Gilbert syndrome (UGT1A1 gene)

The UGT1A1 enzyme processes bilirubin, a yellow waste product. A common reduced version of the gene causes Gilbert syndrome, a harmless, mild jaundice when fasting or ill, and it also affects the HIV drug atazanavir.

What this UGT1A1 variant does

UGT1A1 is the enzyme that attaches a sugar group to bilirubin so the liver can excrete it. This variant tags the common promoter change known as *28, which reduces how much enzyme is produced rather than breaking it, so clearance is slower but present.

The result is Gilbert syndrome: bilirubin runs slightly high, and it rises further during fasting, illness, dehydration, strenuous exercise or stress, which can produce mild visible jaundice that resolves on its own.

Gilbert syndrome is a normal variant, not a disease

This is one of the most common inherited conditions, affecting roughly 3% to 7% of people, and it causes no liver damage and needs no treatment. Its main clinical significance is diagnostic: an isolated raised unconjugated bilirubin on a blood test can prompt an unnecessary hunt for liver disease when the explanation is benign.

Some observational studies have reported slightly lower cardiovascular risk in people with mildly raised bilirubin, since bilirubin is an antioxidant. That association is not established well enough to count as a benefit.

Where it matters for medication

Two drugs are affected clearly. Atazanavir, used in HIV treatment, raises bilirubin further and produces visible jaundice much more often in people with reduced UGT1A1 activity, which is why CPIC rates this level A and suggests considering an alternative where jaundice would lead someone to stop treatment.

Irinotecan, used in colorectal cancer, is cleared by the same enzyme, and people with two reduced-activity copies have a higher risk of severe neutropenia and diarrhoea. The label reflects this, and dose reduction is a recognised approach.

How common it is

In 1000 Genomes reference data, about 44% of European-ancestry individuals carry one copy and 10% carry two, with the highest figures in African-ancestry samples at roughly 50% and 20%, and the lowest in East Asian samples at 22% and 2%.

East Asian populations more often carry a different reduced-function UGT1A1 variant, *6, which is not read here, so a normal result carries less weight there.

What each rs887829 genotype means

rs887829 has three possible genotypes: CC, CT and TT.

Typical bilirubin handling (rs887829 CC). You have the standard version of UGT1A1, the enzyme that processes bilirubin (a yellow waste product from old red blood cells). You clear bilirubin normally and aren't prone to the mild jaundice of Gilbert syndrome.

Mildly reduced bilirubin handling (rs887829 CT). You carry one reduced copy of UGT1A1, so you process bilirubin a little more slowly. This usually causes no symptoms, though it can tip into mild Gilbert-type jaundice when you're fasting or unwell. It can also matter for a few specific drugs like the HIV medication atazanavir.

Gilbert syndrome (rs887829 TT). You have two reduced copies of UGT1A1, which causes Gilbert syndrome: a common, harmless tendency for bilirubin to build up, sometimes giving a faint yellow tinge when you're fasting, stressed or sick. It needs no treatment, but it's worth knowing because it can increase side effects from a few drugs such as the HIV medication atazanavir.

Evidence & sources

Across global populations, about 14% of people carry two copies of this variant, and about 41% carry none.

CPIC provides dosing guidance for atazanavir based on this gene.

This variant appears in 34 published genetic studies: PubMed 19419973 · PubMed 21886157 · PubMed 22085899 · PubMed 22558097 · PubMed 23093944 · PubMed 23281178 · PubMed 23642732 · PubMed 24625756 · PubMed 24816252 · PubMed 25884002 · PubMed 26148204 · PubMed 27073872 · PubMed 31882771 · PubMed 33031748 · PubMed 34343768 · PubMed 34648354 · PubMed 34887591 · PubMed 35050183 · PubMed 35078996 · PubMed 35120996 · PubMed 35347128 · PubMed 35888748 · PubMed 35995766 · PubMed 36357675 · PubMed 36580335 · PubMed 36635386 · PubMed 37277652 · PubMed 38493369 · PubMed 38826804 · PubMed 38869630 · PubMed 39024449 · PubMed 39528826 · PubMed 39789286 · PubMed 42069741.

Common questions

Is Gilbert syndrome dangerous? No. It causes mildly raised bilirubin that can produce visible jaundice when you are fasting, ill or dehydrated, and it does not damage the liver or shorten life. Its value is knowing why a bilirubin result is high so that a benign finding is not investigated as liver disease.

Should I avoid any medicines? Two are worth knowing about: atazanavir, which commonly causes visible jaundice in people with reduced UGT1A1 activity, and irinotecan, where reduced activity raises the risk of severe side effects. Both are prescribing decisions rather than anything to act on yourself.

Related

CYP2C19 metabolizer status (clopidogrel & others) · Drug acetylation speed (NAT2) · Efavirenz / drug metabolism (CYP2B6*6) · Hepatitis C treatment response (IL28B) · Tacrolimus metabolism (CYP3A5 gene) · Thiopurine metabolism (TPMT and NUDT15 genes) · Warfarin dose sensitivity