UGT1A1-related Bilirubin Encephalopathy/Kernicterus in Adults

Abstract

Background and Aims: Bilirubin encephalopathy/kernicterus is very rare in adults. This study is aimed to investigate the clinical manifestations and genetic features of two patients with UGT1A1-related kernicterus. Methods: Sanger sequencing analysis was performed to identify UGT1A1 gene mutations in the patients and their families. Bioinformatics analysis was used to predict the potential functional effects of novel missense mutations. Clinical manifestations and biochemical parameters were collected and analyzed. Results: Two patients with Crigler-Najjar syndrome type II (CNS2) developed kernicterus in adulthood. Sanger sequencing identified a compound heterozygous mutation in the UGT1A1 gene in patient 1, which was inherited from his mother (G71R) and his father (c.-3279T>G; S191F). Patient 2 carried three heterozygous mutations, namely G71R, R209W and M391K; among which, the M391K mutation has not been reported before. Multiple prediction software showed that the M391K mutation was pathogenic. Symptoms were relieved in the two patients after phenobarbital and artificial liver support treatment. Patient 1 also underwent liver transplantation. Conclusions: Adults with CNS2 are at risk for kernicterus. Phenobarbital treatment is beneficial for maintaining bilirubin levels and preventing kernicterus.

Association of direct bilirubin to total bilirubin ratio with 90-day mortality in patients with acute-on-chronic liver failure

“…Notably, the administration of albumin or by pharmacological inhibition of indirect bilirubin production in a genetic model of hyperbilirubinemia could improve neurodevelopment and reduce apoptosis of cerebral cells remarkably (25,26). Similarly, promoting the conversion of indirect bilirubin to direct bilirubin was shown as beneficial in two patients with Crigler-Najjar syndrome type II who developed kernicterus in adulthood (24). Taken together, free bilirubin, DB/TB and indirect bilirubin-albumin ratio are risk factors for neurological dysfunction and nerve damage in patients with liver failure.…”

“…In liver failure, the content of free bilirubin increases due to increased indirect bilirubin, insufficient quantity and/or, decreased binding capacity of albumin (22). Previous clinical and basic studies have found that free bilirubin in serum is an important cause of kernicterus in neonates and adults (4,5,23,24). Recently, a retrospective case-control study showed that the indirect bilirubin-albumin ratio is an independent factor of hepatic encephalopathy in patients with liver failure (aOR:1.63, 95% CI: 1.32~2.00, p < 0.001) (25).…”

Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis

“…These treatments work by increasing the excretion and metabolism of bilirubin from the liver, reducing bilirubin accumulation in the blood and tissues. These findings emphasize the importance of early diagnosis and appropriate management of conditions such as Crigler-Najjar Syndrome Type II to prevent complications and improve patient outcomes (Barateiro et al, 2016;Liaqat et al, 2018;Bai et al, 2021;Cozzi et al, 2022).…”

“…Abnormal bilirubin efflux (Gilbert et al, 2019;Hsu et al, 2022) Type I presents with severe jaundice within the first few days of life without hemolysis and is often accompanied by bilirubin encephalopathy. On the other hand, Type II is heterozygous, has a late onset, and usually manifests as a milder illnesss (Tukey and Strassburg, 2000;Gailite et al, 2018) Phototherapy, phenobarbital (Barateiro et al, 2016;Liaqat et al, 2018;Bai et al, 2021) (Continued on following page)…”

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

“… 44 Crigler-Najjar syndrome (both type I and type II) are rare genetic disorders characterized by a severe deficiency in UGT, resulting in dangerously high levels of unconjugated bilirubin. 45 , 46 Studies have also shown that excessive mucin could be a factor in the formation of brown pigment GSs, as lipopolysaccharides from certain bacteria are potent stimulators of mucin secretion. 14 There are mouse models characterized by hemolysis due to dyserythropoiesis, and excessive mucin production leading to an increased risk of pigment or mixed GSs.…”