Chapter 6.0. History of Paediatric Hepatology in ESPGHAN.

Hepatology played an important role in ESPGAN from the beginning. In 1989, the Hepatology Committee was started. In the early 1990s H for hepatology was included in ESPGHAN. Hepatology Summer schools were held from 1995 and later monothematic conferences met the needs of many young ESPGHAN members. The role of ESPGHAN members in the progress of diagnostic and therapeutic measures in hepatitis B and C will be elucidated (Chapter 6.1) as well as the role of other ESPGHAN members in the understanding of immunological hepatic disorders of childhood (Chapter 6.2). During childhood, many metabolic hepatic disorders threaten the life and health of children making orchestrated measures in diagnostic and therapeutic efforts necessary (Chapter 6.3). The pathophysiology of cholestasis was cleared by the detection of bile salt transporters, which were identified by ESPGHAN members in the Netherlands, France, United Kingdom and Germany (Chapter 6.4). Finally liver transplantation for acute fulminant and chronic end stage liver disease was established as a meanwhile standard treatment option (Chapter 6.5). Immunosupression in liver transplantation was improved and standardized through the cooperation of many ESPGHAN member driven studies (Chapter 6.6).

Intracellular ATP production in CD4+ T cells as a predictor for infection and allograft rejection in trough-level guided pediatric liver transplant recipients under calcineurin-inhibitor therapy.

BACKGROUND: The assessment of cell-mediated immune responses through the measurement of intracellular adenosine-tri-phosphate (iATP) production (Cylex ImmuKnow) as a pharmacodynamic biomarker of immune function represents a potential tool to optimize individual immunosuppressive therapy independent of drug dosage or trough levels. This study aims to investigate the correlations between iATP and adverse events, immunosuppression, calcineurin-inhibitor-trough levels, and age. METHODS: In this prospective trial, 31 nontransplant pediatric subjects and 50 consecutive children were included after they underwent liver transplantation (LTX). During the study period, 4 allograft rejections and 3 acute infections occurred. The patients were treated with cyclosporine, tacrolimus, mycophenolate mofetil, and everolimus either as monotherapy or in combinations. The reactivity of the immune system was measured as iATP concentration in CD4+ T-cells after in vitro stimulation by phytohemagglutinin. RESULTS: The iATP concentrations in patients with intercurrent, clinically significant infections were in the low immune response range (median iATP 181 versus 251 ng/mL, P = 0.308), whereas the patients with incidental allograft rejection had significantly higher iATP concentrations as compared with the event-free group (median iATP 444 versus 251 ng/mL, P = 0.017). However, there was a wide range of iATP concentrations in both nontransplant and LTX patient groups, and no clear iATP cut-off values for an increased risk of infection or rejection could be defined. Post LTX, stable-phase patients showed a significantly lower iATP compared with respective controls (median iATP 297 versus 384 ng/mL, P = 0.013). No significant correlation between calcineurin-inhibitor-trough concentrations and iATP was found. iATP was not correlated with age, but was inversely correlated with time after transplantation. CONCLUSIONS: The observed correlation between clinical events and iATP concentrations is similar to the findings previously reported in adult patients who underwent transplantation. The lack of correlation of iATP with trough drug concentrations suggests that the ImmuKnow assay provides independent information that may be useful to guide immunosuppressive therapy in pediatric (liver) transplant patients. However, the wide range of iATP levels in event-free patients suggests that serial iATP measurements will be necessary to assess and guide the individual immunosuppressive therapy. Further investigations are needed to evaluate and extend these findings.

ABO-incompatible Pediatric Liver Transplantation With Antibody and B-cell Depletion-free Immunosuppressive Protocol in High Consanguinity Communities.

