Dalila Habes

Anti-CD20 monoclonal antibody (rituximab) treatment for Epstein-Barr virus-associated, B-cell lymphoproliferative disease in pediatric liver transplant recipients

Objectives Anti–B-cell immunotherapy has been used with success in adults with posttransplant B-cell lymphoproliferative disease (PTLD), but such treatment has rarely been reported in children. We report the outcome of anti–CD20 antibody (rituximab) therapy for Epstein-Barr virus (EBV)–associated PTLD in six pediatric liver transplant recipients. Methods In these six patients, PTLD was diagnosed within 2 to 4 months after transplantation. The tumors were classified as monomorphic or polymorphic B-cell infiltrate expressing CD20 antigen and EBV genome. Anti-CD20 therapy was associated with withdrawal of tacrolimus or ciclosporine therapy in all patients. Intravenous rituximab was administered at 375 mg/m2 once a week for 3 to 4 consecutive weeks. Results Rituximab treatment was associated with decreased EBV load, disappearance of abnormal serum immunoglobulin concentration, and disappearance of tumoral masses, which occurred 1 to 2.5 months after treatment onset. Despite rituximab therapy, one patient was diagnosed subsequently with a cerebral tumor. Five patients experienced acute liver graft rejection episodes within 10 days to 2.5 months after beginning treatment. In these patients, immunosuppression was reintroduced, but three children experienced fatal chronic rejection, whereas two experienced complete tumor remission. Three children are alive and in complete remission, with normal liver tests, 15 months to 3 years after PTLD onset. Conclusions Rituximab therapy is an interesting approach for children with early EBV-associated PTLD after liver transplantation. It does not prevent cerebral localization, and rapid resumption of immunosuppression may be advisable to prevent lethal chronic liver graft rejection.

Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children.

BACKGROUND Liver involvement in mitochondrial respiratory chain disorders (MRCD) frequently ends in liver failure and death. Because of the high risk of extrahepatic, particularly neuromuscular, manifestations of the disease, the indication of orthotopic liver transplantation (OLT) in these patients remains controversial. We report on 5 such children in whom OLT was carried out, in an attempt to help clarify the matter. PATIENTS Patients 1 and 2 presented with fulminant liver failure at ages 7 and 6 months respectively. Emergency liver transplantation was performed before etiological investigations were completed. Retrospective examination of the explanted livers showed defects in complexes I, III and IV. In patient 1, severe neurological deterioration occurred 2 months after OLT with fatal outcome 9 months later. Patient 2 is alive 22 months after OLT with moderate motor impairment. Patients 3, 4 and 5 presented with progressive liver failure before 6 months of age. Surgical liver biopsies displayed a 50% defect in complex IV (patient 3), a defect in complexes I, IV (patient 4) and in complexes I, III, IV (patient 5). Because there was no clinical extrahepatic involvement on investigations, OLT was carried out in these patients. Patient 3 died of multiple organ failure soon after OLT, patients 4 and 5 are alive respectively 21 months and 12 months after OLT with normal neurological examination. CONCLUSION OLT may be a valid therapeutic option in infants with delayed liver cell failure due to MRCD, only after performing in emergency a thorough inves tigation to exclude clinically significant extrahepatic, especially neuromuscular, involvement.

Long term results of liver transplantation for Wilson’s disease: Experience in France

BACKGROUND & AIMS Liver transplantation (LT) is the therapeutic option for severe complications of Wilsons disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function.

Prophylactic endoscopic sclerotherapy of large esophagogastric varices in infants with biliary atresia

BACKGROUND Esophageal varices-related GI bleeding occurs frequently and early in life in children with biliary atresia and it may be life threatening. OBJECTIVE We report the results of prophylactic sclerotherapy in 13 infants with biliary atresia and large varices. PATIENTS Mean age was 13 months, mean weight was 8.2 kg, mean total serum bilirubin was 258 mumol/L, and mean prothrombin time was 78%. Esophageal varices were grade III (11 patients) or II (2 patients), with red signs in all infants and gastric varices in 12. None had GI bleeding. INTERVENTION Sclerotherapy was performed with the patient under continuous intravenous octreotide therapy in 7 infants. RESULTS In 8 children a complete or almost complete eradication of varices was obtained; none of these children bled later, 4 underwent liver transplantation, 3 are alive without liver transplantation, and 1 died of sepsis after 9 months awaiting liver transplantation. In 4 children a partial eradication was obtained and liver transplantation was performed. None of these children bled. One other child bled to death after 2 sessions of sclerotherapy. LIMITATIONS Four ulcers and 2 stenoses occurred in 6 children with no octreotide versus no ulcer and 1 stenosis in 7 children receiving octreotide. CONCLUSION These results (1) indicate that primary prevention of GI bleeding by sclerotherapy of esophageal varices is technically feasible and fairly effective in infants with biliary atresia and large varices, even in those with end-stage liver disease, (2) suggest that decreasing the risk of bleeding may allow liver transplantation under better conditions, and (3) further suggest that octreotide associated with sclerotherapy lowers the rate of complications.

