Changes

November 2025 — reviewed. A literature search was conducted in October 2025 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to the recommendations have been made.

Update

Goals

To support primary healthcare professionals to: 

• Diagnose Gilbert's syndrome by excluding other causes of hyperbilirubinaemia.
• Give appropriate advice to people with Gilbert's syndrome.
• Be aware of drugs that should be used with caution in people with Gilbert's syndrome.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

What is it?

• Gilbert's syndrome (also known as benign hyperbilirubinaemia) is an inherited (usually autosomal recessive) metabolic disorder characterized by a mild and intermittent elevation of unconjugated (indirect) bilirubin levels, due to defective conjugating enzymes in the liver [Kamal, 2019; King, 2019; De Silva, 2025]. 
  
  • Bilirubin is a normal by-product of red blood cell breakdown. It is bound to uridine diphosphate (UDP)–glucuronic acid in the liver before being secreted into bile, a process called conjugation. 
  • In Gilbert's syndrome, a genetic defect reduces the activity of the enzyme responsible for conjugation (UDP–glucuronyl transferase) [Vítek, 2023; De Silva, 2025]. 
  • The ability to conjugate bilirubin is reduced by 60–70%, causing the serum level of unconjugated bilirubin to mildly increase above the normal upper limit [Claridge, 2011; Satsangi, 2020].
  • There is otherwise normal liver function, and no evidence of haemolysis [Vítek, 2023].

How common is it?

• In western Europe, 5–10% of the population are affected, but many people remain undiagnosed due to the asymptomatic nature of the condition; at least 30% of people with Gilbert's syndrome never develop symptoms.
  • The prevalence of Gilbert's syndrome differs between ethnic groups and is up to approximately 20% in South Asian and some Middle Eastern (Iranian) populations.
• Gilbert's syndrome is more common in males, with a male-to-female ratio ranging from 2:1 to 7:1. 
  • The genetic mutations that lead to Gilbert's syndrome are equally common in males and females, but differences in sex steroid hormones and their effects on bilirubin levels mean that clinically significant Gilbert's syndrome more commonly affects males.
• Gilbert's syndrome is 3-fold more common in people with type 1 diabetes, compared to a healthy control group.
• Gilbert's syndrome is often diagnosed around the time of puberty, supporting a hormonal influence on the manifestation of the condition.

[Claridge, 2011; King, 2019; Satsangi, 2020; Vítek, 2023; De Silva, 2025]

What is the prognosis?

• Elevated unconjugated bilirubin levels resulting from Gilbert's syndrome are often mild and intermittent.
  • Episodes of jaundice may be precipitated (or exacerbated) by physical or psychological stressors, including dieting or fasting, surgery, dehydration, alcohol ingestion, infectious illness, heavy physical exertion, pregnancy, and lack of sleep. These episodes are self-limiting and typically resolve after a few days.
  • Gilbert's syndrome does not progress to chronic liver disease, and life expectancy is normal.
• People with Gilbert's syndrome may be at increased risk of toxic side effects from some medications, including camptothecin (to treat colon cancer) and the antiretrovirals atazanavir and indinavir. Gemfibrozil and statins should also be used with caution in people with Gilbert's syndrome. For more information, see the section on Management.
• Gilbert's syndrome is associated with a possible increased risk of gallstones. For more information, see the CKS topic on Gallstones.
• There have been suggestions of a protective benefit of Gilbert's syndrome via the antioxidant effect of unconjugated bilirubin:
  • Studies have shown a lower incidence of Hodgkin’s lymphoma, endometrial cancer, and cancer-related mortality in people with Gilbert's syndrome than in the general population.
  • It is also associated with reduced prevalence of chronic diseases, particularly cardiovascular diseases (CVDs) and type 2 diabetes mellitus (and associated risk factors), as well as CVD-related and all-cause mortality. The overall mortality rate is lower in people with mild hyperbilirubinaemia due to Gilbert's syndrome than in the general population. 
  • Gilbert's syndrome may protect against metabolic dysfunction associated with steatotic liver disease (MASLD). This is thought to be due to the antioxidant effect of bilirubin, which may reduce inflammation and inhibit the progression of fibrosis.

