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Liver tumors are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic, and surgical challenges sufficient to tax even the most experienced clinician. This article outlines the epidemiology, etiology, pathologic condition, initial workup, and management of hepatocellular carcinoma in children and adolescents.

This ongoing, randomized phase III study assesses the safety and efficacy of entecavir versus placebo in nucleos(t)ide-naïve children (2 to18 years) with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B (CHB). Blinded treatment was administered for a minimum of 48 weeks. After week 48, patients with HBeAg seroconversion continued blinded treatment; those without switched to open-label entecavir. The primary endpoint was HBeAg seroconversion and HBV DNA50 IU/mL at week 48. A total of 180 patients were randomized (2:1) and treated. Baseline median age was 12 years, with approximately 50% of children ages12 to18, and 25% each ages ≥2 to ≤6 and6 to ≤12. Rates for the primary endpoint at week 48 were significantly higher with entecavir than placebo (24.2% [29 of 120] vs. 3.3% [2 of 60]; P = 0.0008). Furthermore, higher response rates were observed with entecavir compared with placebo for the key week 48 secondary endpoints: HBV DNA50 IU/mL (49.2% [59 of 120] vs. 3.3% [2 of 60]; P0.0001); alanine aminotransferase normalization (67.5% [81 of 120] vs. 23.3% [14 of 60]; P0.0001); and HBeAg seroconversion (24.2% [29 of 120] vs. 10.0% [6 of 60]; P = 0.0210). Among entecavir-randomized patients, there was an increase in all efficacy endpoints between weeks 48 and 96, including an increase from 49% to 64% in virological suppression. The cumulative probability of emergent entecavir resistance through years 1 and 2 of entecavir was 0.6% and 2.6%, respectively. Entecavir was well tolerated with no observed differences in adverse events or changes in growth compared with placebo.In childhood CHB, entecavir demonstrated superior antiviral efficacy to placebo with a favorable safety profile. These results support the use of entecavir as a therapeutic option in children and adolescents with CHB.

Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal malformation syndrome characterized by renal cystic dysplasia, central nervous system malformations (typically, posterior occipital encephalocele), and hepatic developmental defects. Two MKS genes, MKS1 and MKS3, have been identified recently. The present study describes the cellular, sub-cellular and functional characterization of the novel proteins, MKS1 and meckelin, encoded by these genes. In situ hybridization studies for MKS3 in early human embryos showed transcript localizations in agreement with the tissue phenotype of MKS patients. Both MKS proteins predominantly localized to epithelial cells, including proximal renal tubules and biliary epithelial cells. MKS1 localized to basal bodies, while meckelin localized both to the primary cilium and to the plasma membrane in ciliated cell-lines and primary cells. Meckelin protein with the Q376P missense mutation was unable to localize at the cell membrane. siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated epithelial cell-line blocked centriole migration to the apical membrane and consequent formation of the primary cilium. Co-immunoprecipitation experiments show that wild-type meckelin and MKS1 interact and, in three-dimensional tissue culture assays, epithelial branching morphogenesis was severely impaired. These results suggest that MKS proteins mediate a fundamental developmental stage of ciliary formation and epithelial morphogenesis.

Purpose of review Long-term survival in paediatric liver transplantation has focused attention on morbidity related to immunosuppression and the need to reduce dependence on calcineurin inhibitors and corticosteroid steroids. Recent findings This review summarizes lessons learnt from paediatric and adult liver and renal transplantation in the use of steroid-free induction, withdrawal or minimization. Large randomized studies in adult liver and renal transplantation have indicated that rejection rates are similar on steroid-free protocols compared with either historical or randomized controls. There are significant differences in infection rates, new onset diabetes mellitus, hypertension and hyperlipidaemia, but 2- and 5-year patient and graft survival were similar, indicating that steroid avoidance was possible with the use of IL-2 receptor antibody protocols. The severity of and fibrosis rate in hepatitis C disease is less on steroid-free regimes. There was no clear effect on the development of other allorecognition or tolerance. Summary Steroid minimization is advantageous for paediatric practice and is safe and effective in the short term. Large-scale paediatric randomized studies are required to evaluate the long-term efficacy of these regimes and the use of IL-2 antibodies on the development of chronic rejection, infection, including posttransplant lymphoproliferative disease, and the development of tolerance.

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Background. Children with primary hyperoxaluria type 1 (PH 1) often develop severe growth failure, which is related to metabolic and endocrine consequences of chronic renal failure, and/or oxalate deposition in bone and cartilage. Combined liver and kidney transplantation (LKT) corrects the underlying metabolic defect and restores renal function in these children. Methods. We therefore analyzed longitudinal growth of 24 children with PHI who underwent LKT at nine European centers. Mean age at LKT was 8.9 years, and mean duration of follow-up was 5.7 years. Results. After LKT mean standardized height tended to increase from -1.79 SD to -1.47 SD until last observation. Mean adult height amounted to 167 cm and 158 cm in boys and girls, respectively. At last observation, seven out of 24 patients were stunted. Within the whole study population, the degree of catch-up growth after LKT was positively associated with degree of stunting at the time of LKT and negatively associated with prednisolone dosage explaining together 39% of the overall variability. Conclusions. Combined LKT does not induce true catch-up growth in the majority of children with PHI. Due to the preexisting growth retardation at the time of LKT, one third of patients end up with a reduced final height.

Intestinal failure-associated liver disease develops in 40% to 60% of infants who require long-term total parenteral nutrition (TPN) for intestinal failure and 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults. The pathogenesis is multifactorial. In infants it is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis. Other important mechanisms include lack of enteral feeding, which leads to reduced gut hormone secretion; reduction of bile flow and biliary stasis, which leads to the development of cholestasis; and biliary sludge and gallstones, which exacerbate hepatic dysfunction. In adults, IFALD is less common and related to age, length of time on PN, total caloric intake, and lipid or glucose overload. In preterm infants, a deficiency of taurine or cysteine may play a role, whereas in both adults and children, choline deficiency may exacerbate IFALD. Lipid emulsions, choline deficiency, and manganese toxicity are associated with both hepatic steatosis and cholestasis in adults and children. Management strategies for the prevention of intestinal failure-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The addition of choline, taurine, and cysteine to PN solutions may also play a role. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gallbladder stasis. Survival after either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years, making this an acceptable therapeutic option in adults and children with irreversible liver and intestinal failure.