Percutaneous Endoscopic Gastrostomy for Continuous Feeding in Children with Chronic Cholestasis

BACKGROUND Malnutrition associated with chronic cholestasis in children often requires continuous enteral feeding through a nasogastric tube, which may be poorly tolerated. METHOD Percutaneous endoscopic gastrostomy was performed in five children (age range, 20 months to 13 years) with severe cholestasis (Alagille syndrome in four; biliary atresia in one) and severe malnutrition (mean weight, -2.6 standard deviations; mean height, -2.7 standard deviations) who were awaiting liver transplantation. The pull-through technique was used in patients under general anesthesia, and the button was set within 2 months. RESULTS Minor wound infection required antibiotic therapy in one patient. In the four children with Alagille syndrome, enteral feeding by means of percutaneous endoscopic gastrostomy was used until liver transplantation for a mean period of 14 months with a mean weight gain of 350 g/mo and a mean height gain of 0.53 cm/mo. Seventeen months to 3 years, 3 months after liver transplantation, all four children were alive and in good clinical condition with normal readings in liver function tests. The technique had to be discontinued in the child with biliary atresia because of secondary occurrence of ascites, gastric intolerance, and refractory wound infection. CONCLUSION Percutaneous endoscopic gastrostomy may be a valuable alternative to nasogastric tube for nutritional support in children with cholestasis and mild portal hypertension.

Sertraline as an Additional Treatment for Cholestatic Pruritus in Children.

Objectives: Pruritus is a severe symptom accompanying chronic cholestasis. It can be debilitating and difficult to control. In children, first-line treatments are ursodeoxycholic acid and rifampicin. Refractory pruritus may require invasive therapies including liver transplantation. Clinical trials based on small samples of adult patients suggest that serotonin reuptake inhibitors can improve pruritus in cholestatic or uremic disease. We performed a prospective, multicenter study to assess efficiency and safety of the serotonin reuptake inhibitor sertraline in treating children with refractory cholestatic pruritus. Methods: Twenty children experiencing refractory cholestatic pruritus related to Alagille syndrome or progressive familial intrahepatic cholestasis were included from 4 centers between 2007 and 2014, and treated with sertraline at a starting dose of 1 mg · kg−1 · day−1 and thereafter individually adapted up to 4 mg · kg−1 · day−1. Before and after 3 months with therapy, pruritus was assessed using a visual itching scale graded on 10 points, a skin scratch marks score and a sleeping impairment score. Results: Sertraline was prescribed at a median daily dose of 2.2 mg · kg−1 · day−1. After 3 months, pruritus improved in 14 out of 20 treated patients, and the median itching score decreased significantly from 8/10 (5–10) to 5/10 (2–10). Likewise, skin scratch marks and sleep quality improved in 9 of these 14 patients. Nonsevere adverse events were reported in 6 children, leading to treatment discontinuation in 3. Conclusion: Our data suggest that sertraline may constitute a useful drug in the management of refractory cholestatic pruritus in children.

Hereditary fructose intolerance: Frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France—Identification of eight new mutations

We investigated the molecular basis of hereditary fructose intolerance (HFI) in 160 patients from 92 families by means of a PCR-based mutation screening strategy, consisting of restriction enzyme digestion and direct sequencing. Sixteen different mutations of the aldolase B (ALDOB) gene were identified in HFI patients. As in previous studies, p.A150P (64%), p.A175D (16%) and p.N335K (5%) were the most common mutated alleles, followed by p.R60X, p.A338V, c.360_363delCAAA (p.N120KfsX30), c.324G>A (p.K108K) and c.625-1G>A. Eight novel mutations were also identified in 10 families with HFI: a one-base deletion (c.146delT (p.V49GfsX27)), a small deletion (c.953del42bp), a small insertion (c.689ins TGCTAA (p.K230MfsX136)), one splice site mutation (c.112+1G>A), one nonsense mutation (c.444G>A (p.W148X)), and three missense mutations (c.170G>C (p.R57P), c.839C>A (p.A280P) and c.932T>C (p.L311P)). Our strategy allows to diagnose 75% of HFI patients using restriction enzymatic analysis and to enlarge the diagnosis to 97% of HFI patients when associated with direct sequencing.

