Steven R. Martin

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Studies of Pediatric Liver Transplantation 2002: Patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada

Abstract:  Studies of Pediatric Liver Transplantation (SPLIT) is a cooperative research network comprising 38 pediatric liver transplant centers in North America. Data from the 1092 patients who have received a first liver transplant since 1995 were analyzed for factors influencing patient survival, graft survival and acute rejection. The 3, 12, 24 and 36 month Kaplan–Meier estimates of patient/graft survival were 90.9/85.5, 86.3/80.2, 84.3/76.0, and 83.8/75.3% respectively. Univariate analysis identified initial diagnosis, type of graft (whole vs. living and cadaveric technical variant), growth failure and continuous hospitalization or ICU admission prior to transplantation as significantly influencing patient and graft survival. Subsequent multivariate analysis identified as risk factors for death: fulminant liver failure (RR = 3.05, p < 0.05), cadaveric technical variant grafts (RR = 1.95, p < 0.05), continuous hospitalization pre‐transplant (RR = 1.79, p < 0.05), height deficit >2 s.d. from mean (RR = 3.22, p < 0.05). Risk factors for graft loss included: fulminant liver failure (RR = 2.27, p < 0.05), cadaveric technical variant grafts, (RR = 1.97, p < 0.05). Eleven percent of the 1092 patients were re‐transplanted; vascular complications, particularly hepatic artery thrombosis (8.3% overall; 36.3% of graft failures), were responsible for the majority of re‐transplants. Infection was the single most important cause of death (40 of 141, 28.4%) and was a contributing cause in 55 (39%), particularly with bacterial or fungal organisms. The cumulative Kaplan–Meier estimates of first rejection at 3, 12, 24 and 36 months were 44.8, 52.9, 59.1, and 60.3%. Initial immunosuppression with tacrolimus reduced the probability of rejection (RR = 0.62, p < 0.05). Eleven percent of rejections were steroid‐resistant; chronic rejection led to 7 of 121 (5.8%) re‐transplants. The SPLIT registry, in compiling data from a large number of centers, reflects the current outcomes for pediatric liver transplants in North America.

Long-Term Follow-up of Chronic Hepatitis B Virus Infection in Children of Different Ethnic Origins

The natural history of chronic hepatitis B in children is influenced by mode of transmission and varies with regional endemicity. Seroconversion rates were studied in 174 hepatitis B e antigen (HBeAg)-positive children who were of different ethnic origins and living in Canada. Overall, 40.2% became anti-HBeAg positive, and 8.6% were hepatitis B surface-antigen positive during a mean follow-up of 4.5 years. Spontaneous seroconversion rates were lower in Asian-born, mainly vertically infected, children, versus those born either in Canada or where horizontal transmission predominates (24% vs. 44%, P=.015). Kaplan-Meier analysis showed that the cumulative persistence of HBeAg after 13 years was 25% in Asian-born children, versus 6% in all others (P<.05). Treatment of 27 children accelerated seroconversion by 3 years, without influencing the proportion seroconverting over time. Thus, although Asian-born children seroconvert more slowly, a large proportion will seroconvert before adulthood. Because treatment appears to accelerate anti-HBe seroconversion, longitudinal studies are required in order to assess the long-term benefits of early treatment.

The Management of Chronic Viral Hepatitis: A Canadian Consensus Conference 2004

Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.

Nonalcoholic fatty liver disease (NAFLD) in children.

Nonalcoholic fatty liver disease (NAFLD) is common in obese children and is a growing problem, given the increase in prevalence of obesity. NAFLD is also associated with diabetes, insulin resistance, hypercholesterolemia, and hypertriglyceridemia. Although mostly benign, some children with NAFLD develop fibrosis and cirrhosis, which necessitates close monitoring. Chronically elevated plasma liver enzyme levels is the most frequent finding. Ultrasound (US) examination allows confirmation of the diagnosis and it is useful for the follow-up. Gradual and sustained weight reduction is a management option that is worth trying initially. Other modalities of management, although interesting, await evidence as well as information on long-term benefits and effects. Sustained increase of transaminases despite weight reduction is a cause for concern and may require a liver biopsy both to assess severity of liver damage and for prognostic purposes.

Normal glomerular filtration rate in long-term follow-up of children after orthotopic liver transplantation.