Summary Liver disease is rare in childhood, but new means of diagnosis and therapy, including transplantation, have altered its natural history and outcome. It is important that paediatricians are aware of these diseases and their management. Chronic liver failure may be caused by unresolved neonatal liver disease, either inherited biliary hypoplasia or extrahepatic biliary atresia, whereas in older children, autoimmune liver disease, cystic fibrosis and non-alcoholic steatohepatitis (fatty liver disease) are the most common causes. Treatment includes specific medication, nutritional support and liver transplantation, which now has a 90% survival with a good quality of life. Children with significant liver disease should be managed by shared care between a regional and a specialist centre.

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly1,2,3. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus7,8. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995–amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

The long-term histological outcome after pediatric liver transplantation (OLT) is not yet fully understood. De novo autoimmune hepatitis, consisting of histological chronic hepatitis associated with autoantibody formation and allograft dysfunction, is increasingly recognized as an important complication of liver transplantation, particularly in the pediatric population. In this study, 158 asymptomatic children with 5-year graft survival underwent protocol liver biopsies (113, 135, and 64 at 1, 5, and 10 years after OLT, respectively). Histological changes we re correlated with dinical,biochemical, and serological findings. All patients received cydosporine A as primary immunosuppression with withdrawal of corticosteroids at 3 months post OLT. Normal or near-normal histology was reported in 77 of 113 (68%), 61 of 135 (45%), and 20 of 64 (31%) at 1, 5, and 10 years, respectively. The commonest histological abnormality was chronic hepatitis (CH), the incidence of which increased with time [25/113 (22%), 58/135 (43%), and 41/64 (64%) at 1, 5, and 10 years, respectively) (P < .0001)]. The incidence of fibrosis associatedwith CH increasedwith time [13/25 (52%), 47/58 (81%), and 37/41 (91%) at 1, 5, and 10 years, respectively) (P < .0001)]. The severity of fibrosis associated with CH also increased with time, such that by 10 years 15% had progressed to cirrhosis. Aspartate aminotransfemse (AST) levels were slightly elevated in children with CH (median levels 52 IU/L, 63 IU/L, and 48 IU/L at 1, 5, and 10 years, respectively), but this did not reach statistical significance compared with those with normal histology. On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity (present in 13% and 10% of children with normal biopsies at 5 and 10 years, respectively, and 72% and 80% of those with CH at 5 and 10 years, respectively) (P < .0001). Four children with CH and autoantibodies, who also had raised immunoglobulin G (IgG) levels and AST greater than 1.5 x normal fulfilled the diagnostic criteria for de novo autoimmune hepatitis (AIH). Another two were found to be hepatitis C positive. No definite cause for CH could be identified in the other cases. In condusion, chronic hepatitis is a common finding in children after liver transplantation and is associated with a high risk of developing progressive fibrosis, leading to cirrhosis. Standard liver biochemical tests cannot be relied on either in the diagnosis or in the monitoring of progress of chronic allograft hepatitis. In contrast, the presence ofautoantibodies is strongly associated with the presence of CH. The cause of chronic hepatitis in transplanted allografts is uncertain but may be immune mediated, representing a hepatitic form of chronic rejection.

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus.

To study the etiology, outcome and prognostic indicators in children with fulminant hepatic failure in the United Kingdom.Retrospective review of all patients17 years with fulminant hepatic failure from 1991 to 2000. Fulminant hepatic failure was defined as presence of coagulopathy (prothrombin time24 seconds or International Normalized Ratio2.0) with or without hepatic encephalopathy within 8 weeks of the onset of symptoms.Liver Unit, Birmingham Children's Hospital, United Kingdom.Ninety-seven children (48 male, 49 female; median age, 27 months; range, 1 day-192.0 months) were identified with fulminant hepatic failure. The etiologies were: 22 metabolic, 53 infectious, 19 drug-induced, and 3 autoimmune hepatitis. The overall survival rate was 61%. 33% (32/97) recovered spontaneously with supportive management. Fifty-five children were assessed for liver transplantation. Four were unstable and were not listed for liver transplantation; 11 died while awaiting liver transplantation. Liver transplantation was contraindicated in 10 children. Of the 40 children who underwent liver transplantation, 27 survived. Children with autoimmune hepatitis, paracetamol overdose or hepatitis A were more likely to survive without liver transplantation. Children who had a delay between the first symptom of liver disease and the onset of hepatic encephalopathy (median, 10.5 days versus 3.5 days), higher plasma bilirubin (299 micromol/L versus 80 micromol/L), higher prothrombin time (62 seconds versus 40 seconds) or lower alanine aminotransferase (1288 IU/L versus 2929 IU/L) levels on admission were more likely to die of fulminant hepatic failure or require liver transplantation (P0.05). On multivariate analysis, the significant independent predictors for the eventual failure of conservative therapy were time to onset of hepatic encephalopathy7 days, prothrombin time55 seconds and alanine aminotransferase/=2384 IU/L on admission.Children with fulminant hepatic failure with severe coagulopathy, lower alanine aminotransferase on admission and prolonged duration of illness before the onset of hepatic encephalopathy are more likely to require liver transplantation. Early referral to a specialized center for consideration of liver transplantation is vital.