[Newsome, 2018; King, 2019; Vítek, 2023; De Silva, 2025]

How should I diagnose Gilbert's syndrome?

• Suspect Gilbert's syndrome if a person has:
  • An incidental finding of an increased serum bilirubin concentration, typically not exceeding 68–85 micromol/L, with otherwise normal liver function tests (LFTs).
  • A single episode (or intermittent episodes) of mild jaundice without clinical evidence of liver disease and associated with physical or psychological stress, including heavy physical exertion, fasting, surgery, dehydration, intercurrent illness, alcohol ingestion, or lack of sleep.
    • Be aware that Gilbert's syndrome is often diagnosed around the time of puberty and is more common in males than females.
• To help confirm the diagnosis of Gilbert's syndrome:
  • Ask:
    • Whether the person has any symptoms — in general, Gilbert's syndrome is asymptomatic. If symptoms, such as abdominal pain, itch, pale stools, and dark urine, are present, consider alternative diagnoses.
    • If there is a family history of Gilbert's syndrome.
  • Examine the person.
    • There may be mild jaundice and signs of precipitating factors, such as dehydration or intercurrent infection.
    • There should be no hepatosplenomegaly or signs of chronic liver disease. If present, see the CKS topic on Jaundice in adults for further information.
  • Arrange blood tests.
    • Check LFTs with unconjugated and conjugated bilirubin levels. Send the blood sample wrapped (for example, in a small envelope) to minimise light exposure, which may lead to conjugation.
    • Check full blood count (FBC) with reticulocyte count and blood film to exclude haemolysis.
• Make a diagnosis of Gilbert's syndrome if the person has:
  • Confirmed unconjugated hyperbilirubinaemia (often noted on several occasions).
  • Otherwise normal LFTs.
  • No evidence of haemolysis (normal FBC, reticulocytes, lactate dehydrogenase, and blood film).
  • No evidence of other causes of liver disease.
  • Recurrent episodes of self-resolving jaundice (especially after heavy physical exertion, fasting, sleep deprivation, alcohol, dehydration, surgery, or an intercurrent illness).
• Consider referral to a gastroenterologist or hepatologist, the urgency depending on clinical judgement, if:
  
  • There is uncertainty about the diagnosis. Genetic testing may be available in some specialist centres to confirm the diagnosis of Gilbert's syndrome, but it is rarely necessary in clinical practice.
  • Other causes of liver disease are suspected.

What else might it be?

• Other causes of unconjugated hyperbilirubinaemia include:
  • Conditions that cause haemolysis, such as:
    • Auto-immune haemolytic anaemias.
    • Sickle cell disease. See the CKS topic on Sickle cell disease for more information.
    • Thalassaemia.
    • Hereditary spherocytosis.
    • Glucose-6-phosphate dehydrogenase deficiency.
    • Prosthetic heart valves.
    • Reabsorption of a large haematoma (excessive haemoglobin breakdown increases bilirubin production).
  • Genetic causes, such as:
    • Crigler–Najjar syndrome type I — a rare, recessively inherited condition in which there is no bilirubin conjugation in the liver, resulting in severe progressive jaundice in neonates in the first few days of life. If left untreated, it leads to bilirubin encephalopathy (kernicterus). Bilirubin levels reach 350–950 micromol/L and life expectancy is usually less than 1 year.
    • Crigler–Najjar syndrome type II — an inherited condition that is thought to be due to a combination of a Gilbert's syndrome defect and a Crigler–Najjar type I defect, in which conjugating enzyme activity is less than 10%. It is less severe than type I and brain damage does not occur. Bilirubin levels are less than 350 micromol/L.
  • Drugs, such as:
    • Methyldopa and sulfasalazine — can cause haemolysis.
    • Rifampicin — can impair hepatic bilirubin clearance.
  • Physiological neonatal jaundice.
    • Harmless unconjugated hyperbilirubinaemia, often with mild clinical jaundice, occurs in all full-term newborn infants. See the CKS topic on Jaundice in the newborn for more information.
• Causes of conjugated hyperbilirubinaemia include:
  • Gallstones. See the CKS topic on Gallstones for more information.
  • Fatty liver disease. See the CKS topic on Fatty liver disease for more information.
  • