Isolated Hepatocyte Transplantation for Crigler-Najjar Syndrome Type 1:

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 × 10 9 hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean ± SD bilirubin level was 530 ± 38 µmol/L before and 359 ± 46 µmol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT034786

Long-term outcome of hepatitis C in children

I.F. = 9.503. Categoria della rivista: ASTROENTEROLOGY & HEPATOLOGY

Hepatocellular carcinoma following chronic delta virus hepatitis in a patient cured of leukemia.

A 20-year-old patient with chronic delta virus hepatitis (CDVH), cured of acute lymphoblastic leukemia (ALL), developed hepatocellular carcinoma (HCC) 14 years after hepatitis B virus (HBV) infection. The association between chronic HBV infection and HCC is well known, but CDVH patients affected by HCC are rarely reported in literature. To our knowledge, the case we describe is the first HCC case reported in literature occurring in a young boy with CDVH. We could expect further similar cases, considering 1) the high prevalence of HDV infection in children affected by ALL in our series, 2) the previous ALL treatment, and 3) a possible natural predisposition to cancer

Serum and bile bilirubin pigments in the differential diagnosis of Crigler-Najjar disease

OBJECTIVE: To differentiate between Crigler-Najjar (CN) disease types 1 and 2. DESIGN: The patterns of serum bilirubins, bile pigment composition, and phenobarbital response were studied. PATIENTS: Three infants, affected by high serum unconjugated bilirubin concentrations, previously classified as type 1 CN. METHODS: Serum and bile bilirubin pigment composition, both before and after phenobarbital (PB) treatment, were determined by alkaline methanolysis and high-pressure liquid chromatography. PB was given for at least 3 weeks by oral administration (5 mg/kg bw per day). RESULTS: No diconjugated bilirubin was found either before or after PB treatment in the serum of the three studied infants. In two patients traces of monoconjugated bilirubin were detected before PB therapy, and the ratio of conjugated/total bilirubin (percent) was increased by the PB response. In the third patient, traces of monoconjugated bilirubin appeared only after PB administration. However, the serum unconjugated bilirubin concentration decreased significantly only in the second patient, following the second cycle of PB treatment, leading to the diagnosis of type 2 CN. The analysis of the methyl ester derivatives of bile pigments was also performed on bile samples obtained in two patients by Entero-Test (R) both before and after PB treatment. An absolute increment in monoesterified bilirubin concentration was found after PB administration, although the percent concentration increased in one case and decreased in the other. No diesterified bilirubin was detected in the bile samples. CONCLUSIONS: The present results show that in types 1 and 2 CN disease it is possible to detect traces of monoconjugated but not diconjugated bilirubin both in serum and in bile. Whereas PB treatment is effective in slightly increasing the serum monoconjugated bilirubin concentration even in type 1 CN disease, the diagnosis of type 1 or 2 is based on finding a substantial decrease of serum unconjugated bilirubin following PB administration

Primary sclerosing cholangitis (PSC): clinical, laboratory and survival analysis in children and adults

BACKGROUND: Primary sclerosing cholangitis (PSC) is an uncommon disorder, rarely diagnosed in children, moreover, data on its natural history and survival are still lacking. AIM: The study was undertaken to compare clinical, laboratory and survival rates in two series of PSC: one in a pediatric group (group A) and the other in an adult population (group B). METHODS: Group A included 9 patients (5 males, 4 females, mean age 10 yrs, range 7-15); group B included 28 patients (19 males, 9 females, mean age 32 years, range 19-60). The mean follow-up was 5.2 years in group A and 6.9 years in group B (range 1-14 years). ERCP and colonoscopy were performed in each case. Survival was analyzed using the Kaplan-Meier method. RESULTS: At presentation children showed significantly higher levels of IgG and AST compared to adults (p<0.05); moreover, interface hepatitis occurred in 50% of children and in 14.2% in adults (p=ns). During follow-up the following major events occurred: oesophageal bleeding (n=2) in group A; progressive liver failure (n=6), cholangiocarcinoma (n=3), colonic cancer (n=1) in group B. Liver transplantation (OLTx) was performed in 4 adults (one died after a retransplantation). No deaths were observed in children. The Kaplan-Meier curve in adults shows a 65% rate of survival at 10 years. CONCLUSIONS: The present findings on PSC suggest a more severe activity of the disease in children than in adults at presentation; nonetheless, the prognosis seems to be better in children than in adults. The Mayo score prognostic index does not predict the development of liver/colonic cancer. A poor outcome (defined as death or being listed for OLTx) only occurred in adult