ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

The role of nutrition in non-alcoholic fatty liver disease treatment in obese children.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs mostly in the context of insulin resistance and obesity. It has rapidly evolved into the most common cause of liver disease among children. The incidence is high in obese children and a greater risk of disease progression is associated with severe obesity, highlighting the role of nutrition. To date, there is no consensus on NAFLD management. This is a narrative review of clinical studies on the potential benefit of nutritional interventions, including lifestyle modifications, vitamins, docosahexaenoic acid, and probiotics in children with NAFLD. The Comité de nutrition de la Société Française de Pédiatrie (CN-SFP) emphasizes the effect of limiting added sugar intake, i.e., fructose or sucrose-containing beverages, and promoting physical activity in the care of NAFLD.

[Liver disease, gastrointestinal complications, nutritional management and feeding disorders in pediatric cystic fibrosis]. / Atteinte hépatique, digestive, prise en charge nutritionnelle et troubles de l'oralité chez l'enfant atteint de mucoviscidose.

In cystic fibrosis (CF), approximately 5-8% of the patients develop multilobular cirrhosis during the first decade of life. Annual screening (clinical examination, liver biochemistry, ultrasonography) is recommended in order to identify early signs of liver involvement, initiate ursodeoxycholic acid therapy and detect complications (portal hypertension and liver failure). Management should focus on nutrition and prevention of variceal bleeding. The gut may also be involved in children with CF. Gastroesophageal reflux is frequent, although often neglected and should be investigated by pH monitoring and impedancemetry, if available. Acute pancreatitis occurs in patients with persistent exocrine pancreatic activity. Intussusception, appendicular mucocele, distal intestinal occlusion syndrome, small bowel bacterial overgrowth and Clostridium difficile colitis should be considered in case of abdominal pain. Preventive nutritional support should be started as soon as possible after diagnosis of CF. Attainment of normal growth is one of the main goals and can be achieved with hypercaloric and salt supplemented food. Pancreatic enzyme replacement therapy should be started as soon as exocrine pancreatic insufficiency is confirmed and ingested immediately prior to meals with intake of fat-soluble vitamins. Curative nutritional interventions are more likely to be effective in the early stages of pulmonary disease. Feeding disorders, related to the physiopathology and the psychologic aspects of the disease are frequent. Repeated corporeal aggressions, associated with inappropriate medical and parental pressure, may increase the child's refusal of food. The multidisciplinary team should guide parents in order to avoid all intrusive feeding practices and promote pleasant mealtimes.

Management of pancreatic, gastrointestinal and liver complications in adult cystic fibrosis.

INTRODUCTION: The gastrointestinal tract is a major source of morbidity in adults with cystic fibrosis (CF), with a wide range of complications, some of them being specific to the underlying disease. STATE OF KNOWLEDGE: Abnormal CFTR function, with reduced bicarbonate and other ion transport levels through the apical surface of epithelial cells, affects the intestinal tract including the pancreas and the liver. Similarly to what is observed in the respiratory tract, gastrointestinal CFTR dysfunction leads to mucus accumulation, dysmotility, small bowel bacterial overgrowth and inflammation with alteration of innate immune responses, all of which being likely to be interrelated. In developed countries, almost half of patients with CF are adults followed in multidisciplinary CF care centres by pneumologists who often have to manage gastrointestinal complications. CONCLUSION: It therefore appears essential that adult gastroenterologists develop the expertise needed for managing CF gastrointestinal complications in close collaboration with multidisciplinary CF care centre teams to improve the quality of life of adults with CF.

[Cystic fibrosis associated with liver disease]. / L'atteinte hépatique de la mucoviscidose.

