Emily R. Perito

Posttransplant metabolic syndrome in children and adolescents after liver transplantation: A systematic review†

During long‐term follow‐up, 18% to 67% of pediatric liver transplant recipients are overweight or obese, with rates varying by age and pretransplant weight status. A similar prevalence of posttransplant obesity has been seen in adults. Adults also develop posttransplant metabolic syndrome and, consequently, cardiovascular disease at rates that exceed the rates in age‐ and sex‐matched populations. Posttransplant metabolic syndrome has never been studied in pediatric liver transplant recipients, and this population is growing as transplant outcomes continue to improve. Here we systematically review the literature for each component of metabolic syndrome—obesity, hypertension, dyslipidemia, and glucose intolerance—in pediatric liver transplant recipients. Their rates of obesity are similar to the rates in children in the general US population. However, hypertension, dyslipidemia, and diabetes are more common than would be expected in transplant recipients according to age, sex, and obesity severity. Immunosuppressive medications are major contributors. The limitations of previous studies, including heterogeneous methods of diagnosis, follow‐up times, and immunosuppressive regimens, hinder the analysis of risk factors. Importantly, no studies have reported graft or patient outcomes associated with components of metabolic syndrome after pediatric liver transplantation. However, if the trends in children are similar to the trends seen in adults, these conditions may lead to significant long‐term morbidity. Further research on the prevalence, causes, and consequences of posttransplant metabolic syndrome in pediatric liver transplant recipients is needed and will ultimately help to improve long‐term outcomes. Liver Transpl, 2012.

Overweight and obesity in pediatric liver transplant recipients: Prevalence and predictors before and after transplant, United Network for Organ Sharing Data, 1987–2010

Perito ER, Glidden D, Roberts JP, Rosenthal P. Overweight and obesity in pediatric liver transplant recipients: Prevalence and predictors before and after transplant, United Network for Organ Sharing Data, 1987–2010. 
Pediatr Transplantation 2012: 16: 41–49.

Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease

Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), therapeutic options and noninvasive markers of disease activity and severity remain limited. We investigated the association between plasma biomarkers and liver histology in order to identify markers of disease activity and severity in patients with biopsy‐proven NAFLD. Thirty‐two plasma biomarkers chosen a priori as possible discriminators of NAFLD were measured in participants enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network. Dichotomized histologic outcomes were evaluated using centrally read biopsies. Biomarkers with statistically significant associations with NAFLD histology were evaluated in multivariable models adjusted for clinical factors. Of 648 participants (74.4% white, 61.7% female, mean age 47.7 years), 58.0% had definite NASH, 55.5% had mild/no fibrosis (stage 0‐1), and 44.4% had significant fibrosis (stage 2‐4). Increased activated plasminogen activator inhibitor 1 had a strong association with definite NASH compared to not NASH or borderline NASH in multivariable analysis (odds ratio = 1.20, 95% confidence interval 1.08‐1.34, P < 0.001). Biomarkers associated with significant fibrosis (versus mild/no fibrosis) in multivariable analysis included higher levels of interleukin‐8, monocyte chemoattractant protein‐1, resistin, soluble interleukin‐1 receptor I, soluble interleukin‐2 receptor alpha, and tumor necrosis factor alpha and lower levels of insulin‐like growth factor 2. Conclusions: Specific plasma biomarkers are significantly associated with disease activity and severity of fibrosis in NAFLD and are potentially valuable tools for noninvasive stratification of patients with NAFLD and identification of targets for therapeutic intervention. (Hepatology 2017;65:65‐77).

Pediatric liver transplantation for urea cycle disorders and organic acidemias: United Network for Organ Sharing data for 2002‐2012

Decision making concerning liver transplantation is unique for children with urea cycle disorders (UCDs) and organic acidemias (OAs) because of their immediate high priority on the waiting list, which is not related to the severity of their disease. There are limited national outcome data on which recommendations about liver transplantation for UCDs or OAs can be based. This study was a retrospective analysis of United Network for Organ Sharing data for liver recipients who underwent transplantation at an age < 18 years in 2002‐2012. Repeat transplants were excluded. Among the pediatric liver transplants, 5.4% were liver‐only for UCDs/OAs. The proportion of transplants for UCDs/OAs increased from 4.3% in 2002‐2005 to 7.4% in 2010‐2012 (P < 0.001). Ninety‐six percent were deceased donor transplants, and 59% of these patients underwent transplantation at <2 years of age. Graft survival improved as the age at transplant increased (P = 0.04). Within 5 years after transplantation, the graft survival rate was 78% for children < 2 years old at transplant and 88% for children ≥ 2 years old at transplant (P = 0.06). Vascular thrombosis caused 44% of the graft losses, and 65% of these losses occurred in children < 2 years old. Patient survival also improved as the age at transplant increased: the 5‐year patient survival rate was 88% for children with UCDs/OAs who were <2 years old at transplant and 99% for children who were ≥2 years old at transplant (P = 0.006). At the last‐follow‐up (54 ± 34.4 months), children who underwent transplantation for UCDs/OAs were more likely to have cognitive and motor delays than children who underwent transplantation for other indications. Cognitive and motor delays for children with UCDs/OAs were associated with metabolic disorders, but they were not predicted by age or weight at transplant, sex, ethnicity, liver graft type (split versus whole), or hospitalization at transplant in univariate and multivariate analyses. In conclusion, most liver transplants for UCDs/OAs occur in early childhood. Further research on the benefits of early transplantation for patients with UCDs/OAs is needed because a younger age may increase posttransplant morbidity. Liver Transpl 20:89‐99, 2014.

