Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.

Autor: Strauss KA; Clinic for Special Children, Strasburg, PA.; Penn-Lancaster General Hospital, Lancaster, PA.; Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA., Ahlfors CE; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA., Soltys K; Department of Surgery, Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA., Mazareigos GV; Department of Surgery, Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA., Young M; Clinic for Special Children, Strasburg, PA., Bowser LE; Clinic for Special Children, Strasburg, PA., Fox MD; Clinic for Special Children, Strasburg, PA.; Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.; Diagnostic Referral Division, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE., Squires JE; Division of Gastroenterology and Hepatology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA., McKiernan P; Division of Pediatric Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh and Pittsburgh Liver Research Center, Pittsburgh, PA., Brigatti KW; Clinic for Special Children, Strasburg, PA., Puffenberger EG; Clinic for Special Children, Strasburg, PA., Carson VJ; Clinic for Special Children, Strasburg, PA., Vreman HJ; Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2020 Jun; Vol. 71 (6), pp. 1923-1939. Date of Electronic Publication: 2020 Feb 05.
DOI: 10.1002/hep.30959
Abstrakt: Background and Aims: We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years.
Approach and Results: Unbound ("free") bilirubin (B f ) was measured in patient sera to characterize the binding of unconjugated bilirubin (B T ) to albumin (A) and validate their molar concentration ratio (B T /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep B T /A at least 30% below intravascular B T binding capacity (i.e., B T /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (L f ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to B T (R 2  = 0.71) and B T /A (R 2  = 0.76), and B f as a percentage of B T correlated inversely to the bilirubin-albumin equilibrium association binding constant (R 2  = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak B T  ≥ 30 mg/dL and B T /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm 2 •nm for 9.2 ± 1.1 hours/day kept B T and B T /A within safe limits throughout childhood, but B T increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized B T and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe.
Conclusion: Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.
(© 2019 by the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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