Liver Microabscesses in a Premature Neonate With Eosinophilic Colitis.

Hepatic abscesses in premature infants are rare with less than 100 case reports documented in literature. We report a case of a premature infant diagnosed with hepatic microabscesses secondary to eosinophilic colitis. A 33 4/7-week preterm female neonate presented with bilious emesis, abdominal distention, and severe hematochezia. Eosinophilic enterocolitis was suspected. Hypoechoic regions in the anterior liver identified on computed tomography were considered liver microabscesses. This unique case exemplifies how prematurity increases the risk of mucosal damage in the presence of eosinophilic colitis causing enteric bacteria to seed into the liver through the portal vein, resulting in hepatic microabscesses.

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management.

BACKGROUND AND AIMS: Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS: Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Frailty in Children with Liver Disease: A Prospective Multicenter Study.

OBJECTIVE: To assess frailty, a measure of physiologic declines in multiple organ systems, in children with chronic liver disease using a novel pediatric frailty tool. STUDY DESIGN: We performed a prospective cross-sectional multicenter study at 17 liver transplantation (LT) centers. 71 children (5-17 years of age), 36 with compensated chronic liver disease (CCLD) and 35 with end-stage liver disease (ESLD) and listed for LT, were assessed for frailty using validated pediatric tools to assess the 5 classic Fried Frailty Criteria-slowness, weakness, exhaustion, diminished physical activity, and shrinkage. Test scores were translated to age- and sex-dependent z scores, generating a maximum frailty score of 10. RESULTS: The median frailty score of the cohort was 4 (IQR 3, 5). Subjects with ESLD had significantly higher frailty scores (median 5; IQR 4, 7) than subjects with CCLD (median 3; IQR 2, 4); (P < .0001). Area under the curve receiver operating characteristic for frailty scores to discriminate between ESLD and CCLD was 0.83 (95% CI 0.73, 0.93). Forty-six percent of children with ESLD were frail and there was no correlation between pediatric frailty scores and physician's global assessments (r = -0.24, 95% CI -0.53, 0.10). CONCLUSIONS: A novel frailty tool assessed additional dimensions of health, not captured by standard laboratory measures and identified the sickest individuals among a cohort of children with chronic liver disease. This tool may have applicability to other children with chronic disease.

A Challenging Case of Severe Infantile Cholestasis in Alpha-1 Antitrypsin Deficiency.

Jaundice in the newborn period can be physiologic and is often due to benign causes. Jaundice due to conjugated hyperbilirubinemia extending beyond the second week of life may be an early sign of several cholestatic or metabolic liver diseases, and it requires logical and timely analysis so that specific treatments can be initiated. Alpha-1 antitrypsin deficiency is the most common genetic cause of pediatric liver disease and transplantation, and it must be considered when evaluating cholestatic infants. Here, we present an unusual case of alpha-1 antitrypsin deficiency with severe infantile cholestasis and rapid decompensation in the first 4 months of life, where in-depth but timely diagnosis was crucial for the appropriate intervention to take place.

The challenges of liver transplantation in children with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) in children can progress to end-stage liver disease requiring liver transplantation. PSC poses many challenges beginning with evaluation and classification of ductal involvement and overlap syndromes, few options for medical management and unique risks in the post-transplant period. The construct that PSC may be an autoimmune disease is based on positive autoantibodies, association with inflammatory bowel disease, linkage to HLA type and overlap/autoimmune sclerosing cholangitis; however, PSC is not responsive to standard immunosuppression. Study of PSC and post-transplant outcomes in children may provide a unique background in which to study this challenging disease. This is particularly intriguing in the subset of patients diagnosed in the first decade of life, suggesting a strong link to predisposing genetic susceptibility and immune dysregulation. Long-term, multicenter effort is likely to be the only mechanism to study this rare disease in children and to improve outcomes in the future.

Total serum bilirubin predicts fat-soluble vitamin deficiency better than serum bile acids in infants with biliary atresia.

OBJECTIVE: Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia. METHODS: Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA. RESULTS: The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998). CONCLUSIONS: We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.

