The Medication Level Variability Index (MLVI) Predicts Poor Liver Transplant Outcomes: A Prospective Multi-Site Study.

Nonadherence to immunosuppressant medications is a leading cause of poor long-term outcomes in transplant recipients. The Medication Level Variability Index (MLVI) provides a vehicle for transplant outcome risk-stratification through continuous assessment of adherence. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study evaluated whether MLVI predicts late acute rejection (LAR). Four hundred pediatric (1-17-year-old) liver transplant recipients were enrolled and followed for 2 years. The a-priori hypothesis was that a higher MLVI predicts LAR. Predefined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescents to pre-adolescents. In the primary analysis sample of 379 participants, a higher prerejection MLVI predicted LAR (mean prerejection MLVI with LAR: 2.4 [3.6 standard deviation] versus without LAR, 1.6 [1.1]; p = 0.026). Fifty-three percent of the adolescents with MLVI>2 in year 1 had LAR by the end of year 2, as compared with 6% of those with year 1 MLVI≤2. A higher MLVI was significantly associated with all secondary outcomes. MLVI, a marker of medication adherence that uses clinically derived information, predicts LAR in pediatric liver transplant recipients.

Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients.

In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.

Cognitive and academic outcomes after pediatric liver transplantation: Functional Outcomes Group (FOG) results.

This multicenter study examined prevalence of cognitive and academic delays in children following liver transplant (LT). One hundred and forty-four patients ages 5-7 and 2 years post-LT were recruited through the SPLIT consortium and administered the Wechsler Preschool and Primary Scale of Intelligence, 3rd Edition (WPPSI-III), the Bracken Basic Concept Scale, Revised (BBCS-R), and the Wide Range Achievement Test, 4th edition (WRAT-4). Parents and teachers completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants performed significantly below test norms on intelligence quotient (IQ) and achievement measures (Mean WPPSI-III Full Scale IQ = 94.7 ± 13.5; WRAT-4 Reading = 92.7 ± 17.2; WRAT-4 Math = 93.1 ± 15.4; p < 0001). Twenty-six percent of patients (14% expected) had 'mild to moderate' IQ delays (Full Scale IQ = 71-85) and 4% (2% expected) had 'serious' delays (Full Scale IQ ≤ 70; p < 0.0001). Reading and/or math scores were weaker than IQ in 25%, suggesting learning disability, compared to 7% expected by CDC statistics (p < 0.0001). Executive deficits were noted on the BRIEF, especially by teacher report (Global Executive Composite = 58; p < 0.001). Results suggest a higher prevalence of cognitive and academic delays and learning problems in pediatric LT recipients compared to the normal population.

Improving long-term outcomes after liver transplantation in children.

The objective was to review the current state of knowledge and recommend future research directions related to long-term outcomes for pediatric liver transplant recipients. A 1-day Clinical Research Workshop on Improving Long-Term Outcomes for Pediatric Liver Transplant Recipients was held on February 12, 2007, in Washington, DC. The speaker topics were germane to research priorities delineated in the chapters on Pediatric Liver Diseases and on Liver Transplantation in the Trans-NIH Action Plan for Liver Disease Research. Issues that compromise long-term well-being and survival but are amenable to existing and new research efforts were presented and discussed. Areas of research that further enhanced the research priorities in the Action Plan for Liver Disease Research included collection of longitudinal data to define emerging trends of clinical challenges; identification of risk factors associated with long-term immunosuppression complications; development of tolerance-inducing regimens; definition of biomarkers that reflect the level of clinical immunosuppression; development of instruments for the measurement of health wellness; identification of risk factors that impede growth and intellectual development before and after liver transplantation and identification of barriers and facilitators that impact nonadherence and transition of care for adolescents.

Cost-effectiveness of coarctation repair strategies: endovascular stenting versus surgery.

