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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Microsomal defects are related to conjugation failure as the consequence of absent UDP-GT activity. The hyperbilirubinemia in Crigler-Najjar syndrome represents a form of congenital nonhemolytic jaundice which is genetically controlled and may be transmitted as a Mendelian dominant. The Crigler-Najjar syndrome is very rare.116 In these patients, the primary enzyme defect involves the complete absence of UDPGT from birth and therefore, only unconjugated bilirubin is found in the serum. Bilirubin is formed continuously from hemoglobin, but the degree of jaundice is fairly constant, indicating that alternate metabolic pathways partly compensate the defect in the hepatic conjugation system. Infants suffering from this disease develop severe jaundice and usually die from kernicterus.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Genetic variants in UGT1A1 are also associated with Crigler-Najjar syndrome, a more-severe inherited state of hyperbilirubinemia [2]. Crigler-Najjar Syndrome is a rare disorder affecting the metabolism of bilirubin, and is divided into two types: type I and type II. More than 40 different deleterious mutations distributed both in the unique and common exons of the UGT1A1 gene have been found in Crigler-Najjar syndrome types I and II [66]. Crigler-Najjar syndrome type I is a very rare disease with less than 1 case per million live births, and an autosomal recessive pattern of inheritance [67]. In Crigler-Najjar syndrome type I, most patients have a mutation in one of the common exons (2 to 5) of UGT1A1 and have complete absence of enzyme activity. Thus patients have difficulties conjugating several substrates (i.e. drugs and xenobiotics) [67–70]. A smaller percentage of patients have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself [26, 68]. This results in severe hyperbilirubinemia, which is characterized by serum bilirubin levels that usually range from 20–50 mg/dL (the normal range for total bilirubin is 0.1–1.0 mg/dL) [71]. As a result, intense jaundice appears in the first days of life and persists thereafter. Some affected infants die within the first year of life of kernicterus (bilirubin accumulation in the basal ganglia and brainstem nuclei), while others survive with little or no neurologic defect [26, 67, 68, 71–73]. Patients do not respond to phenobarbital treatment, which induces glucuronyl transferase induction, and only traces of unconjugated bilirubin can be found in their bile which is often colorless [71]. Phototherapy is the preferred treatment for Crigler-Najjar type I disease. However, since kernicterus can develop at a later age, phototherapy sometimes becomes inadequate at keeping serum bilirubin levels below 15 mg/dL, at which point liver transplantation may be required [71, 74, 75].
The Role of Kinetic Analysis and Mathematical Modeling in the Study of Bilirubin Metabolism in Vivo
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
E. Anthony Jones, Ewart R. Carson, Paul D. Berk
New insights into the physiology of bilirubin metabolism have been obtained through the application of a multicompartmental model of erythrokinetics.46 In this model, the life cycle of the erythrocyte from its earliest differentiation in the bone marrow to its ultimate senescent death and conversion into bilirubin is represented by 20 compartments arranged in series (Figure 9). The model includes inputs of newly synthesized bilirubin into the plasma from the catabolism of senescent red cells and from ineffective erythropoiesis. Thus, of the three most important sources of bilirubin only hepatic-synthesized bilirubin is not represented. Inherent in the model is the assumption that the plasma concentration of bilirubin varies directly with plasma bilirubin turnover (see Equation 13). Furthermore, the model includes nonphysiologic loss pathways of bilirubin from the plasma due to the removal by phlebotomy of cohorts of circulating red cells of variable age. This model was used in the interpretation of the results of a study in which an attempt was made to lower the plasma bilirubin concentration of an adult patient with encephalopathy associated with the Crigler-Najjar syndrome (Type I congenital nonhemolytic jaundice). The procedure employed was to reduce plasma bilirubin turnover by reducing the contribution from circulating senescent red cells. This was achieved by shortening the mean age of circulating erythrocytes by a program of chronic repeated phlebotomy. In the subject of the investigation an initial conventional study of bilirubin metabolism involving the intravenous injection of a tracer dose of labeled bilirubin indicated that the terminal half-life of the plasma disappearance curve was long, the hepatic bilirubin clearance rate very low and the plasma bilirubin turnover rate normal. Similar data have been obtained in other studies of unconjugated bilirubin metabolism in the Crigler-Najjar syndrome.43,44 Surprisingly, as the patient was subjected to the program of chronic phlebotomy the plasma bilirubin concentration did not decrease in parallel with the fall in plasma bilirubin turnover. Indeed, the plasma bilirubin concentration was maintained by a parallel decrease in hepatic bilirubin clearance. Prior to this study it had been assumed that the plasma bilirubin concentration was dependent on plasma bilirubin turnover in the Crigler-Najjar syndrome. The results of this study showed that this assumption was invalid. Furthermore, the model failed to reproduce experimentally observed data, indicating that the particular model structure adopted was inappropriate. Thus, although the original therapeutic goal of reducing the plasma bilirubin concentration was not achieved by phlebotomy, new knowledge was obtained about the pathophysiology of bilirubin metabolism in the Crigler-Najjar syndrome. This study is an important example of the way in which compartmental modeling can be used for predicting and explaining results of physiological experiments and therapeutic regimes and for the testing of hypotheses.
