D. A. Kelly

Indications and outcome of liver transplantation in tyrosinaemia type 1

Abstract A retrospective analysis was performed on 17 patients presenting with tyrosinaemia type 1 (TT1) between 1989–1997; 7 pre 1992 prior to the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) therapy and 10 post 1992. During this time, eight children (5 males) underwent orthotopic liver transplantation (OLT); six prior to the introduction of NTBC in 1992 and two on NTBC therapy. The primary indications for OLT pre-1992 were risk of hepatocellular carcinoma with evidence of hepatic dysplasia in all, associated with liver failure in two, and rise in α-fetoprotein (AFP) in four. Two of the ten treated with NTBC required OLT. The indications were non-response to NTBC in one child and development of hepatic dysplasia associated with poor quality of life in the second patient. Median age for OLT was 64 months (range 5–127 months) with a median weight of 24 kg (range 6–25 kg). The histology of hepatectomy specimens at transplantation showed: cirrhosis in 8, hepatic dysplasia in 6 and hepatocellular carcinoma in 1. Plasma tyrosine and AFP returned to normal in all cases. Urinary succinylacetone reduced but persisted in small amounts (median 7.7 μmol/mmol creatinine). Hypertrophic cardiomyopathy resolved in 3/3 patients. Hypoglycaemia, not responding to dietary therapy or NTBC treatment, resolved post-transplant in one patient. There were two deaths, one from primary non-function and one from chronic rejection. Late complications in survivors (n=6) include post-transplant lymphoproliferative disease of the iris in one child which resolved and renal dysfunction with a fall in glomerular filtration rate in three (50%). Median follow up post OLT is 6.7 years (range 1–7 years). Quality of life post-transplant in survivors is good with unrestricted diet in all. Conclusion Liver transplantation is an effective treatment for TT1 with good quality of life. The current indications of OLT in TT1 are non-response to NTBC, risk of malignancy and poor quality of life related to dietary restriction and frequency of blood sampling.

Clinical features and prognosis of children assessed for isolated small bowel or combined small bowel and liver transplantation

The hepatic histology and clinical status of 37 children on long-term parenteral nutrition (PN) referred for consideration of small bowel transplantation were determined. Seventy five percent of the children had splenomegaly and plasma bilirubin level of greater than 100 mumol/L. All of 21 children who underwent liver biopsy, had increased fibrosis, but only half had established cirrhosis. Thirty-one children were considered to be in need of transplantation (combined liver and bowel transplant, 29; isolated bowel transplant, 2), but only 13 were stable enough to be placed on the transplant list. Seven out of the thirteen children waiting have died because of lack of size-matched organs, and the overall mortality rate of the 37 children was 70%. The main risk factors for death within 6 months were bilirubin level of greater than 100 mumol/L, splenomegaly, and cirrhosis (P = .01). The natural history of PN-associated liver disease is that of progressive liver failure and death 6 to 12 months after onset of cholestasis, defined as bilirubin level of greater than 100 mumol/L. The development of cirrhosis occurs after the onset of jaundice, so early referral may also permit some children to be offered isolated bowel transplantation, which has better outcome than combined liver and bowel transplantation.

Current issues in pediatric transplantation.

Abstract:  Pediatric solid organ transplantation is so successful that >80% of children will survive to become teenagers and adults. Therefore, it is essential that these children maintain a good quality life, free of significant long‐term side effects. While intensive immunosuppressive regimens (containing CsA, tacrolimus, MMF, and steroids) effectively reduce acute or chronic rejection, they can produce long‐term side effects including viral infection, renal dysfunction, hypertension, and stunting. The development of effective methods of diagnosis, prevention, and treatment of CMV means that this is no longer a significant cause of mortality, but morbidity remains high. In contrast, infection rates of EBV remain high in EBV‐negative pre‐transplant patients. However, pre‐emptive reduction of immunosuppression or treatment with rituximab or adoptive T‐cell therapy is effective in preventing/treating post‐transplant lymphoproliferative disease. Recent protocols have concentrated on reducing CsA immunosuppression, to prevent unacceptable cosmetic effects, and to reduce the hypertension, hyperlipidemia, and nephrotoxicity. Both CsA and tacrolimus cause a 30% reduction in renal function, with 4–5% of patients developing severe chronic renal failure. The use of IL‐2 inhibitors for induction therapy with low‐dose calcineurin inhibitors, in combination with renal‐sparing drugs such as MMF or sirolimus for maintenance immunosuppression, should prevent significant renal dysfunction in the future. The concept of steroid‐free immunosuppression with IL‐2 inhibitors, tacrolimus, and MMF is an attractive option, which may reduce stunting and renal dysfunction. However, these regimens may be associated with the increased development of de‐novo autoimmune hepatitis in 2–3% of children. The most important challenge to long‐term survival in transplanted children is the management of non‐adherence and other adolescent issues, particularly when transferring to adult units, as this is the time when many successful transplant survivors lose their grafts.