The cost-effectiveness of stent (ST) implantation for the repair of coarctation of the aorta (CoA) is not documented in the medical literature. Inflation-adjusted hospital costs for ST implantation and for surgical (SU) repair were obtained using the HBOC Cost Accounting System software and evaluated for all patients 5 years of age or older who underwent elective treatment of CoA between July 1997 and June 2001. The average age of the ST group (n = 10) to 9.5 +/- 3.5 years for the SU group (n = 12) (p > 0.10). The ST group had one failure due to inability to cross the CoA (failure rate, 10%). Successful repair was accomplished in all other ST cases and in all SU cases, with no residual systolic gradients at 1-year follow-up. Hospital length of stay for the ST group was 0.8 +/- 1.2 days compared to 3.5 +/- 0.5 days for the SU group (p < 0.001). The mean inflation-adjusted cost for the ST group was dollar 7,148 +/- 2,984 versus dollar 11,769 +/- 3,702 for the SU group (p < 0.005). By intention to treat analysis, the cost of repair in the ST-first group was dollar 8,325 +/- 3,354 given the 10% failure rate (p < 0.04 vs the SU only group). Sensitivity analysis demonstrates that cost of repair is lower with the ST-first strategy compared to SU only until the failure rate of ST implantation exceeds 39%. Repair of CoA using an endovascular stent strategy is cost-effective compared to conventional surgical repair.

Effect of insulinlike growth factor-1 treatment in children with cystic fibrosis.

OBJECTIVES: Malnutrition is common in cystic fibrosis (CF) and adversely affects survival. Because insulinlike growth factor-1 (IGF-1) has insulinlike effects in terms of carbohydrate metabolism and is growth promoting, the authors hypothesized that its use would increase linear growth rate and decrease insulin requirements in children with CF. METHODS: The authors used a double-blind placebo-controlled crossover design. Seven prepubertal children aged 9.6 to 13 years (5 boys and 2 girls) were treated with placebo or IGF-1 for 6 months. After a 6-month washout period, patients received the alternative therapy for 6 months. The primary outcome measure was linear growth rate. Secondary outcome measures were changes in body mass index, body composition determined by dual energy x-ray absorptiometry, forced expiratory volume (FEV(1)), and the blood glucose/insulin ratio. RESULTS: The mean height z score at baseline was -1.5 +/- 0.8. At entry, the mean serum IGF-1 level was 124 +/- 25 ng/mL (normal range, 110-771 ng/mL). With treatment, mean serum IGF-1 levels increased twofold to threefold for all patients. The half-life for IGF-1 was 10.3 hours. We observed no significant difference in linear growth rate, weight gain, rate of accretion of lean body mass, or mean FEV(1) during treatment with IGF-1 compared with placebo. The glucose/insulin ratio, an indirect index of insulin sensitivity, was significantly increased with IGF-1 treatment compared with placebo ( P < 0.02). No adverse events related to IGF-1 were detected. CONCLUSIONS: Treatment with IGF-1 for 6 months did not promote linear growth in prepubertal children with CF. However, the glucose/insulin ratio was increased without changing blood glucose levels with IGF-1 treatment suggesting increased insulin sensitivity.

Predictors of cost of liver transplantation in children: a single center study.

OBJECTIVE: Efforts to decrease the cost of orthotopic liver transplantation (OLT) must address the impact of specific interventions on clinical outcome. We hypothesized that an intervention designed to decrease the length of hospitalization would reduce costs without jeopardizing clinical outcome. We further sought to identify predictors of length of stay and cost for hospitalization after liver transplantation. METHODS: The study group included 47 children who underwent OLT from September 1996 to April 1999, and the control group included 36 children who underwent OLT from March 1994 to August 1996. The intervention was a transition to home program in which patients were discharged to a family living center when they met established clinical criteria and their families met predefined educational goals. We analyzed patients who survived 3 months after OLT. RESULTS: For the intervention group, the mean length of stay, total costs, and surgical costs were 29%, 36%, and 34% lower, respectively. Organ type, height z score, race, hepatic artery thrombosis, early allograft rejection, and participation in the transition to home program predicted length of stay and total costs. CONCLUSION: An early discharge program based on defined criteria can be used to decrease length of stay and cost after OLT without jeopardizing clinical outcome.

Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study.

