Liver abnormalities are frequent and persistent in patients with Fanconi anemia.

ABSTRACT: Liver disease has not been well described in patients with Fanconi anemia (FA). Improvements in outcomes of transplant mean that more individuals with FA are reaching adulthood and new features of the FA phenotype are being discovered. We performed a retrospective review of liver function in a cohort of 97 patients with FA followed-up for at least 10 years at a single center. We identified a high frequency of transaminitis (n = 31, 32%) without elevation of bilirubin and with no evidence of structural hepatic abnormality in patients with FA. Transaminitis was persistent in many cases, sometimes lasting more than a decade without clinical manifestation, although 2 patients with prolonged transaminitis are deceased from liver failure, indicating important long-term clinical consequences. Transaminitis was found in patients who had and had not received transplant but was more frequent in recipients of transplant. Exposure to total body irradiation increased risk (odds ratio, 15.5 [95% confidence interval, 2.44-304.54]; P = .01), whereas treatment with androgens did not. Review of limited numbers of liver biopsies and autopsy material showed a cholestatic pattern of liver injury, with progressive fibrosis, in the majority of patients. Occurrence in cases without transplant as well as cases with transplant argues against a potential diagnosis of atypical liver graft-versus-host disease. Limited data regarding therapy suggest no benefit from treatment with steroids or other immune suppressive medications or ursodeoxycholic acid. Our data show that liver disease is common in patients with FA, and because most children with FA now reach adulthood, end-stage liver disease in young adulthood means systematic testing of potential therapies is urgently needed.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Safety and Immunogenicity of Live Viral Vaccines in a Multicenter Cohort of Pediatric Transplant Recipients.

Importance: Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions. Objective: To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients. Design, Setting, and Participants: This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols. Exposures: Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine. Main Outcome and Measure: Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis. Results: The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination. Conclusions and Relevance: The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

Early allograft dysfunction in a pediatric liver allograft with an occult pathogenic mutation in the urea cycle.

Liver transplantation risks transferring a genetic defect in metabolic pathways, including the urea cycle. We present a case of pediatric liver transplantation complicated by metabolic crisis and early allograft dysfunction (EAD) in a previously healthy unrelated deceased donor. Allograft function improved with supportive care, and retransplantation was avoided. Because hyperammonemia suggested an enzymatic defect in the allograft, genetic testing from donor-derived deoxyribonucleic acid revealed a heterozygous mutation in the ASL gene, which encodes the urea cycle enzyme argininosuccinate lyase. Homozygous ASL mutations precipitate metabolic crises during fasting or postoperative states, whereas heterozygous carriers retain sufficient enzyme activity and are asymptomatic. In the described case, postoperative ischemia/reperfusion injury created a metabolic demand that exceeded the enzymatic capacity of the allograft. To our knowledge, this is the first report of an acquired argininosuccinate lyase deficiency by liver transplantation and underscores the importance of considering occult metabolic variants in the allograft during EAD.

Natural Course of Pediatric Portal Hypertension.

The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free-standing children's hospital. Patients were stratified by etiology of pHTN (intrahepatic disease [IH], defined as cholestatic disease and fibrotic or hepatocellular disease; extrahepatic disease [EH], defined as hepatic vein obstruction and prehepatic pHTN). Patients with EH were more likely to undergo an esophagoduodenscopy for a suspected gastrointestinal bleed (77% vs. 41%; P < 0.01). Surgical interventions differed based on etiology (P < 0.01), with IH more likely resulting in a transplant only (65%) and EH more likely to result in a shunt only (43%); 30% of patients with IH and 47% of patients with EH did not undergo an intervention for pHTN. Kaplan-Meier analysis revealed a significant increase in mortality in the group that received no intervention compared to shunt, transplant, or both and lower mortality in patients with prehepatic pHTN compared to other etiologies (P < 0.01 each). Multivariate analysis revealed increased odds of mortality in patients with refractory ascites (odds ratio [OR], 4.34; 95% confidence interval [CI], 1.00, 18.88; P = 0.05) and growth failure (OR, 13.49; 95% CI, 3.07, 58.99; P < 0.01). Conclusion: In this single institution study, patients with prehepatic pHTN had better survival and those who received no intervention had higher mortality than those who received an intervention. Early referral to specialized centers with experience managing these complex disease processes may allow for improved risk stratification and early intervention to improve outcomes.

Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes.

BACKGROUND: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers. METHODS: Cases of CPSS from Cincinnati Children's Hospital Medical Center and C.S. Mott Children's Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail. RESULTS: A total of 11 cases were identified. Median age was 10 years (range 0-26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up. CONCLUSIONS: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.

Prospective Assessment of Ultrasound Shear Wave Elastography for Discriminating Biliary Atresia from other Causes of Neonatal Cholestasis.

OBJECTIVE: To prospectively assess the diagnostic performance of ultrasound shear wave elastography (SWE) and hepatobiliary laboratory biomarkers for discriminating biliary atresia from other causes of neonatal cholestasis. STUDY DESIGN: Forty-one patients <3 months of age with neonatal cholestasis (direct bilirubin >2 mg/dL) and possible biliary atresia were prospectively enrolled. Both 2-dimensional (2D) and point ultrasound SWE were performed prior to knowing the final diagnosis. Median 2D (8) and point (10) shear wave speed measurements were calculated for each subject and used for analyses. The Mann-Whitney U test was used to compare shear wave speed and laboratory measurements between patients with and without biliary atresia. Receiver operating characteristic curve analyses and multivariable logistic regression were used to evaluate diagnostic performance. RESULTS: Thirteen subjects (31.7%) were diagnosed with biliary atresia, and 28 subjects (68.3%) were diagnosed with other causes of neonatal cholestasis. Median age at the time of ultrasound SWE was 37 days. Median 2D (2.08 vs 1.49 m/s, P = .0001) and point (1.95 vs 1.21 m/s, P = .0014) ultrasound SWE measurements were significantly different between subjects with and without biliary atresia. Using a cut-off value of >1.84 m/s, 2D ultrasound SWE had a sensitivity = 92.3%, specificity = 78.6%, and area under the receiver operating characteristic curve (AuROC) of 0.89 (P < .0001). Using a cut-off value of >320 (U/L), gamma-glutamyl transferase (GGT) had a sensitivity = 100.0%, specificity = 77.8%, and AuROC of 0.85 (P < .0001). Multivariable logistic regression demonstrated an AuROC of 0.93 (P < .0001), with 2 significant covariates (2D ultrasound SWE [OR = 23.06, P = .01]; GGT [OR = 1.003, P = .036]). CONCLUSIONS: Ultrasound SWE and GGT can help discriminate biliary atresia from other causes of neonatal cholestasis.

Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data.

Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child's illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia.

Emerging advancements in liver regeneration and organogenesis as tools for liver replacement.

PURPOSE OF REVIEW: Although the liver possesses a unique, innate ability to regenerate through mass compensation, transplantation remains the only therapy when damage outpaces regeneration, or liver metabolic capacity is irreversibly impacted. Recent insight from developmental biology has greatly influenced the advancement of alternative options to transplantation in these settings. RECENT FINDINGS: Factors known to direct liver cell specification, expansion, and differentiation have been used to generate hepatocyte-like cells from stem and somatic cells for developing cell therapies. Additionally, interactions between hepatic epithelial and nonepithelial cells key to establishing hepatic architecture have been used in tissue engineering approaches to advance self-organizing hepatic organoids and bioartificial liver devices. Simultaneously, recent clinically applicable advances in human hepatocyte transplantation and promotion of innate hepatic regeneration have been limited. SUMMARY: Although mature hepatocytes have the potential to bridge to, or replace whole organ transplantation, limits in the ability to obtain healthy cells, stabilize in-vitro expansion, cryopreserve, and alleviate rejection, still exist. Alternative sources for generating hepatocytes hold promise for cell therapy and tissue engineering. These may allow generation of autologous or universal donor cells that eliminate the need for immunosuppression; however, limits exist regarding hepatocyte maturity and efficacy at liver repopulation, as well as applicability to human chronic liver disease.

Neurologic outcome of urea cycle disorder liver transplant recipients may be predicted by pretransplant neurological imaging.

