Decoding hepatorenal tyrosinemia type 1: Unraveling the impact of early detection, NTBC, and the role of liver transplantation.

Hepatorenal tyrosinemia type 1 (HT-1) is a rare autosomal recessive disease that results from a deficiency of fumaryl acetoacetate hydrolase (FAH), a critical enzyme in the catabolic pathway for tyrosine. This leads to the accumulation of toxic metabolites such as fumaryl and maleylacetoacetate, which can damage the liver, kidneys, and nervous system. The discovery of 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC or nitisinone) has significantly improved the management of HT-1, particularly when initiated before the onset of symptoms. Therefore, newborn screening for HT-1 is essential for timely diagnosis and prompt treatment. The analysis of succinyl acetone (SA) in dried blood spots of newborns followed by quantification of SA in blood or urine for high-risk neonates has excellent sensitivity and specificity for the diagnosis of HT-1. NTBC combined with dietary therapy, if initiated early, can provide liver transplant (LT) free survival and reduce the risk of hepatocellular carcinoma (HCC). Patients failing medical treatment (eg, due to non-adherence), and who develop acute liver failure (ALF), have HCC or evidence of histologically proven dysplastic liver nodule(s), or experience poor quality of life secondary to severe dietary restrictions are currently indicated for LT. Children with HT-1 require frequent monitoring of liver and renal function to assess disease progression and treatment compliance. They are also at risk of long-term neurocognitive impairment, which highlights the need for neurocognitive assessment and therapy.

Liver Biopsy Handling of Metabolic-Associated Fatty Liver Disease (MAFLD): the Children's Hospital of Eastern Ontario grossing protocol.

Metabolic-(non-alcoholic) associated fatty liver disease (MAFLD/NAFLD) has increasingly become a worldwide epidemic. It has been suggested that renaming NAFLD to MAFLD is critical in identifying patients with advanced fibrosis and poor cardiovascular outcomes. There are concerns that the progression to non-alcoholic steatohepatitis (NASH) may become a constant drive in the future healthcare of children and adolescents. There is a necessity to tackle the emerging risk factors for NASH-associated hepatocellular carcinoma (HCC). In this narrative review, we present the current protocol of liver biopsy separated between pre-analytical, analytical, and post-analytical handling. Genetic association investigations have identified single nucleotide polymorphisms implicated in the progression of MAFLD-HCC, many of which seem to belong to the lipid metabolism pathways. PNPLA3 rs738409 variant, TM6SF2 rs58542926 variant, MBOAT7 rs641738 variant, and GCKR variants seem to be significantly associated with NAFLD disease susceptibility. In disclosing the current comprehensive protocol performed at the Children's Hospital of Eastern Ontario, Ottawa, ON, Canada, we support the most recent Kulkarni-Sarin's pledge to rename NAFLD to MAFLD. Grossing of the liver biopsy is key to identifying histologic, immunophenotypical, and ultrastructure data and properly preserving tissue for molecular genomics data.

Handling a biopsy with fatty liver disease Fatty liver disease is increasing worldwide. There is a necessity to tackle the emerging risk factors for the development of liver cancer following years of fatty liver disease. In this paper, we show our protocol at the Children's Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada.

The Benefit of Early and Frequent Antitumor Necrosis Factor-Alpha Trough Level Determination in Very Early-Onset Inflammatory Bowel Disease.

A patient with infantile-onset Crohn's disease had a partial response to corticosteroid therapy that worsened on its tapering, leading to treatment with antitumor necrosis factor-alpha monoclonal antibody therapy. Infliximab rapidly cleared before administration of the third accelerated induction dose with the development of antibodies. Adalimumab was initiated with a good clinical effect but also rapidly cleared, requiring dose intensification to improve drug levels and to maintain a good clinical response. The amount of medication could eventually be decreased. Accelerated induction and maintenance drug monitoring can prevent secondary loss of response in very young children with inflammatory bowel disease.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Care Pattern for Fontan-Associated Liver Disease by Academic Pediatric Hepatologists in Canada.