Prostaglandin E1 (PGE1) and N-acetylcysteine (NAC) have been used as single agents to decrease reperfusion injury and improve outcome after solid-organ transplantation (Tx). We hypothesized that combined treatment with NAC and PGE1 would be safe and reduce reperfusion injury. We therefore carried out a pilot study to assess the safety of this drug combination and gain information regarding the efficacy of treating pediatric liver transplant recipients with NAC and PGE1. The pilot study took the form of an open-label study incorporating 25 pediatric liver transplant recipients (12 children in the treatment group and 13 children as controls). NAC (70 mg/kg) was given intravenously over 1 h following reperfusion and then every 12 h for 6 days. PGE1 (0.4 mg/kg/h) was given as a continuous intravenous infusion for 6 days, starting after the first NAC dose. The primary outcome was the safety of combined treatment with NAC and PGE1. Patient survival, graft survival, allograft rejection within the first 90 days after Tx, peak post-transplant serum alanine aminotransferase (ALT) concentration, post-transplant length of hospitalization, and post-operative complications were secondary outcomes. Post-operative complications occurred at similar rates in both control and treated groups. No complications or adverse events occurred in the treated group as a result of study drugs. The 3-month patient survival rate was 100% for both groups. For the group treated with NAC and PGE1, peak serum ALT was lower and median length of stay was shorter but the differences did not reach statistical significance. The proportion of patients with allograft rejection was not significantly different between the two groups. However, rejection was more severe in the control group than in the treated group. In summary, infusions of NAC and PGE1 were safely administered to pediatric liver transplant recipients. However, a randomized controlled study is needed to determine the efficacy of treatment with NAC and PGE1.

Long-term survival after liver transplantation.

BACKGROUND: Liver transplantation (LT) remains a high-risk operation, especially during the first months after LT when technical complications and preexisting illness exert their influence on survival. However, there are late deaths. The authors have reviewed their experience to identify factors impacting on long-term survival. METHODS: A total of 150 patients who had undergone liver transplantation over an 11-year period were reviewed. Thirty-three patients died after LT (22%). Of these, 18 of 33 (55%) died in the first 3 postoperative months. One hundred thirty-two patients survived beyond 3 months, and 15 patients (11%) suffered late deaths. This review concentrates on the latter group. RESULTS: The primary cause of death was sepsis in 11 of 15 (73%). In two, sepsis complicated retransplantation in chronically debilitated patients. Two additional patients had late-presenting postoperative complications (bile leak or abscess, intestinal obstruction with perforation). In two cases, pneumocystis carinii pneumonia occurred; noncompliance or unplanned discontinuation of prophylaxis was directly responsible. Multiple organ system failure from presumed immunoincompetence developed in four patients; one had undergone bone marrow transplantation for aplastic anemia (AA) after fulminant hepatic failure (FHF). Lymphoproliferative disease (LPD) was the cause of death in 3 of 15 cases (20%). In only three cases was the cause of death related to the patient's primary disease (chronic hepatitis, Alper's syndrome or seizures, and AA with FHF). Pretransplant diagnosis, and UNOS status at the time of LT did not influence the long-term survival. CONCLUSIONS: Long-term survival in patients who have undergone LT was compromised by immunosuppressive complications and sepsis. Early mortality factors, such as UNOS status, age at LT, primary diagnosis, and technical complications do not predict late deaths. In children who adhere to their medical regimen and have good initial allograft function, late postoperative infection, especially with Ebstein-Barr virus, accounts for most of the late mortality. Improved and decreased immunosuppression may further improve these long-term results.

Biliary atresia: pathogenesis and treatment.

Biliary atresia is a disorder of infants in which there is obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow. Untreated, the resulting cholestasis leads to progressive conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. Biliary atresia has an incidence of approximately one in 10,000 live births worldwide. Evidence to date supports a number of pathogenic mechanisms for the development of biliary atresia. An infectious cause, such as by a virus, would seem most pausible in many cases. The clinical observation that biliary atresia is rarely encountered in premature infants would support an agent acting late in gestation. However, no infectious or toxic agent has been conclusively implicated in biliary atresia. Genetic mechanisms likely play important roles, even regarding susceptibility to other specific causes, but no gene whose altered function would result in obstruction or atresia of the biliary tree has been identified. The variety of clinical presentations support the notion that the proposed mechanisms are not mutually exclusive but may play roles individually or in combination in certain patients. Biliary atresia, when untreated, is fatal within 2 years, with a median survival of 8 months. The natural history of biliary atresia has been favorably altered by the Kasai portoenterostomy. Approximately 25 to 35% of patients who undergo a Kasai portoenterostomy will survive more than 10 years without liver transplantation. One third of the patients drain bile but develop complications of cirrhosis and require liver transplantation before age 10. For the remaining one third of patients, bile flow is inadequate following portoenterostomy and the children develop progressive fibrosis and cirrhosis. The portoenterostomy should be done before there is irreversible sclerosis of the intrahepatic bile ducts. Consequently, a prompt evaluation is indicated for any infant older than 14 days with jaundice to determine if conjugated hyperbilirubinemia is present. If infectious, metabolic, endocrine disorders are unlikely and if the child has findings consistent with biliary atresia, then exploratory laparotomy and intraoperative cholangiogram should be done expeditiously by a surgeon who has experience doing the Kasai portoenteostomy. Biliary atresia represents the most common indication for pediatric liver transplantation, representing more than 50% of cases in most series. Transplantation is indicated when symptoms of end stage liver disease occur, including recurrent cholangitis, progressive jaundice, portal hypertension complications, ascites, decreased synthetic function, and growth/nutritional failure.

