Alastair Baker

The frequency and outcome of biliary atresia in the UK and Ireland.

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 1/16700 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 groupB 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.

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.

Nutritional support in critically ill children.

BACKGROUND & AIMS Enteral nutrition is the feeding method of choice during critical illness, but in some cases as few as 25% are fed appropriately. The aim was to retrospectively review the administration of nutrition to critically ill children. METHODS The notes of 95 children over the age of 1 year who were in PICU>or=3 days were reviewed and information related to the delivery of nutrition was obtained. RESULTS Fifty-nine per cent were fed within 24h of admission. Enteral nutrition was administered 54% of the time, 10% required parenteral nutrition and 9.5% received no nutritional support. Children only received a median 58.8 (range 0-277)% of their energy requirements, which could not be optimised until the 10th intensive care day. Energy intake was greater when supplemented with parenteral nutrition. Parenteral nutrition administration was interrupted 3 times while enteral nutrition was stopped 264 times, mainly to allow other clinical procedures to take place. For 75% of the study time, children had abnormal bowel patterns. Seventy-nine per cent were constipated for 3-21 days and 43% had diarrhoea of unknown aetiology. CONCLUSION This was a retrospective study to describe the efficiency of nutritional support in critically ill children. We have shown that it is possible to administer enteral nutrition safely. However, the difference between desirable intake and actual intake achieved suggests that a more pro-active approach should be adopted.

Can energy expenditure be predicted in critically ill children

Objective To determine whether critically ill children are hypermetabolic and to calculate whether predictive equations are appropriate for critically ill children. Design Prospective, clinical study. Setting Pediatric intensive care unit. Patients A total of 57 children (39 boys) aged 9 months to 15.8 yrs. Interventions None. Measurements and Main Results The median resting energy expenditure measurement measured by indirect calorimetry was 37.2 (range, 11.9–66.6) kcal·kg−1·day−1. This was significantly lower than would be predicted using either the Schofield (42.7 [26.9–65.4] kcal·kg−1·day−1) or Fleisch equations (42.8 [20.9–66.2] kcal·kg−1·day−1, p < .001) but significantly higher than the White equation developed specifically for pediatric intensive care units (26.2 [8.5–70.1] kcal·kg−1·day−1, p < .0001). Methods comparison analysis showed the limits of agreement were −484 to 300, −461 to 319, and −3.2 to 854 kcal/day, respectively. Multivariate analysis indicated the following factors contribute to hypometabolism and hypermetabolism: age (p = .006), sex (p = .034), time spent in the pediatric intensive care unit (p = .001), diagnosis (p = .015), weight (p = .009), temperature (p = .04), continuous infusion for sedation (p = .04), and neuromuscular blockade (p = .03). Conclusions Children do not become hypermetabolic during critical illness. These data suggest that agreement between resting energy expenditure and the predictive equations are so broad that they are inappropriate for use in critically ill children.

Post-traumatic Stress Responses Following Liver Transplantation in Older Children

Eighteen children aged between 7 and 16 years who had undergone a liver transplantation were interviewed using the Child Post-Traumatic Stress Reaction Index (CPTS-RI) to discover if they had post-traumatic stress symptoms. A case control design was used to define which factors were important for the development of post-traumatic stress. Results of a one-way analysis of variance (ANOVA), with post-traumatic stress symptom intensity as measured on the CPTS-RI as the dependent variable, revealed a significant difference between the liver transplantation group compared with children who had a chronic life-threatening illness or had undergone a routine surgical operation. A post hoc (Tukeys HSD test) statistical analysis was performed and significance at the .05 level was found between the liver transplantation group and both the chronic illness group and the routine surgical operation group. Our results indicate that the acute life-threat involved in the liver transplantation contributed to the development of post-traumatic stress. It was thought that dissociation may be important in preventing the resolution of the trauma. Additional investigations are needed with larger numbers in a longitudinal study beginning before the transplant to determine the course of the PTSD symptoms and the appropriate timing of interventions to reduce the harmful effects of these symptoms.

Diagnosis of Alagille Syndrome—25 Years of Experience at King's College Hospital

Objective: The aim of the study was to study the clinical and histological features of Alagille syndrome (AGS) at presentation comparing the value of the various modalities before the implementation of genetic diagnosis. Patients and Methods: We performed a retrospective analysis of the records of 117 children diagnosed as having AGS after referral to Kings College Hospital between 1980 and 2005. Results: Cholestasis was seen in 104 of 117 (89%), characteristic facies in 91 of 117 (77%), posterior embryotoxon in 72 of 117 (61%), butterfly vertebrae in 44 of 117 (39%), heart disease (most often peripheral pulmonary stenosis) in 107 of 117 (91%), and renal disease in 27 of 117 (23%). Serum cholesterol levels of >5 mmol/L were seen in 52 of 86 (60.4%). Liver biopsy showed characteristic features of paucity of interlobular bile ducts in 59 of 77 (76.6%) children younger than 16 weeks of age, in 10 of 14 (71.4%) between 16 weeks and 1 year of age, and in 8 of 12 (66.66%) older than 1 year of age. Other biopsy findings were those of nonspecific hepatitis and biliary features. Iminodiacetic acid scans showed no excretion of isotope into the bowel after 24 hours in 21 of 35 (60%), and small/no gallbladder on ultrasound was seen in 29 of 104 (27.8%). Eleven of 117 (9.4%) had a diagnostic laparotomy and operative cholangiography, 2 proceeding to Kasai portoenterostomy before referral to our unit. Conclusions: Clinical features of AGS are not as consistently informative as suggested in the literature. Hypercholesterolaemia is nonspecific but may be a helpful pointer. Histology is not characteristic in 25%; hepatobiliary iminodiacetic acid scan and ultrasound may suggest a false diagnosis of biliary atresia in 60% and 28%, respectively, supporting the concept that infants with liver disease warrant early referral to a specialist centre. The advent of genetic diagnosis will redefine the syndrome with likely effects on the prognosis of the defined group.

