The UGT1A1 gene provides instructions for making an enzyme known as UDP-glucuronosyltransferase 1A1. This enzyme plays a central role in the body’s processing system, particularly in the liver. Its primary function involves a chemical reaction called glucuronidation, where it attaches a specific sugar molecule, glucuronic acid, to various substances. This attachment transforms compounds, making them more water-soluble and easier for the body to eliminate.
The Role of UGT1A1 in Bilirubin Metabolism
The UGT1A1 enzyme manages bilirubin, a yellowish substance that forms during the breakdown of old red blood cells. When red blood cells complete their lifespan, heme is converted into unconjugated bilirubin. This initial form is not water-soluble and can be toxic if it accumulates in the body.
Located predominantly in liver cells, the UGT1A1 enzyme performs the step of “conjugation,” where it chemically links glucuronic acid to unconjugated bilirubin. This transformation converts bilirubin into a water-soluble form, known as conjugated bilirubin. Once conjugated, bilirubin dissolves in bile and is excreted from the body.
Conditions Associated with UGT1A1 Variants
When the UGT1A1 gene has variants, its enzyme’s function can be reduced, leading to elevated bilirubin levels and specific health conditions. These variants alter the enzyme’s ability to process bilirubin effectively. The severity of these conditions depends on how much the enzyme’s function is impaired.
Gilbert’s Syndrome
Gilbert’s syndrome is a common, mild genetic condition affecting bilirubin processing, occurring in an estimated 3% to 15% of Indo-European populations. It results from a specific UGT1A1 gene variant, often UGT1A1\28, which involves an extra pair of DNA building blocks in a regulatory part of the gene. This genetic change leads to the UGT1A1 enzyme operating at approximately 30% of its normal capacity.
Individuals with Gilbert’s syndrome typically experience mild, intermittent episodes of jaundice, where their skin and the whites of their eyes may appear yellowish. These episodes frequently occur during periods of physical stress, such as illness, fasting, intense exercise, or dehydration. Despite the visible jaundice, the condition is harmless and typically requires no specific treatment, as it does not cause liver damage. Many individuals are asymptomatic, discovering their condition incidentally through routine blood tests showing slightly elevated unconjugated bilirubin.
Crigler-Najjar Syndrome
Crigler-Najjar syndrome is a rarer, severe genetic disorder caused by UGT1A1 gene variants. It involves a significant reduction or complete absence of UGT1A1 enzyme function. Severity depends on residual enzyme activity, differentiating two types.
Crigler-Najjar syndrome Type 1 (CNS1) involves a near-complete lack of UGT1A1 enzyme activity. This results in high levels of unconjugated bilirubin accumulating in the blood, which can be toxic to the brain, potentially leading to kernicterus (brain damage). Type 2 (CNS2) is milder, with some residual enzyme function (typically less than 20% of normal activity). Individuals with CNS2 generally have lower bilirubin levels and a reduced risk of severe neurological complications, often responding to phenobarbital.
Newborn Jaundice
Newborn jaundice, characterized by yellowing of a baby’s skin and eyes, is a common condition in the first few days of life. This is largely due to the temporary immaturity of the infant’s UGT1A1 enzyme system. At birth, a newborn’s UGT enzyme activity is only about 1% of an adult’s.
As the UGT1A1 enzyme system matures over the first few weeks, bilirubin conjugation and excretion improve. Most cases of newborn jaundice are mild and resolve within two to three weeks, peaking around 48 to 96 hours after birth. However, UGT1A1 gene variants can exacerbate this physiological jaundice, contributing to higher or more prolonged bilirubin levels.
UGT1A1 and Drug Metabolism
Beyond its role in bilirubin processing, the UGT1A1 enzyme also metabolizes various medications. Individuals with reduced UGT1A1 enzyme activity due to genetic variants may process these medications differently, which can affect drug effectiveness or lead to adverse reactions. This interaction between genes and drug response is a field known as pharmacogenomics.
The chemotherapy drug irinotecan is an example of a medication influenced by UGT1A1 activity. Irinotecan is used to treat certain cancers, including metastatic colorectal cancer. In the body, irinotecan is converted into an active metabolite called SN-38. The UGT1A1 enzyme then inactivates SN-38 by attaching a glucuronic acid molecule.
Individuals with UGT1A1 variants, particularly those homozygous for the UGT1A1\28 allele, have reduced enzyme activity, leading to less efficient breakdown of SN-38. This can result in higher levels of active SN-38 circulating in the body, increasing the risk of severe side effects such as severe diarrhea and a low white blood cell count (neutropenia). Knowing a patient’s UGT1A1 status helps doctors adjust irinotecan doses to minimize severe toxicities. The FDA recommends dose reductions for patients with the UGT1A1\28/\28 genotype. Other medications, such as the HIV protease inhibitor atazanavir, are also processed by the UGT1A1 enzyme, and its activity can influence their metabolism and side effects.
Genetic Testing and Management
Genetic testing for UGT1A1 variants is a way to determine an individual’s gene makeup. This testing typically involves analyzing a blood or saliva sample to identify variations in the UGT1A1 gene. Reasons for UGT1A1 genetic testing include investigating persistent elevated bilirubin levels, which aids in diagnosing conditions like Gilbert’s syndrome or Crigler-Najjar syndrome.
Testing is also performed before initiating treatment with certain medications, such as the chemotherapy drug irinotecan. Identifying UGT1A1 variants in advance allows healthcare providers to anticipate drug metabolism issues and tailor medication dosages. For instance, Gilbert’s syndrome often requires no specific treatment beyond reassurance and avoiding triggers that can temporarily raise bilirubin levels. In contrast, management for Crigler-Najjar syndrome Type 1 involves intensive phototherapy to lower bilirubin, with liver transplantation being the only cure. For individuals receiving irinotecan, dose adjustments, such as a 20-25% reduction for those with specific UGT1A1 variants, can lower the risk of severe side effects.