Recurrence of primary sclerosing cholangitis in pediatric liver transplant recipients.

There is little detailed clinical information on recurrent primary sclerosing cholangitis (rPSC) after liver transplantation in children. Our purpose was to describe the characteristics of children who had experienced rPSC after liver transplantation so that we could identify potential risk factors for recurrence. Clinical information for pediatric patients undergoing transplantation for primary sclerosing cholangitis (PSC) was retrospectively reviewed, and variables related to the pretransplant diagnosis of PSC and posttransplant variables were abstracted. The studied variables included the following: cytomegalovirus/Epstein-Barr virus status, early/late rejection, induction regimen, immunosuppression in the first year, steroid-resistant rejection, diagnosis of inflammatory bowel disease, and human leukocyte antigen markers commonly associated with PSC. A diagnosis of rPSC was made on the basis of radiographic features, histology, or both. Twelve patients underwent liver transplantation for PSC between 1993 and 2012. Patients received tacrolimus for maintenance immunosuppression after induction with steroids (n = 6) or thymoglobulin (n = 6). Three patients were diagnosed with rPSC 44, 60, and 62 months after transplantation. A fourth patient underwent retransplantation for graft failure with features of both hepatic artery stenosis and rPSC. This patient had distinct histological features of rPSC in the second graft. Three of the 4 patients were 7 years old or younger at the diagnosis of PSC. The patient and graft survival rates were similar for the steroid and thymoglobulin groups. All 4 children with rPSC received steroid-free thymoglobulin induction. In conclusion, our observation of an association between thymoglobulin, and age less than 10 years at the diagnosis of PSC, and rPSC adds to the existing suggestion of a link between the immune environment and the pathogenesis of rPSC. Defining the natural history of rPSC and searching for the etiology and risk factors of rPSC are important for the long-term outcomes of pediatric patients.

Chronic granulomatous disease presenting as aseptic ascites in a 2-year-old child.

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected after identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children.

An objective measure to identify pediatric liver transplant recipients at risk for late allograft rejection related to non-adherence.

Non-adherence to a prescribed immunosuppressive regimen increases risk for late allograft rejection (LAR). We implemented a protocol for immunosuppression management which decreased variation in calcineurin inhibitor blood levels in pediatric liver transplant recipients by controlling for confounders such as physician practice variability. We hypothesized that patients with increased variation in tacrolimus blood levels despite implementation of the immunosuppression management protocol were at increased risk for LAR. We conducted a single center retrospective cohort study of 101 pediatric liver transplant recipients who were at least one year post liver transplantation and receiving tacrolimus for immunosuppression. The primary outcome variable was biopsy proven allograft rejection. Primary candidate predictor variables were the standard deviation (SD) of tacrolimus blood levels (a marker of drug level variability), mean tacrolimus blood level, age, and insurance type. SD of tacrolimus blood levels was determined for each patient from a minimum of four outpatient levels during the study period. Unadjusted and adjusted logistic regression models were used to determine the prognostic value of candidate predictors. The median and interquartile range of the SD of tacrolimus blood levels was 1.6 (1.1, 2.1). Eleven episodes of LAR occurred during the study period. Ten of the 11 episodes occurred in patients with tacrolimus blood level SD > 2. Insurance type, mean tacrolimus blood level and SD of tacrolimus blood levels were significantly related to LAR in the unadjusted analyses (p<0.05). A multivariable model including age, insurance type, mean and SD of tacrolimus blood levels was significantly associated with LAR (validated C-statistic = 0.88, p = 0.012). The adjusted odds of rejection for a one unit increase in the SD of tacrolimus blood level was 3.49 (95% CI 1.31 to 9.29). Effects of age and insurance status on LAR did not provide independent prognostic value after controlling for SD. Variation in tacrolimus blood levels is associated with an increased risk of LAR in pediatric liver transplant recipients. Despite standardized management of tacrolimus levels to control for confounders, some patients were found to have significant variability of tacrolimus blood levels. This may be due to non-adherence and amenable to targeted psychosocial and behavioral interventions to prevent LAR.