Plasma microRNA levels in male and female children with cystic fibrosis.

A gender gap exists in cystic fibrosis (CF). Here we investigate whether plasma microRNA expression profiles differ between the sexes in CF children. MicroRNA expression was quantified in paediatric CF plasma (n = 12; six females; Age range:1-6; Median Age: 3; 9 p.Phe508del homo- or heterozygotes) using TaqMan OpenArray Human miRNA Panels. Principal component analysis indicated differences in male versus female miRNA profiles. The miRNA array analysis revealed two miRNAs which were significantly increased in the female samples (miR-885-5p; fold change (FC):5.07, adjusted p value: 0.026 and miR-193a-5p; FC:2.6, adjusted p value: 0.031), although only miR-885-5p was validated as increased in females using specific qPCR assay (p < 0.0001). Gene ontology analysis of miR-885-5p validated targets identified cell migration, motility and fibrosis as processes potentially affected, with RAC1-mediated signalling featuring significantly. There is a significant increase in miR-885-5p in plasma of females versus males with CF under six years of age.

UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;1. Patient populations involved in AYP transition. 2. Risks of failing transition or poor transition. 3. Models of AYP transition. 4. Patient and carer/parent perspective in AYP transition. 5. Surgical perspective.(AU)

Successful long-term outcome of liver transplantation in late-onset lysosomal acid lipase deficiency.

Late-onset LAL deficiency, previously referred to as cholesteryl ester storage disorder, is a rare lysosomal storage disorder characterized by accumulation of cholesteryl esters. It has a heterogeneous clinical phenotype including abdominal pain, poor growth, hyperlipidemia with vascular complications and hepatosplenomegaly. End-stage liver disease may occur, but there are few reports of successful LT. There are also concerns that systemic manifestations of the disease might persist post-LT. We report a case with excellent outcome eight yr following LT. The subject was noted to have asymptomatic hepatosplenomegaly during an intercurrent illness, and LAL deficiency was confirmed with compound heterozygosity in the LIPA. Despite dietary fat restriction, he developed signs of progressive liver disease and subsequently developed hepatopulmonary syndrome. He underwent cadaveric LT at the age of nine and a half yr and recovered with prompt resolution of hepatopulmonary syndrome. Eight yr post-transplant he has normal growth, normal lipid profile, and liver and renal function tests. Liver histology showed no evidence of disease recurrence at this stage. LT in this subject resulted in an excellent functional correction of late-onset LAL deficiency.

Outcome of children with hereditary tyrosinaemia following newborn screening.

BACKGROUND: Nitisinone has transformed the management of hereditary tyrosinaemia type 1 (HT1). However, the risk of developing hepatocellular carcinoma is related to the age at which treatment is commenced. Little data on the outcome of children treated pre-emptively exist. AIM: To describe the outcome of children with HT1 treated with nitisinone following selective newborn screening (NBS) and to compare their outcome with index siblings who had presented clinically. SUBJECTS: 12 children with HT1 were detected by NBS. Seven children were screened for HT1 because of an affected sibling (n=5). Four children were detected due to raised tyrosine concentrations on routine NBS and one child was born in a country with universal NBS for HT1. OUTCOME: Nitisinone was commenced at 4 (1-52) days old. 6 children had an initial coagulopathy which resolved after 4 (1-7) days treatment. Currently at median age 8.5 (3-12.5) years all are clinically normal, with normal liver function tests and imaging. Those of school age are in normal classes but four have reported learning difficulties. Five index siblings presented clinically with acute liver failure (four) and chronic liver disease (one) at median 4 (1.5-17) months. One died of liver failure prior to nitisinone's availability. Four were treated with nitisinone; one failed to respond and underwent liver transplantation and three responded. One responder died from complications of prematurity and the remaining two have compensated liver disease. SUMMARY: Children with HT1 treated with nitisinone following NBS have an excellent outcome. CONCLUSIONS: Universal NBS for HT1 should be introduced in the UK.