The success of orthotopic liver transplantation as a life-saving treatment has led to new indications and a greater competition for organ grafts. Pediatric patients with acute liver-related crises can benefit from orthotopic liver transplantation, but organ availability in the limited time can be a major obstacle. Crossing ABO blood group barriers could increase the organs available to such patients. Methods: From November 2010 to June 2015, 176 children aged 0.2-to18 y were transplanted in the King Faisal Specialist Hospital and Research Center. Out of those, 19 children were transplanted across blood group barriers (ABO incompatible). The underlying diseases were biliary atresia (n = 6); progressive familial intrahepatic cholestasis type 2 (n = 4); Crigler-Najjar syndrome (n = 3); hepatoblastoma (n = 2); and urea cycle disorder, Caroli disease, cryptogenic cirrhosis, and neonatal sclerosing cholangitis (n = 1 each). Immunosuppression consisted of basiliximab, mycophenolate, tacrolimus, and steroids. Pretransplant prophylactic plasmapheresis, high-dose immunoglobulins, and rituximab were not administered. Results: The grafts were from living donors (n = 17) and deceased donors (n = 2). Living donor morbidity was nil. The recipient median age was 21 mo (5-70 mo). After a median follow-up of 44 mo, 2 recipients (10%) died because of sepsis, 1 because of uncontrolled acute myeloid leukemia. The overall rejection rate was 7%, and no grafts were lost because of antibody-mediated rejection (AMR). HLA matching was 3.8 of 6 (A, B, DR), and there were 2 patients presented with acute cellular rejection, 1 patient with AMR, and 1 patient with biliary strictures. Conclusions: ABO incompatible liver transplantation is a feasible and life-saving option even with antibody and B-cell depletion-free protocol without increasing the risks for AMR. We speculate that this excellent result is most likely because of presence of relatively low titer ABO isoagglutinins and the high HLA match compatibility caused by habit of longstanding interfamilial marriages as typical of Saudi Arabia.

Transcapsular arterial neovascularization after liver transplantation in pediatric patients indicates transplant failure.

PURPOSE: To identify transcapsular arterial neovascularization with Doppler ultrasonography (US) in pediatric patients after liver transplantation and to assess the frequency of the finding, its underlying causes, and its relevance in terms of clinical outcome. MATERIALS AND METHODS: The study was approved by the local ethics committee, with waived informed consent. All pediatric patients who underwent liver transplantation between January 2000 and December 2003 were retrospectively evaluated. Patients were followed up until June 2008, by using a predefined US protocol with prospective documentation. Of 182 consecutive liver transplantations performed in 162 patients (mean age, 4.5 years; range, 0.1-18.4 years) in this period, 25 patients with a total of 27 liver transplantations underwent US examinations conducted by multiple investigators and were primarily excluded. Student t tests and χ(2) tests were performed where appropriate. The Tarone-Ware test was used to compare transplant survival times. RESULTS: Transcapsular arterial neovascularization was noticed in 13 of 137 patients (9.5%) and in 13 of 155 liver transplants (8.4%). The mean time until arterial neovessels appeared was 157 days after liver transplantation (median, 97 days; range, 19-477 days). Arterial neovascularization was associated with pronounced transplant malperfusion and inflammatory changes (P < .001). Patients with transcapsular arterial neovascularization had a significantly shorter mean transplant survival time (1426.4 days ± 244.5 [standard error], with 95% confidence interval: 947.23, 1905.23, vs 2526.4 days ± 92.1, with 95% confidence interval: 2345.84, 2706.97; P = .008) and a higher retransplantation rate (53.8% vs 19.7%, P = .009). CONCLUSION: Transcapsular arterial neovascularization, detected with color Doppler US, occurred in 9.5% (13 of 137) of pediatric patients and 8.4% (13 of 155) of liver transplants and was associated with underlying malperfusion and inflammation. The diagnosis of transcapsular arterial neovascularization was associated with reduced graft survival times and a high retransplantation rate. The negative prognostic value of the sign may assist in a strategy of organ allocation.

Implications for the usage of the left lateral liver graft for infants ≤10 kg, irrespective of a large-for-size situation--are monosegmental grafts redundant?

Organ donor shortage for infant liver transplant recipients has lead to an increase in splitting and living donation. For cases in which even transplantation of the left lateral graft (Couinaud's segments II + III) results in a "large for size situation" with an estimated graft body weight ratio (GBWR) of >4%, monosegmental liver transplantation was developed. This, however, bears complications because of greater parenchymal surface and suboptimal vascular flow. We exclusively use the left lateral graft from living donors or split grafts. Temporary abdominal closure is attempted in cases of increased pressure. We report of 41 pediatric transplants in 38 children ≤10 kg. Within this group, there were 23 cases with a GBWR of ≥4, and 15 cases with a GBWR <4. There was no statistical difference in vascular or biliary complications. Despite a more frequent rate of temporary abdominal closure, we did not find a higher rate of intra-abdominal infections. Overall, patient and graft survival was excellent in both groups (one death, three re-transplants). We noticed, however, that the ventro-dorsal diameter of the graft appears to be more relevant to potential graft necrosis than the actual graft size. In conclusion, the usage of monosegmental grafts seems unnecessary if transplantation of left lateral grafts is performed by an experienced multidisciplinary team, and temporary abdominal closure is favored in cases of increased abdominal pressure.

Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation.

The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx). METHODS: One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively. RESULTS: In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8). CONCLUSIONS: This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.

De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis.

Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations of the bile salt export pump (BSEP [ABCB11]), an ATP-binding cassette (ABC)-transporter exclusively expressed at the canalicular membrane of hepatocytes. An absence of BSEP from the canalicular membrane causes cholestasis and leads to liver cirrhosis, which may necessitate liver transplantation in early childhood. We report on the first case of a child with PFIC-2 suffering from repeated posttransplant recurrence of progressive intrahepatic cholestasis due to autoantibodies against BSEP. These antibodies occurred after transplantation and were detected in the patient's serum and at the canalicular membrane of two consecutive liver transplants. The antibodies were reactive toward the first extracellular loop of BSEP, were of high affinity, and inhibited transport activity of BSEP, thus causing severe cholestasis. The patient had three homozygous, missense changes in the BSEP gene. Their combination resulted in the complete absence of BSEP, which explains the lack of tolerance, a prerequisite of autoantibody formation toward BSEP. The findings illustrate a novel disease mechanism due to a new class of functionally relevant autoantibodies resulting in cholestasis and subsequent liver failure.

A new pediatric liver transplantation program in Southern Germany. The Heidelberg experience.

pLTx is a highly complex procedure. It can only be performed safely by experienced teams. Starting a new pLTx program in a country with established centers must therefore avoid a learning curve. We have initiated a liver transplantation program for children in 2003. Medical standards were defined by a team of surgeons, pediatricians, radiologists, anesthesiologists, and pathologists before the first transplantation. An external expert in the field of pLTx supervised the whole process. In a pilot phase, six children weighing more than 20 kg were successfully transplanted. Following this series, the clinical pathways were re-evaluated, and the program was opened for children of all age groups. Between 2003 and 2008, 32 children received 34 organs. Sixty-eight percent of patients received a split-liver, 26% a full size organ, and 6% a reduced size graft. Four LRLTx were performed. Patient survival rate was 91%. We conclude that a new pLTx program can be established without a significant learning curve regarding mortality if a strict strategy of team-building is followed. In the pilot phase, small children and infants have to be referred and transplanted in an established center. An interdisciplinary team of specialists closely working together is the key for sustained success.

Liver transplantation in children with progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) is caused by mutations of the bile salt export pump or the multidrug resistance P-glycoprotein, resulting in chronic hepatic failure. Partial external diversion of bile or ileal bypass is effective in some cases and, in others, liver transplantation (OLT) is necessary. Forty-two children were included in this study. Twenty-six children suffered from PFIC type 2 and 16 from PFIC type 3. Symptoms included pruritus, cholestasis, liver cirrhosis, and growth retardation. Seventeen patients received external biliary diversion. Ten had to undergo OLT in the following course. As of this report, three of the remaining patients were on the wait list for OLT. Twenty-three children received a liver graft primarily with excellent outcome. Our data show that OLT is the option of choice in symptomatic PFIC and whenever liver cirrhosis is present. We suggest a very restrictive recommendation of external biliary diversion. However, gene therapy may be a future option for children with PFIC.

De novo autoimmune hepatitis after liver transplantation.

The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non-immune mediated liver diseases. They coined the term "de novo autoimmune hepatitis". Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres. The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1-positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP-autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value - which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur. Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo-antigens, neo-antigens in the liver, or self-antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co-stimulatory signals leading to the breaking of self-tolerance. The development of this disease in the presence of treatment with calcineurin inhibitors supports the view held by most specialists in autoimmune hepatitis that these drugs, even though effective in acute disease, are not helpful in the long-term management of autoimmune liver diseases.

Partial external biliary diversion in bile salt export pump deficiency: Association between outcome and mutation.

AIM: To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency. METHODS: Mutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [3H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays. RESULTS: A girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients' native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute, respectively. CONCLUSION: In summary, our findings suggest that residual function of BSEP as well as substrate specificity influence the therapeutic effectiveness of PEBD in progressive familial intrahepatic cholestasis type 2 (PFIC-2).

Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations.

