Biodistribution of adult derived human liver stem cells following intraportal infusion in a 17-year-old patient with glycogenosis type 1A.

INTRODUCTION: Current treatment of inherited liver inborn errors of metabolism in children consists in appropriate diet and drugs and, for unstable patients, final orthotopic liver transplantation. Unfortunately, liver transplantation remains not easily available because of organ shortage and imposes inherent risks and lifelong immunosuppressive therapy. Therefore alternative treatments are required. Hepatocytes transplantation and its limitations led to consider innovative alternative such as transplantation of adult derived human liver stem cells (ADLHSC). These cells present high proliferative capacity, good resistance to cryopreservation and ability to differentiate into hepatocyte-like cells displaying mature hepatocyte functions. AIM: Biodistribution of ADHLSC had never been assessed after infusion through the portal vein in patients. This information is required to determine the safety of the method. METHODS: ADHLSC were efficiently labelled with 111-Indium DTPA radiotracer and SPECT imaging was used for the acquisition of whole body imaging to document short term biodistribution of ADHLSC. RESULTS: Following infusion through the portal vein, ADHLSC diffused homogenously throughout the liver and remained strictly within the targeted organ. Images were acquired until 5 days after infusion. At that time, no signal was observed in any other organs except the liver. Urinary excretion of 111-Indium DTPA was also monitored. CONCLUSION: For the first time, we documented the short term biodistribution of ADHLSC within the liver after infusion through the portal vein.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents.

BACKGROUND & AIMS: This multi-center study aimed to prospectively evaluate the safety and efficacy of a genotype-based Pegylated Interferon alfa-2a/Ribavirin therapy in treatment-naïve hepatitis C virus (HCV), positive HCV serology, and quantifiable HCV RNA, infected children. METHODS: Eighteen children with genotypes 2 and 3 patients (group A) were assigned to medication for 24weeks, and 47 children with genotypes 1, 4, 5 and 6 patients (group B) for 48weeks. RESULTS: Early response at week 12 was observed in 83% of group A patients and in 57% of group B patients (p<0.05). End of treatment response was achieved in 94% of patients in group A and in 57% in group B (p<0.001). Sustained virologic response was maintained in 89% of patients in group A and in 57% of patients in group B (p<0.01). Ten patients stopped prematurely the treatment, 2 for serious adverse event (acute hepatitis and thyrotoxicosis), and 8 because of no virologic response at week 24. Peginterferon alfa-2a and Ribavirin dose was adjusted in 15 patients (23%), 11 for neutropenia (17%), and 3 patients (5%), for anemia, respectively. Treatment-related adverse events included fever and flu-like symptoms (54%), irritability-depression-change of mood (34%), vomiting (23%), abdominal pain (38%), loss of appetite (21.5%) and dermatitis (29%). No influence on height growth was observed. CONCLUSIONS: Pegylated inteferon alfa-2a and Ribavirin treatment allowed to achieve SVR in 57% of pediatric patients with genotypes 1, 4, 5 and 6, and in 94% of genotypes 2 and 3. These results show an improved SVR as compared to reference series in adults with similar regimen.

Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives.

Liver cell transplantation is an attractive technique to treat liver-based inborn errors of metabolism. The feasibility and efficacy of the procedure has been demonstrated, leading to medium term partial metabolic control of various diseases. Crigler-Najjar is the paradigm of such diseases in that the host liver is lacking one function with an otherwise normal parenchyma. The patient is at permanent risk for irreversible brain damage. The goal of liver cell transplantation is to reduce serum bilirubin levels within safe limits and to alleviate phototherapy requirements to improve quality of life. Preliminary data on Gunn rats, the rodent model of the disease, were encouraging and have led to successful clinical trials. Herein we report on two additional patients and describe the current limits of the technique in terms of durability of the response as compared to alternative therapeutic procedures. We discuss the future developments of the technique and new emerging perspectives.

Chronic hepatitis B infection: long term comparison of children receiving interferon alpha and untreated controls.

OBJECTIVES: To investigate the virological outcome of chronic hepatitis B (CH-B) in children who received interferon alpha (IFN) compared with no treatment. METHODS: Seventy-four children with CH-B (median age, 6.1 years; 44 boys) selected from a cohort of 158 cases were included and divided into two groups: IFN-treated (n = 37) and control (n = 37). The controls were matched with the treated children by baseline alanine aminotransferase (ALT) levels, sex and age. The Kaplan-Meier method was performed to estimate the time to clearance of hepatitis B e antigen (HbeAg) and hepatitis B surface antigen (HbsAg). RESULTS: Mean duration of follow-up was comparable in two groups (5.2 +/- 3.8 years in treatment group versus 5.2 +/- 3.7 years in control group, NS). HBeAg and HBsAg loss occurred in 20 (54.1%) and three treated children versus 13 (35.1%) and one untreated children (NS), respectively. The 7-year cumulative HBeAg and HBsAg clearance rates were 47.5% and 8.9% after the first visit in the treatment group versus 33.5% and 4.0% in untreated children (NS), respectively. Elevated baseline ALT (two times upper limit of normal) had a significant effect on the long-term cumulative rate of HBeAg seroconversion in treated patients (P = 0.01) but not in the untreated group. CONCLUSIONS: These findings show that the overall long-term virological outcome does not differ significantly between IFN-treated and untreated children but that a significant benefit of treatment on the long term rate of HBeAg seroconversion is obtained in children with higher baseline ALT levels.

Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up.

Hepatocyte transplantation is an investigational alternative to orthotopic liver transplantation to treat liver based inborn errors of metabolism. We report successful hepatocyte transplantation in a 4-year-old girl with infantile Refsum disease. Hepatocytes were isolated from the left liver segment of two male donors using a classic two-step perfusion method. Fresh cells were transplanted first and then cryopreserved cells, for a total of 2 billion cells. Total bile acids and abnormal dihydroxycoprostanoïc acid markedly decreased in the patient's serum, indicating resolution of cholestasis and re-population of liver cells. Pipecholic acid decreased by 40% and c26:c22 fatty acid ratio by 36% after 18 months. Donor chromosomes sequences were detected on biopsy posttransplant, indicating engraftment. Hepatocyte transplantation is a safe and promising technique in the treatment of rare inborn errors of metabolism. Future improvements of cell viability and prevention of apoptosis may increase engraftment and subsequent re-population.