UNLABELLED: Liver transplantation treats the hepatic affectation of UCDs; however, irreversible neurologic damage pretransplant is difficult to assess providing transplant teams with ethical dilemmas for liver transplantation. The purpose of our study was to determine whether pretransplant neuroimaging can predict developmental outcomes post-liver-transplant in children with UCDs. METHODS: Patients undergoing liver transplantation for UCDs at Cincinnati Children's Hospital Medical Center between 2002 and 2012 were identified. Neurologic assessments prior to and after transplantation were categorized into mild, moderate, or severe disability. Neuroimaging data were categorized into mild, moderate, or severe by a single pediatric neuroradiologist. RESULTS: Fifteen patients were identified of whom eight had neuroimaging prior to transplantation. Of the eight patients that had neuroimaging, four were categorized as severe, one moderate, and three no-to-mild delay. All four patients whose imaging was severe were found to have moderate-to-severe neurologic delay. Of the three patients with no-to-mild changes on neuroimaging two of three were found to have no-to-mild delay on developmental assessments after transplantation. CONCLUSION: Neuroimaging may be a helpful tool in determining developmental prognosis and outcomes post-liver-transplantation for UCDs. Further studies maybe needed to validate our preliminary findings.

Magnetic resonance elastography of the liver in patients status-post fontan procedure: feasibility and preliminary results.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of performing magnetic resonance elastography (MRE) as a screening tool for elevated liver stiffness in patients' status-post Fontan procedure. BACKGROUND: With greater numbers of Fontan patients surviving far into adulthood, a factor increasingly affecting long-term prognosis is the presence of hepatic congestion and fibrosis. If detected early, steps can be taken to potentially slow or halt the progression of fibrosis. MRE is a relatively new, noninvasive imaging technique, which can quantitatively measure liver stiffness and provide an estimate of the extent of fibrosis. METHODS: A retrospective study was conducted using MRE to evaluate liver stiffness in patients with a history of Fontan procedure. An MRE was performed in the same session as a clinical cardiac MRI. The liver was interrogated at four slice locations, and a mean liver stiffness value was calculated for each patient using postprocessing software. The medical records were reviewed for demographic and clinical characteristics. RESULTS: During the time frame of this investigation, 17 MRE exams were performed on 16 patients. All patients had elevated liver stiffness values as defined by MRE standards. The median of the individual mean liver stiffness values was 5.1 kPa (range: 3.4-8.2 kPa). This range of liver stiffness elevation would suggest the presence of mild to severe fibrosis in a patient with standard cardiovascular anatomy. We found a significant trend toward higher liver stiffness values with greater duration of Fontan circulation (rs = 0.55, P = .02). CONCLUSION: Our preliminary findings suggest that MRE is a feasible method for evaluating the liver in Fontan patients who are undergoing surveillance cardiac MRI. Further investigation with histologic correlation is needed to determine the contributions of hepatic congestion and fibrosis to the liver stiffness in this population.

Management and long-term consequences of portal vein thrombosis after liver transplantation in children.

Portal vein thrombosis (PVT) occurs in ≤12% of pediatric recipients of liver transplantation (LT). Known complications of PVT include portal hypertension, allograft loss, and mortality. The management of PVT is varied. A single-center, case-control study of pediatric LT recipients with portal vein (PV) changes after LT was performed. Cases were categorized as early PVT (if PVT was detected within 30 days of transplantation) or late PVT (if PVT was detected more than 30 days after transplantation or if early PVT persisted beyond 30 days). Two non-PVT control patients were matched on the basis of the recipient weight, transplant indication, and allograft type to each patient with PVT. Thirty-two of the 415 LT recipients (7.7%) received 37 allografts and developed PVT. In comparison with control patients, a higher proportion of patients with PVT had PVT present before LT (13.3% versus 0%, P = 0.01). Patients with early PVT usually returned to the operating room, and 9 of 15 patients (60%) had PV flow restored. Patients with late PVT had lower white blood cell (4.9 [1000/µL] versus 6.8 [1000/µL], P < 0.01) and platelet counts (140 [1000/µL] versus 259 [1000/µL], P < 0.01), an elevated international normalized ratio (1.2 versus 1.0, P < 0.001), and more gastrointestinal bleeding (25% versus 8.3%, P = 0.03) compared to controls. Patients with PVT were also less frequently at the expected grade level (52% versus 88%, P < 0.001). The patient survival rates were 84%, 78%, and 78% and 91%, 84%, and 79% for cases and controls at 1, 5, and 10 years, respectively. The allograft survival rates were 90%, 80%, and 80% for cases and 94%, 89%, and 87% for controls at 1, 5, and 10 years, respectively. In conclusion, patients with early and late PVT had preserved allograft function, and there was no impact on mortality. Patients diagnosed with early PVT often underwent operative interventions with successful restoration of flow. Patients diagnosed with late PVT experienced variceal bleeding, and some required portosystemic shunting procedures. Academic delays were also more common. In late PVT, the clinical presentation dictates care because the optimal management algorithm has not yet been determined. Multi-institutional studies are needed to confirm these findings and improve patient outcomes.