Biliary atresia--surgical management and treatment options as they relate to outcome.

Results show that the use of sequential surgical treatment, employing Kasai portoenterostomy in infancy, followed by selective liver transplantation for children with progressive hepatic deterioration yields improved overall survival. All children with successful Kasai portoenterostomy procedures who do not require OLT are survivors. Using newer transplant techniques, the 5-year survival rate for children who receive transplants with a primary diagnosis of biliary atresia was 82%. This yields an overall survival rate of 86% in this entire study population. Limited donor availability and increased complications after liver transplantation in infants less than 1 year of age mitigate against the use of primary liver transplantation without prior portoenterostomy for infants with biliary atresia. At present, these two operative procedures should be used as sequential and complementary modes of treatment rather than as competitive procedures. When biliary atresia is not recognized in infancy and established cirrhosis has resulted, primary transplantation should be offered as the initial surgical treatment.

Expansion of transplanted hepatocytes during liver regeneration.

BACKGROUND: Successful clinical application of hepatocyte transplantation has been limited by poor engraftment of the recipient liver by transplanted hepatocytes. METHODS: To address the hypothesis that liver regeneration induced by an acute hepatotoxic injury promotes expansion of transplanted hepatocytes, we injected beta-galactosidase-labeled hepatocytes intrasplenically into mice 24 hr after treatment with carbon tetrachloride (CCl4) and into untreated controls. RESULTS: Macroscopic examination of whole liver segments identified clusters of transplanted hepatocytes uniformly spread on the capsular surface of the recipient liver and in the liver core following the distribution pattern of portal vein branches. Frozen sections showed that although the degree of initial engraftment of transplanted hepatocytes was similar in CCl4-treated and control livers, there was a fourfold increase of engrafted hepatocytes in CCl4-treated livers 10 days after transplantation which persisted to 28 days. CONCLUSIONS: We conclude that the number of transplanted hepatocytes increases in response to regeneration signal triggered by an acute hepatocyte-specific liver injury.

Resistance to growth hormone in children with chronic liver disease.

Malnutrition adversely affects mortality and morbidity before and after liver transplantation. Outcome might be improved if liver transplant recipients were in a better nutritional state at the time of transplantation. In this review, we will examine the potential use of GH and IGF-I to improve nutritional status in patients with cirrhosis. Patients with cirrhosis have low circulating IGF-I levels in the face of elevated serum GH concentrations. IGFBP-3 levels are low while IGFBP-1 levels are high. In patients with cirrhosis, IGF-I levels do not increase in response to treatment with GH. Patients with cirrhosis are insensitive to GH, and rhGH treatment is not likely to reverse malnutrition. The pathobiology of GH insentivity may reflect decreased nutritional intake, low GH receptor density, decreased IGF-I half-life and hepatic insensitivity to insulin.

A liver-specific isoform of the betaine/GABA transporter in the rat: cDNA sequence and organ distribution.

We report the cloning of a 2.2 kb cDNA encoding a Na(+)-and Cl- dependent betaine/GABA (gamma-aminobutyric acid) transporter from rat liver poly(A+) RNA. 5'-RACE revealed an additional 355 bases 5' to the 2.2 kb cDNA sequence. Northern analysis demonstrated two (2.2 kb and 2.6 kb) mRNA isoforms in rat liver. Betaine transporter mRNA was also detected in the brain, spleen, lung, and kidney using the 2.2 kb cDNA clone as a probe. Only the 2.6 kb mRNA from the liver hybridized with the 5'-RACE product.