Fontan-Associated Liver Disease (FALD) is a common extracardiac complication seen in patients following the Fontan procedure. There are no consensus guidelines on screening and management of children with FALD. Objective: The current study aims to determine academic pediatric hepatologists' practices and identify variability in management provided to children with FALD in Canada. Methods: Using the infrastructure of the Canadian Pediatric Hepatology Research Group, a nationwide survey was distributed electronically to all pediatric hepatologists practicing in university-affiliated hospitals. Results: Twelve pediatric hepatologists from 12 of 13 academic centers (92%) responded to the survey. The institutions of only 2 (17%) physicians offer post-Fontan care with a multidisciplinary team, both from different provinces. The screening for other comorbidities, use of noninvasive modality, and timing of liver biopsy for estimation of liver fibrosis and screening for esophageal varices differ from program to program. The frequency of outpatient clinic follow-up varies significantly. Education and counseling concerning liver health are generally used as treatment; only 58% of academic centers have a formal adult care transition plan. Conclusions: Significant discrepancies exist in the care provided to children with FALD by hepatologists practicing in academic centers across Canada. Future study is needed to develop a standardized protocol for managing and following children and youth with FALD.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Prevalence and risk factors for non-alcoholic fatty liver in children and youth with obesity.

BACKGROUND: Non- Alcoholic Fatty Liver (NAFL) is a spectrum of liver diseases (LD) that ranges from benign fatty infiltration of the liver to cirrhosis and hepatic failure. Hepatic ultrasound (US) and serum alanine aminotransferase (ALT) are often used as markers of NAFL. Our aim is to describe prevalence of NAFL and associated findings on ultrasound (US) and biochemical parameters in a population of children and adolescents with obesity at the Children's Hospital of Eastern Ontario. METHODS: Children with Obesity (BMI >95th percentile) ages 8-17 years presenting to the Endocrinology and Gastroenterology clinics, without underlying LD were prospectively recruited from 2009 to 2012. Fasting lipid profile, HOMA IR) and serum adiponectin levels were measured. NAFL was defined as ALT > 25 and >22 IU/mL (males and females respectively) and/or evidence of fatty infiltration by US. Logistic regression was performed to assess associations. RESULTS: 97 children with obesity included in the study (Male 43%). Mean age was 12.9 ± 3.2 years (84% were older than 10 y). Mean BMI-Z score was 3.8 ± 1.4. NAFL was identified in 85%(82/97) of participants. ALT was elevated in 61% of patients. Median triglyceride (TG) level was higher in children with NAFL(1.5 ± 0.9 vs. 1.1 ± 0.5 mmol/L, p = 0.01). Total cholesterol, HDL, LDL and Non HDL cholesterol were similar in both groups(p = 0.63, p = 0.98, p = 0.72 and p = 0.37 respectively). HOMA IR was ≥3.16 in 53% of children(55% in those with NAFL and 40% in those without NAFL). Median serum adiponectin was 11.2 µg/ml(IQR 7.3-18.3) in children with NAFL vs. 16.1 µg/ml(IQR 9.0-21.9) in those without NAFL(p = 0.23). Liver US was reported as normal in 30%, mild fatty infiltration in 38%, moderate in 20% and severe in 12%. TG were significantly higher(1.5 mmol/L vs. 1.0 mmol/L, p < 0.01) and HDL-C was lower(1.0 mmol/L vs. 1.1 mmol/L, p = 0.05) in children with moderate and severe NAFL by US. BMI-Z score, HOMA IR, serum adiponectin and HDL levels were not associated with NAFL, however TG were significantly associated(OR = 3.22 (95% CI: 1.01-10.25, p = 0.04)). CONCLUSION: NAFL is highly prevalent in obese children and youth. Elevated TG levels are associated with NAFL; these findings may serve as a noninvasive screening tool to help clinicians identify children with obesity needing liver biopsy and/or more aggressive therapeutic interventions.

