Disease burden of Crigler–Najjar syndrome: Systematic review and future perspectives

Abstract

Background and Aim Crigler–Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5′‐diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients. Methods A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS. Results Twenty‐eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS‐I]), unconjugated bilirubin levels increase 3–6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS‐I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS‐I and is increasingly associated with excellent long‐term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression. Conclusions Crigler–Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease‐modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

“…In the past, bilirubin has been negatively viewed as a toxic bile substance and a biomarker for liver dysfunction. This was mostly reflected from the severe hyperbilirubinemia observed in the extremely rare Crigler–Najjar syndrome with levels in the 400–700 μM range, which can cause brain damage in infants [ 44 ]. The past two decades of heme oxygenase and bilirubin research has shown that bilirubin has many health benefits [ 1 , 2 , 45 ].…”

Pediatric metabolic liver diseases: Evolving role of liver transplantation

“…Crigler-Najjar syndrome (CNS) is an AR disorder caused by a defect in the UGT1A1 gene, the product of which (uridine diphosphate glucuronyl transferase) is responsible for the conjugation of bilirubin before its excretion. With an estimated incidence of one per 750000-1000000 live births, CNS is considered an “ultra-rare orphan disease”[ 71 ]. Type 1 is characterized by a complete absence of the enzyme whereas type 2 has 10% of the functioning enzyme[ 71 ].…”

“…With an estimated incidence of one per 750000-1000000 live births, CNS is considered an “ultra-rare orphan disease”[ 71 ]. Type 1 is characterized by a complete absence of the enzyme whereas type 2 has 10% of the functioning enzyme[ 71 ]. In type 1 CNS, the exceptionally high unconjugated bilirubin leads to irreversible brain injury in the basal ganglia, hippocampus, subthalamic nuclei and cranial nerves (kernicterus)[ 71 ].…”

“…Type 1 is characterized by a complete absence of the enzyme whereas type 2 has 10% of the functioning enzyme[ 71 ]. In type 1 CNS, the exceptionally high unconjugated bilirubin leads to irreversible brain injury in the basal ganglia, hippocampus, subthalamic nuclei and cranial nerves (kernicterus)[ 71 ]. Type 2 CNS usually responds to phenobarbitone therapy, however it is not effective in type 1 where phototherapy may help lower bilirubin levels.…”

Hereditary Unconjugated Hyperbilirubinemia (Combination of Crigler-Najjar Syndrome Type Ii and Gilbert's Syndrome)

“…Среди лабораторных показателей зарегистрировано лишь повышение уровня неконъюгированного билирубина, который достигал 270 мкмоль/л (медиана -170 мкмоль/л). При молекулярно-генетическом исследовании UGT1А1 выявлены мутации в 4 Случай из практики у части пациентов наблюдается промежуточная концентрация НБ [8]. При этом весьма сложно по клинической картине провести четкое разграничение между данными патологическими состояниями.…”