Impaired Neurocognitive Performance in Children after Liver Transplantation.

OBJECTIVES: To assess longitudinal neurocognitive development after liver transplantation and evaluate factors associated with neurocognitive performance. STUDY DESIGN: Data from neurocognitive testing of 65 children (aged <18 years) who underwent liver transplantation at Oslo University Hospital between 1995 and 2018 were collected from the testing program after transplantation. The parent-reported version of the Behavior Rating Inventory of Executive Function was used to assess executive function. RESULTS: A total of 104 neurocognitive tests were conducted on 65 patients. At the first test, conducted at a median of 4.1 years (IQR, 1.5-5.3 years) after transplantation and at a median age of 6.7 years (IQR, 5.4-10.5 years), the mean full-scale IQ (FSIQ) was 91.7 ± 14, and the mean verbal comprehension index was 92.0 ± 14.5. In the 30 patients tested more than once, there was no significant difference in FSIQ between the first test at a median age of 5.8 years (IQR, 5.2-8.5 years) and the last test at a median age of 10.8 years (IQR, 9.8-12.9 years) (87.4 ± 12.9 vs 88.5 ± 13.2; P = .58). Compared with the patients who underwent transplantation a age >1 year (n = 35), those who did so at age <1 year (n = 30) had a lower FSIQ (87.1 ± 12.6 vs 96.6 ± 13.8; P = .005) and lower verbal comprehension index (87.3 ± 13.8 vs 95.4 ± 13.0; P = .020). Age at transplantation (P = .005; adjusted for cholestasis: P = .038) and transfusion of >80 mL/kg (P = .004; adjusted for age at transplantation: P = .046) were associated with FSIQ. CONCLUSIONS: Young age at transplantation and large blood transfusions during transplantation are risk factors for poor neurocognitive performance later in life. Children who undergo transplantation before 1 year of age have significantly lower neurocognitive performance compared with those who do so later in childhood. Cognitive performance did not improve over time after transplantation.

Outcome for biliary atresia patients treated at a low-volume centre.

OBJECTIVES: The importance of case load for treatment of extrahepatic biliary atresia (BA) is debated. The aim of this study was to register results of BA treatment in a small volume centre. METHODS: Retrospective chart review study of patients with BA treated from 2000 to 2017. The institutional review board approved the study. RESULTS: Forty-five babies were identified of which 42 (93%) are alive. Forty-one patients had a Kasai portoenterostomy (PE), two had a hepaticojejunostomy and two had a primary liver transplantation. The age at PE/hepaticojejunostomy was median 63 (4-145 days). Seven surgeons performed the operations, and the median duration of the diagnostic work-up was 8 (3-24) days. Clearance of jaundice was achieved in 23/43 (53%) babies, and 3- and 5-year native liver survival was 47% and 40%, respectively. Clearance of jaundice post-PE/hepaticojejunostomy was a strong predictor of native liver survival (adjusted OR: 0.027; 95%; p = .009). Plasma level of conjugated bilirubin at time of referral was also a significant predictor of native liver survival (adjusted OR: 1.053; p = .017). CONCLUSION: A small volume centre may achieve satisfactory results for BA patients. The study has, however, identified factors that may further improve results; earlier referral, optimizing diagnostic work-up and establishing one dedicated surgical team.

No effect of treatment with intravenous ganciclovir on Epstein-Barr virus viremia demonstrated after pediatric liver transplantation.

EBV after pediatric LT is a risk factor for PTLD. We wanted to evaluate the effect of intravenous ganciclovir on EBV viremia and to identify risk factors for chronic EBV viremia. All pediatric patients who underwent LT in Norway from 2002 until 2015 were reviewed. Twenty-two of 38 patients with viremia were treated with intravenous ganciclovir for a median of 22 (21-38) days. Treated and untreated patients were not different with respect to EBV seroconversion prior to transplantation or age at transplantation, but treated patients had significantly earlier viremia after transplantation (P=.005). There was no difference in the proportion of patients with reduction in virus load in patients treated with ganciclovir compared to untreated patients at 8 weeks. After 1 year, five of 19 patients treated with ganciclovir and six of 14 untreated patients had reduced virus load compared to start of viremia (P=.27). In conclusion, treatment with intravenous ganciclovir did not change the proportion of patients with reduction in EBV load at 8 weeks and 1 year after viremia. Younger age at transplantation, short time from transplantation to viremia, and lack of EBV seroconversion prior to transplantation were significant predictors of chronic EBV viremia.

Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Impaired motor competence in children with transplanted liver.