Liver glycogen storage diseases due to phosphorylase system deficiencies: Diagnosis thanks to non invasive blood enzymatic and molecular studies

Glycogen storage disease (GSD) due to a deficient hepatic phosphorylase system defines a genetically heterogeneous group of disorders that mainly manifests in children. We investigated 45 unrelated children in whom a liver GSD VI or IX was suspected on the basis of clinical symptoms including hepatomegaly, increased serum transaminases, postprandial lactatemia and/or mild fasting hypoglycemia. Liver phosphorylase and phosphorylase b kinase activities studied in peripheral blood cells allowed to suspect diagnosis in 37 cases but was uninformative in 5. Sequencing of liver phosphorylase genes was useful to establish an accurate diagnosis. Causative mutations were found either in the PYGL (11 patients), PHKA2 (26 patients), PHKG2 (three patients) or in the PHKB (three patients) genes. Eleven novel disease causative mutations, five missense (p.N188K, p.D228Y, p.P382L, p.R491H, p.L500R) and six truncating mutations (c.501_502ins361pb, c.528+2T>C, c.856-29_c.1518+614del, c.1620+1G>C, p.E703del and c.2313-1G>T) were identified in the PYGL gene. Seventeen novel disease causative mutations, ten missense (p.A42P, p.Q95R, p.G131D, p.G131V, p.Q134R, p.G187R, p.G300V, p.G300A, p.C326Y, p.W820G) and seven truncating (c.537+5G>A, p.G396DfsX28, p.Q404X, p.N653X, p.L855PfsX87, and two large deletions) were identified in the PHKA2 gene. Four novel truncating mutations (p.R168X, p.Q287X, p.I268PfsX12 and c.272-1G>C) were identified in the PHKG2 gene and three (c.573_577del, p.R364X, c.2427+3A>G) in the PHKB gene. Patients with PHKG2 mutations evolved towards cirrhosis. Molecular analysis of GSD VI or IX genes allows to confirm diagnosis suspected on the basis of enzymatic analysis and to establish diagnosis and avoid liver biopsy when enzymatic studies are not informative in blood cells.

Hepatorenal Syndrome: Diagnosis and Effect of Terlipressin Therapy in 4 Pediatric Patients

100 rome (HRS) is a for g in patients with end H epatorenal synd m of prerenal kidney failure occurrin -stage liver disease or acute liver failure. Two types of HRS have been identified. Type 1 is an acute and rapidly progressive form that often develops after a precipitating factor such as gastrointestinal bleeding or spontaneous bacterial peritonitis. Type 2 is a slowly progressive form of renal failure that often occurs spontaneously in chronic ascites settings. The hallmark of HRS is severe vasoconstriction of the renal circulation to compensate for the characteristic circulatory disorders of advanced cirrhosis (1,2). HRS diagnosis is based on criteria established by the International Ascites Club (IAC) (3). Although recently revised, they remain difficult to apply to young children because of the lack of specific pediatric criteria (4). HRS is a potentially reversible condition, but its natural prognosis is poor, especially for type 1. Liver transplantation (LT) is the only treatment that ensures long-term survival, and thus it remains the principal treatment in both adults and children (4,5). Vasoconstrictor therapy with vasopressin analogues, mainly terlipressin, has been shown to improve renal function and survival in adults (4). To our knowledge, there is no published data on the use of vasopressin analogues in the treatment of children with HRS. We report on 4 children with end-stage liver disease who received terlipressin treatment for renal failure compatible with HRS.

Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients.

Mycophenolate mofetil (MMF) is now commonly used in pediatric liver transplant recipients, but no clear recommendations about the dosing regimen have been made for this population. The aim of this study was to determine the MMF dosage required for pediatric liver transplant recipients to achieve an area under the plasma concentration–time curve from 0 to 12 hours (AUC0‐12) for mycophenolic acid (MPA) greater than 30 mg hour/L. A pharmacokinetic study of 15 children (median age = 8.3 years, range = 1.1‐15.2 years) was performed at a median of 11.0 months (range = 0.5‐88.0 months) after liver transplantation. MMF was initially introduced at a median starting dose of 300 mg/m2 twice a day (range = 186‐554 mg/m2 twice a day). Thirteen of the 15 patients had an MPA AUC0‐12 value less than 30 mg hour/L. The MMF dosage had to be increased in all patients except 1. The MMF dosage required to reach an MPA AUC0‐12 value greater than the defined target of 30 mg hour/L ranged from 371 to 1014 mg/m2/day. For 2 patients who received rifampin in addition to MMF, the MPA AUC0‐12 value remained low despite a 2‐fold increase in the MMF dosage. In conclusion, an initial MMF dose of 600 mg/m2 twice a day led to MPA AUC0‐12 values greater than the 30 mg hour/L threshold except when rifampin was coadministered. Because of the important interindividual variability of MPA pharmacokinetics, therapeutic drug monitoring is recommended for optimizing the daily MMF dosage. Furthermore, these results suggest that the coadministration of MPA with rifampin should be avoided. Liver Transpl 17:1152–1158, 2011.