Calcineurin inhibitor drugs (CNI), cyclosporin and tacrolimus are potent immunosuppressants, which have improved survival after liver transplantation. We evaluated long-term renal function in children receiving calcineurin inhibitors after liver transplantation. A retrospective analysis of all children undergoing orthotopic liver transplantation (OLT) from 1989 to 1999 who survived 1-yr post-transplantation was performed. All received prednisolone and either cyclosporin and azathioprine or tacrolimus. Steroids were withdrawn at 3 months and cyclosporin/tacrolimus monotherapy was initiated 12 months post-OLT. Calculated glomerular filtration rate (cGFR) was calculated using the modified Counahan-Barratt formula and measured pretransplant, 3, 6 and 12 months post-transplant and annually thereafter. Data were analysed in a serial manner to evaluate the trend of cGFR over time selectively using the Wilcoxon signed rank test and paired t-tests as appropriate. A total of 113 patients (65 males:48 females) were followed up for more than 1 yr (maximum 5 yr). Median (range) age at transplantation was 26 months (3-177). There was a significant fall of 35% in cGFR at 3 months compared with the pretransplant value (p = 0.001). By 12 months following the reduction in immunosuppression dosage, renal function stabilized with a slight improvement in cGFR which reached 76% of the pretransplant value at 5 yr (p < 0.001). Children who were

The development of transitional care is one of the major challenges for the twenty-first century as the survival rates and medical outcomes for child and adolescent recipients of solid organ transplants continue to improve. Such developments must include pediatric and adult care providers and require training of professionals in both arenas. Transition is a process in which the transfer to adult care is only one event within that process. The key elements of transition for pediatric recipients are discussed, and the importance of a coordinated, structured, multidisciplinary approach involving the adolescents themselves is highlighted.

Combination of cyclosporine (CsA) and tacrolimus immunosuppression post-liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty-six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre- and post-LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2, respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT.

Adolescence is a difficult time for transplant recipients; they must learn to take responsibility for their own behavior and medication, and to balance their developing sexuality in a body that has been transformed by the adverse effects of immunosuppression. More than 80% of children survive transplantation to adolescence and adulthood, thus long-term outcome and tailoring of immunosuppression is of great importance. To date, the most experience with long-term immunosuppression regimens is cyclosporine, which is well tolerated and effective. Long-term adverse effects include hypertension, nephrotoxicity, and post-transplant lymphoproliferative disease (PTLD). The recent development of tacrolimus has improved the cosmetic adverse effects related to cyclosporine, but has similar rates of hypertension and nephrotoxicity, and possibly a higher rate of PTLD. There has been a recent, welcome development in renal sparing drugs, such as mycophenolate mofetil, which has no cosmetic adverse effects, does not require drug level monitoring and is thus particularly attractive to teenagers. Recent surveys demonstrate recovery of renal function with mycophenolate mofetil, if started prior to irreversible renal dysfunction. There are currently little published data on the use of sirolimus (rapamycin) in the pediatric population, but preliminary studies suggest that the future use of interleukin-2 receptor antibodies may be beneficial for immediate post-transplant induction of immunosuppression. It is important when planning immunosuppression for adolescents to consider the effects of drug therapy on both males and females in order to maintain fertility and to ensure safety in pregnancy. Noncompliance is a problem in this age group, but adequate practical measures and support should reduce noncompliance, and allow good, long-term graft function.

Summary. Introduction. Gingival overgrowth associated with immunosuppression following liver transplantation is a commonly recognized clinical problem. The aims of this study were to determine the incidence of gingival overgrowth in a group of children post liver transplantation and to compare gingival overgrowth in children receiving FK506 with those receiving cyclosporin. Methods. Seventy-nine children (aged 15–196 months) undergoing liver transplantation at Birmingham Children's Hospital between October 1998 and October 2000 were studied. Gingival overgrowth was assessed in a blinded fashion and scored in a previously validated manner. Gingival overgrowth scores of the patients on each immunosuppressant drug were then compared. Results. Fifty-two patients were treated with cyclosporin and 27 treated with tacrolimus. Eighteen children were also receiving nifedipine (also known to cause gingival overgrowth) and were considered separately. Of the 41 children receiving cyclosporin alone, 26 exhibited gingival overgrowth compared to zero of 20 patients receiving tacrolimus alone. Those children treated with immunosuppression plus nifedipine developed gingival overgrowth, however, this was much less marked in the tacrolimus group. Conclusion. Tacrolimus, unlike cyclosporin, is not associated with gingival overgrowth when used for immunosuppression following liver transplantation in children, and may be the drug of choice for children.

Adolescence is a difficult time for transplant recipients, who need to cope with the challenges of becoming independent from their parents, as well as taking responsibility for their own behavior and medication. They need to balance their developing sexuality with a body image which may be affected by the side-effects of immunosuppression. It is now anticipated that more than 80% of children will survive their transplant to become teenagers and adults, and it is therefore important to ensure that immunosuppressive medication is acceptable, convenient for drug level monitoring and free of significant long-term side-effects.

Summary. Objective. To determine whether cytomegalovirus (CMV) is associated with gingival overgrowth in paediatric liver graft recipients treated with cyclosporin. Study design. Thirty-four children, 25 of whom were under 5 years of age, who had undergone liver transplantation, were examined. An Index of Severity of Gingival Overgrowth was used to measure the prevalence and severity of the gingival overgrowth. The trough cyclosporin level was recorded and the CMV status of the patient matched to the dental findings. The association between the severity of gingival overgrowth and CMV infection was examined using the contingency coefficient. An anova was used to assess the association between the circulating trough cyclosporin concentration and the severity of gingival overgrowth. Pearson's Product Moment Correlation Coefficient was used to examine the association between the duration of exposure to cyclosporin and the severity of gingival overgrowth. Results. There was a significant inverse association between the duration of exposure to cyclosporin and the severity of gingival overgrowth. There was no relationship between the trough cyclosporin concentration and the severity of gingival overgrowth. There was no association between CMV and gingival overgrowth. Conclusion. Gingival overgrowth was related to the duration of cyclosporin therapy but was neither more prevalent nor more severe in subjects who were CMV seropositive.

