Evaluation of the diagnostic accuracy of CEUS in children with benign and malignant liver lesions and portal vein anomalies.

OBJECTIVE: Comparison of the diagnostic findings of MRI, CT and CEUS in children with benign and malignant and portal venous anomalies of the liver. MATERIALS/METHODS: Retrospective analysis of the diagnostic findings of CEUS, MRI and CT scans in 56 children (age 0-17 years) with a total of 60 benign and malignant liver lesions and anomalies of the portal vein/perfusion. All patients underwent CEUS using sulphur hexafluoride microbubbles and a multi-frequency probe (1-5 MHz, 6-9 MHz). Cine-loops were stored up to 3 minutes. MRI was performed in 38 lesions. CT was performed in 8 lesions. RESULTS: Out of the 56 patients 49 liver lesions (48 benign, 1 malignant), 9 anomalies of the portal vein/perfusion and 2 of the biliary system were detected. 16/49 lesions were analyzed histopathologically. Using CEUS, the characterization of the lesions was possible in 45 out of 49 cases. In 32 cases, CEUS provided the exact diagnosis. Only two benign lesions were falsely categorized as malignant.Findings of MRI and CEUS were concordant in 84% of cases (n = 32/38). CEUS considered 1 benign lesion to be malignant. 2 lesions were not detectable and in 3 lesions no definite diagnosis was established using MRI.Findings of CT and CEUS were concordant in 5 of 8 cases. In 21 lesions CEUS as the only imaging modality was found to be sufficient for diagnostics. CONCLUSION: Despite the restricted indications for using CEUS in children, it offers a high diagnostic detection rate (93%) for characterization of liver lesions and portal vein anomalies.

Kinetics of interleukin-6, procalcitonin, and C-reactive protein after pediatric liver transplantation.

In the early phase after pediatric liver transplantation (pLT) several concomitant factors may reduce the performance of established sepsis markers. To date, their clinical interpretation is hindered by a lack of information on their postoperative kinetics. To gather more information on the postoperative course and their changes in bacterial sepsis, we prospectively studied C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) on 9 perioperative days in 25 consecutive pLTs. After an initial postoperative peak, IL-6 and CRP levels significantly re-increased in patients with bacterial sepsis (P < .001). In contrast, PCT had very high postoperative levels; therefore severe infection was a comparatively inferior trigger for PCT elevation compared with the initial operation. The area under the receiver operating characteristic curve to diagnose postoperative sepsis for PCT was only 0.52, compared with 0.95 for IL-6 and 0.89 for CRP. None of the studied biomarkers were depressed by poor graft function. In conclusion, PCT performs poorly as a biomarker for sepsis in the early phase after pLT. With a rapid decline of initially elevated levels, IL-6 provides the best kinetics for detection of postoperative bacterial sepsis.

Growing experience with mTOR inhibitors in pediatric solid organ transplantation.

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single-arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low-dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.

European biliary atresia registries: summary of a symposium.

Biliary atresia (BA) is a rare but potentially devastating disease. The European Biliary Atresia Registry (EBAR) was set up to improve data collection and to develop a pan-national and interdisciplinary strategy to improve clinical outcomes. From 2001 to 2005, 100 centers from 22 countries registered with EBAR via its website (www.biliary-atresia.com). In June 2006, the first meeting was held to evaluate results and launch further initiatives. During a 5-year period, 60 centers from 19 European countries and Israel sent completed registration forms for a total of 514 BA patients. Assuming the estimated incidence of BA in Europe is 1:18,000 live births, 35% of the expected 1488 patients from all EBAR participating countries were captured, suggesting that reporting arrangements need improvement. At the meeting, the cumulative evaluation of 928 BA patients including patients from other registries with variable follow-up revealed an overall survival of 78% (range from 41% to 92%), of whom 342 patients (37%) have had liver transplants. Survival with native liver ranged from 14% to 75%. There was a marked variance in reported management and outcome by country (e.g., referral patterns, timing of surgery, centralization of surgery). In conclusion, EBAR represents the first attempt at an overall evaluation of the outcome of BA from a pan-European perspective. The natural history and outcome of biliary atresia is of considerable relevance to a European population. It is essential that there is further support for a pan-European registry with coordination of clinical standards, further participation of parent support groups, and implementation of online data entry and multidisciplinary clinical and basic research projects.

[Congenital absence of the portal vein (CAPV). Two cases of Abernethy malformation type 1 and review of the literature]. / Der kongenitale portosystemische Shunt. Zwei Fallvorstellungen einer Abernethy-Malformation Typ 1 und Uberblick über die Literatur.

The Abernethy malformation is a rare congenital portosystemic shunt in which the blood directly drains into the systemic vein bypassing the liver either through a complete (type 1) or a partial shunt (type 2). The diagnosis is most frequently established primarily with ultrasound. CT and MRI are used for further classification of the shunt and assessment of accompanying liver tumors and malformations. There is a wide spectrum of therapeutic options ranging from noninvasive conservative treatment to liver transplantation. The main prognostic factors are the occurrence of concomitant hepatic neoplasms and hepatic encephalopathy. We report two cases diagnosed with a type 1 shunt, hepatic encephalopathy, and associated liver tumors who underwent successful liver transplantation after having considered all therapeutic options.

Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach.

BACKGROUND: Progressive familial intrahepatic cholestasis results in fibrosis, cirrhosis, and liver insufficiency if untreated. Medical therapy often fails and partial external biliary diversion has been recommended to prevent early liver transplantation. We present a new technique of performing a laparoscopic partial external biliary diversion and report our experience in a first series of infants. METHODS: From October to November 2004, four consecutive patients with progressive familial intrahepatic cholestasis underwent the laparoscopic partial biliary diversion procedure. A three-trocar technique was used. A proximal jejunal conduit was constructed after exteriorization of the small bowel via the infraumbilical trocar incision. After repositioning of the bowel, an isoperistaltic cholecystojejunostomy was carried out laparoscopically. The distal jejunal conduit was placed as a stoma at the right abdominal trocar site. RESULTS: There were no intraoperative events. The mean duration of the operation was 156.5 min. The postoperative course was uneventful in all patients with full enteral feedings on day 2. The laboratory and clinical signs of cholestasis were reduced up to a mean follow-up of 2 months (range, 1.5-2.5). CONCLUSION: The laparoscopic partial biliary diversion procedure is feasible with all the benefits of minimally invasive surgery. Long-term results remain to be evaluated.

Expression of the chemokine receptor CXCR3 and its ligand IP-10 during human cardiac allograft rejection.

BACKGROUND: Chemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of their expression or function after human cardiac transplantation. METHODS AND RESULTS: We analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3(+) T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-sectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3(+) T-cell infiltration. In particular, the expression of CXCR3 was temporally and spatially associated with CD3(+) T-cell infiltrates and correlated with the histopathological diagnosis of acute rejection (OR, 11.73 and 4.05, respectively; P<0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsies developed intimal thickening by intravascular ultrasound. In these patients, there was a trend for persistent expression of CD3- and CXCR3-expressing infiltrates in the later part of the first posttransplant year. The chemokines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were examined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, Mig, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43; P=0.01). CONCLUSIONS: The presence of CXCR3(+) T cells and the CXCR3 ligand IP-10 within endomyocardial biopsies is strongly associated with acute rejection. The CXCR3-IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.

Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo.

This study addresses a mechanism by which lymphocytes may promote vascular endothelial growth factor (VEGF) expression and angiogenesis in immune inflammation. Resting human umbilical endothelial cells (HUVECs) were found to express low levels of VEGF messenger RNA (mRNA) by reverse transcription polymerase chain reaction and ribonuclease protection assay with little or no change in expression following activation by cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1, interferon gamma, or IL-4. In contrast, treatment of HUVECs and monocytes with soluble CD40 ligand (sCD40L) resulted in a marked dose-dependent induction of VEGF mRNA (approximately 4-fold), which peaked between 1 and 5 hours post-stimulation. Transient transfection of HUVECs was performed with a luciferase reporter construct under the control of the human VEGF promoter. Treatment of transfected HUVECs with sCD40L was found to enhance luciferase activity (approximately 4-fold) compared with controls, similar to the relative fold induction in mRNA expression in parallel cultures. Thus, CD40-dependent VEGF expression was a result of transcriptional control mechanisms. Treatment of HUVECs with sCD40L was also found to function in vitro to promote growth and proliferation in a VEGF-dependent manner, and CD40-dependent HUVEC growth was comparable to that found following treatment with recombinant human VEGF. Furthermore, subcutaneous injection of sCD40L in severe combined immunodeficient and nude mice induced VEGF expression and marked angiogenesis in vivo. Taken together, these findings are consistent with a function for CD40L-CD40 interactions in VEGF-induced angiogenesis and define a mechanistic link between the immune response and angiogenesis. (Blood. 2000;96:3801-3808)

Auxiliary partial orthotopic liver transplantation for acute liver failure in two children.

Acute liver failure in children and adults is associated with a high mortality rate. At present the treatment of choice is orthotopic whole-liver transplantation. However, allogeneic liver transplantation necessitates lifelong immunosuppressive therapy, which is associated with substantial risks to the patient. Temporary auxiliary partial orthotopic liver transplantation has been developed recently as an alternative, enabling the native liver to regenerate while avoiding the risks of long-term immunosuppressive treatment. Here we describe two cases of partial orthotopic liver transplantation in children. Auxiliary partial orthotopic liver transplantation was performed in two boys (5 and 6 years old) suffering from acute liver failure of unknown origin. The native left lateral liver lobes (segment II and II) were removed and replaced by left lateral liver grafts from young blood-group-compatible adults. In the first child the native liver, which was 80% necrotic at time of transplantation, showed regeneration within two weeks and the partially necrotic graft could be surgically removed on day 15 after auxiliary transplantation. Four years after transplantation, the child is in excellent condition with normal liver function and does not require any treatment. In the second case the native liver (90% necrotic at time of transplantation) regenerated within 6 weeks of transplantation, at which time the transplanted liver was removed. The patient developed aplastic anemia and died 2 months after transplantation from candida sepsis. The conclusion was that auxiliary partial liver transplantation in childhood provides a valuable option to maintain liver function in acute liver failure until functional recovery of the native liver. The main advantage over whole-liver transplantation is the chance to avoid lifelong immunosuppression. However, there is a higher surgical risk. Therefore, auxiliary transplantation should be considered carefully in every case of acute liver failure in children.

