Does High-Intensity Exercise Cause Acute Liver Injury in Patients with Fontan Circulation? A Prospective Pilot Study.

The Fontan procedure results in chronic hepatic congestion and Fontan-associated liver disease (FALD) characterized by progressive liver fibrosis and cirrhosis. Exercise is recommended in this population, but may accelerate the progression of FALD from abrupt elevations in central venous pressure. The aim of this study was to assess if acute liver injury occurs after high-intensity exercise in patients with Fontan physiology. Ten patients were enrolled. Nine had normal systolic ventricular function and one had an ejection fraction < 40%. During cardiopulmonary exercise testing, patients had near-infrared spectroscopy (NIRS) to measure oxygen saturation of multiple organs, including the liver, and underwent pre- and post-exercise testing with liver elastography, laboratory markers, and cytokines to assess liver injury. The hepatic and renal NIRS showed a statistically significant decrease in oxygenation during exercise, and the hepatic NIRS had the slowest recovery compared to renal, cerebral, and peripheral muscle NIRS. A clinically significant increase in shear wave velocity occurred after exercise testing only in the one patient with systolic dysfunction. There was a statistically significant, albeit trivial, increase in ALT and GGT after exercise. Fibrogenic cytokines traditionally associated with FALD did not increase significantly in our cohort; however, pro-inflammatory cytokines that predispose to fibrogenesis did significantly rise during exercise. Although patients with Fontan circulation demonstrated a significant reduction in hepatic tissue oxygenation based on NIRS saturations during exercise, there was no clinical evidence of acute increase in liver congestion or acute liver injury following high-intensity exercise.

Quality improvement project to improve vaccinations in the pediatric liver transplant population.

OBJECTIVES: A quality improvement approach was used to increase pediatric liver transplant recipient live and inactive vaccination rates by assessing titers and recommending vaccinations. METHODS: A new screening and immunization process for both live and inactive vaccines was discussed with families at their annual visit. Antibody titers for varicella, measles, mumps, rubella, Haemophilus influenzae type B, hepatitis A, and hepatitis B were obtained. Specific criteria were developed for live virus vaccination candidacy. Vaccines were recommended based on patient titers and vaccination candidacy criteria. Surveillance for adverse effects to live vaccines was performed. Repeat titers were obtained approximately 1-month post-vaccine administration. RESULTS: After PDSA cycle 1, 99% (71/72) of pediatric liver transplant patients had titers obtained. Live vaccines were recommended for 32 patients and 16 (50%) were vaccinated. Inactive vaccines were recommended to 64 patients, and 31 (48%) were vaccinated. Eight of 13 (62%) patients with follow-up titers achieved immunity for inactive vaccines. Zero patients had an adverse reaction to any live vaccine. Ten of 12 (83%) patients with follow-up titers achieved immunity from live vaccines. The most common barriers to receive live vaccines included not scheduling appointment with primary care provider (n = 3) and "non-vaccinators" (n = 3). CONCLUSIONS: Administering live and inactive vaccines to select pediatric liver transplant patients appears to be safe and effective in our studied population. For PDSA cycle 2, we will continue our current practice and consider offering vaccines in transplant clinic, since this was a barrier to vaccination identified during PDSA cycle 1.

Liver failure and x-linked immunodeficiency type 47.

Patients with defects in the ATP6AP1 gene have rarely been described. ATP6AP1-related disorders are a subtype of CDG, which result in enzyme deficiencies affecting multiple organ systems ranging from mild to life-threatening. Of the 13 patients described, all had hepatopathy, but this is the first case to be successfully transplanted. We describe two brothers who developed hyperbilirubinemia shortly after birth and progressed to liver failure, case 1 by 12 months of age, with successful transplant 2 years later, and case 2 by 4 months of age, who passed away while awaiting liver transplant. Both boys were found to have a new variant in the ATP6AP1 gene: c.932/p.Leu311Gln. Although the identified ATP6AP1 gene variant was classified as unknown significance at the time, both children's phenotypes fit with what has been described for ATP6AP1-related disorders. Therefore, this result appears to have been diagnostic for both boys. This rare type of CDG, X-linked immunodeficiency type 47 (OMIM #300972), particularly in patients who progress to liver failure requiring transplant, should be included on the differential of liver failure in infants and toddlers, and its gene should be added to the diagnostic workup for such cases.

