phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3) helps to increase UDPGT enzyme production, which would make it conceptually possible to medically control the bilirubin level, although this is rarely necessary, particularly in adults (usually the level of total serum bilirubin in Gilbert syndrome patients vary from 1 to 6 mg/dL). Crigler–Najjar syndrome, type I is associated with mutation(s) that result in a complete absence of normal UGT1A1 enzyme, which causes a severe hyperbilirubinemia with levels of total serum bilirubin from 20 to 45 mg/dL. Phenobarbital treatment does not help to lower bilirubin level, because it only increases the amount of mutated UGT1A1 enzyme, which is still unable to catalyze the glucuronidation of bilirubin, which on the other hand makes phenobarbital treatment diagnostically relevant. Crigler–Najjar syndrome, type II is associated with other mutation(s) that lead to a reduced activity of the mutated UGT1A1 enzyme, which causes a hyperbilirubinemia with levels of total serum bilirubin from 6 to 20 mg/dL. In this case phenobarbital treatment helps to lower bilirubin lever by more than 30%. Hyperbilirubinemia, familial transient neonatal (also called breastfeeding jaundice) is associated with mutation(s) that alone do not lead to bilirubin level increase in female patients, but their children when breastfed develop from mild to severe hyperbilirubinemia by receiving steroidal substances (with milk) inhibiting glucuronidation of unconjugated bilirubin that may lead to jaundice and even kernicterus. Pharmacogenetics Genetic variations within the UGT1A1 gene have also been associated with the development of certain drug toxicities. The UGT1A1*28 variant, the same allele behind many cases of Gilbert syndrome. The UGT1A1*28 has been associated with an increased risk for neutropenia and Diarrhea in patients receiving the chemotherapeutic drug irinotecan due to the insufficient excrete the active metabolite SN‐38, which primarily undergoes glucuronidation in livers. The U.S. Food and Drug Administration recommends on the irinotecan drug label that patients with the *28/*28 genotype receive a lower starting dose of the drug. The *28 allele has also shown associations with an increased risk for developing diarrhea in patients receiving irinotecan. The UGT1A1*6 variant, more common in Asian populations than the *28 variant, has also shown associations with the development of irinotecan toxicities. Patients who are heterozygous or homozygous for the *6 allele may have a higher risk for developing neutropenia and diarrhea as compared to those with the UGT1A1*1/*1 genotype. Interactive pathway map See also Glucuronosyltransferase Lucey-Driscoll syndrome Neonatal jaundice Cancer pharmacogenomics References Further reading