Estimation of fish and ω-3 fatty acid intake in pediatric nonalcoholic fatty liver disease.

Aims: Fish and &ohgr;-3 fatty acids are reported to be beneficial in pediatric nonalcoholic fatty liver disease (NAFLD), but no studies have assessed their relation to histological severity. The objectives of this study were to evaluate the dietary intake of fish and &ohgr;-3 fatty acids in children with biopsy-proven NAFLD, and examine their association with serological and histological indicators of disease. Methods: This was a cross-sectional analysis of 223 children (6–18 years) who participated in the Treatment of Nonalcoholic Fatty Liver Disease in Children trial or the NAFLD Database study conducted by the Nonalcoholic Steatohepatitis Clinical Research Network. The distribution of fish and &ohgr;-3 fatty acid intake was determined from responses to the Block Brief 2000 Food Frequency Questionnaire, and analyzed for associations with serum alanine aminotransferase, histological features of fatty liver disease, and diagnosis of steatohepatitis after adjusting for demographic, anthropometric, and dietary variables. Results: The minority of subjects consumed the recommended 8 ounces of fish per week (22/223 [10%]) and 200 mg of long-chain &ohgr;-3 fatty acids per day (12/223 [5%]). Lack of fish and long-chain &ohgr;-3 fatty acid intake was associated with greater portal (P = 0.03 and P = 0.10, respectively) and lobular inflammation (P = 0.09 and P = 0.004, respectively) after controlling for potential confounders. Conclusions: Fish and &ohgr;-3 fatty acid intake was insufficient in children with NAFLD, which may increase susceptibility to hepatic inflammation. Patients with pediatric NAFLD should be encouraged to consume the recommended amount of fish per week.

Dietary treatment of nonalcoholic steatohepatitis.

Purpose of reviewNonalcoholic steatohepatitis (NASH) is increasing in prevalence, in tandem with the U.S. obesity epidemic, in both children and adults. Identifying specific dietary components that drive NASH is important for successful management of this disease. Recent findingsWeight loss of 5–10% improves NASH. In addition, fructose and trans-fats, two components of the Western ‘fast-food’ diet, have unique metabolic effects that suggest they may be key contributors to NASH. However, further research is needed to clarify the utility of restricting these nutrients in treating NASH. SummaryOverall reductions in body weight, through reduced calorie intake and increased physical activity, are the current mainstays of NASH treatment. Reducing fructose and trans-fat intake, independent of weight loss, may be critical to improving or preventing progression of NASH.

Nonstandard Exception Requests Impact Outcomes for Pediatric Liver Transplant Candidates.

Nonstandard exceptions requests (NSERs), in which transplant centers appeal on a case‐by‐case basis for Pediatric End‐Stage Liver Disease/Mayo End‐Stage Liver Disease points, have been highly utilized for pediatric liver transplant candidates. We evaluated whether NSE outcomes are associated with waitlist and posttransplant mortality. United Network for Organ Sharing (UNOS) Scientific Registry of Transplant Recipients data on pediatric liver transplant candidates listed in 2009–2014 were analyzed after excluding those granted automatic UNOS exceptions. Of 2581 pediatric waitlist candidates, 44% had an NSE request. Of the 1134 children with NSERs, 93% were approved and 7% were denied. For children 2–18 years at listing, NSER denial increased the risk of waitlist mortality or removal for being too sick (subhazard ratio 2.99, 95% confidence interval [CI] 1.26–7.07, p = 0.01 in multivariate analysis). For children younger than 2 years, NSER denial did not impact waitlist mortality/removal. Children with NSER approved had reduced risk of graft loss 3 years posttransplant in univariate but not multivariable analysis (odds ratio 0.73, 95% CI 0.53–1.01, p = 06). Those with NSER denial had a higher risk of posttransplant death than those with no NSER (hazard ratio 2.43, 95% CI 0.99–5.95, p = 0.05, multivariable analysis), but NSER approval did not impact posttransplant death. Further research on NSER utilization in pediatric liver transplant is needed to optimize organ allocation and outcomes for children.