Background. Cyclosporine A (CyA) and tacrolimus are the principal immunosuppressive agents used for OLT in children. However, progressive deterioration of renal function from calcineurin inhibitor toxicity after OLT has been widely reported. The aim of this study was to assess long-term renal function in children after OLT Methods. We reviewed all OLT patients surviving >1 year at Sainte Justine Hospital from 1987 to 2003. The GFR (ml/min/1.73m2) was measured yearly by the Tc-99m DTPA single injection technique Results. In all, 101 OLT patients (27 tyrosinemia, 33 biliary atresia, 5 fulminant hepatic failure, 36 miscellaneous) were studied. Median age at OLT was 35 months (range 6-178 months) in tyrosinemia group and 58 months (range 1–226 months) in the “Others” (P = NS), median pediatric end-stage liver disease score was respectively 3 (range −9 to 21) and 15 (–9 to 35), (P=0.001), and median follow-up was 6 (range 1–14) and 6 (range 1–17) (P = NS) years, respectively. Median annual GFR values in tyrosinemia fluctuated between 61 and 104 ml/min/1.73m2, with an improving tendency, and 94–121 ml/min/1.73m2 in the Others. GFR did not differ on CyA vs. tacrolimus treatment. The median duration of therapy with calcium-channel blocker in the tyrosinemia group was 5 (1–13) vs. 2 (1–13) years in the Others. Conclusions. Median GFR remained normal in most nontyrosinemia patients (Others). Tyrosinemia patients remained stable at a lower GFR. CyA administration in three daily doses and prolonged calcium-channel blocker therapy may have contributed to this stability. Impairment of kidney function was associated with congenital kidney disease, toxic kidney injury, and portal hypertension.

Biliary Atresia in Canada: The Effect of Centre Caseload Experience on Outcome

Objectives: Biliary atresia (BA) is a leading cause of end-stage paediatric liver disease. Standard BA treatment is sequential surgery with an initial Kasai procedure (KP) followed by liver transplant (LT) for patients who progress to liver failure. A key determinant for the post-KP patient survival with their native liver is patient age at KP (older age, poorer outcome). Recently, European studies have reported that caseload experience influences prognosis with centres managing <5 cases per year (UK) or <2 cases per year (France) having worse survival. Our study investigates the effect of caseload experience on outcomes of Canadian patients with BA. Patients and Methods: A national database of cases with BA, born from 1992 to 2002, was examined. Patients were grouped according to treatment centre size (A: on average <1 case per year; B: 1 to 3 cases per year; and C: >3 cases per year). Overall patient, post-KP native liver, and LT survivals were compared between centres. Outcome parameters were reevaluated for patients grouped by the largest Canadian centre (>5 cases per year) and all other centres (<5 cases per year). Results: Two-hundred thirty patients were identified among 6 group A, 4 group B, and 2 group C centres. The overall median age at KP was 64 days. There were no significant differences in patient, post-KP native liver, or LT survivals between the sized centres and even the largest centre, with the overall 4-year post-KP native liver survival being 39%. Conclusions: Caseload experience does not importantly affect the outcomes for Canadian children with BA. Although outcomes in Canada are comparable to those elsewhere, national policies directed towards timely referral and earlier age at KP rather than centralisation of care are needed.

Centrilobular fibrosis in long-term follow-up of pediatric liver transplant recipients.

Background. Centrilobular fibrosis after liver transplant in adults is caused mainly by viral hepatitis, chronic rejection, and azathioprine toxicity. The aim of this study was to investigate possible etiologies and the long-term outcome of this lesion in children. Methods. We identified centrilobular fibrosis in 12 of 117 pediatric liver transplant recipients who were investigated for persistent elevations in aminotransferases. Etiologic factors, histologic features on serial biopsies, and clinical and biochemical changes over time were noted for 8 recipients in whom a readily identifiable cause was not apparent. Results. Centrilobular fibrosis developed a mean of 1.7 years (range: 30 days–3.6 years) posttransplantation in patients receiving cyclosporine, azathioprine, and prednisone. Centrilobular fibrosis was always associated with portal fibrosis and, in six recipients, with persistent, low-grade, cellular rejection. None demonstrated chronic cholestasis, ductopenia, or identifiable vasculopathy. Ischemic, viral, and autoimmune etiologies were excluded. Discontinuing azathioprine did not lead to biochemical or histological improvement. After changing to tacrolimus, aminotransferases normalized in three recipients and repeat biopsies in six were unchanged during a further 2 years of follow-up. Conclusions. Centrilobular fibrosis may develop in a small number of pediatric liver transplant recipients, resulting in considerable difficulties in biopsy interpretation. It is not associated with viral hepatitis nor with classical features of chronic rejection. The prognostic significance of centrilobular fibrosis is uncertain, although no child has required retransplantation in up to 12 years of follow-up. A role for a low-grade, chronic form of cellular rejection heralded by persistent, variable, and otherwise unexplained elevations in aminotransferases is suggested.

Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease.

Wilsons disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14–21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 ± 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.

Differing Patterns of Liver Disease Progression and Hepatitis C Virus (HCV) Quasispecies Evolution in Children Vertically Coinfected with HCV and Human Immunodeficiency Virus Type 1

ABSTRACT Hepatitis C virus (HCV) quasispeciation was studied in two children vertically coinfected with HCV and human immunodeficiency virus type 1 (HIV-1). HCV quasispecies diversification and liver injury were more significant in patient C1, who was immunocompetent with anti-HIV therapy, than in patient C2, who was immunosuppressed, in consistency with modulation of HCV quasispeciation and liver injury by immunocompetence in coinfected children.