates of impaired cognitive functioning. We aimed to assess the potential effects of immunosuppressive therapy on executive functioning measured by the Children's Color Trail Test and the cognitive functioning module of the PedsQL (cogPedsQL) in liver transplanted children to explore potential targets for intervention to improve executive functioning. METHODS: We performed a cross-sectional study in 155 children (78 girls) aged 10.4 (2-18) years at 5.0 (0.1-17) years after liver transplantation, with follow-up at 6 months in n = 114. Executive functioning was assessed by Children's Color Trail Test (ages 8-16) and by patients and parent-proxy cogPedsQL (ages 5-18/2-18, respectively). Results were correlated with clinical parameters. Stability of results over time was compared between n = 23 patients who for clinical reasons switched from twice daily calcineurin inhibitor (CNI) to once-daily slow-release tacrolimus (Tac) during the study period, and patients with unchanged CNI. RESULTS: Worse executive functioning was associated with longer stay in the intensive care unit and longer time elapsed since transplantation. No difference was found between users of cyclosporine and Tac. Children on once-daily slow-release Tac performed better than children on twice-daily Tac. In children who switched from twice-daily CNI to once-daily Tac, parent-proxy cogPedsQL improved significantly compared to stable results in the nonswitch group. CONCLUSIONS: In addition to a strong impact of disease burden around transplantation, executive functioning appears to deteriorate over time. Although there is no clear-cut advantage of any CNI, once-daily Tac appears to be advantageous compared to twice-daily Tac.

Pediatric cirrhotic cardiomyopathy: Impact on liver transplant outcomes.

In adults, cirrhotic cardiomyopathy (CCM) has a significant incidence and impact on liver transplantation. For pediatric liver transplantation (pLT), data on liver-induced cardiac changes are scarce, and in particular, the comparison between cirrhotic and noncirrhotic liver disease has not been investigated. We retrospectively evaluated cardiac changes associated with CCM by echocardiography and 12-lead electrocardiogram in 198 pLT-candidates (median age 4.1 years) 4.2 before and 12 months after pLT. Results were correlated with the stage of liver fibrosis and cholestasis before transplantation. The left ventricular end-diastolic diameter (LVIDd) z score, left ventricular mass z score, and left ventricular mass index were significantly higher in cirrhotic patients (-0.10 versus 0.98, P < 0.001; -1.55 versus -0.42, P = 0.001; 78.99 versus 125.64 g/m2 , P = 0.001, respectively) compared with children with noncirrhotic liver disease. Pathological z scores (>2SDS) for the LVIDd occurred more frequently in cirrhotic patients compared with patients with noncirrhotic liver disease (31/169 versus 1/29; P = 0.03) and were significantly associated with cholestasis. All observed cardiac changes were reversible 1 year after pLT. Pathological LVIDd z scores correlated highly with intensive care unit (ICU) stay (9.6 days versus 17.1 days, respectively, P = 0.002) but not with patient survival pre-LT or post-LT. In contrast to other studies, prolonged QTc time was not associated with liver cirrhosis in our patients. In conclusion, CCM-associated cardiac changes in pLT candidates with cirrhotic liver disease are frequent, mild, and associated with cholestasis and reversible after pLT. They may impact peritransplant care and posttransplant hospitalization time. Further prospective evaluation is warranted. In particular, for QTc time prolongation etiological factors, possible protective effects of ursodeoxycholic acid treatment and the use as a screening parameter for CCM should be verified. Liver Transplantation 24 820-830 2018 AASLD.

Predictive Factors for Survival in Children Receiving Liver Transplants for Wilson's Disease: A Cohort Study Using European Liver Transplant Registry Data.