Variability of diagnostic approach, surgical technique, and medical management for children with biliary atresia in Canada - Is it time for standardization?

BACKGROUND: The Canadian 4-year native liver survival rate for biliary atresia (BA) after Kasai Portoenterostomy (KP) is 39%. The Canadian Biliary Atresia Registry (CBAR) was used to examine variability of surgical and medical management of BA. METHODS: Gastroenterologists and surgeons in all 14 Canadian pediatric tertiary centers were invited to complete an online survey of their BA management practices. RESULTS: Of gastroenterologists, diagnostic procedures included liver biopsy (92%), HIDA scan (58%), and percutaneous cholangiogram (46%). Surgeons reported Roux-en-Y lengths of 20-50cm with 78% avoiding diathermy at the portal plate; 16% performed laparoscopic exploration, but none laparoscopic KP. Postoperative corticosteroids and antibiotics were used by 24% and 85% of gastroenterologists, respectively, with similar rates for surgeons. At discharge, gastroenterologists prescribed oral antibiotics (80%), and ursodeoxycholic acid (95%), while surgeons reported lower rates (62% and 55%). Considerable variation existed in follow-up monitoring. No center had a standard protocol for evaluating suspected cholangitis. There was a lack of consensus for defining failed KP and referral criteria for transplant evaluation. CONCLUSION: In Canada, treatment of BA is not centralized, and there is variability in diagnostic approaches and management. Collaboration through CBAR will allow for implementation and evaluation of standardized surgical and medical management with a goal to improve outcomes. LEVEL OF EVIDENCE: Survey study. Level IV evidence.

Comparison of two common outpatient preparations for colonoscopy in children and youth.

Colonoscopies are often performed in children for diagnostic and therapeutic purposes. Our study compared two bowel-cleansing solutions: sodium picosulphate, magnesium oxide, and citric acid (Pico-Salax) with liquid magnesium citrate as preparations for colonoscopy. A retrospective chart review of all patients seen in the Gastroenterology outpatient clinic and who underwent bowel cleansing in preparation for colonoscopy from February to December 2006 was undertaken. Thirty-two children received Pico-Salax and 36 received liquid magnesium citrate. The tolerability of both solutions was similar. Most children in both groups had liquid stools and complete colonoscopies. Bowel preparation for a colonoscopy can be successfully achieved using either Pico-Salax or liquid magnesium citrate.

Health status ten years after pediatric liver transplantation--looking beyond the graft.

BACKGROUND: Little is known about long-term health after pediatric orthotopic liver transplantation (OLT). This study aimed to characterize the health status of recipients 10 years after OLT, with an emphasis on transplant-related morbidity and quality of life. METHODS: We performed a retrospective database review of 32 children who underwent OLT before October 1992 at one center and were alive after 10 years. Outcome measures were assessed 10 years after OLT. Cantril's self-anchoring scale was used for global quality of life assessment. RESULTS: Synthetic liver function at 10 years was preserved in all patients. The annual rate of episodes of acute rejection dropped markedly after the first year (1.4 at year 1 to 0.19 rejections/patient/year at year 10). Histologically confirmed chronic rejection developed in eight (25%) patients. At 10 years, long-term complications included mild to severe chronic renal failure (77%), mild chronic anemia (59%), and hypertension (25%). Significant growth retardation (z-score < -2), hyperlipidemia, and diabetes were uncommon. Infection requiring hospitalization occurred in 81% of the patients, with varicella zoster virus as the most common pathogen. Epstein-Barr virus-related malignancies affected 22% of patients. Ten-year survivors perceived quality of life as very good. Self-reporting of drug nonadherence by seven (22%) adolescents may have contributed to development of late onset rejection in this subgroup. Conclusions. Children who are 10-year survivors of OLT have excellent graft function and, despite chronic extrahepatic morbidities, a self-reported high quality of life.