Orthotopic liver transplantation for unresectable hepatoblastoma : a single center's experience

BACKGROUND/PURPOSE Complete surgical resection after chemotherapy is the definitive treatment for hepatoblastoma. However, orthotopic liver transplantation (OLT) is now accepted as a treatment modality for patients with unresectable tumours. The aim of this study was to review a single centers experience of OLT for unresectable hepatoblastoma. METHODS A retrospective review of 8 patients with unresectable hepatoblastoma who were referred for liver transplantation was conducted. RESULTS The patients assessed had an age range of 5 to 105 months at presentation; median, 24 months, (5 boys; 3 girls). Two patients have familial adenomatous polyposis, and one has right hemihypertrophy. All 8 patients had received standard chemotherapy according to SIOP (International Society of Pediatric Oncology) protocols. Extrahepatic metastases were found in 3 patients at diagnosis, but none had detectable metastases at the time of OLT. Four patients continued chemotherapy while awaiting OLT. Three patients received whole grafts, and 5 received reduced grafts. The median follow-up period was 22 months (range, 2 to 78 months). Five patients are alive and well, although 1 patient had a second OLT for biliary cirrhosis secondary to biliary stricture at 6 years. Three patients died: one 26 days post OLT of sepsis and two of disease recurrence at 22 months and 70 months posttransplant. The actuarial survival rate is 88% and 65% at 1 and 5 years, respectively, whereas the overall survival rate is 62.5%. CONCLUSION OLT for unresectable hepatoblastoma without extra hepatic metastases is highly successful with a low recurrence rate.

Hyperinsulinism in tyrosinaemia type I

SummaryTyrosinaemia type I (TT I) (McKusick 276700) is a heterogeneous disorder with a broad spectrum of clinical phenotypes. Although histological abnormalities of the pancreas are well recognized, there are only incidental reports of pancreatic dysfunction manifested as insulin-dependent diabetes mellitus. We report three subjects with TT I and acute liver dysfunction who had hyperinsulinism in early infancy. Hypoglycaemia persisted despite dietary treatment and one patient had inadequate lipolysis at the time of hypoglycaemia. All three patients were successfully treated with diazoxide (10 mg/kg per day) and chlorthiazide (35 mg/kg per day) and treatment was gradually withdrawn after 9, 13 and 34 months, respectively. The mechanism of pancreatic dysfunction in TT I is unknown but may be related to the toxic metabolites that accumulate in this condition. We conclude that hyperinsulinism is not a rare complication in TT I. In patients with persistent hypoglycaemia, C-peptide should always be measured. Treatment with diazoxide and chlorthiazide is highly effective, appears to be safe, and does not need to be continued lifelong.

Cardiomyopathy in tyrosinaemia type I is common but usually benign.

SummaryTyrosinaemia 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.

Neonatal liver transplantation for fulminant hepatitis caused by herpes simplex virus type 2

Neonatal herpes simplex virus (HSV) infection can cause skin disease or disseminated infection, resulting in hepatitis, pneumonitis, intravascular coagulopathy, or encephalitis (1). It is usually acquired perinatally, with a high mortality rate in disseminated disease (1–3). We describe a 12-day-old girl with fulminant hepatitis and fulminant hepatic failure (FHF) secondary to HSV type 2 infection who underwent a successful liver transplantation (LT).

Renal function following liver transplantation for unresectable hepatoblastoma

Abstract: 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 Childrens 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 Schwartzs 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.

Parents in transition: Experiences of parents of young people with a liver transplant transferring to adult services.

Predictors of successful transition from pediatric to adult services include ability to self‐manage and engage with healthcare services. Parents have a key role in healthcare management throughout childhood and adolescence including encouraging development of self‐management skills in their children. Transition to adult services can be challenging for parents and young people, yet parents’ views regarding transition remain largely unexplored. Nine parents of pediatric liver transplant recipients (15.2–25.1 yr) participated in semistructured interviews. Interviews were analyzed using IPA. Analysis revealed three key themes: “emotional impact of transplantation,” “protection vs. independence,” and “ending relationships and changing roles.” Parents expressed the dichotomous nature of the desire to promote independence in their child while still maintaining control and protection, and discussed how changing roles and relationships were difficult to navigate. Parents are important facilitators of young peoples development of self‐management skills for successful transfer to adult services. Parents should be supported to move from a “managerial” to a “supervisory” role during transition to help young people engage independently with the healthcare team. Findings support the development of interventions for parents to emphasize their role in transition and guide the transfer of self‐management skills from parent to young person.

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.