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Test Catalog

Test ID: UGTFG    
UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1, including irinotecan, atazanavir, nilotinib, pazopanib, and belinostat

 

Identifying individuals who are at risk of hyperbilirubinemia

 

Follow-up testing for individuals with a suspected UGT1A1 variant, who had negative TA repeat region testing

 

Establishing a diagnosis of Gilbert, Crigler-Najjar syndrome type I or type II

 

Establishing carrier status for Gilbert, Crigler-Najjar syndrome type I or type II

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This is a full gene sequencing test for UGT1A1 that includes the TA repeat region of the promoter and all intron/exon boundaries. Results are interpreted for the purposes of UGT1A1 drug metabolism and hereditary hyperbilirubinemia syndromes (Gilbert syndrome and Crigler-Najjar syndrome).

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

See UGT1A1 Test-Ordering Algorithm in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The UGT1A1 gene is part of a gene complex located on chromosome 2 that encodes several enzymes called uridine diphosphate (UDP)-glycuronosyl transferases. These enzymes perform a chemical reaction called glucuronidation, a major pathway that enhances the elimination of small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble metabolites that can be excreted from the body.

 

The UGT1A1 enzyme, primarily found in the liver, is responsible for the gluronidation of bilirubin, converting it from the toxic form of bilirubin (unconjugated bilirubin) to its nontoxic, water-soluble form (conjugated bilirubin). Genetic variants in UGT1A1 may cause reduced or absent UGT1A1 enzymatic activity, resulting in conditions associated with unconjugated hyperbilirubinemia including Gilbert syndrome and Crigler-Najjar syndromes types I and II.

 

Gilbert syndrome is the most common hereditary cause of increased bilirubin and is characterized by total serum bilirubin levels of 1 to 6 mg/dL. Gilbert syndrome is generally considered to be an autosomal recessive disorder, although autosomal dominant inheritance has been suggested in some cases.(1) Gilbert syndrome is caused by a 25% to 50% reduction in glucuronidation activity of the UGT1A1 enzyme and is characterized by episodes of mild intermittent jaundice and the absence of liver disease.

 

Crigler-Najjar syndromes types I and II (CN1 and CN2) are autosomal recessive disorders caused by more severe reductions in UGT1A1 glucuronidation activity. CN1 is the most severe form, with complete absence of enzyme activity and total serum bilirubin levels of 20 to 45 mg/dL. Infants with CN1 present with jaundice shortly after birth that persists thereafter.(2) CN2 is milder than CN1, with at least partial UGT1A1 activity and total serum bilirubin ranging from 6 to 20 mg/dL. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN2; CN1 does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause bilirubin-induced brain damage, known as kernicterus. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation.

 

In addition to the role of UGT1A1 in bilirubin metabolism, this enzyme also plays a role in the metabolism of several drugs. UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The combination of neutropenia with diarrhea can be life-threatening.(3,4)

 

Additional drugs have also been associated with an increased risk for adverse outcomes in patients with reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 variants associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).

 

The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. In this assay, the promoter, exons, and exon-intron boundaries are assessed for variants.(5)

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided that includes assessment of risk for UGT1A1-associated adverse drug reactions as well as interpretation for hyperbilirubinemia syndromes.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic hematopoietic stem cell transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic hematopoietic stem cell, a pretransplant DNA specimen is recommended for testing.

 

UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's UGT1A1 status.

 

Absence of a detectable gene variant does not rule out the possibility that the patient may have a genetic cause for increased unconjugated bilirubin.

 

Rare variants exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733

2. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97

3. Goetz MP, Safgren S, Goldberg RM, et al: A phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005 ASCO Annual Meeting Abstract No: 2014

4. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005. Pfizer

5. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

6. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158

7. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther 2015 doi: 10.1002/cpt.269

8. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396

9. US Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Accessed November 2015. Available at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

10. UDP-Glucuronosyltransferase Alleles Nomenclature page. Accessed March 2018. Available at www.pharmacogenomics.pha.ulaval.ca/ugt-alleles-nomenclature/

Special Instructions Library of PDFs including pertinent information and forms related to the test