UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Variants in the UGT1A1 gene are also responsible for the more common and mild hyperbilirubinemia observed in the 3–7% of the United States population with Gilbert’s syndrome [42]. Gilbert’s syndrome is associated with homozygous (TA)7TAA alleles (versus (TA)6TAA in wild-type individuals), referred to as UGT1A1*28 as previously described [6, 7, 12, 43, 50]. The UGT1A1 promoter can also consist of (TA)5TAA and (TA)8TAA alleles, although these alleles are poorly studied. Such variation leads to up to a 70% reduction in UGT1A1 activity [44, 49] resulting in an elevated level of unconjugated bilirubin in the bloodstream. Hyperbilirubinemia in Gilbert’s syndrome is typically benign, with serum bilirubin concentrations rarely exceeding 5 mg/dL and typically fluctuating between 1.3 and 3 mg/dL [39]. There are usually no serious consequences associated with this disease; mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic. Gilbert’s syndrome is thus considered an entirely benign and clinically inconsequential entity requiring neither treatment nor long-term medical attention, although mild hyperbilirubinemia is sometimes mistaken for a sign of occult, chronic, or progressive liver disease [50]. Gilbert’s syndrome is generally considered to be an autosomal recessive disorder. However, some cases of heterozygosity and compound heterozygosity have been reported in patients with Gilbert syndrome, predominantly among the Asian population [33].
Blood and immune system disorders
Steve Hannigan in Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Gilbert syndrome is a disorder that results in impairment of the removal of bile pigment (bilirubin) from the liver. It is characterised by jaundice that is most evident on the face, the palms of the hands and the soles of the feet. This is a result of an abnormal increase in bilirubin levels in the blood. This disorder is thought to be caused by decreased activity of an enzyme system known as bilirubin-uridine diphosphate glucuronyl transferase (bilirubin-UGT). The gene responsible for this disorder is located on the long arm of chromosome 2.
SBA Answers and Explanations
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury in SBAs for the MRCS Part A, 2018
Gilbert syndrome is an autosomal recessive inherited metabolic disorder (although occasionally inherited in an autosomal dominant fashion depending on the type of mutation), causing increased levels of unconjugated bilirubin in the blood. It is a common hereditary cause of hyperbilirubinaemia. There is decreased activity of the enzyme glucuronyltransferase, which conjugates bilirubin in the liver. Bilirubin is excreted from the body only in the conjugated form. Typical presentation is painless jaundice during an intercurrent illness.
Neonatal hyperbilirubinaemia and type I diabetes: an unsolved enigma
Published in Paediatrics and International Child Health, 2020
Jogender Kumar, Jaivinder Yadav
In spite of intensive research on the association between type 1 diabetes mellitus (T1DM) and neonatal hyperbili-rubinaemia, the mystery remains unsolved. A recently article by Liao et al. in Paediatrics and International Child Health estimated that neonates with hyperbilirubinaemia might have a 66% higher risk of developing T1DM in childhood [1]. Around 60% of term and 80% of preterm neonates have physiological jaundice. Bilirubin is known for its anti-oxidant and anti-inflammatory properties and is considered to have a protective effect against hypertension, ischaemic heart disease, type II diabetes (T2D), metabolic syndrome and obesity [2]. Bilirubin is protective against complications of T2D and is being explored as a potential biomarker and therapeutic target for type I diabetic nephropathy [3,4]. Individuals with Gilbert syndrome are protected against diabetes and its complications by virtue of elevated bilirubin levels [5]. Bilirubin production peaks at the time of maximum oxidative stress (probably a protective agent) in the newborn [6,7]. The results of Liao et al.’s study raise serious concerns over the existence of this natural anti-oxidant and need to be explained.
Liver Cirrhosis in a Patient with Crigler Najjar Syndrome
Published in Fetal and Pediatric Pathology, 2018
Zeren Barış, Figen Özçay, Yusuf Usta, Gonca Özgün
Interestingly, Sun et al, studied liver biopsies of 15 patients with CN2 and 44 patients with Gilbert syndrome, reporting only minimal inflammation and fibrosis [4]. Inflammation and fibrosis were slightly but not significantly higher in patients with CN2 than for those with Gilbert syndrome. Data from the literature indicates that the degree of inflammation and fibrosis in the liver increases as the enzyme activity decreases [2,4]. Although our patient had a homozygous mutation, which was related with CN1, her unconjugated bilirubin levels were lower than 20 mg/dl, without phototherapy. In this point of view, she is unique for presenting with severe fibrosis with such a mild clinical picture. Whether any specific type of UGT1A1 mutation leads to a tendency of fibrosis in liver is another aspect of investigation.
Effects of common genetic variants of human uridine diphosphate glucuronosyltransferase subfamilies on irinotecan glucuronidation
Published in Toxicology Mechanisms and Methods, 2023
Kouji Tagawa, Yoshihiro Maruo, Yu Mimura, Shinichi Ikushiro
The limitations of our study are as follows. First, we only compared the glucuronidation activity between each UGT1A and UGT1A variant toward SN-38, and did not consider the UGT1A isoform distribution in the human body. If UGT1A10 is expressed more than UGT1A7, the variants of UGT1A10 may be increasingly associated with irinotecan toxicity. Moreover, gastrointestinal toxicity due to SN-38 is caused not only by insufficient SN-38, but also by deconjugation via bacteria (Takasuna et al. 1998). Therefore, we should also consider this bacterial effect. Second, we only examined the relationship between UGT1As and their variants and SN-38 glucuronidation, and we did not consider the relationship between UGT2As and glucuronidation activity toward SN-38. Third, we did not examine the effect of multiple variants of UGT1As. Teng et al. (2007) reported that patients with two variants (UGT1A1*6 and UGT1A7*3) were seen in 30% of Gilbert syndrome and 7% of the control cohort. Patients with these variants may have more severe irinotecan toxicity than patients with either variant. To overcome these limitations, further analysis of patients who show severe adverse effects should be performed.
Related Knowledge Centers
- Jaundice
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- Menstruation
- Mutation
- Liver
- Bilirubin
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- Dominance
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