Background and Aim Life expectancy in patients with cystic fibrosis (CF) has recently improved due to numerous factors, including a multidisciplinary approach to their management. Prolonged survival may have led to an increasing impact of liver disease on the prognosis of CF patients. The aim of this study was to assess the role of liver transplantation in patients with CF. Methods The factors influencing outcome in 24 patients (15 adults and nine children) with CF who have received single liver transplantation, triple heart-lung-liver transplantation (tx) or died while being assessed for triple grafting, were analyzed. Results Median age at tx in single liver recipients (13 years) was lower than in triple graft recipients (21 years) and those who died (23 years). All patients who received single liver tx made an excellent recovery, including significant improvement of their respiratory function (mean forced vital capacity (FVC) increased from 61% before transplantation to 82% of expected, 6–9 months after tx). Four out of five patients who received triple tx died (0–2 months) after operation. On the basis of our retrospective review, we propose modifications to an existing scoring system for liver tx assessment in CF by scoring additional points for elevated white blood count, bilirubin, and impaired pulmonary function. These changes will need to be evaluated prospectively to confirm their predictive value. Conclusions Liver transplantation is effective therapy in young patients with cystic fibrosis, portal hypertension and hepatic dysfunction, and is indicated before a critical stage of deteriorating lung function is reached. In patients with both end-stage liver and lung disease, triple tx has a poor prognosis. Pre-emptive liver tx in younger patients with CF not only has a better outcome but improves lung function.

Catastrophic genomic alterations may drive aggressive cancer phenotypes. We describe a diagnostically challenging and rapidly fatal case of medullary thyroid carcinoma (MTC) occurring in a young, morbidly obese man presenting with diffuse bone marrow involvement and disseminated intravascular coagulation. Whole-exome (WES) and shallow whole-genome sequencing (sWGS) were carried out for the primary tumour, adjacent normal, bone marrow tissues, multiple metastases and blood samples derived from the patient. We identified three germline single nucleotide polymorphisms (SNPs) within the RET proto-oncogene that remained undetected using routine hospital genetic testing procedures. One variant (L769L) has been previously reported to be associated with aggressive MTC presentation yet remains untested for in the routine diagnosis of MTC. Supported by findings from both WES and sWGS, we report for the first time in thyroid cancer on the occurrence of a “chromothripsis-like pattern”, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, along with dramatic widespread copy number aberrations across both primary tumour and bone marrow samples. Based on the somatic variants identified, we describe the evolutionary pathway of the case, showing that bone marrow metastasis occurred separately to other metastatic sites. The presence of disease-associated SNPs within the RET proto-oncogene supports their inclusion as part of routine genetic testing for MTC cases. The copy number aberrations and chromothripsis-like pattern affected a much broader range of genes than single mutations and may have led to the widespread chromosomal instability evident, possibly contributing to the rapid fatal course of the case. These results provide a rationale for the application of comprehensive genomic analysis of cancers presenting with unusual and aggressive phenotypes to facilitate more appropriate therapeutic options and diagnoses. Citation Format: Darran P. O'Connor, Sudipto Das, Deirdre Kelly, Bruce Moran, Kathleen Han, Niall Mulligan, Ciara Barrett, Patrick Buckley, Peter McMahon, J McCaffrey, Henrik van Essen, Kate Connor, Bauke Ylstra, Diether Lambrechts, William M. Gallagher, Catherine M. Kelly. Post-mortem examination of an aggressive case of medullary thyroid cancer characterised by catastrophic genomic abnormalities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3397. doi:10.1158/1538-7445.AM2017-3397

e20557 Background: Patients with synchronous de novo EGFR sensitising and resistance mutations are rare. Little is known about the response of these patients to EGFR TKIs, especially in a Caucasian population. Methods: We identified NSCLC patients found to have EGFR mutations using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing using a large multi-institutional database. Baseline clinical characteristics, response rate, progression free survival (PFS) and overall survival (OS) were calculated. Results: From 2008-2015, we observed de novo synchronous EGFR sensitising and resistance mutations in 12 patients representing an overall incidence of 3.6% of EGFR mutants and 0.4% of all NSCLC patients tested. Seven patients were treated using EGFR TKI therapy with erlotinib. In all cases, T790M (n = 4,50%) or S768I (n = 4, 50%) occurred concurrently with another sensitising EGFR mutation, either L858R (n = 4, 34%) or exon 19 deletion (n = 8, 66%). Objective responses were seen in two patients (29%). Three further patients had stable disease lasting 6, 23 and 54 months respectively. The median progression-free survival was 24 months and the median overall survival was 34 months. All patients with baseline EGFR S768I mutations (n = 3) had an objective response or stable disease on erlotinib while two of four patients with T790M demonstrated de novo resistance. Conclusions: This is the largest Irish review of synchronous de novo EGFR mutations. The incidence of co-occurring EGFR mutations was 0.4% and erlotinib demonstrated activity in this cohort of patients. Ongoing trials will determine whether next-generation EGFR TKIs such as osimertinib are preferable as first-line therapy in these patients.