In cystic fibrosis (CF), approximately 5-10% of the patients develop multilobular cirrhosis during the first decade of life. Most of these will develop signs of portal hypertension with complications, mainly variceal bleeding during the second decade, while liver failure is usually late, after the pediatric age. Annual screening for liver disease is recommended in order to initiate ursodeoxycholic acid, that may halt the progression of liver disease. Liver disease should be considered if at least two of the following variables are present: hepatomegaly and/or splenomegaly; persistent abnormalities of liver enzymes, and pathological ultrasonography of the liver. A liver biopsy is indicated if there is diagnostic doubt. All CF patients with liver disease need annual follow-up in order to evaluate the progression to cirrhosis, and screen for portal hypertension and liver failure. Management should focus on nutrition and prevention of variceal bleeding. The decision for a liver transplant is evaluated with the transplant team, taking into account the liver function and complications of portal hypertension as well as CF related extrahepatic involvement.

The long-term outcome of hepatic artery thrombosis after liver transplantation in children: role of urgent revascularization.

Hepatic artery thrombosis (HAT), one of the most severe complications of pediatric orthotopic liver transplantation (OLT), often compromises graft and/or child survival. Of 590 OLT performed in 516 children over a 20-year period, 45 were complicated by early HAT, during the first 2 weeks after transplantation. Systematic Doppler ultrasonographic detection of HAT allowed successful surgical revascularization in 19 instances, resulting in a 20-year graft survival rate of 77% versus 24% of cases when revascularization was not attempted or failed. A combination of surgical emergency revascularization, biliary interventional radiology, biliary surgery and/or retransplantation resulted in an 80% 20-year patient survival rate, identical to that of transplanted children who did not experience early HAT. The majority of long-term survivors with their initial graft had normal liver tests, no biliary dilation on ultrasonography and minimal or moderate fibrosis on liver histology. A failed attempt at revascularization did not significantly alter patient survival. Despite these encouraging results, for the children and their parents to overcome the entire process in terms of reoperations, repeated radiological interventions, number of hospitalizations and emotional stress, remains an ordeal of such magnitude that it justifies renewed efforts to progress in the prevention of this complication.

[Biliary atresia: a condition requiring urgent diagnosis and treatment]. / Atrésie des voies biliaires : une urgence diagnostique et thérapeutique.

Every neonatal jaundice lasting more than 2 weeks needs urgent investigations, beginning with examination of stools colour, and blood tests with total and conjugated serum bilirubin. If neonatal cholestasis (NC) is confirmed, vitamin K should be immediately injected, and the child should be referred to a specialised centre for investigations and treatment. Biliary atresia (BA) is the first cause of NC. Its diagnosis is urgent, since the chance of success of the conservative surgical treatment (Kasai operation or variants) decreases rapidly as the age at surgery increases. Normal ultrasound scans cannot rule out BA. After prompt work-up looking for the main other causes of NC, BA can often be strongly suspected before surgery, and is confirmed by operative findings and cholangiogram if needed. In case of failure to restore the biliary drainage, biliary cirrhosis progresses and leads to liver transplantation, generally in the first years of life. Currently, more than 90 % of children with BA can live, with a close to normal quality of life for most of them. Early diagnosis and treatment of BA contribute to decrease the needs for liver transplantation in infancy and childhood.

Rationale for monitoring cyclosporine concentration at 2 hours after administration in infants posttransplantation.

Therapeutic drug monitoring is critical to avoid overimmunosuppression or underimmunosuppression in young pediatric transplant recipients. The objective of this study was to examine cyclosporine (CsA) trough (C0) and 2-hour post-dose (C2) concentrations in the early period after liver transplantation (OLT) to determine whether CsA C2 monitoring is justified. Seventeen infants younger than 2 years treated with CsA (Neoral) were monitored at C0. The biopsy-proved acute rejection rate was 65% at 3 months post-OLT. No correlation was observed between values at C0 and C2. Poor absorption of CsA was observed in most infants during the first 2 weeks post-OLT, as well as interindividual variability in CsA clearance. Exposure to CsA could not be estimated using either C0 or C2 determinations in the early post-OLT period. As a marker of poor absorption, C2 is useful but does not indicate delayed or rapid clearance of drug without simultaneous measurement of concentration at C0. We suggest the use of both C0 and C2 monitoring, or AUC monitoring on an individual basis during at least the first 2 weeks post-OLT.

[Inaugural trunk dystonia revealing Langerhans cell histiocytosis]. / Manifestations pseudoneurologiques révélatrices d'une histiocytose langerhansienne.

Langerhans cell histiocytosis (LCH) is a multisystemic disease, which may present with neurological involvement. We report the case of a 20-month-old girl with initial liver and skin involvement. Initial symptoms were recurrent episodes of trunk dystonia, lasting approximately 2 months prior to the diagnosis of LCH. No brain MRI abnormality was demonstrated at initial work-up and over 7 years of follow-up, except for a postpituitary involvement noted after 3 years of follow-up. These episodes of dystonia subsided during the first week of specific LCH chemotherapy (vinblastine and steroid), suggesting that they may have resulted from hepatalgia related to the histiocytic infiltration of the liver.

De novo malignancy after solid organ transplantation in children.

The aim of this study was to assess the prevalence of de novo malignancy after solid organ transplantation in childhood. A retrospective questionnaire-based survey was sent to 9 referral centers for pediatric organ transplantation in France. Among 1326 children who underwent solid organ transplantation since 1996, 80 (6%) presented with de novo malignancy posttransplantation during childhood: posttransplant lymphoproliferative disease was the most common (5% of pediatric recipients) comprising 80% of all tumors, with a disproportionately high prevalence among combined liver and small bowel recipients (18%). Various solid tumors were observed mainly among kidney recipients. No skin cancer was reported.

Acquired renal cystic disease after liver transplantation in children.

To our knowledge, the development of renal cystic disease that may contribute to kidney dysfunction has never been reported after liver transplantation. Herein we have reported on the fortuitous finding of renal cystic lesions upon computed tomographic scans (CT) in 33 (30%) of 108 pediatric liver transplant recipients who were the subjects of a prospective study evaluating long-term kidney dysfunction at 10 years after liver transplantation. The renal lesions had 2 different appearances: that of simple renal cysts and that of round lesions that were spontaneously hyperdense before contrast injection. These high-density lesions had a low signal on T2 weighted sequences, but 70% of them had been missed at ultrasonography. Their aspect upon CT and magnetic resonance favored cystic lesions filled with hemorrhagic or milk calcium content. Both types of cystic lesions were associated in 14 children. The renal lesions were significantly associated with moderate renal dysfunction, biopsy-proven chronic liver graft rejection, and thrombosis of the retrohepatic vena cava. The physiopathology of these lesions is undetermined. Two important questions need to be clarified with respect to the risk of progression of renal dysfunction associated with individual volume changes and/or increased number of renal cysts, as well as the risk of renal cancer as has been reported in dialyzed patients with acquired cystic kidney disease.

Portal vein thrombosis during antineoplastic chemotherapy in children: report of five cases and review of the literature.

We report five paediatric cases of portal vein thrombosis (PVT) occurring during chemotherapy, observed in two institutions over an 8-year time period. These children aged 2.5-15 years were treated for Burkitt's lymphoma, Ewing's tumour, small cell bone tumour or medulloblastoma. PVT was diagnosed on colour Doppler ultrasonography (US). In four patients, thrombosis occurred 2-45 days after severe hepatic veno-occlusive disease (HVOD) secondary to intensive chemotherapy containing busulfan. In one case, PVT occurred in the absence of HVOD in a patient with pre-existing periportal lymphomatous infiltration. Four patients experienced persistent portal hypertension, which resulted in death in one. PVT during chemotherapy in children is a rare event and appears to be closely related to intensive chemotherapy containing busulfan and to be associated with HVOD.

Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial.