OBJECTIVES: Although reduced cognitive function has been demonstrated after liver transplantation in children, few data are available concerning motor competence. METHODS: Thirty-five children ages 4 to 12 years were tested using Movement Assessment Battery for Children (M-ABC) test at a median of 5.1 (3.9-6.9) years after liver transplantation and compared with reference material of healthy children. RESULTS: Children with transplantation had worse M-ABC score 8.0 (interquartile range 5.0-11.5), compared with healthy children 3.5 (1.0-6.0) (P < 0.0001). All of the subscores (manual dexterity [P < 0.0001], ball skills [P = 0.0037], and balance [P = 0.0032]) were significantly worse in the children with liver transplantation compared with the healthy reference group. Twenty-nine percent of the children with liver transplantation had impaired motor competence, compared with 9% of a healthy reference group. Seventeen of the patients with transplantation were retested 1 year later, and 11 were tested 4 years later with no changes in total M-ABC score. Ball skill competence was worse 4 years after first assessment (P = 0.013). For children with transplantation and cholestatic liver disease (n =26), renal function was a significant predictor for total M-ABC score (P = 0.018). CONCLUSIONS: Children with liver transplantation had impaired motor competence compared with healthy children. Ball skills developed adversely several years after liver transplantation, and motor competence did not improve with time after transplantation. Renal function was a significant predictor for motor competence in children with liver transplantation and cholestatic liver disease.

Effect of operator experience and frequency of procedure performance on complication rate after ultrasound-guided percutaneous liver biopsies.

OBJECTIVE: The aim of the present study was to assess whether the complication rate after ultrasound-guided percutaneous liver biopsies in children is affected by how frequently the procedure is performed by the operator. METHODS: Medical charts and ultrasound descriptions of 311 ultrasound-guided percutaneous liver biopsy procedures performed by 18 radiologists at a single center from 2000 to 2011 were reviewed. Postbiopsy ultrasound the following day was performed after 97% of the procedures. RESULTS: There were no differences in the procedure-associated rate of major bleeding incidents (2.2% vs 0.8%, P = 0.38), minor bleeding incidents (15.2% vs 10.2%, P = 0.31), or abdominal pain (13.0% vs 10.6%, P = 0.61) among operators who performed ≤10 procedures and those who performed >10 procedures during the study period. A higher rate of minor bleeding incidents were recorded after liver biopsy when operators had performed <10 biopsies compared with operators who had performed >20 pediatric liver biopsies during the study period (odds ratio 3.4 [1.3-9.1], P = 0.02). No association between the number of biopsies performed by the operator during the 2 years preceding the date of the biopsy and complications was found. CONCLUSIONS: Major complications are infrequent after pediatric liver biopsies and no relation between operator experience and major complications was found. We found a significant, but minor, effect of operator procedure frequency on the rate of minor bleeding incidents after ultrasound-guided pediatric liver biopsies.

Clinical experience with microdialysis catheters in pediatric liver transplants.

Ischemic vascular complications and rejection occur more frequently with pediatric liver transplants versus adult liver transplants. Using intrahepatic microdialysis catheters, we measured lactate, pyruvate, glucose, and glycerol values at the bedside for a median of 10 days in 20 pediatric liver grafts. Ischemia (n = 6), which was defined as a lactate level > 3.0 mM and a lactate/pyruvate ratio > 20, was detected without a measurable time delay with 100% sensitivity and 86% specificity. Rejection (n = 8), which was defined as a lactate level > 2.0 mM and a lactate/pyruvate ratio < 20 lasting for 6 or more hours, was detected with 88% sensitivity and 45% specificity. With additional clinical criteria, the specificity was 83% without a decrease in the sensitivity. Rejection was detected at a median of 4 days (range = 1-7 days) before alanine aminotransferase increased (n = 5, P = 0.11), at a median of 4 days (range = 2-9 days) before total bilirubin increased 25% or more (n = 7, P = 0.04), and at a median of 6 days (range = 4-11 days) before biopsy was performed (n = 8, P = 0.05). In conclusion, microdialysis catheters can be used to detect episodes of ischemia and rejection before current standard methods in pediatric liver transplants with clinically acceptable levels of sensitivity and specificity. The catheters were well tolerated by the children, and no major complications related to the catheters were observed.

Inflammatory markers sampled by microdialysis catheters distinguish rejection from ischemia in liver grafts.