Calcineurin-inhibitor related nephrotoxicity- reversibility in paediatric liver transplant recipients.

Aim. To study the efficacy of mycophenolate mofetil (MMF) as renal rescue in paediatric liver transplant recipients with calcineurin-inhibitor- (CI) related nephrotoxicity. Methods. Pediatric liver transplant recipients with stable graft function and a glomerular filtration rate (GFR) <80 ml/min/1.73 m2 were enrolled. MMF was introduced at 20 mg/kg/day and increased to 40 mg/kg/day after 1 week. CI dose was then reduced 6 weeks to achieve blood levels 25% of baseline. GFR was reassessed after 6 and 12 months. Results. Fourteen children with a median (range) interval from transplant of 57 (4-111) months were studied. Their median (range) GFR in ml/min/1.73 m2 increased from a baseline of 52 (31–71), to 69 (38–111) and 73 (35–98) at 6 and 12 months, respectively (P =0.00014). Side effects of MMF include leucopaenia in two and backache in one, two of whom discontinued MMF. Acute allograft rejection occurred in three children. All 14 are well with a median (range) follow-up of 24 (14–38) months from MMF introduction. Conclusion. MMF allows the recovery of renal function from CI related nephrotoxicity in more than 70% of paediatric liver transplant recipients with renal impairment.

Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation.

Background. Osteodystrophy is a well-described complication of chronic liver disease. Previous reports in adults and children undergoing liver transplantation (LT) were discordant, with the former showing no improvement of bone disease in the first year after transplantation and the latter demonstrating remarkable benefit from it. Our aim was to perform a pilot study on osteodystrophy in children undergoing LT and evaluate the contribution of growth on bone mineral density (BMD) changes. Methods. We studied six patients (two male), with a median age at transplantation of 8.8 (range 3.8–16.6) years. Indications for transplantation were biliary atresia and progressive familial intrahepatic cholestasis (three patients each). BMD was studied with dual-energy x-ray absorptiometry and biochemical markers of liver and bone function in patients before and at 3, 6, and 12 months after LT. Results. Median L2-L4 spinal BMD was 0.54 g/cm2 (range 0.29–0.87) before LT, and 0.58 g/cm2 (0.27–0.86) at 3 months, 0.66 g/cm2 (0.36–1.00) at 6 months, and 0.76 g/cm2 (0.44–1.02) at 12 months after LT (P =0.005). Median height was 133 (range 93–167) cm before LT, and 134 (93–167) at 3 months, 136 (97–167) at 6 months, and 139 (102–167) at 12 months after LT. There was direct correlation between height gain and total body BMD improvement (r =0.929, P =0.007). Conclusion. BMD in children with chronic cholestatic liver disease improves remarkably by 12 months after LT. Catch-up growth in children can account for the different effect of LT on bone density between adult and pediatric populations in the first year after surgery.

Liver transplantation for alpha-1-antitrypsin deficiency in children.

Abstract Alpha‐1‐antitrypsin (a1‐ AT) deficiency is an inborn error of metabolism, which can cause liver disease. The condition is one of the most common genetic disorders in the Caucasian population. Here we review our experience with 21 children suffering from end‐stage liver disease due to a1‐AT deficiency. All children are PIZZ homozygotes. Nineteen of them initially presented with neonatal jaundice and two with hepatosplenomegaly in childhood. Twenty‐five liver transplantions were performed. All children are currently alive at a median follow‐up of 40 months. Liver replacement provides the only definite treatment for children with end‐stage liver disease associated with a1‐AT deficiency. Excellent results can be achieved by reducing waiting time for transplantation and by early referral to a liver transplant centre.

Neonatal herpes simplex virus infection presenting as acute liver failure : Prevalent role of herpes simplex virus type I

Background: Acute liver failure (ALF) in neonates is rare but carries a high mortality without liver transplantation. Herpes simplex virus (HSV) is one of the microbes that more commonly causes ALF and is potentially treatable; hence, early diagnosis and treatment are important to avoid progression to liver failure. Patients and Results: We have analysed retrospectively the case notes of 11 patients with HSV-induced ALF. A history of possible herpes infection was elicited in 5 parents, but HSV had not been suspected clinically. All patients were asymptomatic when discharged from postnatal units and were presented with nonspecific symptoms of poor feeding and lethargy within 2 weeks from birth. Seven of the 11 patients had HSV-1 infection, 4 HSV-2. Only 2 patients who received early treatment with intravenous acyclovir survived. Conclusions: HSV-related ALF in the neonatal period carries high morbidity and mortality and needs a high index of suspicion so that life-saving treatment can be started promptly. Both HSV-1 and HSV-2 can cause severe neonatal infection. It is important to recognise HSV infection in women of childbearing age and their sexual partners.