Gilbert Syndrome: High Bilirubin — Should You Worry?

Bilirubin comes mainly from the breakdown of haemoglobin in ageing red cells. This primary, unconjugated form is poorly soluble in water and travels in the blood bound to albumin. In the liver, the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) attaches glucuronic acid to it; the resulting conjugated (direct) bilirubin is water-soluble and is excreted in bile into the gut. In people with Gilbert syndrome this enzyme's activity is reduced, so conjugation is slower and unconjugated bilirubin accumulates in the serum.

An important practical point follows from this study: the genetic variant itself is very common (about 40% of alleles in the healthy group studied), but the full picture of Gilbert syndrome appears only in some people, usually homozygotes. That is why so many people carry the 'Gilbert gene' and never find out from their results, while others have clearly raised bilirubin. Other factors, among them sex, can influence how high bilirubin stays.

Variability is a hallmark of Gilbert syndrome. The same patient can have bilirubin only slightly above the range one day and several times higher on another. The best-documented triggers are fasting or drastic calorie restriction, infections and fever, dehydration, strong physical or mental stress, lack of sleep, menstruation and intense exercise. Many people notice a yellowish tinge to the whites of the eyes when they 'haven't eaten' for a long time or have had flu.

The phenomenon is so reproducible that it was once used diagnostically in the so-called fasting test. In a 2001 Japanese study (Ishihara et al.), a 24-hour restriction to 400 kcal was compared in 56 healthy volunteers and 28 patients with diagnosed Gilbert syndrome: people with a UGT1A1 mutation showed a larger rise in bilirubin in response to fasting than people without one. Today the fasting test is not recommended as a routine method — it is much simpler to assess the pattern of laboratory results and, if in doubt, to run a UGT1A1 genetic test.

What does this mean for you? If you know or suspect you have Gilbert syndrome, do not over-interpret a single result taken fasting after a sleepless night, during an infection or after a hard workout. Bilirubin under such conditions will be higher than usual, and it does not mean the liver is getting worse. On the other hand, genuinely missing a real problem is possible, so a new, clearly higher level than your usual values, especially with other symptoms, should be a reason to consult.

Diagnosis rests on three pillars. First: mildly raised total bilirubin in which the unconjugated (indirect) fraction clearly dominates — which is why it matters to measure direct and indirect bilirubin and not just the total. According to the ACG (American College of Gastroenterology) guideline, raised total bilirubin should be split into fractions, and a raised conjugated fraction usually indicates hepatocellular disease or impaired bile flow. Second: normal ALT, AST, ALP and GGT. Third: no signs of haemolysis — normal blood count, haemoglobin and reticulocyte count, and, if in doubt, LDH and haptoglobin.

The syndrome typically appears around puberty or in young adults and is diagnosed more often in men (who usually have higher bilirubin than women). Typical total bilirubin values are usually only a little above the upper limit, up to about 3 mg/dL (about 50 µmol/L); temporarily, during fasting or infection, they can be higher. Remember to convert units: 1 mg/dL of bilirubin is about 17 µmol/L, and reference ranges depend on the laboratory.

Reviews of hyperbilirubinaemia point out that, besides Gilbert syndrome, disorders of bilirubin metabolism include the rare Crigler-Najjar, Dubin-Johnson and Rotor syndromes, as well as acquired liver diseases such as steatosis, viral hepatitis, cirrhosis or biliary tumours. This is why a diagnosis of Gilbert syndrome requires the picture to be clearly typical. If bilirubin rises gradually over time, or other abnormalities or symptoms accompany it, the doctor should look further.

Bilirubin is not merely 'waste'. It has strong antioxidant properties, and in observational studies a higher bilirubin level was linked with a lower frequency of cardiovascular disease. This led to the hypothesis that people with Gilbert syndrome might be partly protected against atherosclerosis. Reviews (among them Vítek and Tiribelli, 2023) even describe possible benefits regarding diseases of civilisation, cancers and neurodegenerative diseases. Before you take this as good news, though, it is worth looking at what the best data actually show.

In practice, tell yourself this: Gilbert syndrome is not a risk factor for heart disease and is probably slightly favourably associated with it, but it does not exempt you from checking blood pressure, lipids and glucose, or from regular physical activity. It is not a 'shield', just a small statistical difference at population level.

Although the syndrome itself is benign, reduced UGT1A1 activity matters for some drugs metabolised by the same route. Cancer drugs are the best described. In a literature review in Pharmacotherapy (Ha et al., 2017) it was noted that Gilbert syndrome affects about 10% of the population and that the UGT1A1*28 allele can reduce glucuronidation by about 30%, which increases the toxicity of some anticancer drugs. The authors also underline a paradox: many dosing recommendations use bilirubin as a surrogate marker of liver function, and in a person with Gilbert syndrome bilirubin is high while the liver works normally — and clear guidance on adjusting doses in such cases is lacking.

The most frequently cited example is irinotecan, a drug used in colorectal cancer among others, whose active metabolite is inactivated precisely by UGT1A1; in carriers of a variant that reduces this enzyme's activity the risk of severe adverse effects (neutropenia, diarrhoea) is higher. Likewise, some antiviral drugs used in HIV (e.g. atazanavir) raise unconjugated bilirubin more strongly in people with the UGT1A1*28 allele. If you have Gilbert syndrome, the key practical rule is: tell every doctor who prescribes cancer treatment or long-term drug therapy, and do not let the raised bilirubin be read as liver failure.

A systematic review of studies on nutrition in Gilbert syndrome (Goluch et al., 2024, 19 studies) indicates that interventions without excessive calorie restriction, including fats and bioactive compounds from vegetables and fruits, may prevent jaundice episodes, but the authors stress the need for further research. This is not proof of the effectiveness of any specific 'Gilbert diet' — rather a confirmation of the general rule not to starve and to eat a varied diet.

For most people the most important thing to know about Gilbert syndrome is that a bilirubin result that looks alarming is often the expression of a harmless genetic trait. At the same time the diagnosis itself should not be brushed aside: correct splitting of bilirubin into fractions, excluding haemolysis and liver disease, and awareness of drug interactions are the three elements that separate a calm life with Gilbert syndrome from needless fear or a missed disease. If you have this diagnosis, put it in your medical record and remember: we treat the person, not the number.