Solitary rectal ulcer syndrome in children and adolescents.

Objectives: The aim of this study was to describe the presenting symptoms, endoscopic and histologic findings, and clinical courses of pediatric patients diagnosed with solitary rectal ulcer syndrome (SRUS). Methods: We describe 15 cases of SRUS diagnosed at our institution during a 13-year period. Cases were identified by review of a pathology database and chart review and confirmed by review of biopsies. Data were collected by retrospective chart review. Results: Presenting symptoms were consistent but nonspecific, most commonly including blood in stools, diarrhea alternating with constipation, and abdominal/perianal pain. Fourteen of 15 patients had normal hemoglobin/hematocrit, erythrocyte sedimentation rate, and albumin at diagnosis. Endoscopic findings, all limited to the distal rectum, ranged from erythema to ulceration and polypoid lesions. Histology revealed characteristic findings. Stool softeners and mesalamine suppositories improved symptoms, but relapse was common. Conclusions: SRUS in children presents with nonspecific symptoms and endoscopic findings. Clinical suspicion is required, and diagnosis requires histologic confirmation. Response to present treatments is variable.

Under Utilization of Pancreas Transplants in Cystic Fibrosis Recipients in the United Network Organ Sharing (UNOS) Data 1987–2014

Despite a high prevalence of pancreatic endocrine and exocrine insufficiency in cystic fibrosis (CF), pancreas transplantation is rarely reported. United Network for Organ Sharing (UNOS) data were used to examine utilization of pancreas transplant and posttransplant outcomes in CF patients. Between 1987–2014, CF patients (N = 4600) underwent 17 liver–pancreas, three lung–pancreas, one liver–lung pancreas, four kidney–pancreas, and three pancreas‐only transplants. Of the 303 CF patients who received liver transplantation, 20% had CF‐related diabetes (CFRD) before transplantation, and nine of those received a liver–pancreas transplant. Of 4241 CF patients who underwent lung transplantation, 33% had CFRD before transplantation, and three of those received a pancreas transplant. Of 49 CF patients who received a liver–lung transplant, 57% had CFRD before transplantation and one received a pancreas transplant. Posttransplantation diabetes developed in 7% of CF pancreas transplant recipients versus 24% of CF liver and 29% of CF lung recipients. UNOS has no data on pancreas exocrine insufficiency. Two‐year posttransplantation survival was 88% after liver–pancreas transplant, 33% after lung–pancreas transplant, and 100% after pancreas–kidney and pancreas‐only transplants. Diabetes is common pretransplantation and posttransplantation in CF solid organ transplant recipients, but pancreas transplantation remains rare. Further consideration of pancreas transplant in CF patients undergoing other solid organ transplant may be warranted.

Metabolic Syndrome Components After Pediatric Liver Transplantation: Prevalence and the Impact of Obesity and Immunosuppression

Metabolic syndrome is associated with long‐term morbidity and mortality after adult liver transplantation (LT). Whether pediatric LT recipients have a higher prevalence of metabolic syndrome remains controversial. In a cross‐sectional study, we evaluated pediatric LT recipients aged 8–30 years using National Health and Nutrition Examination Survey (NHANES) protocols. LT recipients were matched by gender, race/ethnicity, and age with controls from NHANES. Pediatric LT recipients (n = 83), after adjusting for overweight/obesity and glucocorticoid use, had increased prevalence of prehypertension and hypertension, impaired glucose tolerance (IGT; 2‐h glucose after oral glucose tolerance test ≥140 mg/dL), and low high‐density lipoprotein compared to matched NHANES controls (n = 235) despite a lower prevalence of overweight/obesity. Among LT recipients, the adjusted odds of IGT doubled for every 7.5 years taking calcineurin inhibitors (odds ratio = 2.10, 95% confidence interval 1.06–4.17 per 7.5 years taking calcineurin inhibitors, p = 0.03). Among all subjects with IGT, LT recipients had a lower prevalence of overweight/obesity and less insulin resistance (homeostatic model assessment of insulin resistance) than did controls with IGT. Among normal weight subjects, LT recipients were significantly more likely than controls to have prehypertension/hypertension, IGT, low high‐density lipoprotein, and metabolic syndrome. Pediatric LT recipients have unique metabolic syndrome profiles and risk factors and will require tailored screening and management protocols.