Growth hormone insensitivity in children with biliary atresia.

Malnutrition is a critical predictor of mortality and morbidity in children with biliary atresia who undergo orthotopic liver transplantation. Growth hormone (GH) enhances nitrogen retention in patients with chronic obstructive lung disease, sepsis, and in fasted adult volunteers. The goal of this study was to assess the acute response to recombinant human GH (rhGH) treatment in children with biliary atresia to determine whether GH therapy was likely to improve pretransplant nutritional status. Five children, aged 10-32 months, with biliary atresia and persistent cholestasis despite surgical attempts to reestablish bile flow, were studied. All five children had portal hypertension, conjugated hyperbilirubinemia, and decreased serum albumin concentrations. Length, weight, and growth velocity were decreased in all five children. Despite adequate energy and protein intake, fat stores were depleted in all five subjects, and somatic protein stores were diminished in all except one child. Baseline serum concentrations of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were low (8.4 +/- 2 ng/ml and 0.2 +/- 0.1 mg/l respectively). In the four children who completed the study, serum IGF-I and IGFBP-3 levels did not change after treatment with rhGH (0.1 mg/kg/day) for 4 days. Our findings indicate that children with biliary atresia awaiting liver transplantation are insensitive to GH and that treatment with GH is unlikely to promote anabolism. A rationale exists for examining the effect of treatment with IGF-I, which mediates the anabolic effects of GH.

Fasting enhances taurine transport by rat liver plasma membrane vesicles.

Hepatic taurine stores are maintained by biosynthesis from the sulfur-containing amino acids, methionine and cysteine, and by uptake via a Na(+)- and Cl(-)-dependent transport system, which is specific for beta-amino acids. We hypothesized that liver stores of taurine are maintained by enhanced hepatic transport during fasting when dietary sources for taurine and its precursors are diminished. Liver plasma membrane vesicles, enriched for the basolateral domain, were prepared from adult male rats fasted for 72 h and from control rats. The maximum velocity for Na(+)-dependent taurine uptake was twofold greater for the fasted group compared with the control group (0.87 +/- 0.09 vs. 0.31 +/- 0.03 nmol.mg protein-1.min-1). The apparent Michaelis constant for taurine was also greater for fasted compared with control (154.0 +/- 0.5 vs. 80.0 +/- 2.0 microM). gamma-Aminobutyric acid, but not alanine or glutamine, abolished the effect of fasting on hepatic taurine transport. To determine the effect of fasting independent of changes in the lipid microenvironment, taurine uptake was measured in proteoliposomes reconstituted by inserting detergent-solubilized membrane proteins into asolectin vesicles. Taurine uptake by proteoliposomes reconstituted from membranes prepared from the fasted group was significantly greater than from the control group. We conclude that Na(+)-dependent taurine transport is enhanced in liver plasma membranes prepared from fasted rats. Our findings imply that enhanced taurine uptake with fasting is due to either an increased number of functional carriers or activation of existing transporters.

Antenatal diagnosis of choledochal cyst.

We report five infants in whom antenatal diagnosis of choledochal cyst was established by ultrasonography, and we review the seven previously reported cases. All but one infant had cystic dilatation of the common bile duct (type 1 cysts), and all infants were diagnosed during the second or third trimester. Eight of 12 infants (67%) developed jaundice in the first few days of life, but only 25% had a palpable abdominal mass. Seven of nine infants (78%) demonstrated complete obstruction of the distal common bile duct on intraoperative cholangiography. Liver histology was available for six patients. Five of six had cirrhosis or fibrosis with bile duct proliferation. All of the infants with fibrosis or cirrhosis had distal common bile duct obstruction. Despite liver biopsy findings of extensive fibrosis plus ascites with failure to thrive in one of our patients, all five patients demonstrated clinical and biochemical improvement following surgical excision and porto- or choledochoenterostomy. All were free of symptoms by 6 months of age. Congenital choledochal cyst should be considered in the differential diagnosis of any sonolucent abdominal mass of the fetus. Neonates with distal common bile duct obstruction and fibrosis in association with presumed choledochal cyst should have prompt surgical exploration, intraoperative cholangiography, and close postoperative follow-up. The long-term outcome with prompt surgical correction is excellent.