BACKGROUND: Autosomal recessive mutations in deoxyguanosine kinase (DGUOK) have been identified in the hepatocerebral form of mitochondrial DNA (mtDNA) depletion syndrome. OBJECTIVES: To describe the clinical spectrum of DGUOK-related mtDNA depletion syndrome in 6 children and to summarize the literature. RESULTS: We identified pathogenic mutations in DGUOK in 6 children with the hepatocerebral form of mtDNA depletion syndrome. We describe the clinical, neuroradiologic, histologic, and genetic features in these children. All children showed severe hepatopathy, while involvement of other organs (skeletal muscle and brain) was variable. We identified 5 novel mutations (1 of them in 2 children) and 2 previously described mutations. Three different mutations affected the initial methionine, suggesting a mutational hot spot. One of our patients underwent liver transplantation; pathologic findings revealed (in addition to diffuse hepatopathy) a hepatocellular carcinoma, implying a possible link between mtDNA depletion syndrome and tumorigenesis. CONCLUSION: We studied 12 children with infantile hepatoencephalopathies and mtDNA depletion syndrome and found pathogenic DGUOK mutations in 6, suggesting that this gene defect is a frequent but not an exclusive cause of the hepatic form of mtDNA depletion syndrome.

Diaphragmatic hernia resulting in enterothorax following pediatric liver transplantation: a rare complication.

Diaphragmatic hernia is a rare complication following solid organ transplantation. We here report three pediatric patients suffering from posttransplant enterothorax. One patient with biliary atresia presented with clinical signs of peritonitis without showing pulmonary symptoms four weeks following liver transplantation. The second patient was admitted with suspected pneumonia, whereas the third patient presented with recurrent abdominal pain over weeks and physical examination revealed the unexpected diagnosis of enterothorax. All patients received split liver transplants. Unspecific clinical signs mislead to suspected infectious complication under immunosuppression. No apparent risk factors for diaphragmatic hernia could be identified. Diaphragmatic hernia can present with a variety of atypical clinical symptoms. Severe or prolonged abdominal complains should lead to x-ray examination. We speculate that the split liver technique used in our center could lead to this rare complication due to the different anatomic position of the liver transplant in the abdomen.

Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial.

BACKGROUND: Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection. We aimed to compare these drugs in children undergoing liver transplantation. METHODS: This 12-month multicentre, open-label, parallel-group, randomised study compared a dual tacrolimus regimen (tacrolimus/corticosteroids, n=93) with a triple ciclosporin microemulsion regimen (ciclosporin microemulsion/corticosteroids/azathioprine, n=92) in children who had had liver transplants (age < or =16 years, bodyweight < or =40 kg). Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion. Primary endpoint was the incidence of and time to first histologically proven acute rejection. We excluded patients from analysis if they did not receive the study drug, or were given incorrect medication. Otherwise patients were analysed in accordance with their random treatment allocation, irrespective of whether they switched medication during the trial. FINDINGS: Median age was 22 months (IQR 9-56) in the tacrolimus group and 17 months (9-54) in the ciclosporin microemulsion group. We noted no difference between treatment groups with respect to patient survival (93.4% vs 92.2%; p=0.77) or graft survival (92.3% vs 85.4%; p=0.16) at month 12 after transplant. The acute rejection free rate at study end (Kaplan-Meier method) was 55.5% for patients on tacrolimus and 40.2% for patients on ciclosporin microemulsion (p=0.0288). The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0% for tacrolimus-treated patients and 70.4% for ciclosporin-microemulsion-treated patients (p<0.0001). Overall, incidence of adverse events did not differ between groups. INTERPRETATION: Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children.

Cognitive abilities in children after liver transplantation.

BACKGROUND: The authors investigated the cognitive status during the late postoperative phase in children who had undergone liver transplantation (LTx). METHODS: The authors examined 44 children who had undergone liver transplantation at their center. The children were 8.9+/-2.3 (mean+/-SD) years of age and had received the transplant 6.1+/-2.6 years previously. In 24 of the 44 children, a living-related transplantation had been carried out. Cognitive abilities were assessed with the three subscales of the Kaufman Assessment Battery for Children (K-ABC): the sequential processing scale (SES), the simultaneous processing scale (SIS), and the achievement scale (AS). RESULTS: The children scored below the population mean but within the normal range on all subscales of the K-ABC. In the SIS and the AS, age at transplantation influenced the cognitive outcome, as the children who were younger at transplantation scored significantly better than the older children and their results were within the normal range. However, for the SES, no such differences were found. A multiple regression analysis revealed that duration of illness and height at transplantation predicts the performance in the SIS and the AS. To a lesser degree, type of transplantation (cadaveric vs. living-related) predicts performance in the AS. Performance in the SES was not predicted by any of these variables. Time since LTx and type of immunosuppressive regimen were not associated with the cognitive status after transplantation. CONCLUSIONS: Children who are younger, with a shorter duration of illness, and who are more physically developed before LTx have a better prognosis regarding their mental development. However, this result does not hold for sequential processing functions, which showed no relationship with any of these variables. This could indicate differential effects of liver disease and consecutive metabolic derangements on brain development during the preoperative phase.

