Super selective percutaneous transhepatic coil embolization of intrahepatic pseudoaneurysm after pediatric liver transplantation: a case report.

BACKGROUND: Intrahepatic arterial pseudoaneurysms are a rare, life-threatening complication after pediatric liver transplantation. Treatment of choice represents interventional radiological management with endovascular embolization of the segmental artery proximal and distal to the aneurysm. However, this technique results in loss of arterial perfusion distal to the aneurysm with subsegment arterial ischemia. CASE PRESENTATION: We report a case of a 1-year-old girl with a pseudoaneurysm in the split-liver graft. Direct percutaneous, transhepatic access to the pseudoaneurysm was performed followed by super selective coil application into the aneurysm. CONCLUSION: Super selective percutaneous, transhepatic coil application is feasible even in pediatric patients after liver transplantation and results in preservation of the entire course of the liver artery.

Tacrolimus Aggravated Tube Feeding Syndrome with Acute Renal Failure in a Pediatric Liver Transplant Recipient.

Acute renal failure can be caused by calcineurin inhibitors (CNIs), due to arteriolopathy and altered tubular function. Within this context, we present the case of a 14-month-old liver transplant recipient who suffered an acute polyuric renal failure during a short episode of hypercaloric feeding. In our case, CNI-induced distal RTA led to nephrocalcinosis and therefore to secondary nephrogenic diabetes insipidus. The diet with high renal solute load consequently resulted in an acute polyuric renal failure with severe hypernatremic dehydration. In conclusion, a hypercaloric diet in children with potentially impaired renal function due to therapy with CNIs requires precise calculation of the potential renal solute load and the associated fluid requirements.

Glucose Metabolism and Associated Outcome After Pediatric Liver Transplantation.

BACKGROUND: Despite hypoglycemia and hyperglycemia being frequently observed in the early postoperative phase, information on glucose metabolism after pediatric liver transplantation (pLT) is scarce. METHODS: The goal of this retrospective single-center study, which included 46 patients who consecutively underwent 55 liver transplantations, was to gather data on glucose uptake, the prognostic relevance of hyperglycemia, and the safety of insulin administration in patients after pLT. RESULTS: In this study population, glucose intake to keep blood sugar levels (BSLs) within the targeted range of 120 to 200 mg/dL (6.7-11.1 mmol/L) increased rapidly over the first few postoperative days and was significantly correlated with graft function. There was no association between a postoperative daily mean BSL >200 mg/dL and specific posttransplant complications (acute rejection, infection, need for retransplantation, and/or death). High postoperative mean 7-day BSLs were associated with poor glucose metabolism and an increase in morbidity and 6-month posttransplant mortality. Hypoglycemia was not observed under insulin administration. CONCLUSIONS: With high BSLs being associated with poor glucose metabolism, it is likely that the critical illness itself, in addition to poor graft function, causes the increase in morbidity and mortality, with hyperglycemia serving as a marker.

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.

Taking the next step forward - Diagnosing inherited infantile cholestatic disorders with next generation sequencing.

Identifying rare genetic forms of infantile cholestasis is challenging due to their similar clinical presentation and their diverse etiology. After exclusion of common non-genetic causes a huge list of rare differential diagnosis remains to be solved. More than 90 genes are associated with monogenic forms of infantile cholestasis, thus preventing routine genetic workup by Sanger sequencing. Here we demonstrate a next generation sequencing approach to discover the underlying cause in clinically well characterized patients in whom common causes of infantile cholestasis have been excluded. After validation of the analytical sensitivity massive parallel sequencing was performed for 93 genes in six prospectively studied patients. Six novel mutations (PKHD1: p.Thr777Met, p.Tyr2260Cys; ABCB11: p.Val1112Phe, c.611+1G > A, p.Gly628Trpfs*3 and NPC1: p.Glu391Lys) and two known pathogenic mutations were detected proving our multi gene panel for infantile cholestasis to be a sensitive and specific method overcoming the complexity of the phenotype-based, candidate gene approach. Three exemplary clinical cases of infants with cholestasis are presented and discussed in the context of their genetic and histopathological findings (autosomal recessive polycystic kidney disease, atypical PFIC and Niemann-Pick syndrome type C1). These case reports highlight the critical impact of integrating clinical, histopathological and genetic data during the process of multi gene panel testing to ultimately pinpoint rare genetic diagnoses.

High levels of procalcitonin in the early phase after pediatric liver transplantation indicate poor postoperative outcome.

BACKGROUND/AIMS: To date, no data is available about procalcitonin (PCT) levels and its relevance to morbidity and graft function in the early phase after pediatric liver transplantation (pLTx). The aim of this study was to analyse the prognostic relevance of early postoperative PCT elevations in pediatric liver recipients. METHODOLOGY: Thirty pediatric patients who underwent 32 liver transplantations were included into this observational single-center study. RESULTS: Patients with high PCT levels on postoperative day (POD) 2 had higher International Normalized Ratio values on POD 5 (p<0.05) and suffered more often from primary graft non-function (p<0.05). They also had a longer stay in the pediatric intensive care unit (p<0.01) and on mechanical ventilation (p=0.001). There was no correlation between PCT elevation and systemic infection. However, PCT levels were correlated with peak serum lactate levels immediately after graft reperfusion and elevation of serum aminotransferases on POD 1 (r2=0.61, p<0.001). CONCLUSIONS: High levels of PCT after pLTx are an early indicator of poor postoperative outcome and may reflect ischemia induced liver cell injury within the context of an ischemia- reperfusion injury.

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.