Staged biliary reconstruction after liver transplantation: A novel surgical strategy for high acuity pediatric transplant recipients.

INTRODUCTION: Biliary complications after pediatric orthotopic liver transplantation remain causes of significant patient morbidity. Staged operative approach in complex hepatobiliary surgery has improved postoperative outcomes but has not been evaluated in pediatric orthotopic liver transplantation. We sought to analyze the outcomes of staged biliary reconstruction after orthotopic liver transplantation in high acuity patients. METHODS: A retrospective analysis of 43 pediatric orthotopic liver transplantations at our center (January 2013 through December 2017). Median follow-up was 25 months. Variables were compared for group I: 1-stage orthotopic liver transplantation with biliary anastomosis (n = 6) versus group II: staged biliary reconstruction orthotopic liver transplantation (n = 37). RESULTS: Comparing groups I and II, median age (7.3 vs 4.8 years), weight (27 vs 19 kg), proportion of urgent orthotopic liver transplantation (50% vs 65%), partial graft orthotopic liver transplantation (33% vs 35%), and intraoperative red blood cell transfusion volume (11 vs 21 mL/kg) were comparable. Roux-en-Y hepaticojejunostomy was performed in 67% (group I) and 49% (group II). There was no biliary complication in both groups. For groups I and II, 3-year survival rates for graft (100% vs 92%, P = .477) and patient (100% vs 97%, P = .679) were comparable. CONCLUSION: Our study showed excellent outcomes with staged biliary reconstruction orthotopic liver transplantation in high acuity pediatric transplant recipients. This is the first report showing clinical applicability of staged biliary reconstruction orthotopic liver transplantation in children.

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.

The Consensus from the Mycobacterium avium ssp. paratuberculosis (MAP) Conference 2017.

On March 24 and 25, 2017 researchers and clinicians from around the world met at Temple University in Philadelphia to discuss the current knowledge of Mycobacterium avium ssp. paratuberculosis (MAP) and its relationship to human disease. The conference was held because of shared concern that MAP is a zoonotic bacterium that poses a threat not only to animal health but also human health. In order to further study this problem, the conferees discussed ways to improve MAP diagnostic tests and discussed potential future anti-MAP clinical trials. The conference proceedings may be viewed on the www.Humanpara.org website. A summary of the salient work in this field is followed by recommendations from a majority of the conferees.

Resolution of Crohn's disease and complex regional pain syndrome following treatment of paratuberculosis.

A cohort of family members with various chronic diseases including Crohn's disease, asthma, complex regional pain syndrome, hypothyroidism, type 1 diabetes mellitus, and lymphangiomatosis and/or evidence of infection by Mycobacterium avium subsp. paratuberculosis (MAP) are described in this series of case reports. MAP was cultured from the blood of three members affected by the first five diseases and there was accompanying elevated anti-MAP IgG in two members. The patient affected by the sixth disease has a markedly elevated anti-MAP titer. The two patients affected by the first four diseases have been treated with a combination of anti-MAP antibiotics and ultraviolet blood irradiation therapy with resolution of the disease symptomatology and inability to culture MAP in post treatment blood samples. These case reports of patients with MAP infections provide supportive evidence of a pathogenic role of MAP in humans.

Ten-year secular trend of overweight and obesity in school children in south-eastern Poland.

OBJECTIVE: To examine the trend in prevalence of overweight and obesity in schoolchildren from south-eastern Poland over a 10-year period. MATERIALS AND METHOD: A cross-sectional study was conducted in randomly selected primary schools. In total, 4,248 children (2,182 boys and 2,066 girls), mean age 10.5±2.4 years, were examined in 1998, and 2,412 children (1,184 boys and 1,228 girls), mean age 10.5±2.3 years in 2008. In each school the entire population was studied. RESULTS: In 2008, the prevalence of overweight in girls was 13.3% and obesity 7.7%, compared to 12.0% and 10.1% in 1998. The decrease in obesity prevalence was statistically significant. In boys, the prevalence of overweight in 2008 was 14.2% and obesity 6.4%, compared to 10.5% and 6.8% in 1998. The increase in overweight prevalence among boys was statistically significant. CONCLUSIONS: A trend toward stabilization of the prevalence of overweight and obesity was noted in school children from south-eastern Poland between 1998-2008. The declining prevalence of obesity in girls and increased prevalence of overweight in boys demonstrates that in this age group of children the secular trend is gender dependent.

