De novo hepatocellular carcinoma post-multivisceral transplantation in a child.

De novo hepatocellular carcinoma (HCC) post-transplantation in patients without viral hepatitis is extremely rare, with only three reported adult cases in the English literature. Here, we present a case of de novo HCC that developed in a 7-year-old female, who at 8 months of age received a liver, small bowel, spleen, and pancreas transplantation 6.5 years ago for gastroschisis and total parenteral nutrition (TPN)-related cirrhosis. The post-transplant course was complicated by Epstein-Barr virus (EBV) infection, post-transplant lymphoproliferative disease, and subsequent development of multifocal EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT) in the small bowel 1 year and 10 months after transplantation, respectively. This was managed by reducing immunosuppression with rituximab and EBV-specific cytotoxic T-cell therapy. She was noted to have a new lesion in her transplanted liver graft 6.5 years post-transplantation that was diagnosed as HCC. The HCC was resected, and the patient remained clinically stable for 7 months. At that time, recurrence of the HCC was discovered on MRI. She passed away 6 months after. To the best of our knowledge, this is the first reported occurrence of de novo HCC post-transplantation in the pediatric population that is unrelated to viral hepatitis in either recipient or donor.

Stevens-Johnson syndrome after Mycoplasma pneumonia infection in pediatric post-liver transplant recipient: case report and review of the literature.

Although Mycoplasma pneumonia infection is relatively common among school-aged children, it rarely leads to SJS. Herein, we report a seven-yr-old girl who presented with a Mycoplasma pneumonia infection that progressed to SJS five months after liver transplant. We suggest that children presenting with symptoms of Mycoplasma pneumonia infection in the immunosuppressed post-liver transplant setting be properly diagnosed and treated rapidly, as well as observed for symptoms of SJS and potentially serious extrapulmonary complications.

Anti-lymphocyte therapy successfully controls late "cholestatic" rejection in pediatric liver transplant recipients.

Rejection is independently associated with liver graft loss in children. We report the successful rescue of grafts using ATG+/-OKT3 in late rejection associated with cholestasis. Retrospective chart review was performed after IRB approval. Between 2003 and 2010, 14 pediatric liver transplant recipients received anti-lymphocyte treatment for "cholestatic" rejection. Median age at transplantation was 12.7 yr (range 0.9-23.4), eight were boys, and immunosuppression was tacrolimus based. Median time from transplantation to rejection was five yr (range 1.1-10.5). Median peak total bilirubin was 11.1 mg/dL (range 1.4-18). All showed moderate to severe acute rejection and hepatocellular cholestasis on histology. ATG/OKT3 was started as first-line therapy in six and in the remaining eight as second-line therapy after failure of pulse steroids. Thirteen responded with normalization of aminotransferases and bilirubin, median time 16 wk (range 7-112); one non-adherent recipient has still not achieved normal graft function at last follow-up. Patient survival is 100%, with no re-transplantation and no post-transplant lymphoproliferative disease, median follow-up 2.9 yr (range 1.1-7.2). Cholestasis associated with acute rejection occurring late after liver transplantation may herald steroid resistance. First-line therapy with anti-lymphocyte preparations, prophylactic anti-microbial therapy, and close monitoring allow excellent rates of patient and graft survival.

Improving adherence to medications in pediatric liver transplant recipients.

We describe results from a clinical program, which aimed at improving adherence to medications in children who had a liver transplant. We followed the medical outcomes of 23 children and adolescents who participated in a clinical adherence-improvement protocol during the years 2001-2002. The protocol included identification of non-adherent patients by examining tacrolimus blood levels and intervention by increasing the frequency of clinic visits for non-adherent patients. In the two-yr preintervention (1999-2000), there was no improvement in any of the outcomes. After the intervention, the number of patients with high alanine aminotransferase levels (100 and above) decreased significantly, from eight before the intervention to four afterwards. Other outcomes, including the number of rejection episodes (three before, none after) and the degree of adherence to tacrolimus, also improved, but the improvement did not reach statistical significance. Although non-adherent patients were called to clinic more often under the protocol, the intervention did not lead to increased outpatient costs. This adherence--improvement intervention appears to be promising in improving outcomes in pediatric liver transplant recipients. Larger, controlled studies are needed to establish the efficacy of this or other approaches.

Detection of liver kidney microsomal type 1 antibody using molecularly based immunoassays.

AIMS: To assess the diagnostic value of two commercial molecularly based immunoassays detecting liver kidney microsomal type 1 antibody (LKM1). METHODS: The performance of Varelisa and LKM1 enzyme linked immunosorbent assay (ELISA) was compared with immunofluorescence, and two validated research techniques-an in house ELISA and a radioligand assay measuring antibodies to P4502D6. Thirty serum samples from three patients with autoimmune hepatitis type 2 covering immunofluorescence titres of 1/10 to 1/10 240 and 55 LKM1 negative controls were tested. RESULTS: All 30 sera that were LKM1 positive by immunofluorescence were positive by the in house ELISA, the radioligand assay, and LKM1-ELISA, and 29 were also positive by Varelisa. None of the 55 sera negative for LKM1 by immunofluorescence was positive by the in house ELISA and radioligand assay, but one was positive by Varelisa and 14 were positive using the LKM1-ELISA. Agreement between immunofluorescence, the in house ELISA, the radioligand assay, and Varelisa was high (kappa > 0.8), and agreement between immunofluorescence and LKM1-ELISA was moderate (kappa = 0.63). CONCLUSION: The assay kit marketed as Varelisa allows accurate detection of LKM1.