Treatment of copper associated liver disease in childhood.

BACKGROUND/AIMS: Copper associated liver disease is accompanied with high liver copper concentrations and progressive liver disease in infancy or childhood. The disease is thought to be due to excessive dietary copper overload (copper-enriched water supply) and in addition to be based on a genetic predisposition. Treatment with penicillamine in Indian childhood disease, which probable has the same etiology, is effective when it is started early enough as well as in Wilson's disease. We aimed to describe the clinical features of copper associated liver disease and report our experience with different treatment options in German children. METHODS/RESULTS: Two boys presented at the age of 6 and 10 months with abdominal distension due to hepatosplenomegaly. The diagnosis of copper associated liver disease was made based on feeding history, standard liver function parameters, liver biopsy and assessment of dry weight copper concentration and urinary excretion of copper. Both had micronodular cirrhosis, ballooning of hepatocytes and Mallory bodies. In child A improvement of liver function was observed after introduction of penicillamine therapy and copper-reduced diet. The treatment was stopped after 18 months, when normalisation of copper concentration in the liver had occured. In child B acute liver failure developed despite initiation of treatment. The boy was transplanted successfully. Both children are presently healthy 10 years after transplantation and 4 years after begin of chelating therapy, respectively. CONCLUSIONS: We conclude, that early chelating therapy with penicillamine can be successful in children with copper associated liver disease. In case of delayed diagnosis and acute liver failure liver transplantation is necessary. Our case reports highlight the urgent need of rapid diagnosis of copper associated liver disease in order to initiate early chelating therapy. Copper associated liver disease should obviously be considered in liver disease of unknown origin. Possible causes of excessive dietary copper intake should be ascertained.

[Long-term ursodeoxycholic acid treatment of cholestatic liver diseases in childhood--clinical and biochemical effects]. / Langfristige Ursodeoxycholsäurebehandlung cholestatischer Lebererkrankungen des Kindesalters--klinische und biochemische Effekte.

BACKGROUND: In adults with chronic cholestatic liver disorders, controlled studies have shown a reduction of clinical, biochemical and possibly histological parameters during long-term medication with ursodeoxycholic acid (UDCA). It is not yet clear, however, whether similar effects can be achieved in children. Therefore, we retrospectively evaluated the use of UDCA in typical liver diseases of childhood. METHOD: 20 children were treated for at least 6 months (age at start of therapy 5-87, median 24 months; diagnosis: biliary atresia n = 10, Alagille's syndrome n = 4, intrahepatic biliary hypoplasia n = 3, Byler disease n = 3). Pruritus, liver cell injury, cholestasis, synthetic liver function and weight and height for age before medication with UDCA (7-26, mean 13 mg/kg BW/d) was compared to values after 3, 6, 12, 18 and 24 months of therapy, with special attention towards possible adverse effects. RESULTS: No adverse effects of UDCA necessitating modification of therapy were encountered. During the first year of medication, weight for age improved in 15 patients, but pruritus in only four. During UDCA treatment, GIDH and gamma GT decreased significantly. GOT and GPT declined in the majority of patients. No significant changes of bilirubin and parameters of liver synthesis were seen. CONCLUSION: Long-term medication with UDCA appears to be safe in children. Thus, controlled studies of UDCA medication in children are justified, and are urgently needed to further investigate the prognostic significance of the positive effects of UDCA identified in this retrospective analysis.

The use of plasma levels for FK 506 dosing in liver-grafted patients.

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i.e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.

[Chronic recurrent aphthous stomatitis in a 15-year-old carrier of x-chromosome inherited cytochrome b558-negative septic granulomatosis]. / Chronisch rezidivierende Stomatitis aphthosa bei einer 15jährigen Konduktorin für x-chromosomal vererbte Cytochrom b558-negative septische Granulomatose.

A 15-year-old girl, suffering from recurrent stomatitis since the age of 7 years, turned out to be heterozygous for x-linked cytochrome b558-negative chronic granulomatous disease. Two different populations of neutrophils were found in her peripheral blood: one normal (ca. 44%) and one cytochrome b558-negative (ca. 56%) subpopulation which was unable to produce H2O2. There was no history of chronic granulomatous disease in the maternal family line and the blood from the mother and from the grandmother contained a single normal population of neutrophils only. Therefore a recent mutation in one of the x-chromosomes of maternal or paternal origin is most likely. We wish to emphasize that the possibility of a carrier status for chronic granulomatous disease should be considered if recurrent aphthous stomatitis occurs (especially in context with discoid lupus). An easy flow cytometrical method for H2O2 measurement on the single cell level is advised as a screening test [5]. Genetic counselling is a most important consequence of the correct diagnosis.