Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Exchangeable copper: a reflection of the neurological severity in Wilson's disease.

BACKGROUND AND PURPOSE: The severity of Wilson's disease (WD) is linked to free copper accumulating in the liver and brain. Exchangeable copper (CuEXC) is a new technique to determine plasmatic copper and is useful in the diagnosis of WD. It is hypothesized that it may also enable a good evaluation of extra-hepatic involvement and its severity. METHODS: Forty-eight newly diagnosed WD patients were prospectively evaluated using hepatic, neurological, ophthalmological and brain magnetic resonance imaging (MRI) scores. Three phenotypic presentations were distinguished: pre-symptomatic, hepatic and extra-hepatic. CuEXC was determined in addition to standard copper assays before decoppering therapy. Correlations between biological parameters and the different scores were determined and compared in the hepatic and extra-hepatic groups. RESULTS: Extra-hepatic patients had significantly higher CuEXC values than those with the hepatic form (P < 0.0001). The overall ability of CuEXC to separate the two forms was satisfactory, with an area under the curve of 0.883 (95% confidence interval 0.771-0.996) and an optimal threshold for extra-hepatic diagnosis of 2.08 µmol/l (sensitivity 85.7%; specificity 94.1%). In extra-hepatic patients, CuEXC was the only biological marker to be positively correlated with the Unified Wilson Disease Rating Score (r = 0.45, P = 0.016), the Kayser-Fleischer ring score (r = 0.46, P = 0.014) and the brain MRI score (r = 0.38, P = 0.048), but it was not correlated with the hepatic score. CONCLUSIONS: Exchangeable copper determination is useful when diagnosing WD as a value >2.08 µmol/l is indicative of the severity of the extra-hepatic involvement. In the case of purely hepatic presentation, atypical or mild neurological signs, it should encourage physicians to search for lesions in the brain and eyes.

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 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.

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.

Current lifestyle of young adults after liver transplantation during childhood.

The authors studied the psychosocial adjustment of pediatric liver transplant (LT) recipients reaching adulthood. The study comprised phone interviews of 116 volunteers aged 17-33 years. Results were compared to those for healthy peers and 65 patients who were eligible for inclusion but did not participate. Participants' median age at LT was 6 years and the median period since LT was 15 years. Of the 116 participants, 76% considered their quality of life as good or very good. Seventy-five patients (65%) were attending schools, 27 of whom were 2 years or more below the age-appropriate level. Of the remaining 41 patients, 26 had a job and 15 were unemployed. Poor compliance with medications was reported by 52 patients (45%). Alcohol consumption was lower than in the reference population (p < 0.001). Anxiety, loneliness and negative thoughts were expressed by 53, 84 and 47% of the participants, respectively. Thirteen patients (11%) were being cared for by psychologists or psychiatrists. The 65 nonparticipants had greater psychological problems than the participants, and a lower educational level. In conclusion, after LT in early life, most patients displayed psychological vulnerability during early adulthood. The educational level of patients was lower than that of theirs peers.

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.

An update on the physiopathology and therapeutic management of cholestatic pruritus in children.

Pruritus is a disabling symptom accompanying chronic cholestasis. In extreme cases, the refractory nature of pruritus can result in a need for invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway (similar to that associated with pain) regulated by several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adults, there is no consensus in children, in light of the difficulty of conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of specific therapies that should be associated with skin hydration and with non-specific treatment of cholestasis including ursodeoxycholic acid. Pruritus should be assessed as objectively as possible between each line of therapy. Rifampicin, a potent CYP3A4 inducer, is the first-line treatment of cholestatic pruritus. Second-line therapies require evaluation of the child in an expert center and are discussed on a case-by-case basis depending on the underlying disease and the experience of the center. These include inhibitors of serotonin reuptake (sertraline), opioid antagonists (naloxone), or ASBT inhibitors. Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases. The aim of the current update is to review the physiopathologic mechanisms implicated in cholestatic pruritus and to propose potential therapeutic strategies in children.

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.

[Physiopathology and management of cholestatic pruritus in children]. / Physiopathologie et prise en charge thérapeutique du prurit cholestatique de l'enfant.

Pruritus is a disabling symptom accompanying chronic cholestasis. In some cases, refractory pruritus may require invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway and several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adult patients, there is no consensus in children, given the difficulty in conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of therapy that should always be associated with local cutaneous care and with nonspecific treatment of cholestasis including ursodeoxycholic acid therapy. Pruritus should be assessed as objectively as possible between each therapeutic step. Rifampicin, an enzyme inducer, is the specific first-line treatment of cholestatic pruritus. The second-line therapies require evaluation of the child in an expert center and are discussed on a case-by-case basis depending on the underlying disease, the experience of the center and the will of the child and his family. It could be inhibitors of serotonin reuptake (sertraline) or an opioid antagonist (naloxone). Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases.

[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.

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.

Reversal of hypoxemia by inhaled nitric oxide in children with severe hepatopulmonary syndrome, type 1, during and after liver transplantation.