e15076 Background: With the advent of colon cancer screening, patients with early stage colon cancer will be more common in our clinics. The evidence supporting the absolute benefit of chemotherapy in resected Stage II and (to a lesser extent) Stage IIIA disease is poor. Not all patients benefit from chemotherapy and toxicity is a problem. There is a need for validated biomarkers to assess individual patient recurrence risk and discriminate absolute treatment benefit. Several studies have validated the role of the OncotypeDX testing in Stage II/IIIA disease. Our objective is to characterize whether this test impacted oncologists’ decisions in treating patients with Stage II/IIIA in the adjuvant setting. Methods: :The Onco typeDX assay is a multi-gene reverse-transcriptase-polymerase-chain-reaction test that analyses the expression of 12 genes involved in key biologic pathways in colon cancer. Stage II and Stage IIIA colon cancers were studied in affiliated hospitals of our region in southwest Ireland. All data collected is prospective and each colon cancer was assigned a recurrence risk score. Oncologists were blinded to this score and the decision to prescribe adjuvant chemotherapy was recorded. After un-blinding the score, a second decision was recorded and comparisons made. Results: :From August 2015 to September 2016, 70 patients have been recruited with M: F of 2:1. Median age at diagnosis was 65 years. Most patients (80%) had stage II disease, 11 of whom had mismatch repair loss on IHC. OncotypeDX testing has been carried out and reported for 59 patients (85%), MMR intact. Recurrence scores: < 30 in 46 patients (77.9%), 30-40 in 10 patients, and > 40 in 3 patients. The treatment plan was altered in 16 patients (27%), of whom 12 patients (20%) received none or less intense chemotherapy. Conclusions: We have shown that the decision to prescribe adjuvant chemotherapy was changed in 27% of patients. This test has helped to define patients with low scores, where chemotherapy-related toxicity is a concern especially in older patients. Absolute benefit of adjuvant chemotherapy versus the risk of toxicity should be discussed. . Hospital managers may be interested in cost savings due to a reduction in chemotherapy use.

Liver transplantation has transformed survival for children with liver disease necessitating the transfer of a growing number of patients to the adult healthcare service. The impact of transfer on outcomes remains unclear. The aim of this single-center study of 137 consecutive pediatric liver transplant recipients was to examine the effect of transfer on patient and graft survival. The median time from transplant to transfer was 10.4 years and the median age of the patients at transfer was 18.6 years. After transfer, there were 5 re-transplants and 12 deaths in 14 patients. The estimated posttransfer 10-year patient and graft survival was 89.9% and 86.2%, respectively. Overall, 4 patients demonstrated graft loss as a consequence of chronic rejection. Graft loss was associated with older age at first transplant (p = 0.008). When compared to young adult patients transplanted in the adult center, the transferred patients did not have inferior graft survival from the point of transfer (HR 0.28; 95% CI 0.10-0.77, p = 0.014). This suggests that transfer did not impact significantly on graft longevity. In conclusion, pediatric liver transplant recipients who undergo transfer to the adult service have good long-term outcomes.

The rapid development of new diagnostic tests and improved therapy, especially the success of liver transplantation, has changed the outcome for children with liver disease, many of whom survive into adolescence without liver transplantation. The indications for transplantation in adolescence are similar to pediatric indications and reflect the medical advances made in this specialty that allow later transplantation. These young people need a different approach to management that involves consideration of their physical and psychological stage of development. A focused approach to their eventual transition to adult care is essential for long-term survival and quality of life.

Background. Proton Magnetic Resonance Spectroscopy (1H-MRS) is a non-invasive imaging technique that enables quantification of neurochemistry in vivo and thereby facilitates investigation of the biochemical underpinnings of human cognitive variability. Studies in the field of cognitive spectroscopy have commonly focused on relationships between measures of N-acetyl aspartate (NAA), a surrogate marker of neuronal health and function, and broad measures of cognitive performance, such as IQ.Methodology/Principal Findings. In this study, we used 1H-MRS to interrogate single-voxels in occipitoparietal and frontal cortex, in parallel with assessments of psychometric intelligence, in a sample of 40 healthy adult participants. We found correlations between NAA and IQ that were within the range reported in previous studies. However, the magnitude of these effects was significantly modulated by the stringency of data screening and the extent to which outlying values contributed to statistical analyses.Conclusions/Significance. 1H-MRS offers a sensitive tool for assessing neurochemistry non-invasively, yet the relationships between brain metabolites and broad aspects of human behaviour such as IQ are subtle. We highlight the need to develop an increasingly rigorous analytical and interpretive framework for collecting and reporting data obtained from cognitive spectroscopy studies of this kind.

Liver disease in the UK stands out as the one glaring exception to the vast improvements made during the past 30 years in health and life expectancy for chronic disorders such as stroke, heart disease, and many cancers. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost fi ve-times. Liver disease constitutes the third commonest cause of premature death in the UK and the rate of increase of liver disease is substantially higher in the UK than other countries in western Europe. More than 1 million admissions to hospital per year are the result of alcohol-related disorders, and both the number of admissions and the increase in mortality closely parallel the rise in alcohol consumption in the UK during the past three decades. The new epidemic of obesity is equally preventable. Of the 25% of the population now categorised as obese, most will have non-alcoholic fatty liver disease many (up to 1 in 20 of the UK population) will have ongoing infl ammation and scarring that fi nally leads to cirrhosis. Of those patients with cirrhosis, 5-10% will get liver cancer. This increasing burden of liver disease is added to by chronic viral hepatitis; annual deaths from hepatitis C have almost quadrupled since 1996 and about 75% of people infected are estimated to be still unrecognised. The same applies to chronic hepatitis B infection, in which progression to cirrhosis and liver cancer also happens. The number of silently infected individuals in the UK is increasing every year as a result of immigration from countries with a high prevalence of hepatitis B and hepatitis C infections. Costs to the UK's National Health Service are equally staggering, with estimates of £3.5 billion per year for alcohol-related health problems and £5.5 billion per year for the consequences of obesity. Obesity costs are almost certainly an underestimate now that the disorder is recognised as an important factor in several common cancers, including breast cancer and colon cancer.1 Obesity is a factor in metabolic disorders-the basis of diabetes, hypertension, cardiac diseases, and strokes. Furthermore, the poorest and most susceptible in society have the highest incidence of liver disorders, making liver disease a major issue for health inequalities. Of particular concern is the 2013 National Confi dential Enquiry into Patient Outcome and Death (NCEPOD) report,2 which showed that the care of patients acutely sick with liver disease dying in hospital was judged to be good in less than half of patients; other unacceptable fi ndings were the inadequate facilities and lack of expertise of those caring for patients. Also, it is increasingly evident that defi ciencies exist in primary care, which has crucial opportunities for early diagnosis and prevention of progressive disease. The aim of this Commission is to provide the strongest evidence base through involvement of experts from a wide cross-section of disciplines, making fi rm recommendations to reduce the unacceptable premature mortality and dsease burden from avoidable causes and to improve the standard of care for patients with liver disease in hospital. From the substantial number of recommendations given in our Commission, we selected those that will have the greatest eff ect and that need urgent implementation. Although the recommendations are based mostly on data from England, they have wider application to the UK as a whole, and are in accord with the present strategy for health-care policy by the Scottish Health Boards, the Health Department of Wales, and the Department of Health and Social Services in Northern Ireland. Our ten key recommendations are based on the strong evidence base and are in line with reports in 2014 of several other enquiries, including from the 2014 All Party Parliamentary Group on Hepatology3 and the All Party Parliamentary Group on alochol misuse. Results showing the value of a minimum unit price policy in targeting heavy drinkers were published in The Lancet in May, 2014, and the European Observatory on Health Polcy, together with the Department of Health and NHS England, has drawn attention to four areas of premature mortality, including liver disease, in which the UK lags behind other European countries. Such stark contrasts with our European neighbours are unacceptable and in this Commission we give clear, evidence-based policy proposals for the UK Government to use in closing the gap in liver disease.