Rejection and ischemia are serious complications after liver transplantation. Early detection is mandatory, but specific markers are largely missing, particularly for rejection. The objective of this study was to explore the ability of microdialysis catheters inserted in liver grafts to detect and discriminate rejection and ischemia through postoperative measurements of inflammatory mediators. Microdialysis catheters with a 100-kDa pore size were inserted into 73 transplants after reperfusion. After the study's completion, complement activation product 5a (C5a), C-X-C motif chemokine 8 (CXCL8), CXCL10, interleukin-1 (IL-1) receptor antagonist, IL-6, IL-10, and macrophage inflammatory protein 1ß were analyzed en bloc in all grafts with biopsy-confirmed rejection (n = 12), in grafts with vascular occlusion/ischemia (n = 4), and in reference grafts with a normal postoperative course of circulating transaminase and bilirubin levels (n = 17). The inflammatory mediators were elevated immediately after graft reperfusion and decreased toward low, stable values during the first 24 hours in nonischemic grafts. In grafts suffering from rejection, CXCL10 increased significantly (P = 0.008 versus the reference group and P = 0.002 versus the ischemia group) 2 to 5 days before increases in circulating alanine aminotransferase and bilirubin levels. The area under the receiver operating characteristic curve was 0.81. Grafts with ischemia displayed increased levels of C5a (P = 0.002 versus the reference group and P = 0.008 versus the rejection group). The area under the curve was 0.99. IL-6 and CXCL8 increased with both ischemia and rejection. In conclusion, CXCL10 and C5a were found to be selective markers for rejection and ischemia, respectively.

Early bedside detection of ischemia and rejection in liver transplants by microdialysis.

This study was performed to explore whether lactate, pyruvate, glucose, and glycerol levels sampled via microdialysis catheters in the transplanted liver could be used to detect ischemia and/or rejection. The metabolites were measured at the bedside every 1 to 2 hours after the operation for a median of 10 days. Twelve grafts with biopsy-proven rejection and 9 grafts with ischemia were compared to a reference group of 39 grafts with uneventful courses. The median lactate level was significantly higher in both the ischemia group [5.8 mM (interquartile range = 4.0-11.1 mM)] and the rejection group [2.1 mM (interquartile range = 1.9-2.4 mM)] versus the reference group [1.5 mM (interquartile range = 1.1-1.9 mM), P < 0.001 for both]. The median pyruvate level was significantly increased only in the rejection group [185 µM (interquartile range = 155-206 µM)] versus the reference group [124 µM (interquartile range = 102-150 µM), P < 0.001], whereas the median lactate/pyruvate ratio and the median glycerol level were increased only in the ischemia group [66.1 (interquartile range = 23.9-156.7) and 138 µM (interquartile range = 26-260 µM)] versus the reference group [11.8 (interquartile range = 10.6-13.6), P < 0.001, and 9 µM (interquartile range = 9-24 µM), P = 0.002]. Ischemia was detected with 100% sensitivity and greater than 90% specificity when a positive test was repeated after 1 hour. In 3 cases of hepatic artery thrombosis, ischemia was detected despite normal blood lactate levels. Consecutive pathological measurements for 6 hours were used to diagnose rejection with greater than 80% sensitivity and specificity at a median of 4 days before the activity of alanine aminotransferase, the concentration of bilirubin in serum, or both increased. In conclusion, bedside measurements of intrahepatic lactate and pyruvate levels were used to detect ischemia and rejection earlier than current standard methods could. Discrimination from an uneventful patient course was achieved. Consequently, intrahepatic graft monitoring with microdialysis may lead to the earlier initiation of graft-saving treatment.

Evaluation of risk factors for bleeding after liver biopsy in children.

OBJECTIVES: Acetylsalicylic acid is used in liver-transplanted children to prevent thrombosis of the hepatic artery. We evaluated whether acetylsalicylic acid and other risk factors were associated with bleeding after percutaneous liver biopsy. METHODS: Medical charts, laboratory results, imaging studies, and anesthesia charts of 275 ultrasound-guided liver biopsy procedures in 190 children were reviewed. A total of 178 biopsies were performed on native livers and 97 on transplanted livers. RESULTS: Three major and 28 minor bleeding incidents were found. The mortality rate was 0%. Acetylsalicylic acid had been given the last 5 days before 55 of the biopsy procedures and no increased risk of bleeding was found (odds ratio 0.96 [0.37-2.26]; P = 1.00). Low-molecular-weight heparin and biopsies from focal lesions were risk factors for bleeding complications. Acute liver failure was associated with increased risk for major complications (odds ratio 26.1 [3.3-205]; P = 0.01) and was a risk factor for major bleeding. Postbiopsy ultrasound the day after the procedure (n = 266 [96% of 275 biopsies]) revealed minor bleeding after 7.1% of the biopsies and after 2.6% of the ultrasounds revealed unsuspected bleeding, but none of these required intervention. CONCLUSIONS: Ultrasound-guided liver biopsy in children is a procedure with a low rate of major complications and a high rate of minor bleeding not requiring intervention. Treatment with low-dose acetylsalicylic acid did not increase bleeding incidence or total complication rate. Low-molecular-weight heparin and biopsies from focal lesions were risk factors for bleeding complications. Routine ultrasound the day after the procedure did not change handling of the patients.