BACKGROUND: The hepatopulmonary syndrome with profound hypoxemia is a rare but severe complication for children with liver cirrhosis. It can be reversed by liver transplantation (LT), which is now regarded as a good indication. However, previous reports have described cases of transient or fatal deteriorations of intrapulmonary shunting after pediatric liver transplantation with dramatically worsening hypoxemia. METHODS AND RESULTS: A similar case during and after LT in a 4-year-old girl with severe hepatopulmonary syndrome is described with prompt reversal of hypoxemia by inhaled nitric oxide, which was discontinued definitely until day 14 after LT. CONCLUSIONS: During or after LT, worsening hypoxemia may be improved by using inhaled nitric oxide in pediatric patients undergoing liver transplantation for liver cirrhosis and hepatopulmonary syndrome. The mechanisms are unclear, but may involve mismatching lung ventilation-perfusion. However, additional clinical reports are necessary before accepting these results.

Postshunt encephalopathy in liver transplanted children with portal vein thrombosis.

BACKGROUND: Surgical portosystemic shunting has been reported to alleviate successfully portal hypertension in liver transplanted recipients with portal vein thrombosis. METHODS: We report two liver transplanted children with portal vein thrombosis who developed post-shunt acute encephalopathy. In one child, a mesocaval H-type shunt was created surgically because of bleeding related to Roux-en-Y loop varices at 3 months posttransplantation; in the other, a large spontaneous splenorenal shunt was discovered at the time of diagnosis of portal vein thrombosis on day 34 posttransplantation and was preserved. RESULTS: Post-shunt encephalopathy developed 6 months and 2.7 years after transplantation, causing death in one child. CONCLUSIONS: This report illustrates the risk and the possible dismal outcome of post-shunt encephalopathy in liver transplanted children. Therapeutic procedures other than portosystemic shunting that will restore an hepatopetal portal flow to the liver graft should be considered in liver-transplanted children with portal vein thrombosis.

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.

[Treatment of acute liver failure in children]. / Traitement de l'insuffisance hépatique aiguë de l'enfant.

Among the main causes of acute liver failure (ALF) in children, metabolic diseases (especially in infants), viral and toxin or drug induced hepatitis are the most frequent. The cause remains, however, undetermined in about 30% of the cases. Management must be conducted in a pediatric hepatology unit or intensive care unit in relation with a pediatric transplant team in order: 1) to perform urgent etiological diagnosis; 2) to initiate specific therapy and symptomatic treatment; 3) to evaluate the severity and prognosis of liver disease for selection of children for emergency liver transplantation; 4) to evaluate contraindications to liver transplantation. The overall survival of post-emergency liver transplantation for ALF in children averages 65%.

[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.

[Severe Reye syndrome: report of 14 cases managed in a pediatric intensive care unit over 11 years]. / Syndrome de Reye sévère: à propos de 14 cas pris en charge dans une unité de réanimation pédiatrique pendant 11 ans.

UNLABELLED: Idiopathic Reye syndrome is a rare disease revealed by unexplained encephalopathy and microvesicular liver steatosis. Some clinical and epidemiological studies mainly performed in English speaking countries questioned the reality of Reye syndrome because numerous know inherited metabolic diseases, and some of them unrecognized, could mimick this disorder. We focused in our study on severe forms of Reye syndrome admitted to a pediatric intensive care unit. METHODS: Retrospective study over the last eleven years (1991-2001) included all the pediatric patients admitted to our tertiary referral center with the classical American Reye syndrome criteria (e.g. CDC). Extensive metabolic screening was performed in all cases, except for the ultimately dead patients. RESULT: Fourteen patients (mean age 52 months) were included. Fever always occurred before their admission and aspirin (n = 12) or acetaminophen (n = 7) was prescribed. Median Glasgow scale was 7 on admission. Mean amoniac plasma level was 320 mumol/L and alanine-aminotransferase peak plasma level 1475 +/- 1387 IU/L. Mechanical ventilation was started in ten children and six of them underwent continuous venovenous hemofiltration. Three patients ultimately died and 11 survived with a mean five years follow-up without relapses or neurological impairment. Any of them demonstrated inherited metabolic disease except for one infant with hereditary fructose intolerance. CONCLUSION: Unlike widespread opinion, severe Reye syndrome without identified metabolic disorders seems to not disappear in our country. Reye syndrome remains a potentially life threatening disease and raises for aggressive treatment of brain edema. If aspirin and Reye syndrome association are not formally documented in France, cautiousness must be kept in mind and all the aspirin adverse effects notifications should be addressed to the public drugs survey network.

[Inaugural acute cholestasis of Kawasaki disease]. / Cholestase aiguë inaugurale d'une maladie de Kawasaki.

BACKGROUND: Hepatic dysfunction with mild obstructive jaundice occurs occasionally in Kawasaki disease. Acute episode of cholestasis as a presenting symptom has never been reported. CASE REPORT: A 14 year-old-boy was admitted with fever and cholestasis. He subsequently developed the classical manifestations of Kawasaki disease. No signs of liver cell injury or hepatic failure were present. Bacteriological cultures and seroimmunologic markers for viral infection remained negative. There was no ultrasonic abnormality of bile ducts. The child was given intravenous gamma globulins and salicylate. The outcome was favourable without any cardiovascular complications. CONCLUSION: A persistent febrile cholestasis of unknown etiology should evoke the diagnosis of Kawasaki disease.