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Hepatology. 2019 Sep 25. doi: 10.1002/hep.30959. [Epub ahead of print]

Crigler-Najjar syndrome type 1: pathophysiology, natural history, and therapeutic frontier.

Author information

1
Clinic for Special Children, Strasburg, PA, USA.
2
Penn-Lancaster General Hospital, Lancaster, PA, USA.
3
Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA.
4
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Surgery, Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
6
Department of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
7
Diagnostic Referral Division, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
8
Division of Gastroenterology and Hepatology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
9
Division of Pediatric Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh and Pittsburgh Liver Research Center, Pittsburgh, PA, USA.
10
Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

Abstract

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. Unbound ('free') bilirubin (Bf ) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT ) to albumin (A) and validate their molar concentration ratio (BT /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 BT /A at least 30% below intravascular BT binding capacity (i.e. BT /A=1.0). Categorical clinical outcomes were ascertained by chart review, and a novel measure was used to quantify liver fibrosis. Unbound bilirubin had a non-linear relationship to BT (R2 = 0.71) and BT /A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin-albumin equilibrium association binding costant (R2 = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3±1.1 mg/dL•day. Four (14%) neonates developed kernicterus between 14 and 45 days of age; peak BT ≥30 mg/dL and BT /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/cm2 •nm for 9.2 ± 1.1 hours/day kept BT and BT /A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by age 18 years. Liver transplantation (n=17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

PMID:
31553814
DOI:
10.1002/hep.30959

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