Characteristics of successful recruitment in prospective pediatric pharmacogenetic studies.

BACKGROUND: There is a need to explore feasible means of accruing an appropriate study cohort to help fill the knowledge gap between pharmacogenetic contributions to drug response and clinical application in the pediatric population. OBJECTIVES: The aim of this study was to identify factors affecting recruitment of eligible subjects in pharmacogenetic studies at a large Midwestern pediatric academic medical center. The objectives were to evaluate recruitment success of ongoing trials and ascertain contributors to differential recruitment rates. We hypothesized that studies with good recruitment of eligible subjects would share characteristics not present in studies with lower than anticipated recruitment. The goal was to better understand barriers to good recruitment in pharmacogenetic studies to help inform future trial and infrastructure design. METHODS: Investigators designed a survey with proposed elements of success, which was then completed by lead and/or site investigators of all pharmacogenetics studies at the institution. Results were evaluated using an investigator-developed likelihood of success scoring system. RESULTS: Two studies recruited >95% of the approached eligible patients; 4 studies were consistent with investigator-anticipated recruitment (>50%), and 1 study did not meet expected recruitment. A study's total score on the investigator-devised scoring tool correlated well with the proportion of approached patients recruited (Pearson's correlation, r = 0.82; P < 0.001). Multiple factors impacted successful recruitment into these pharmacogenetic studies. Features of studies with successful recruitment included standardized clinical care, an ongoing team-patient relationship, severe and/or life-threatening outcome measures, study coordinator with experience in clinical research, a study medication with few or no alternative treatment options, and active involvement of the research team in clinical care. CONCLUSIONS: A scoring system for study characteristics may be useful to calculate the risk of failure for successful recruitment, allow discrimination among characteristics contributing to the risk, and permit study design alterations to improve likelihood of successful recruitment in pediatric pharmacogenetic studies.

Renal function in the long term after pediatric liver transplantation: is there a need for protocol kidney biopsies?

PURPOSE OF REVIEW: With improving survival rates following solid organ transplantation, assessment of its success has broadened with a focus on long-term outcomes, including nongraft-related medical outcomes and family and patient perceptions of quality of life. Posttransplant renal dysfunction contributes to long-term morbidity and mortality following pediatric liver transplantation. In this review, we provide an overview of our understanding and approach to managing posttransplant renal dysfunction and highlight the existing gaps in knowledge in this area. RECENT FINDINGS: The literature regarding renal dysfunction following liver transplant primarily focuses on the experience in the adult population. Studies on children are limited by small numbers and varying definitions of outcomes. Thus, lessons in the current literature must be closely examined before they can be extrapolated and applied to children. SUMMARY: The current literature validates that posttransplant renal dysfunction is a frequent and important outcome for adults and children. Although the characteristics of children at high risk are less clear, calcineurin inhibitor minimization is considered a viable strategy for preserving renal function. The risk-benefit ratio of kidney biopsy in children and the possibility of renal preservation via immunosuppression withdrawal are intriguing concepts that remain to be defined.

Nonimmune complications after transplantation.

As posttransplant longevity has increased, nonimmune complications related to the transplant and posttransplant course have emerged as important factors in defining long-term outcomes. The incidence of, and risk factors for these complications may vary by transplanted organ based on immunosuppressive protocols and preexisting risk factors. This article discusses the relevant nonimmune complications associated with posttransplant care, with a focus on risk factors and management strategies.

Ductal plate malformation-like arrays in early explants after a Kasai procedure are independent of splenic malformation complex (heterotaxy).