Pediatric transplantation: the Hamburg experience.

BACKGROUND: Since starting our program in 1989, 455 pediatric orthotopic liver transplantations have been performed using all techniques. In April 2001, we experienced our last in-hospital death of a pediatric liver-transplant recipient. Since then, all our liver-transplant children (n=170) were able to be discharged from the hospital. The aim of this study is to analyze the actual status of pediatric liver transplantation at the University of Hamburg and to find future perspectives to improve the results after pediatric liver transplantation. METHODS: From May 4, 2001 until September 8, 2004, 22 (13%) whole organs, 18 (11%) reduced-size organs, 79 (47%) split organs, and 51 (30%) organs from living donors were transplanted into 142 patients. One hundred forty-one were primary liver transplants, 25 retransplants, 3 third, and 1 fourth liver transplants. Of the 170 orthotopic liver transplantations (OLT), 31 (18%) were highly urgent (United Network of Organ Sharing [UNOS] I). RESULTS: After 170 consecutive pediatric liver transplants, no patients died during the hospital course (100% patient survival<3 months), but overall, 5 (2.9%) recipients died during further follow-up. The 3-month and actual graft survival rates are 93% and 85%, respectively. Twenty (11.8%) children had to undergo retransplantation. However, patient survival was not sustained by longer graft survival. Analyzing our series, we see that graft survival after reduced-size liver transplantation showed a significantly lower rate versus living-donor liver transplantation. CONCLUSION: The learning curve in pediatric liver transplantation has reached a turning point where immediate patient survival is considered the rule. The challenge is to increase graft survival to the same level. The long-term management of the transplant patients, with the aim of avoiding late graft loss and achieving excellent quality of life, will become the center of the debate.

Renal failure and hypertension in Alagille syndrome with a novel JAG1 mutation.

Renal failure and hypertension in Alagille syndrome with a novel JAG1 mutation: Alagille syndrome is an autosomal dominant disorder involving liver, heart, eyes, face, skeleton, and other organs. Various renal abnormalities have also been associated with Alagille syndrome, whereas renal vascular hypertension combined with renal insufficiency has been reported in several cases. We describe a patient with a novel frameshift mutation (c.1880_1881insA) in the JAG1 gene who presented with chronic renal failure and hypertension but without evidence of renal vascular or aortic stenosis. The patient's chronic renal failure had persisted for several years. His high blood pressure seemed to be due to renal parenchymal changes and was treated with ACE-inhibitors without worsening his renal function. This novel JAG1 mutation revealed great variability of the phenotype. The patient's daughter suffered from severe paucity of intrahepatic bile ducts and received a liver transplant at the age of two years. These findings are discussed including a review of the literature.

Cognitive performance of children who have undergone liver transplantation.

BACKGROUND: We investigated the cognitive status and quality of life (QoL) in the late postoperative phase of children who had undergone liver transplantation (LTx). METHODS: The sample consisted of 29 children who had undergone LTx at our center. The children were at least 6 years of age and had received the transplant between 3 and 10 years (mean 6.4 years) previously. In 16 of the 29 children, a living-related transplantation had been performed. Cognitive function was assessed with the three subscales of the Kaufman Assessment Battery for Children (K-ABC): the sequential processing scale, simultaneous processing scale, and achievement scale. QoL was measured with a specific questionnaire for children. RESULTS: The children scored below the population mean but within the normal range on all subscales of the K-ABC, except for the sequential processing scale, on which the children scored significantly below the norm and below their own performance on the simultaneous processing scale. Scores were below average for everyday and psychic functions and in the normal range for social and physical functions on the QoL questionnaire. Age at transplantation and achievement in the K-ABC were highly negatively correlated. A multiple regression analysis revealed that age and height at transplantation, and also to a lesser degree the type of transplantation, predict the level of cognitive functioning in the late postoperative phase. CONCLUSION: We conclude that the cognitive functions and QoL of children in the late postoperative phase who have undergone LTx are at the lower end of the norm in the long-term follow-up. Children who are younger and more physically developed at the time of transplantation will have a better mental-development prognosis.