Raised Bilirubin, Normal Liver Tests: Gilbert’s or Haemolysis?
Raised Bilirubin, Normal Liver Tests: Gilbert's or Haemolysis?
Explain an isolated raised bilirubin in an adult whose liver enzymes are normal. Enter the total and direct (conjugated) bilirubin and the upper limit, and the page gives the conjugated fraction, then uses anaemia and haemolysis markers and the drug history to decide between Gilbert’s syndrome, haemolysis, a drug effect and a conjugated hyperbilirubinaemia that needs investigating — following the 2018 British Society of Gastroenterology guideline. Adults only.
Why is the bilirubin raised?
Total and direct bilirubin + haemolysis → Gilbert's, haemolysis or conjugatedA 24-year-old man with a viral illness has a total bilirubin of 38 µmol/L (upper limit 21) and a direct bilirubin of 6 µmol/L. ALT, AST and ALP are normal, haemoglobin is normal, he takes no regular drugs, and he has barely eaten for two days.
Conjugated fraction and the decision
Unconjugated = total − direct
Below 50% conjugated (the unconjugated fraction is the majority) + normal enzymes + no haemolysis → Gilbert’s syndrome (BSG 2018)
50% or more conjugated → not Gilbert’s: liver or biliary cause until shown otherwise
- 50%
- the BSG guideline’s test is that the majority of the bilirubin is unconjugated; there is no agreed adult percentage beyond this
- direct bilirubin
- a method-defined measurement: it includes delta (albumin-bound) bilirubin, and methods differ between laboratories
- haemolysis screen
- reticulocyte count, LDH, haptoglobin and a blood film, asked for when the patient is anaemic
Worked example
A 24-year-old man with a viral illness has a total bilirubin of 38 µmol/L (upper limit 21) and a direct bilirubin of 6 µmol/L. ALT, AST and ALP are normal, haemoglobin is normal, he takes no regular drugs, and he has barely eaten for two days.
Conjugated fraction = 6 ÷ 38 × 100 = 16%; unconjugated = 38 − 6 = 32 µmol/L
Well under half the bilirubin is conjugated → unconjugated hyperbilirubinaemia
Liver enzymes normal, not anaemic, no interacting drug
→ Gilbert's pattern; illness and fasting explain why it was found now
Confirm by repeating when well, with a full blood count; reassure. Mention it before any irinotecan
Causes of an isolated raised bilirubin in adults
| Pattern | Clues | Next step |
|---|---|---|
| Gilbert’s syndrome | Unconjugated majority, normal enzymes, no anaemia; higher when fasting or ill | Repeat when well with a full blood count; reassure |
| Haemolysis | Anaemia, raised reticulocytes and LDH, low haptoglobin | Blood film, direct antiglobulin test |
| Ineffective erythropoiesis or haematoma | Macrocytosis, thalassaemia trait, recent bleed or surgery | B12 and folate, haemoglobin studies |
| Drug effect | Atazanavir | None usually; review if jaundice troubles the patient |
| Crigler-Najjar type 2 | Much higher unconjugated bilirubin, direct fraction below 15% | Specialist referral |
| Conjugated hyperbilirubinaemia | Half or more conjugated | Ultrasound, repeat liver panel, drug review |
Gilbert’s syndrome: benign, common, and worth naming
An isolated raised bilirubin — jaundice or a high number with normal ALT, AST and ALP — is one of the commonest liver questions in general practice. The 2018 BSG guideline on abnormal liver blood tests turns it into two checks. First, split the bilirubin into its direct (conjugated) and indirect (unconjugated) parts; the indirect bilirubin calculator does the subtraction, and the bilirubin unit converter and direct bilirubin unit converter convert units. Outside the newborn period most bilirubin should be conjugated, so when the majority is unconjugated the problem lies before the liver’s conjugating step. Second, exclude haemolysis: if the patient is anaemic, a reticulocyte count, LDH and haptoglobin. If neither applies, the guideline says the cause is virtually always Gilbert’s syndrome.
Gilbert’s syndrome is an inherited reduction in the activity of the conjugating enzyme, UGT1A1, carried by 5 to 8% of people. It is harmless, and the guideline is explicit that people should be fully reassured. It fluctuates: fasting, intercurrent illness, stress and heavy exercise all raise the unconjugated bilirubin, which is why it is so often discovered during an unrelated illness. It matters in one place: drugs cleared by UGT1A1. Irinotecan’s prescribing information warns of more severe neutropenia in people homozygous for UGT1A1*28, the usual Gilbert’s genotype.
There is no agreed percentage that separates unconjugated from conjugated hyperbilirubinaemia in adults. The BSG uses “the majority”, and this page therefore splits at 50%; textbook figures of 15 or 20% exist but are not from a guideline, and direct-bilirubin methods differ between laboratories, so the same serum can give different fractions in different places. At totals only slightly above the limit the fraction is imprecise. Newborns are a different problem with their own thresholds — see the neonatal phototherapy threshold calculator. This page supports, and does not replace, clinical judgement.
Frequently asked questions
How is Gilbert’s syndrome diagnosed?
From the pattern, repeated: a raised bilirubin that is mostly unconjugated, normal liver enzymes and no evidence of haemolysis on a full blood count. The BSG guideline suggests repeating on a fasting sample with a full blood count, when the bilirubin should rise further and there should be no anaemia.
What percentage of direct bilirubin means unconjugated hyperbilirubinaemia?
There is no agreed adult cut-off. The BSG guideline asks whether the majority of the bilirubin is unconjugated — below half conjugated. Figures of 15% and 20% appear in textbooks, and direct bilirubin methods differ between laboratories.
Why does bilirubin go up when fasting or ill in Gilbert’s?
Fasting and illness reduce the liver’s ability to conjugate bilirubin and increase the amount presented to it, and in Gilbert’s syndrome there is little spare conjugating capacity. Within two days of fasting the unconjugated bilirubin typically rises two- to threefold, then falls once eating resumes.
Does Gilbert’s syndrome matter for medicines?
Occasionally. Irinotecan, a chemotherapy drug, is cleared by the same enzyme, and its prescribing information warns of more neutropenia in people homozygous for UGT1A1*28. Atazanavir inhibits the enzyme and raises unconjugated bilirubin in anyone.
Related calculators
References
- Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6–19. British Society of Gastroenterology, Association of Clinical Biochemistry and Laboratory Medicine and British Association for the Study of the Liver.
- Fargo MV, Grogan SP, Saguil A. Evaluation of jaundice in adults. Am Fam Physician. 2017;95(3):164–168.
- Medscape Reference. Unconjugated hyperbilirubinemia workup: approach considerations, Crigler-Najjar syndrome, Gilbert syndrome. Accessed September 2026.
- Camptosar (irinotecan hydrochloride) injection, US prescribing information: Warnings and precautions — increased risk of neutropenia in patients homozygous for the UGT1A1*28 allele.
Not medical advice. For healthcare professionals and education. Reference intervals vary by laboratory and assay — always use your own laboratory's. Never base a dose or a treatment decision on this page alone. Full disclaimer at calcengines.com/disclaimer/