Selenium homocholic acid taurocholate scanning, selenium-75-labeled bile acid, a novel method for testing the function of the terminal ileum in small bowel transplant recipients: a pilot study.

INTRODUCTION: The terminal ileum (TI) is important for the active reabsorption of bile salts and is the site of allograft rejection; disruption of enterohepatic circulation (EHC) may give insights to inflammatory and other physiologic processes at the TI. SUBJECTS AND METHODS: Four children aged 5 to 12 years who had received small bowel transplantation (SBTx), 3 recovering from post-transplant lymphoproliferative disease (PTLD) and 1 with acute rejection, were studied. Two of the 4 had stoma reversal. Another child (15 years) with progressive familial intrahepatic cholestasis (PFIC) and pruritus, despite liver transplantation and biliary diversion, was studied. Selenium homocholic acid taurocholate scanning ((75)SeHCAT) capsule was given orally (n = 3) or via introducer during endoscopy (n = 2); a baseline whole-body gamma camera scan was done 4 hours later and on days 1 to 5. RESULTS: The normal 3-day bile salt retention is 30% to 70% of baseline and normal adult biological half-life, t½ is 62 ± 17 hours. The results in children with a stoma were very low (0.1% at 7.6 hours; 5% at 17 hours). The children with reversed stoma had retention and t½ closer to the reference range (18% at 29 hours; 22% at 33 hours). The child with PFIC + biliary diversion had an initial very high gamma emission from the stoma bag suggesting excellent reabsorption of bile salts from his TI, but retention was 0.6% and t½ 9.8 hours, demonstrating efficient biliary diversion. CONCLUSION: These results confirm children with stomas malabsorb bile acids, which can be ameliorated after stoma closure. SeHCAT demonstrated that the biliary diversion was working well and may be helpful in preoperative assessment of abnormal EHC. The role of SeHCAT in SBTx requires further evaluation.

Rejection is less common in children undergoing liver transplantation for hepatoblastoma.

To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post-transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation.

Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.

A male infant was diagnosed with atypical hemolytic uremic syndrome (aHUS) at the age of 5.5 months. Sequencing of the gene (CFH) encoding complement factor H revealed a heterozygous mutation (c.3644G>A, p.Arg1215Gln). Despite maintenance plasmapheresis he developed recurrent episodes of aHUS and vascular access complications while maintaining stable renal function. At the age of 5 years he received an isolated split liver graft following a previously established protocol using pretransplant plasma exchange (PE) and intratransplant plasma infusion. Graft function, renal function and disease remission are preserved 2 years after transplantation. Preemptive liver transplantation prior to the development of end stage renal disease is a valuable option in the management of aHUS associated with CFH mutations.

British paediatric surveillance unit study of biliary atresia: outcome at 13 years.

BACKGROUND: Little information is available on contemporary, prospectively collected data on the long-term outcome of national cohorts of children with biliary atresia. OBJECTIVE: This study aimed to describe the current outcome of a national cohort of children with biliary atresia. PATIENTS AND METHODS: All 93 cases of biliary atresia in the United Kingdom and Ireland diagnosed between March 1993 and February 1995 were followed up prospectively. RESULTS: A total of 91 children underwent Kasai portoenterostomy in 15 individual centres. Only 2 centres treated more than 5 children annually. Median age at last follow-up was 12 years (range 0.25-14). Fifteen children (16%) have died: 10 after unsuccessful portoenterostomy, 1 of sepsis after successful portoenterostomy, and 4 after liver transplantation. Forty-two (45%) underwent liver transplantation at a median age of 1 year (range 0.5-9), with 90% survival. All 41 children with failed portoenterostomy (and 2 without portoenterostomy) died or underwent liver transplantation at a median age of 0.8 years (range 0.25-6.5). When the portoenterostomy was successful, 40 of 50 patients (80%) are alive without liver transplantation. The 13-year actuarial survival without liver transplantation is 43.8% overall and is better in children treated at centres that treat more than 5 cases yearly (54% vs 27.3%, P = 0.005). CONCLUSIONS: If the portoenterostomy is successful, then few children with biliary atresia will need transplantation before adolescence. Children with biliary atresia should be treated in experienced centres to maximize the chance of successful surgery.

Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase γ (POLG1).

We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase γ gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease.

Renal tubular function in children with tyrosinaemia type I treated with nitisinone.

BACKGROUND: Tyrosinaemia type I (TTI) is an inherited deficiency in the enzyme fumarylacetoacetate hydrolase and is frequently complicated by renal tubular dysfunction which may persist in some patients after hepatic transplantation. Nitisinone has revolutionized the management of TTI but its effect on renal tubular dysfunction has not been described in a large cohort of patients. AIMS: To document the incidence and progression of renal tubular dysfunction in children with TTI treated with nitisinone at a single centre. SUBJECTS: Twenty-one patients with TTI from a single centre were treated with nitisinone for at least 12 months. Median age at first treatment was 17 weeks (range 1 week to 27 months). Nine patients (43%) presented in acute liver failure, seven (33%) had a chronic presentation and five (24%) were detected pre-clinically. METHODS: A retrospective case analysis of plasma phosphate, urinary protein/creatinine ratio and tubular reabsorption of phosphate was performed for all patients as markers of tubular function. Renal ultrasounds were examined for evidence of nephrocalcinosis and where available, skeletal radiographs for rickets. RESULTS: All patients had biochemical evidence of renal tubular dysfunction at presentation. After nitisinone and dietary treatment were started, all three markers normalized within one year. Four children had clinical rickets at presentation (which improved), of whom one had nephrocalcinosis, which did not reverse on nitisinone. No child redeveloped tubular dysfunction after commencing nitisinone. All patients with TTI had evidence of tubular dysfunction at presentation and in all cases this resolved with nitisinone and dietary control. CONCLUSION: The tubulopathy associated with TTI is reversible.

Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase gamma (POLG1).

We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase gamma gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease.

Is serum gentamicin level a good predictor of graft injury in intestinal transplantation?

INTRODUCTION: Following intestinal transplant (SBT), the early diagnosis and treatment of rejection is a major management aim. The diagnosis of rejection is based on histology of stomal biopsies. Oral gentamycin (2.5 mg/kg) was used for selective decontamination of the digestive system. Our hypothesis was that gentamycin might be absorbed in the presence of graft dysfunction. AIM: Our goal was to assess the correlation between serum gentamycin level and the health of the intestinal graft. SUBJECTS AND METHODS: Among 33 SBT performed from 1993 to 2005, serum gentamycin levels were performed once weekly or more often when there was a suspicion of rejection. All data were analyzed retrospectively. RESULTS: Adequate trough levels were achieved for only 23 patients, six of whom had histologically proven rejection and only one did not have a raised gentamycin content. Five patients with raised levels but no rejection included two with severe intestinal ischemia and three with bowel obstruction/ileus. Four of the five patients required laparotomies. CONCLUSION: We concluded that in our study raised serum gentamycin levels were a good predictor of rejection or significant injury to the graft.

The usefulness of bone marrow aspiration in the diagnosis of Niemann-Pick disease type C in infantile liver disease.

BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lysosomal storage disease which may present in infancy with cholestatic jaundice and/or hepatosplenomegaly. In cholestatic patients with splenomegaly, a bone marrow aspirate has been advocated as a relatively accessible tissue to demonstrate storage phenomena. Typically in patients with NPC, macrophages with abnormal cholesterol storage, so called foam cells, can be detected in the bone marrow. AIM: To review our experience of bone marrow aspiration in children with NPC presenting with infantile liver disease. METHODS: A retrospective analysis of 11 consecutive children (8 males) from Birmingham Children's Hospital with NPC presenting with infantile liver disease was undertaken. The diagnosis of NPC was confirmed in all cases by demonstrating undetectable or low rates of cholesterol esterification and positive filipin staining for free cholesterol in cultured fibroblasts. RESULTS: The median age at presentation was 1.5 months (range 0.5-10). Bone marrow aspirates showed storage cells in only 7/11 cases. Bone marrow aspirates which had storage cells were undertaken at a median age of 11 months while those with no storage cells were undertaken at median age 2.3 months. The overall sensitivity of bone marrow aspirates for detecting storage cells in children presenting with infantile liver disease was 64%; however, for children who had bone marrow aspirates in the first year of life it was only 57%. CONCLUSIONS: The sensitivity of bone marrow aspirate for the diagnosis of NPC disease in patients presenting with infantile liver disease was lower than previously reported. Where NPC is suspected clinically, definitive investigations should be undertaken promptly. There is a need to develop sensitive screening methods for NPC in children presenting with infantile liver disease.

Cardiomyopathy in tyrosinaemia type I is common but usually benign.

UNLABELLED: Tyrosinaemia type I (TTI) is an inherited multisystemic disorder of tyrosine metabolism. In addition to hepatic and renal involvement, cardiomyopathy is an important clinical manifestation. OBJECTIVE: To evaluate the incidence and outcome of cardiomyopathy in TTI. SUBJECTS AND METHODS: A retrospective study was performed of 20 consecutive children with TTI (12 male, 8 female) referred to a single centre between 1986 and 2002. All were initially treated with standard dietary therapy and, since 1992, with nitisinone. The indications for orthotopic liver transplantation (LT) changed during the study. Serial echocardiography was undertaken in all subjects. RESULTS: 9/20 (45%) children had an acute hepatic presentation. Five (25%) received dietary treatment followed by LT, and 14 (70%) were treated with nitisinone at presentation. 6/20 (30%) had cardiomyopathy at initial assessment, with interventricular septal hypertrophy being the commonest finding (5/6). Cardiomyopathy was significantly less common in those treated initially with nitisinone. After a median follow-up of 3.6 (0.45-13.5) years, 5/6 (83%) had complete resolution of cardiomyopathy and 1/6 showed significant improvement. No child with a normal initial echocardiography subsequently developed cardiomyopathy. CONCLUSION: Cardiomyopathy is a common manifestation of TTI and it has a favourable long-term outcome. Children initially treated with nitisinone are less likely to develop this complication.

Paracetamol induced hepatotoxicity.

AIM: To identify the clinical and biochemical risk factors associated with outcome of paracetamol induced significant hepatotoxicity in children. METHODS: Retrospective case notes review of those with paracetamol overdose admitted from 1992 to 2002. Patients were analysed in two groups: group I recovered after conservative treatment and group II developed progressive liver dysfunction and were listed for liver transplantation. RESULTS: Of 51 patients (6 males, 45 females, aged 0.8-16.1 years), 6 (aged <7 years) received cumulative multiple doses, and 45 a single large overdose (median 345 mg/kg, range 91-645). The median (range) interval to hospital at presentation post-ingestion was 24 hours (4-65) and 44 hours (24-96) respectively in groups I and II. Patients received standard supportive treatment including N-acetylcysteine. All children in group I survived. In group II, 6/11 underwent orthotopic liver transplantation (OLT) and 2/6 survived; 5/11 died awaiting OLT. Cerebral oedema was the main cause of death. Children who presented late to hospital for treatment and those with progressive hepatotoxicity with prothrombin time >100 seconds, hypoglycaemia, serum creatinine >200 micromol/l, acidosis (pH <7.3), and who developed encephalopathy grade III, had a poor prognosis or died. Although hepatic transaminase levels were markedly raised in both groups, there was no correlation with necessity for liver transplantation or death. CONCLUSION: Accidental or incidental paracetamol overdose in children may be associated with toxic liver damage leading to fulminant liver failure. Delayed presentation and/or delay in treatment, and hepatic encephalopathy > or =grade III were significant risk factors, implying poor prognosis and need for OLT. Prompt identification of high risk patients, referral to a specialised unit for management, and consideration for liver transplantation is essential.