Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Recreational Exposure during Algal Bloom in Carrasco Beach, Uruguay: A Liver Failure Case Report.

In January 2015, a 20-month-old child and her family took part in recreational activities at Carrasco and Malvín beaches (Montevideo, Uruguay). An intense harmful algae bloom (HAB) was developing along the coast at that time. A few hours after the last recreational exposure episode, the family suffered gastrointestinal symptoms which were self-limited except in the child's case, who was admitted to hospital in Uruguay with diarrhea, vomiting, fatigue, and jaundice. The patient had increased serum levels of liver enzymes and bilirubin and five days later presented acute liver failure. She was referred to the Italian Hospital in Buenos Aires, being admitted with grade II-III encephalopathy and hepatomegaly and requiring mechanical respiratory assistance. Serology tests for hepatitis A, B, and C, Epstein-Barr virus, and cytomegalovirus were negative. Laboratory features showed anemia, coagulopathy, and increased serum levels of ammonium, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. Autoimmune Hepatitis Type-II (AH-II) was the initial diagnosis based on a liver kidney microsomal type 1 antibodies (LKM-1) positive result, and twenty days later a liver transplant was performed. The liver histopathology had indicated hemorrhagic necrosis in zone 3, and cholestasis and nodular regeneration, which were not characteristic of AH-II. LC/ESI-HRMS (liquid chromatography electrospray ionization high-resolution mass spectrometry) analysis of MCs in the explanted liver revealed the presence of Microsytin-LR (MC-LR) (2.4 ng·gr-1 tissue) and [D-Leu¹]MC-LR (75.4 ng·gr-1 tissue), which constitute a toxicological nexus and indicate a preponderant role of microcystins in the development of fulminant hepatitis.