Severe T-cell immunodeficiency after solid organ or bone marrow transplantation may result in the uncontrolled outgrowth of latently Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6 by a monoclonal anti-IL-6 antibody could contribute to the control of BLPD. Safety and efficacy were assessed in 12 recipients of transplanted organs who had BLPD refractory to the reduction of immunosuppression over 8 days. Five patients received 0.4 mg/kg per day. The next 7 patients received 0.8 mg/kg per day. Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients was discontinued early (days 10 and 13, respectively) because of disease progression. Treatment tolerance was good, and no major side effects were observed. High C-reactive protein levels were found in 9 patients before treatment but were normalized under treatment in all patients, demonstrating efficient IL-6 neutralization. Complete remission (CR) was observed in 5 patients and partial remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because of disease progression, and 3 patients died while in CR (chronic rejection in 2 patients and BLPD sequelae in 1 patient). These data suggest that the anti-IL-6 antibody is safe and should be further explored in the treatment of BLPD.

CTLA-4/CD 28 region polymorphisms in children from families with autoimmune hepatitis.

Susceptibility to autoimmune hepatitis is associated with particular human leucocyte antigen class II alleles. However, non-HLA genetic factors are likely to be required for development of the disease. Among the candidate genes, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD28 genes, located on chromosome 2q33 in humans, encode a cell surface molecule playing a dominant role in the regulation of T-cell activation. The CTLA-4 and CD28 polymorphisms were investigated in children from 32 families with autoimmune hepatitis (AIH). The transmission/disequilibrium test revealed increased transmission of the (AT)8 (dinucleotide repeat) and A (exon 1) alleles of CTLA-4 gene from heterozygous parents to affected offspring (87.5% and 83.5%) with type 1 AIH, compared with unaffected offspring (50.0% for both, p = 0.009 and 0.02, respectively). In contrast, no deviation in transmission for CTLA-4 polymorphisms was found between type 2 AIH patients and unaffected offspring. No evidence for association was found between CD28 gene polymorphism or D2S72 genetic marker and both types of AIH. This study identified the CTLA-4 gene polymorphism as a non-HLA determinant that predisposes to AIH type 1 in children. The genetic heterogeneity seen in the present study provides a new argument in favor of pathogenic differences between type 1 and type 2 AIH.

Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.

BACKGROUND/AIM: Variceal bleeding is the most severe complication in patients with cystic fibrosis-associated liver cirrhosis, who often do not have severe respiratory failure. The advent of liver transplantation has broadened the treatment options. The purpose of this study was to report our experience with the management of portal hypertension. METHODS: Clinical and biochemical features, outcome of liver disease and management of portal hypertension were analyzed retrospectively in 44 children with cystic fibrosis-associated liver cirrhosis. RESULTS: The mean age at diagnosis of liver cirrhosis was 9 years. Eighty-six per cent of the children developed esophageal varices, 50% of whom bled early in their second decade. Injection sclerotherapy of esophageal varices did not prevent recurrence of bleeding in five of seven children. Elective surgical portosystemic shunting was successfully performed in nine of 11 patients considered being at high risk of bleeding or with recurrent bleeding episodes but without severe pulmonary failure and liver dysfunction, allowing prolonged post-operative survival up to 15 years. Two of three children who underwent isolated liver transplantation for severe portal hypertension died post-operatively. CONCLUSIONS: Management emphasis in cystic fibrosis patients with liver cirrhosis should be on control of bleeding and variceal decompression. These results suggest that surgical portosystemic shunting may be considered to relieve portal hypertension in patients without progressive liver failure and severe lung disease as an alternative to liver transplantation. With this policy, patients may be stabilized for many years until progression of liver or lung diseases indicates liver or lung-liver transplantation.

[Fulminant hepatitis in two children treated with sulfasalazine for Crohn disease]. / Hépatite fulminante chez deux enfants traités par la salazopyrine pour une maladie de Crohn.