Acute liver failure in childhood is a rare but fatal disease with a mortality of 70% without transplantation. The aetiology depends on age. In neonates, sepsis or an inherited metabolic liver disease is most likely, whereas viral hepatitis or drug-induced liver failure, especially following paracetamol overdose, is common. The clinical presentation includes jaundice, coagulopathy and encephalopathy. Early diagnosis is essential in order to prevent complications such as cerebral oedema, gastrointestinal bleeding and renal failure. Poor prognostic features include a reduction in liver size, a rising bilirubin with fall in hepatic transaminases, and increasing coagulopathy. Early supportive management, particularly intravenous N-acetylcysteine, may be effective but, in most instances, liver transplantation will be the definitive treatment and thus early referral to a specialist unit for liver transplantation is mandatory.

Background Primary hyperoxaluria type 1 (PH1) is a rare condition in which deficiency of the liver enzyme alanine:glyoxylate aminotransferase leads to renal failure and systemic oxalosis. Combined liver-kidney transplantation (LKT) is recommended for end-stage renal failure (ESRF) in adults, but management of infants and young children is controversial. We retrospectively reviewed six children who underwent LKT for PH1. Methods The median age at diagnosis was 1.8 years (range 3 weeks to 7 years). Two children presented with severe infantile oxalosis at 3 and 9 weeks, five patients had ESRF with nephrocalcinosis and systemic oxalosis, (median duration of dialysis 1.3 years), and one had progressive chronic renal failure. Four children underwent combined LKT, one child staged liver then kidney, and one infant had an isolated liver transplant. The median age at transplantation was 8.9 years (range 1.7-15 years). Results Overall patient survival was four out of six. The two infants with PH1 and severe systemic oxalosis died (2 and 3 weeks post-transplant) due to cardiovascular oxalosis and sepsis. The other four children are well at median follow-up of 10 months (range 6 months to 7.4 years). No child developed hepatic rejection and all have normal liver function. Renal rejection occurred in three patients. Despite maximal medical management, oxalate deposits recurred in all renal grafts, contributing to graft loss in one (one of the infants who died), and significant dysfunction requiring haemodialysis post-transplant for 6 months. Conclusions LKT is effective therapy for primary oxalosis with ESRF but has a high morbidity and mortality rate in children who present in infancy with nephrocalcinosis and systemic oxalosis. We feel that earlier LKT, or pre-emptive liver transplantation, may be a better therapeutic strategy to improve the outlook for these patients.

Orthotopic liver transplantation is established treatment for children with acute and chronic liver failure. Despite advances in pre- and postoperative management, innovative surgical techniques and new immunosuppressive drugs, acute and chronic rejection remains a problem. In addition, well established adverse effects of commonly used immunosuppressive drugs are no longer accept able. More potent, but less toxic, immunosuppressive agents have been developed and some novel compounds are now entering routine practice. Cyclosporin was the cornerstone of immunosuppressive therapy until the introduction of its novel pharmaceutical form (Neoral) with improved bioavailability, lower inter- and intraindividual pharmacokinetic variability and improved graft survival. Recently, tacrolimus, a macrolide drug with a similar mode of action, but much higher potency, was introduced and, at present, is the only agent which can successfully replace cyclosporin as a first-line immunosuppressive drug. Mycophenolate mofetil has recently been approved for use in adult and paediatric renal transplant recipients. It has a similar mode of action to cyclosporin and tacrolimus, but acts at a later stage of the T cell activation pathway. Administration with standard immunosuppressive drugs reduces the incidence of acute rejection and enables cyclosporin and tacrolimus dose reduction, thus reducing the risk of associated toxic effects. Phase I and II trials with sirolimus (rapamycin), a macrolide antibiotic, have shown comparable immunosuppressive action, when administered in conjunction with standard immunosuppressants. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in paediatric transplant recipients. Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects. FTY720 is a novel synthetic immunosuppressive compound which induces a reduction in peripheral blood lymphocyte count through apoptotic T cell death or accelerated trafficking of T cells into lymphatic tissues. Experimental animal studies demonstrated synergistic action in combination with low dose cyclosporin or tacrolimus, potentiating their immunosuppressive effects. Further studies are being carried out to determine its potential for application in organ transplantation. Despite this rapid development of novel compounds, it will take many years before they may become part of standard protocols in paediatric transplantation medicine. Further development and research of efficacy and tolerability of existing drugs is, therefore, vital.