Sirolimus for pediatric liver transplant recipients with post-transplant lymphoproliferative disease and hepatoblastoma.

Sirolimus is a promising immune suppressive agent, with the potential to reduce calcineurin inhibitor associated nephrotoxicity, halt progression of chronic rejection and prevent tumor proliferation. The aim of this study was to review the experience using sirolimus in pediatric liver transplant recipients at a single center. Database and medical charts of all pediatric liver transplant recipients receiving sirolimus at the Hospital for Sick Children in Toronto were reviewed. Eight patients received sirolimus between October, 2000 and September, 2002. Indications for using sirolimus were post-transplant lymphoproliferative disease (PTLD) (n = 6) and hepatoblastoma (n = 2). Two patients with PTLD concurrently had renal impairment and chronic rejection. Sirolimus dosages ranged between 1.5 and 5 mg once daily. Median duration of follow-up was 17 months. Persistently elevated liver transaminase levels in the two children with chronic rejection decreased during sirolimus therapy. Recurrence of PTLD occurred in one patient. Two patients were diagnosed with acute cellular rejection after transition to maintenance sirolimus monotherapy. Resolution of adverse effects including mouth sores (n = 3), leg swelling (n = 2) and hyperlipidemia (n = 3) occurred either spontaneously or with dose reduction. Sirolimus was discontinued in four patients because of persisting bone marrow suppression, interstitial pneumonitis, life-threatening sepsis and refractory diarrhea. Children with PTLD or hepatoblastoma may benefit from immune suppression with sirolimus after liver transplantation. Further multi-center, prospective, randomized controlled trials will be instrumental to further the knowledge of long-term efficacy, safety and tolerability of sirolimus for selected children following liver transplantation.

Caracterización de pacientes infectados por Helicobacter pylori en el Hospital Nacional de Niños, San José, Costa Rica. 1995-1997 / Caracterization of infect patient with Helicobacter pylori in the Hospital Nacional de Niños, San José, Costa Rica. 1995-1997

OBJETIVO: Determinar el grado de infección de la población en estudio y establecer su correlación con los síntomas, la endoscopía y la histopatología. DISEÑO: Estudio retrospectivo, descriptivo. SITIO DE REALIZACION: Gastroenterología, Hospital Nacional de Niños, San José, Costa Rica. PACIETES Y METODOS: Revisión de expedientes atendidos en Gastroenterología de Febrero de 1995 a febrero de 1997 por dolor abdominal crónico, halitosis, vómitos o hematemesis u otros síntomas a quienes se les realizó endoscopía, biopsia y cultivo. RESULTADOS: Se revisaron 450 expedientes, de los cuales se excluyeron 181 por no tener reportes de laboratorio completos. Total incluidos 269, 137 (50,9 por ciento) niños y 132 (49,1 por ciento) niñas, edad promedio 7,33 años en su mayoría procedente de San José (62 por ciento). El síntoma más frecuente fue dolor abdominal crónico por 186 (69 por ciento), seguido por halitosis en un 39,8 por ciento. En 148 (55 por ciento) se documentó gastritis crónica activa. Se reportaron 60 cultivos positivos por Helicobacter pylori (22,3 por ciento), de los cuales 40 (66,6 por ciento) se correlacionaron con algún grado de nodularidad por endoscopía y 52 (86,7) tenían evidencia histológica de la infección. De los pacientes que consultaron por dolor abdominal 120 (63,5 por ciento) asociaron evidencia endoscópica de H.Pylori y 106 (57 por ciento) por histología. CONCLUSIONES: La gastritis por Helicobacter pylory es una entidad clínica asociada a dolor abdominal crónico y halitosis, por lo tanto debe hacerse diagnóstico diferencial con esta patología ante la presencia de estos síntomas y no aducir que el origne del dolor sea por causa no orgánica.