A novel assay for detecting antibodies to cytochrome P4502D6, the molecular target of liver kidney microsomal antibody type 1.

Liver Kidney Microsomal type 1 (LKM1) antibody, the diagnostic marker of autoimmune hepatitis type 2, is also found in a proportion of patients with hepatitis C virus infection (HCV). It is detected conventionally by the subjective immunofluorescence technique. Our aim was to establish a simple and objective enzyme-linked immunosorbent assay (ELISA) that measures antibodies to cytochrome P4502D6 (CYP2D6), the target of LKM1. An indirect ELISA using eukaryotically expressed CYP2D6 was designed. Absorbance values obtained against a reference microsomal preparation were subtracted from those obtained against a microsomal preparation over-expressing CYP2D6, thus removing the non-CYP2D6-specific reaction. Sera from 51 LKM1 positive patients (21 autoimmune hepatitis and 30 with HCV infection), 111 LKM1 negative patients with chronic liver disease (including 20 with HCV infection) and 43 healthy controls were tested. Of 51 patients positive by immunofluorescence, 48 were also positive by ELISA while all the 154 LKM1 negative subjects were also negative by ELISA. There was a high degree of association between IFL and ELISA as demonstrated by a kappa reliability value of 0.96. The absorbance values by ELISA correlated with immunofluorescence LKM1 titres both in autoimmune hepatitis (r = 0.74, p < 0.001) and HCV infection (r = 0.67, p < 0.001). The simple, objective ELISA described has the potential to replace the standard immunofluorescence technique.

De-novo autoimmune hepatitis after liver transplantation.

BACKGROUND: Late graft dysfunction that does not result from recognised causes, such as rejection, infection, or vascular or biliary complications, can occur after liver transplantation. We investigated a particular type of unexplained graft dysfunction that is associated with autoimmune features in children who underwent transplantation at our unit between 1991 and 1996. METHODS: Seven (4%) of 180 liver-transplant recipients developed an unexplained but characteristic form of graft dysfunction (five boys, two girls; median age at presentation 10.3 years, range 2.0-19.4). The median period after surgery was 24 months (6-45). The indications for transplantation had been extrahepatic biliary atresia (four patients), Alagille's syndrome (one), drug-induced acute liver failure (one), and alpha1-antitrypsin deficiency (one). Four patients were on triple immunosuppression with cyclosporin, azathioprine, and prednisolone; and three were on tacrolimus. Immunoglobulin measurements, autoantibody studies, serological studies, and HLA typing were undertaken. Liver-biopsy samples were taken. FINDINGS: Infectious and surgical complications were excluded. Liver-biopsy samples showed the histological changes of chronic hepatitis, including portal and periportal hepatitis with lymphocytes and plasma cells, bridging collapse, and perivenular-cell necrosis without changes typical of acute or chronic rejection. All patients had high concentrations of IgG (median 22 g/L [range 17.2-34.4]) and high titres of autoantibodies. All but one patient responded to prednisolone 2 mg/kg daily and an increase in or addition of azathioprine (1.5 mg/kg daily) within a median of 32 days (7-316). One responder relapsed owing to poor compliance but went into remission after treatment was restored. All six respondents remain in remission on a reduced dose of prednisolone (5-10 mg/day) and 1.5 mg/kg daily azathioprine at a median of 283 days (range 108-730) follow-up. INTERPRETATION: Our data show that symptoms of autoimmune hepatitis, which are responsive to the classical treatment for this condition, can appear in liver-transplant patients while they are on anti-rejection immunosuppression. Whether the liver damage in these patients is a form of rejection or the consequence of autoimmune attack has yet to be established.

Biliary atresia: the King's College Hospital experience (1974-1995)

UNLABELLED: The survival experience of 338 infants born with biliary atresia between January 1973 and December 1995 was analyzed. All the infants had their initial surgery at a single UK centre. These infants were divided into three groups based on year of birth; group 1 (1970s, n = 38); group 2 (1980s, n = 182), and group 3 (1990s, n = 118). The data from group 1 were incomplete and selected, and comparisons with the remaining groups were therefore restricted. However, all infants who had been treated since 1980 underwent portoenterostomy or hepaticojejunostomy and were included. RESULTS: In the whole cohort there were 89 deaths (26%), 79 children (23%) who underwent liver transplantation and 170 children (50%) who were alive at last follow-up. The 5- and 10-year actuarial survival for group 2 was 50% and 41%, respectively and the 5-year actuarial survival for group 3 was 60%. Overall, 57 children have survived to 10 years after surgery for biliary atresia. There has been a progressive fall in the age at surgery from a median of 77 days in group 1, through 69 days in group 2 to 56 days in group 3 (P < .0001). However, there was no significant difference in outcome to 5 years between the age cohorts (< 40 days, 41 to 60 days, 61 to 99 days, and > or = 100 days; P > .1) for the infants treated since 1980 (n = 200). CONCLUSIONS: Portoenterostomy is an effective long-term procedure for biliary atresia in about 40% to 50% of infants. The remaining 50% to 60% will require transplantation mostly within 2 years of age, although there is also a continuing need beyond 5 and 10 years. The age at surgery has limited usefulness as a predictor of survival after portoenterostomy and certainly should not be used to dictate primary treatment.