Vascular complications after orthotopic split liver transplantation in children result in significant post-operative complications.A review of children undergoing liver transplantation from 2004 to 2006 was undertaken. The data was obtained based on a proforma-based analysis.Seven of 106 transplants were identified to have hepatic venous outflow obstruction (HVOO) of whom five were males and two were females. Median age at transplant was 8 years (range 3 years 4 months-15 years). The median donor-to-recipient weight ratio was 2.78 (range 0.97-6.15). ANASTOMOTIC TECHNIQUE: Hepatic vein-IVC in four, Hepatic vein-hepatic vein (HV-IVC) confluence in two and cavo hepatic in one. Ascites was the commonest post op manifestation of HVOO. Although Doppler USG was useful in identifying the venous outflow obstruction, venography confirmed the exact site of obstruction aiding in therapeutic dilatation. Three of seven cases had early onset (1 month) while 4/7 had late onset (1 month). 5/7 underwent venography and dilatation, of whom three are well and one is awaiting a repeat venography and dilatation. 2/7 died without intervention and 1/7 died in the waiting list for retransplantation.The diagnosis of HVOO requires a high index of suspicion, prompting early venography to manage HVOO successfully. Technical steps to avoid HVOO are to keep the hepatic vein-caval anastomosis short and wide with triangulation and to avoid graft rotation at the hepato caval junction.

Aim—To investigate the prevalence, distribution, and clinical details of paediatric hepatitis C virus (HCV) infection in the UK and Ireland. Methods—Active monthly surveillance questionnaire study coordinated through the British Paediatric Surveillance Unit, to all consultant paediatricians in 1997 and 1998. Results—A total of 182 HCV infected children were reported from 54 centres and by paediatricians from eight diVerent specialties. In 40 children HCV was acquired through mother to child transmission (MTC children); 142 were infected by contaminated blood products (n = 134),organ transplantation (n = 2), needles (n = 4), or unknown risk factor (n = 2). Intravenous drug use was the risk factor for 35 mothers of MTC children.Twelve children were coinfected with HIV and four with HBV. Recent serum aspartate aminotransferase or alanine aminotransferase values were at least twofold greater than the upper limit of normal in 24 of 152 children; this occurred in five of 11 HIV coinfected children. Liver histology, available in 53 children, showed normal (7%), mild (74%), moderate (17%), or severe (2%) hepatitis. Twenty eight children had received therapy with interferon alfa. Conclusion—Most current paediatric HCV infection in UK and Ireland has been acquired from contaminated blood products, and most children are asymptomatic. There is a need for multicentre trials to inform clinical practice and development of good practice guidelines in this area. Long term follow up of this cohort of HCV infected children is planned to help determine the natural history over the long term of HCV acquired during infancy and childhood. (Arch Dis Child 2000;82:286‐291)

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatment with the oral nucleoside analogue lamivudine. Children aged 2 to 12 years were randomized to receive twice-daily doses of 0.35, 1.5, or 4 mg of lamivudine solution per kg of body weight or once-daily doses of 3 mg of lamivudine solution per kg. Adolescents aged 13 to 17 years received lamivudine at 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken on days 1 and 28. Lamivudine was rapidly absorbed following oral administration, with the maximum concentration in serum being reached 0.5 to 1 h postdosing. Apparent oral clearance (CL/F) was higher in younger children and decreased with age, with CL/F values for adolescents reaching those seen for adults by the age of 12. All doses produced a dramatic fall in serum hepatitis B virus (HBV) DNA levels, with a median reduction of ≥99.5% after 4 weeks of treatment and with the levels returning to the baseline levels posttreatment. The correlation of dose, area under the concentration-time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhibition and a reduction of the amount of HBV DNA of approximately 3 log 10 ) at 3 mg/kg/day, with no discernible increase in effect seen whether the drug was given at 4 mg/kg twice daily or whether it was given once daily or twice daily. The limit of detection of the assay (2.5 pg/ml) was reached for some but not all patients across the dose ranges, with the smallest number ( n = 2) of those having values negative by the Chiron Quantiplex assay being in the lowest-dose group. The 13- to 17-year-olds showed a similar overall response in terms of the HBV DNA level reduction compared to that for patients younger than age 13. Analysis of the same samples by PCR, which has a lower limit of sensitivity than the Chiron Quantiplex assay, also showed average drops in HBV DNA levels of about 3 log 10 at 4 weeks for patients for which the AUC was ≥4,000 ng · h/ml, confirming the conclusions given above. Lamivudine treatment was well tolerated at all doses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in children (ages 2 to 12 years) with chronic hepatitis B provides levels of exposure and trough concentrations similar to those seen in adults following the receipt of doses of 100 mg. The 100-mg dose is being evaluated in a large phase III study with HBV-infected pediatric patients.

Summary Background Biliary atresia is an obliterative cholangiopathy of infancy that is fatal if untreated. Surgical treatment, the Kasai portoenterostomy, may restore bile flow and clear jaundice, and, if successful, achieve a 10-year survival of 90% with a native liver. The outcome of a 2-year cohort of children with biliary atresia in the UK and Ireland was assessed to find the current frequency, the factors influencing outcome, and the medium-term need for liver transplantation. Methods Cases diagnosed between March, 1993, and February, 1995, were notified by paediatricians to the British Paediatric Surveillance Unit via a monthly reporting system. Confirmed cases were followed up by postal questionnaires to notifying paediatricians. Findings 93 cases were confirmed, a frequency of 1/16 700 livebirths. Primary surgery was done in 91 children in 15 surgical centres with an early success rate for clearing jaundice of 55% overall. Centres were grouped according to caseload; group A had more than 5 cases/year and group B fewer than 5 cases/year. Early success was higher in group-A centres, odds ratio 2·02 (95% CI 0·86–4·73), but this did not reach statistical significance. Of 41 children in whom surgery was unsuccessful in clearing jaundice 9 (22%) died and 30 (73%) underwent liver transplantation. Survival without liver transplantation and overall survival were both significantly greater in group-A centres, rate ratios 0·48 (95% CI 0·27–0·86) and 0·32 (0·11–0·94). Actuarial 5-year survival without transplantation was 61·3% in group-A centres and 13·7% in group-B centres. Actuarial 5-year overall survival was 91·2% in group A and 75% in group B. Once centre size was taken into account, no other factor, including age at surgery, was predictive of survival without transplantation or overall survival. Interpretation The outcome of children with biliary atresia is related to the caseload of the surgical centre where they have their primary surgery. Children with biliary atresia should be managed in surgical centres with a caseload of more than five cases annually.