[Liver transplantation in Norway through 25 years]. / Levertransplantasjon i Norge gjennom 25 år.

BACKGROUND: In Norway, liver transplantation has been the treatment of choice for irreversible acute and chronic liver failure for 25 years. The aim of this article is to present a summary of the results obtained. MATERIAL AND METHODS: All liver transplants performed in Norway in the period 25.02.84-31.12.08 have been reviewed retrospectively with respect to patient and donor epidemiology, survival and recurrence. RESULTS: 651 transplants have been performed in this period. The annual number of transplants increased gradually up to the year 2000 (31), and more steeply afterwards - to 79 in 2008. Also the number of organ donations has increased and reached 98 (20 pr. million inh.) in 2008. 5-year patient survival was 53 % in the period 1984-1994. In the period 2001-2008, 1-year survival was 90 % and 5-year survival was 83 %. INTERPRETATION: The gradual improvement of results should be interpreted in light of improvements within transplant surgery, medicine and anaesthesiology and the increased local experience due to the increasing number of transplants performed. The transplant centre at Rikshospitalet has developed into being among the largest of its kind within the Nordic Countries and the results compare well with the best international data.

Utility of ERCP in neonatal and infant cholestasis.

BACKGROUND AND STUDY AIMS: In neonates and infants with biliary obstruction, the diagnosis is important to establish early. Despite the use of several noninvasive imaging modalities, a definite diagnosis of biliary atresia (BA) or other pancreaticobiliary disorders may be difficult to ascertain. In this paper, we report our experience with endoscopic retrograde cholangiopancreaticography (ERCP) in the clinical situation of neonatal and infant jaundice. PATIENTS AND METHODS: Between 1999 and 2006, we performed 23 ERCP procedures in 22 neonates and infants with the provisional diagnosis of biliary obstruction where other imaging was inconclusive. The mean age was 2.4 months and the mean weight was 4.8 kg. A pediatric videoendoscope with an outer diameter of 7.5 mm was used in all patients. RESULTS: ERCP was successful in 20 of 23 patients. BA was suggested in 6 patients, all subsequently verified by surgery. Detailed visualization of biliary structures important for planning of treatment was performed in children with choledochal cysts and spontaneous biliary perforation. Cannulation of the ampulla failed in 3 patients, of whom 1 had BA, 1 a choledochal stone, and 1 bile plug syndrome. Only 1 therapeutic ERCP was performed in a child with a stone completely obstructing the ampulla. The only complications were 1 asymptomatic case of hyperamylasemia and 1 of mild cholangitis successfully treated with antibiotics. CONCLUSIONS: ERCP is feasible and safe in the workup of neonatal cholestasis where other imaging modalities are inconclusive. Despite the expanding role of magnetic resonance cholangiography, ERCP may still have a role in the multidisciplinary workup of these patients.

[Autoimmune hepatitis in children]. / Autoimmune leversykdommer hos barn.

BACKGROUND: Autoimmune mechanisms are involved in the pathogenesis of autoimmune hepatitis and primary sclerosing cholangitis. The disorders are rare but important to diagnose, as immunomodulating therapy can prevent liver failure. Cases of "overlap syndrome" between autoimmune hepatitis and primary sclerosing cholangitis are described. MATERIAL AND METHODS: We have studied the medical records of children diagnosed with hepatitis and cholangitis treated at Rikshospitalet University Hospital from 1986 through 2004. Symptoms, findings and disease course are presented. A general overview is given of autoimmune hepatitis, primary sclerosing cholangitis and overlap syndrome in children. RESULTS: 18 children were identified; 11 with autoimmune hepatitis, six with primary sclerosing cholangitis and one with overlap syndrome. Four of the children with primary sclerosing cholangitis had inflammatory bowel disease; two of them had ulcerative colitis and two had Crohn's disease. The patient with overlap syndrome had ulcerative colitis. Pathology was found in the liver biopsies of all the children. Sixteen patients were treated with prednisolone and azathioprine. Most of the children responded to immunomodulating therapy with normalization of liver function tests. Many relapsed while tapering steroids. None of the patients have needed a liver transplant. CONCLUSION: It is important to diagnose children with autoimmune liver disease, as children tend to respond well to immunomodulating therapy.