Biliary atresia has at least 2 proposed forms, the common perinatal and the less common embryonic subtype with earlier onset and/or extrahepatic developmental anomalies. Histologic evidence of ductal plate malformation (DPM)-like change in liver has been proposed both as a marker for the embryonic type and as a predictor of poor outcome after Kasai portoenterostomy. We investigated the prevalence of DPM-like change in liver explants in usual biliary atresia (BA) and in BA with splenic malformation syndrome (BASM). Liver sections from 8 patients with BA and 6 with BASM, all of whom had a Kasai procedure followed by explant before age 2 years, were analyzed using hematoxylin and eosin, trichrome, CK7, and AE1/AE3 stains. Each block was scored for inflammation and fibrosis. We estimated the number of portal areas per block and counted the number of definite and possible examples of DPM-like change, defined as a circumferential duct complex arranged around a fibrovascular core. We assessed whether the frequency per portal area was related to low and high scores for either inflammation or fibrosis. Definite and possible examples of DPM-like arrays were present in about 10% of portal areas in both patient groups, but these were unevenly distributed. There was no statistical difference between BA and BASM in terms of the number of examples per portal area. No correlation existed between degree of fibrosis and the intensity of portal inflammation and the number of DPM-like arrays. Ductal plate malformation-like arrays do not distinguish perinatal BA from BA associated with heterotaxy in liver explants after a failed Kasai procedure.

PEGylated bioactive molecules in biodegradable polymer microparticles.

Injectable peptide and oligonucleotide biotherapeutics offer great promise for treatment of serious chronic diseases but almost always need further formulation work to increase stability and circulation lifetimes. Covalent attachment of poly(ethylene glycol) (PEG) will increase circulation lifetimes up to a week or so and decrease degradation in favorable cases. Encapsulation in biodegradable polymer microparticles has been highly successful, mostly for peptides to provide sustained release up to several months after injection. Although products are on the market using these technologies, PEGylation and microparticle encapsulation each have drawbacks that prevent more widespread use. When they are combined, the limitations of one technology may be resolved by the other. Work in several laboratories on encapsulation of PEGylated bioactive molecules has revealed a synergy. Activity reduction and restricted circulation lifetimes for PEGylated bioactive agents is addressed by microencapsulation and using a lower PEG molecular weight. Chemical degradation, excessive burst release and limited drug content are typical problems for microparticles that are ameliorated by using PEGylated actives. The case for synergy between PEGylation and microencapsulation is illustrated in this review by work with several proteins and peptides including insulin, and the oligonucleotide therapeutic, pegaptanib.

High prevalence of alpha-1-antitrypsin heterozygosity in children with chronic liver disease.

OBJECTIVE: Alpha-1-antitrypsin (A1AT) deficiency is the most common genetic cause of liver disease in children; however, the role of polymorphic heterogeneity in the A1AT gene as a modifier of other forms of pediatric liver disease is not clear. We hypothesized that non-M A1AT allele variants are more common in children with chronic liver disease than in the general population. METHODS: A retrospective, single-center study was performed in which A1AT phenotypes were obtained by reviewing charts of children with chronic liver disease. Chi-square analysis was used to compare allele frequencies in the population of children with liver disease with published epidemiologic data and to compare allele frequencies among disease subgroups. RESULTS: The frequency of A1AT Z and other alleles was increased in children with chronic liver disease (n = 241) when compared with the published reference database (P < 0.001). This increase remained significant when the population was divided into disease subsets: biliary atresia (n = 67) and other liver disease (n = 174) (P < 0.001 for both). Among children with biliary atresia referred for liver transplant evaluation, the presence of a non-M allele was associated with a lower mean age at transplant listing than the MM phenotype (235 vs 779 days, P = 0.036) and more frequent loss of native liver by 24 months of age (90% vs 65%, P = 0.04). CONCLUSIONS: A1AT non-M alleles are more frequent in children with chronic liver disease than in the general population. We speculate that these non-M alleles may act as genetic modifiers in pediatric liver disease in general and modulate disease progression in children with biliary atresia in particular.

Logistic regression.

The Medical Subject Headings (MeSH) thesaurus used by the National Library of Medicine defines logistic regression models as "statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable." Logistic regression models are used to study effects of predictor variables on categorical outcomes and normally the outcome is binary, such as presence or absence of disease (e.g., non-Hodgkin's lymphoma), in which case the model is called a binary logistic model. When there are multiple predictors (e.g., risk factors and treatments) the model is referred to as a multiple or multivariable logistic regression model and is one of the most frequently used statistical model in medical journals. In this chapter, we examine both simple and multiple binary logistic regression models and present related issues, including interaction, categorical predictor variables, continuous predictor variables, and goodness of fit.

Outcomes after liver transplantation: keep the end in mind.

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.