Liver transplantation (LT) is a rescue therapy for life-threatening complications of Wilson's disease (WD). However, data on the outcome of WD patients after LT are scarce. The aim of our study was to analyze a large pediatric WD cohort with the aim of investigating the longterm outcome of pediatric WD patients after LT and to identify predictive factors for patient and transplant survival. This is a retrospective cohort study using data of all children (<18 years) transplanted for WD enrolled in the European Liver Transplant Registry from January 1968 until December 2013. In total, 338 patients (57.6% female) transplanted at 80 different European centers (1-26 patients per center) were included in this study. The median age at transplantation was 14.0 years (interquartile range [IQR], 11.2-16.1 years); patients were followed up for a median of 5.4 years (IQR, 1.0-10.9 years) after LT. Overall patient survival rates were high with 87% (1-year survival), 84% (5-year survival), and 81% (10-year survival); survival rates increased considerably with the calendar year (P < 0.001). Early age at LT, living donation, and histidine tryptophan ketoglutarate preservation liquid were identified as risk factors for poor patient survival in the multivariate analysis. LT is an excellent treatment option for pediatric patients with WD and associated end-stage liver disease. Longterm outcome in these patients is similar to other pediatric causes for LT. Overall patient and graft survival rates improved considerably over the last decades. To improve future research in the field, the vast variability of allocation strategies should be harmonized and a generally accepted definition or discrimination of acute versus chronic WD needs to be found.

Bi-nucleation of podocytes is uniformly accompanied by foot processes widening in renal disease.

Background: Podocytes are terminally differentiated glomerular cells expressing a highly complex architecture and lacking the ability to proliferate. However, during renal injury or stress these cells can re-enter into the cell cycle but fail to divide. As a consequence, bi- and multi-nucleated podocytes can be identified in renal biopsies from patients with various kidney diseases. It is still unclear whether the occurrence of such cells is dependent on or correlates with renal damage and if bi- or multi-nucleation results in ultrastructural alterations such as e.g. foot process effacement. Therefore, we investigated the frequency, correlation with clinical parameters and morphological consequences of podocyte bi- or multi-nucleation in a cohort of 377 patients suffering from different renal diseases. Methods: Renal biopsies from patients with minimal change disease (MCD; n = 93), IgA-glomerulonephritis (IgA-GN, n = 95), lupus nephritis (LN; n = 90) and diabetic nephropathy (DN; n = 99) were investigated for the occurrence of bi-nucleated or multi-nucleated podocytes using semi-thin sections and light-microscopy at 1000× magnification. The frequency of bi-nucleation and multi-nucleation in podocytes was correlated with clinical parameters and markers of renal injury. In addition, ultrastructural morphological features associated with podocyte bi- or multi-nucleation were analysed by scanning transmission electron microscopy at various magnifications. Results: Ultrastructural analysis of podocyte nuclear morphology revealed a broad spectrum of nuclear appearances. Therefore, podocytes were classified in cells with mono-nucleated, lobulated, potential bi-nucleated, symmetrically bi-nucleated, asymmetrically bi-nucleated and multi-nucleated nuclear morphology. In 65-80% of all investigated glomeruli only mono-nuclear podocytes were identified. The highest frequency of bi-nucleated podocytes was found in patients with IgA-GN (18.6%) and the lowest in patients with DN (5.6%). The proportion of bi-nucleated podocytes with asymmetric nuclear morphology was about 50% of all bi-nucleated podocytes and independent of the underlying renal disease. In addition, ultrastructural analysis by electron microscopy showed significant widening of foot processes in bi-nucleated compared with mono-nucleated podocytes. Interestingly, foot process width of podocytes with lobulated nuclei was also significantly increased compared with podocytes with normal mono-nuclear morphology. Furthermore, podocyte density per glomerular area was significantly lower in glomeruli with bi-nucleated podocytes. Due to the relatively low frequency of bi- and multi-nucleated podocytes, correlations with clinical parameters were weak and dependent on renal disease. Conclusions: The frequency of bi-nucleated podocytes was highest in IgA-GN but can also be observed in all investigated renal diseases. In podocytes with altered nuclear morphology particularly in bi- and multi-nucleated podocytes ultrastructural analysis of podocytes revealed significant widening of foot processes as a potential maladaptive structural consequence.