Respiratory syncytial virus and pediatric liver transplant: one center's experience.

Respiratory syncytial virus (RSV) is a ubiquitous virus responsible for acute infections of the respiratory tract in patients of all ages. RSV presents significant health risks to immunocompromised patients. Two patients, 1 before a liver transplant and 1 after a liver transplant, died of a severe RSV infection. Because of the high risk of death, we recommend expanding the criteria for palivizumab prophylaxis to 2 types of patients: (1) patients with chronic liver disease or who have received a liver transplant and are 24 months old or less and (2) transplant recipients with underlying pulmonary conditions who are less than 36 months old. Further research is indicated in pediatric solid-organ transplant centers to evaluate the effective management of RSV infection to prevent morbidity.

Childhood obesity: knowledge, attitudes, and practices of European pediatric care providers.

OBJECTIVE: To determine and compare attitudes, skills, and practices in childhood obesity management in 4 European countries with different obesity prevalence, health care systems, and economic situations. METHODS: A cross-sectional survey was distributed to primary health care providers from France, Italy, Poland, and Ukraine. The questionnaire was returned by 1119 participants with a response rate of 32.4%. RESULTS: The study revealed that most of the primary health care providers were convinced of their critical role in obesity management but did not feel sufficiently competent to perform effectively. The adherence to recommended practices such as routine weight and height measurements, BMI calculation, and plotting growth parameters on recommended growth charts was poor. Most primary health care providers recognized the need for continuing professional education in obesity management, stressing the importance of appropriate dietary counseling. CONCLUSIONS: The study underlines insufficient implementation of national guidelines for management of obesity regardless of the country and its health system. It also makes clear that the critical problem is not elaboration of guidelines but rather creating support systems for implementation of the medical standards among the primary care practitioners.

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney-liver complications.

Improved neonatal medical care and renal replacement technology have improved the long-term survival of patients with ARPKD. Ten-yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra- and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto-systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat-soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato-biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age-matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64-80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato-biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver-kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver-kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.

Identifying youth nonadherence in clinical settings: data-based recommendations for children and adolescents with inflammatory bowel disease.

BACKGROUND: To examine the validity of patient self-report of thiopurine adherence in pediatric inflammatory bowel disease (IBD) against an objective electronic monitoring adherence measure, and to investigate the role of youth and maternal involvement in remembering to take daily medications as predictors of medication adherence. METHODS: Fifty-one youths with IBD, ages 11-18 years, participated. Youths completed questionnaire assessments of their own and their maternal caregiver's involvement in remembering to take daily medications at baseline, completed monthly interviews assessing thiopurine adherence over the past week for a period of 6 months, and utilized a Medication Events Monitoring System (MEMS) electronic monitor for their thiopurine medication for 6 months. Participants were grouped into adherent (at least 80% of doses taken based on objective MEMS caps) or nonadherent for analyses. RESULTS: Youths who were nonadherent based on electronic monitoring overestimated their adherence by 23%, whereas adherent youths overestimated their adherence by only 2%, and as such patient self-report offered little utility in identifying youths who were nonadherent. Youths who reported high levels of involvement in remembering to take their medications were nearly eight times less likely to be nonadherent. CONCLUSIONS: The current findings provide evidence that clinicians who work with children and adolescents with IBD may benefit from modifying their approach to nonadherence screening. Asking about youth involvement in remembering daily medications may be more informative than asking them to recall their medication-taking behavior over the last week in identifying those at highest risk for nonadherence.

Type 2 Abernethy malformation presenting as a portal vein-coronary sinus fistula.

We report the case of a child with Abernethy malformation with an anomalous connection between the portal vein and the coronary sinus. After 30 months of close follow-up, the patient developed hepatoblastoma, a previously documented complication of the Abernethy malformation. This case reports a unique variant of Abernethy malformation and documents the first reported case of hepatoblastoma in a patient with type 2 Abernethy malformation.

HIDA, percutaneous transhepatic cholecysto-cholangiography and liver biopsy in infants with persistent jaundice: can a combination of PTCC and liver biopsy reduce unnecessary laparotomy?