Regioselectivity significantly impacts microsomal glucuronidation efficiency of R/S-6, 7-, and 8-hydroxywarfarin
Published in Xenobiotica, 2019
So-Young Kim, Drew R. Jones, Ji-Yeon Kang, Chul-Ho Yun, Grover P. Miller
UGT1A1 is the most abundantly expressed hepatic UGT1A family enzymes (Strassburg et al., 1998). Common UGT1A1 substrates include estrogens (Cheng et al., 1998), bilirubin (Bosma et al., 1994), and many drugs like irinotecan (Iyer et al., 1998), tranilast (Danoff et al., 2003), and some nonsteroidal anti-inflammatory drugs (NSAIDS) (Kuehl et al., 2005). Bilirubin was an effective inhibitor of R/S-7-hydroxywarfarin glucuronidation, thereby implicating UGT1A1 in metabolism. Moreover, the observed IC50 value (4.3 μM) was almost identical to that reported for the inhibition of fluoroquinoline glucuronidation by bilirubin (4.8 μM) (Tachibana et al., 2005). The biological importance of this pathway could be significant, because R/S-7-hydroxywarfarin is the most abundant warfarin metabolite in plasma (Jones et al., 2011; Locatelli et al., 2005). As a major route of warfarin oxidation, UGT1A1 may facilitate this process to improve inactivation of both drug enantiomers (Bratton et al., 2012). Conversely, this beneficial effect would not be expected for patients with Gilbert or Crigler–Najjar syndrome, in which UGT1A1 variants impair activity toward substrates (Udomuksorn et al., 2007).
What’s next in gene therapy for Crigler-Najjar syndrome?
Published in Expert Opinion on Biological Therapy, 2023
Sem J Aronson, Giuseppe Ronzitti, Piter J Bosma
Crigler-Najjar syndrome (CN) is a recessively inherited error of bilirubin metabolism characterized by unconjugated hyperbilirubinemia, due to impaired function of uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1) [1,2]. This enzyme deficiency restricts glucuronidation and subsequent elimination of unconjugated bilirubin (UCB) via bile. In patients with the most severe phenotype, where UGT1A1 activity is completely absent, UCB accumulates in the body to serum levels > 340 uM leading, without adequate treatment, to bilirubin-induced encephalopathy (kernicterus) and death [1,3].
Liver Cirrhosis in a Patient with Crigler Najjar Syndrome
Published in Fetal and Pediatric Pathology, 2018
Zeren Barış, Figen Özçay, Yusuf Usta, Gonca Özgün
Our patient was born at term to non-consanguineous parents. Her birth weight was normal (3.5 kg) and there were no prenatal problems. She had persistent unconjugated hyperbilirubinemia from birth. Her bilirubin levels were between 15 and 20 mg/dl and she was treated with phototherapy during her neonatal period. Hemolytic disorders were excluded and metabolic screening was normal. Home phototherapy was recommended after first month of age with the diagnosis of Crigler Najjar syndrome (CN). Nevertheless, she was lost to follow up for several years.