UNLABELLED: The main adverse effects of salazopyrin are usually dose-dependent and mild. Exceptionally, idiosyncratic reactions occur which may be life-threatening. CASE REPORTS: Two 10-year old children were treated for Crohn's disease with salazopyrin. At day 21 and day 10 respectively, pharyngitis, rash, and fever were noted. During the following days, high-grade fever persisted, while jaundice, severe cytolysis and acute liver failure also occurred. Drug hepatotoxicity was suspected and salazopyrin was withdrawn on day 29 and day 24 respectively. Development of hepatic encephalopathy led to urgent liver transplantation in both cases. CONCLUSION: Salazopyrin is a possible cause of fulminant immunoallergic hepatitis. Prompt therapeutic interruption is urgent, but it may not alter the outcome and or preclude the need for liver transplantation. We suggest that salazopyrin therapy be avoided in pediatric inflammatory bowel disease whenever possible, and that the use of pure amino-salicylates be preferred.

[Favorable outcome of treatment with NTBC of acute liver insufficiency disclosing hereditary tyrosinemia type I]. / Evolution favorable sous traitement par NTBC de l'insuffisance hépatique aiguë révélatrice de la tyrosinémie héréditaire de type I.

BACKGROUND: Hereditary tyrosinemia type I is a disease with a severe prognosis. Main causes of death are acute liver failure, neurologic crises and hepatocarcinoma. NTBC, which acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase, prevents the formation of toxic metabolites involved in hepatic, renal and neurologic lesions. CASE REPORTS: Results of NTBC therapy used in three infants with type I tyrosinemia who presented with acute liver failure are reported. The diagnosis relied on the finding of high plasmatic levels of tyrosine and methionine, and abnormal urinary excretion of succinyl acetone and delta aminolevulinic acid. Treatment with NTBC was initiated within 2 to 8 days from onset of symptoms. Signs of liver failure resolved after 3 weeks therapy. After 12 to 39 months of follow-up, outcome remains favorable. CONCLUSION: The results reported here highlight the efficiency of NTBC in type I tyrosinemia with early acute onset. However, the long term outcome needs to be determined with regards to prevention of hepatocarcinoma and toxicity of the drug.

Acute pancreatitis after orthotopic liver transplantation in children: incidence, contributing factors, and outcome.

BACKGROUND: Acute pancreatitis after orthotopic liver transplantation is a well-known complication in adults that has never been described in children. In adults, end-stage liver disease related to hepatitis B, intraoperative pancreatic injury caused by extensive peripancreatic dissection, the type of biliary anastomosis performed, and numerous drugs, have all been described as predisposing factors in acute pancreatitis after liver transplantation. The current retrospective review was undertaken to identify the incidence, the contributing factors, and the outcome of acute pancreatitis after liver transplantation in children. METHODS: During a 10-year period, 375 children underwent 434 liver transplantations in the authors' institution. In seven patients (1.9%), clinical acute pancreatitis developed after orthotopic liver transplantation. Indication for initial liver transplantation was biliary atresia (n = 3), acute liver failure (n = 3), and type 1 Crigler-Najjar syndrome. In all seven patients, liver graft function was initially adequate. The diagnosis of acute pancreatitis was based on clinical, biochemical, ultrasonographic, and surgical signs. RESULTS: In six patients, acute pancreatitis appeared within the first week after transplantation. The diagnosis was confirmed by abdominal laparotomy in five children. In the current series, emergency liver transplantation (p < 0.001), retransplantations (p < 0.001), and infectious peritonitis (p < 0.001) were contributing factors. Despite supportive measures, three patients died (43%) because of multiple organ dysfunction syndrome. CONCLUSIONS: Acute pancreatitis is an uncommon but life-threatening complication after liver transplantation in children. Early diagnosis and aggressive treatment of infectious complications are major elements in the management of acute pancreatitis after liver transplantation.