BACKGROUND: Historically, HIDA is the initial diagnostic test in the evaluation of biliary atresia (BA). Non-excreting HIDA scans can yield false-positive results leading to negative laparotomy. OBJECTIVE: Cholestatic infants must be evaluated promptly to exclude biliary atresia (BA) and other treatable hepatic conditions. Intraoperative cholangiogram (IOC) is the gold standard for diagnosing BA, but requires surgical intervention. Percutaneous transhepatic cholecysto-cholangiography (PTCC) and liver biopsy are less invasive and have been described in small case series. We hypothesized that PTCC and liver biopsy effectively exclude BA, thus avoiding unnecessary IOC. MATERIALS AND METHODS: Retrospective review of cholestatic infants who underwent PTCC, biopsy or cholescintigraphy at a tertiary children's hospital from August 1998 to January 2009. Group differences were evaluated and the receiver operator curve and safety of PTCC determined. RESULTS: One-hundred twenty-eight cholestatic infants were reviewed. Forty-six (36%) underwent PTCC. Forty-one out of 46 (89%) had simultaneous PTCC and liver biopsy. PTCC was completed successfully in 19/23 (83%) children despite a small or absent GB on initial US. Negative laparotomy rate was 1/6 (17%) for simultaneous PTCC/liver biopsy. Complications occurred in 4/46 including bleeding (n=2), fever with elevated transaminases (n=1) and oxygen desaturations (n=1). CONCLUSION: PTCC, particularly when performed in combination with simultaneous liver biopsy, effectively excludes BA in cholestatic infants with acceptable morbidity. PTCC can frequently be performed when a contracted gallbladder is seen on initial US exam. Negative laparotomy rate is lowest when PTCC is coupled with simultaneous liver biopsy.

Predictors of nonalcoholic steatohepatitis in obese children.

As the prevalence of childhood obesity increases, the incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) also escalates. This study's purpose was to identify the clinical criteria to aid in determining when a liver biopsy is indicated for this growing population because currently no guidelines exist. We performed a retrospective chart review on all patients who were seen in the Nutrition Exercise and Weight Loss Kids™ Program at the Children's Hospital of Wisconsin from July 2003 through December 2004. We analyzed only individuals who underwent liver biopsy with the following criteria: (1) no evidence of other liver disease and (2) aspartate transaminase or alanine aminotransferase greater than 200 IU/L or any elevation of or for more than 6 months. Of the 284 patients reviewed, only eight patients (3%) met the criteria for analysis. Biopsy results demonstrated that 100% had histological evidence of NASH with steatosis, and seven of the eight (87.5%) had NASH with fibrosis, cirrhosis, or both. Obese children with an aspartate transaminase or alanine aminotransferase greater than 200 IU/L or any elevation of aspartate transaminase or alanine aminotransferase for more than 6 months, have a strong likelihood of having NASH with or without fibrosis, cirrhosis, or both.

Obesity in pediatric celiac disease.

BACKGROUND AND AIM: Celiac disease (CD) is a T cell-mediated chronic autoimmune enteropathy occurring in genetically susceptible individuals, and manifested by a permanent intolerance to gluten-containing products. CD commonly presents in children as failure to thrive and malabsorption or after screening high-risk groups such as people with diabetes. Almost half of adult patients with CD have a body mass index (BMI) >25 at diagnosis. Classic symptoms like diarrhea are less common in obese patients. Few children have been reported with CD and obesity. Because many children with newly diagnosed CD are identified by screening high-risk groups, obesity is more common than previously suspected. The aim of the study was to estimate the prevalence of obesity at diagnosis in children with CD and to describe the clinical characteristics of this group. PATIENTS AND METHODS: This is a retrospective study of 143 patients with CD diagnosed between 1986 and 2003 at Children's Hospital of Wisconsin. Data collected included patient's age, sex, ethnicity, presenting signs and symptoms, BMI, celiac antibody titers, small-intestinal biopsy results, and follow-up weight 1 year after initiating a gluten-free diet (GFD). RESULTS: Seven of the 143 (5%) patients had BMI >95th percentile. The most common presenting symptoms among obese patients were abdominal pain, diabetes, and diarrhea. Symptoms improved in all of the patients on a GFD. BMI decreased in 4 (50%), increased in 2 (25%), and was not available in 1 patient at 1 year after starting on GFD. CONCLUSIONS: Obesity is more common in children with CD than previously recognized. In the appropriate clinical setting, CD must be considered even in obese children.