View source for Phenotype:UGT1A1 poor metabolizer

A '''UGT1A1 poor metabolizer''' (PM) is a person who carries two reduced-function ''UGT1A1'' alleles and therefore has substantially reduced UGT1A1 enzyme activity. It is one of the three metabolizer phenotypes assigned from ''UGT1A1'' genotype, the others being the [[Phenotype:UGT1A1 intermediate metabolizer|intermediate metabolizer]] and the [[Phenotype:UGT1A1 normal metabolizer|normal metabolizer]]. UGT1A1 has no ultrarapid phenotype. This page describes the poor-metabolizer phenotype; the enzyme itself, including its history and the Gilbert syndrome story, is covered at [[Enzyme:UGT1A1]].

The UGT1A1 poor-metabolizer phenotype has a feature no other phenotype page in this category shares: it is, biochemically, a named clinical condition in its own right. The reduced UGT1A1 activity of the poor metabolizer is the molecular basis of '''Gilbert syndrome''', the common, benign, inherited mild unconjugated hyperbilirubinemia. A UGT1A1 poor metabolizer and a person with Gilbert syndrome are, in genotype terms, the same person.

== Genotype basis ==
The poor-metabolizer phenotype is produced by a ''UGT1A1'' diplotype combining two reduced-function alleles. The clinically important alleles:

* '''\*28''' (the A(TA)7TAA promoter variant, TA7), the classic Gilbert syndrome allele, common in all populations and most frequent in African-ancestry populations.
* '''\*6''' (Gly71Arg), a reduced-function allele common in East Asian populations and uncommon elsewhere.
* '''\*37''' (the A(TA)8TAA promoter variant, TA8), a more severely reduced-function allele found in some African-ancestry populations.

Diplotypes such as ''\*28/\*28'', ''\*6/\*6'', and ''\*37/\*37'' produce the poor-metabolizer phenotype. The ''\*28/\*28'' genotype is the one most often quoted in the irinotecan literature. The full allele catalogue is described on the [[Enzyme:UGT1A1]] page.

== Population frequency ==
The UGT1A1 poor-metabolizer phenotype is found in roughly 10% of European-ancestry populations, 5 to 10% of African-ancestry populations, and 1 to 5% of East Asian populations. The figure for Gilbert syndrome quoted in general medicine, often around 5 to 10% of the population, is the same phenomenon counted the same way.

== Clinical consequences ==
'''Irinotecan (clearance; raised exposure of the toxic metabolite).''' The cytotoxic medicine [[Irinotecan|irinotecan]] is converted in the body to its active metabolite SN-38, and UGT1A1 is the enzyme that glucuronidates SN-38 to an inactive form for excretion. A UGT1A1 poor metabolizer clears SN-38 slowly, accumulates it, and is at markedly elevated risk of severe neutropenia and severe diarrhea. The Dutch Pharmacogenetics Working Group recommends a starting-dose reduction of about 30% for ''\*28/\*28'' patients receiving irinotecan in standard regimens, with the option to titrate upward if severe neutropenia does not occur.<ref name="hulshof2023">Hulshof EC, Deenen MJ, Nijenhuis M, et al. Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan. ''European Journal of Human Genetics''. 2023 Sep;31(9):982-987. PMID: 36443464.</ref>

'''Atazanavir (hyperbilirubinemia).''' The HIV protease inhibitor [[Atazanavir|atazanavir]] inhibits UGT1A1. Given to a UGT1A1 poor metabolizer, whose UGT1A1 activity is already low, atazanavir reliably produces clinically apparent unconjugated hyperbilirubinemia and visible jaundice. The jaundice is biochemically benign but is cosmetically distressing and a frequent reason for patient-initiated discontinuation; CPIC recommends considering an alternative protease inhibitor in poor metabolizers for whom the jaundice would be unacceptable.<ref name="gammal2016">Gammal RS, Court MH, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. ''Clinical Pharmacology and Therapeutics''. 2016 Apr;99(4):363-369. PMID: 26417955.</ref>

'''Bilirubin and Gilbert syndrome.''' The poor metabolizer has a reduced capacity to conjugate bilirubin and therefore a mildly raised unconjugated bilirubin, most visible during fasting, intercurrent illness, or physical stress. This is Gilbert syndrome, and on its own it is benign and requires no treatment; its main clinical importance is that it must not be mistaken for a sign of liver disease or hemolysis.

== See also ==
* [[Enzyme:UGT1A1]], the enzyme, its history, and its full substrate spectrum.
* [[Phenotype:UGT1A1 intermediate metabolizer]], [[Phenotype:UGT1A1 normal metabolizer]], the sibling phenotypes.
* [[Irinotecan]], [[Atazanavir]] (representative affected medicines); [[Gilbert syndrome]], [[Bilirubin]] (the endogenous context).
* [[:Category:Pharmacogenomic phenotypes]]

== References ==

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[[Category:Pharmacogenomic phenotypes]]