[Scrotal ultrasound in children and adolecents with duplex Doppler analysis of intratesticular arteries]. / Hodensonografie bei Kindern und Jugendlichen mit Bestimmung Doppler-sonografischer Referenzwerte der intratestikulären Arterien.

PURPOSE: Scrotal ultrasound, color Doppler and spectral Doppler analysis of intratesticular arteries are the most common and important examinations in boys with scrotal pain. In the existing literature information concerning feasibility and reference values of color Doppler and spectral Doppler in small testes is inconsistent. MATERIALS AND METHODS: In the present study 102 boys from 2 days to 16 years old without present or anamnestic scrotal disease were examined in a standardized manner. Using linear scanners (9 - 14 mHz), testicular volumetry and spectral Doppler analysis of typical intratesticular arteries were performed and the paratesticular structures were examined. For analysis we grouped the testes by volume and compared the measured values V. max syst., V. max enddiast., and RI. RESULTS: In all test subjects a complete examination with spectral Doppler analysis of intratesticular arteries could be performed. With increasing testicular volume, there is a linear increase in blood flow velocities V. max syst. and V. enddiast. Irrespective of age and testicular volume, the RI of the intratesticular arteries is 0.54 ± 0.08. CONCLUSION: In contrast to published data, this study shows that color Doppler and spectral Doppler of testicular arteries can be regularly performed even in small testes of less than 1 ml. Reference values for blood flow velocities and RI were found and should improve the diagnostic value of testicular ultrasound examinations in children.

[Chronically ill children become grown-up. What does the internist learn from the pediatrician?]. / Chronisch kranke Kinder werden erwachsen. Was lernt der Internist vom Pädiater?

Transition from the protective, child and family centered pediatric care to the adult health care system with the expectation of patient self care and self management, is challenging the adolescent as well as his adult specialist. The young patients often show a delayed somatic and psychosocial development and oppose not only against their parents but also against their medical team. Adult specialists feel not well trained and experienced in dealing with adolescents. They are worried about the difficulties in the guidance of the patients and the non adherence to therapeutic recommendations. Due to medical progress, many children with severe or/and fatal chronic disorders are now surviving into adulthood. Profound knowledge of diseases that were known until now almost exclusively in the pediatric population as well as an awareness of normal physical, mental and psychosocial development of childhood and adolescence is not training content of German internists. The intention of this article is to discuss some of the experiences of pediatricians that might be helpful to internists to take better care for these special young patients.

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.

Expansion of the donor pool in liver transplantation: the Hannover experience 1996-2002.

In the past decade liver transplantation has become the standard therapy for terminal liver failure. An increasing organ shortage, specific regional allocation systems within the Eurotransplant area and the lack of an efficient system to identify donors have resulted in decreasing numbers of liver transplants. Approximately 20% of patients are dying on the waiting list, a list that has exploded in numbers and waiting time in the past 3 years. In particular children and small adults are put at a disadvantage since standard donors have standard size livers. Two options to solve this dilemma are the expanded use of split-liver and living-donor liver transplantation. The specific experiences applying these techniques at the Medizinische Hochschule Hannover are discussed and compared with the results given in the European Liver Transplant Registry. The retrospective analysis demonstrates a shift in the use of resources, with decreasing numbers of full-size cadaver liver transplants and an increase in split- and living-donor liver transplantation. Both techniques are limited to specific patient populations, a notion that has to be considered in the comparison of results and outcome. According to our experience the full-size cadaver liver is still the standard option, while other techniques require careful attention to the chosen recipient population, advanced surgical skills and, for living donors, as a sine qua non the prerequisite of nihil nocere.

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.

Development of liver size and perfusion after reduced-size liver transplantation in children.

The technique of segmental liver transplantation (s-LTx) provides a method to overcome the shortage of suitable livers for small recipients. Patient survival rates are parallel to those obtained with whole liver transplantation (w-LTx). For long-term rehabilitation, adaptive liver growth and adequate perfusion is crucial; however, morphometric and hemodynamic parameters in growing children with s-LTx are not available. Seventeen children who received a s-LTx and 25 with a w-LTx who had follow-up evaluation 1 and 2 yr after LTx were studied. Mean age at time of transplantation was 4.3 +/- 3.5 yr for s-LTx and 10.3 +/- 6.0 yr for w-LTx, mean height 98 +/- 21 cm and 122 +/- 30 cm respectively. At follow-up evaluation mean values for liver enzymes, bilirubin and prothrombin time were in the normal ranges for both groups. Liver dimensions were measured by gray scale ultrasound, and hemodynamic parameters by Doppler sonography in the portal vein and hepatic artery using an Acuson 128 machine. Maximal (Vmax), minimal (Vmin) and time-average velocity (TAV) were measured and the resistive index (RI) calculated. We found that 1 and 2 yr after LTx liver dimensions were at a mean in the upper normal range of healthy controls. Spleen size was above the normal range and did not show any tendency towards regression. Mean Vmax in the hepatic artery in s-LTx and w-LTx was 48 cm/sec vs. 28 cm/sec after 1 yr and 30 cm/sec vs. 35 cm/sec after 2 yr, the RI 0.66 vs. 0.55 and 0.59 vs. 0.73, respectively (p for all parameters > 0.05). Maximal portal vein flow was 25 cm/sec in s-LTx vs. 29 cm/sec in w-LTx. Blood flow calculated by vessel diameter and TAV showed no statistical difference between both groups. In conclusion, liver size after s-LTx and w-LTx was increased to the upper normal range, and portal vein blood flow velocities were within the normal range. Vmax in the hepatic artery was reduced in s-LTx; however, the reduction was to the same extent as in w-LTx. In the view of long-term functional adaptation, s-LTx is not inferior to w-LTx.

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)