The stem cell factor (SCF)/c-kit ligand/receptor system has been implicated in stem (oval) cell activation following liver injury in the rat. The aim of this study was to determine the role of the SCF/c-kit system in pediatric human liver during acute and chronic liver injury. Tissue was obtained from hepatectomy specimens of patients undergoing liver transplantation for extrahepatic biliary atresia (EHBA) and fulminant hepatic failure (FHF). Specific expression of mRNA for c-kit and beta-actin was measured by ribonuclease protection and by immunohistochemistry to localize c-kit in tissue sections. Expression of c-kit was detected at relatively consistent levels in normal and cirrhotic (EHBA) livers. However, in FHF, c-kit mRNA levels were elevated in 3 of 6 specimens. Immunolocalization highlighted the presence of small numbers of c-kit-positive cells in the portal tracts of normal livers with increased numbers in cirrhotic livers. The highest c-kit staining, however, was observed in FHF, in which, in addition to the cells in the portal tracts, discrete c-kit-positive cells were also found integrated into bile ducts. Colocalization studies demonstrated some of the c-kit-positive cells to be of mast cell, leukocyte, and hematopoietic cell origin. However, there remained a subset that was also negative for these markers. The up-regulation of c-kit receptor expression in diseased livers suggests an involvement of this receptor/ligand system in hepatic repair mechanisms, and we speculate that c-kit-positive cells may represent a hepatic progenitor cell population. The origin and growth/differentiation potential of these c-kit-positive cells is under investigation.

Protein-energy malnutrition is an inevitable consequence of chronic liver disease, particularly in the developing infant. Severe malnutrition with loss of fat stores and muscle wasting affects between 60% and 80% of infants with liver disease ( Beath, 1993a ; Holt et al, 1997 ). Reduced energy intake secondary to anorexia, vomiting and fat malabsorption, in association with a disordered metabolism of carbohydrate and protein, increased energy requirements and vitamin and mineral deficiencies, contributes towards growth failure. Reversal of malnutrition is one of the key aims of liver transplantation and is achieved in the majority of long-term survivors. The aetiology of persistent growth failure posttransplantation is multifactorial and is related to pre-operative malnutrition, glucocorticoid administration, feeding problems and post-operative complications. Strategies to prevent pre- and post-transplant growth failure include early referral for liver transplantation and a multidisciplinary approach to nutritional support, which may increase survival and improve the quality of life and outcome of liver transplantation.

The existence of progenitor (stem) cells in the human liver remains a matter of debate. In rodent models of hepatocarcinogenesis and injury, oval cells proliferate in the periportal regions of the portal tracts and are suggested to derive from a stem cell compartment, because they are capable of differentiating into hepatocytes or biliary epithelial cells. In this study, the rat oval cell marker, OV-6 has been used to investigate the hypothesis that there are stem cells present in fetal and pediatric human liver. The pattern of OV-6 expression was compared with the established adult biliary cell markers human epithelial antigen-125 (HEA-125) and cytokeratin-19 (CK-19). In normal pediatric liver (n = 7), bile ducts and ductules were immunostained with CK-19 and HEA-125, whereas OV-6 staining was consistently negative. In fetal tissue (n = 10), ductal plate cells, primitive bile ducts, and hepatoblasts were stained with CK-19 and HEA-125 although only some of the ductal plate cells and hepatoblasts were OV-6 positive. In biliary atresia (n = 6) and α1, anti-trypsin deficiency (α1,AT) (n = 4), CK-19 and HEA-125 immunostained ductular proliferative cells that tended to form finely anastomosing ductules, whereas OV-6 staining was found more on discrete cells confined to portal tract margins. Additionally, in diseased liver, OV-6 was strongly positive in hepatocyte lobules with greatest intensity in the periseptal regions. This widespread hepatocyte OV-6 positivity suggests that the antibody may identify cells of a less differentiated phenotype (transitional hepatocytes) that have replaced the mature cells. Therefore, it is proposed that in human liver, OV-6 is recognizing cells with a progenitor stem cell-like phenotype with the capacity to differentiate into OV-6 positive ductular cells or lobular hepatocytes.

Most metabolic liver diseases that affect pediatric patients present in the neonatal period with either cholestasis or acute liver failure. Metabolic liver disease in the older child has considerable overlap with adult patients. New diagnostic methods and therapy, including liver transplantation, has radically changed the outcome of many metabolic liver diseases.

Total parenteral nutrition (TPN)-induced liver disease develops in 40-60% of infants who require long-term TPN for intestinal failure. The clinical spectrum includes cholestasis, cholelithiasis, hepatic fibrosis with progression to biliary cirrhosis, and the development of portal hypertension and liver failure in a significant number of children who are totally parenterally fed. The pathogenesis is multifactorial and is related to prematurity, low birth weight, and duration of TPN. The degree and severity of the liver disease is related to recurrent sepsis including catheter sepsis, bacterial translocation, and cholangitis. Lack of enteral feeding leading to reduced gut hormone secretion, reduction of bile flow, and biliary stasis may be important mechanisms in the development of cholestasis, biliary sludge, and cholelithiasis. Although it is unlikely that modern TPN solutions have a major role in the etiology of TPN liver disease, manganese toxicity recently has been recognized in children with hepatic dysfunction on TPN. Although there is a definite relationship with the degree of manganese toxicity and hepatic decompensation, it is not yet clear whether this is a primary mechanism or whether the high levels are related to reduced biliary excretion of manganese. The management strategies for the prevention of TPN-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The administration of ursodeoxycholic acid may improve bile flow and reduce gall bladder and intestinal stasis. As survival from isolated intestinal transplantation improves, this therapeutic option should be considered before TPN liver disease becomes irreversible and combined liver and small bowel transplantation is required.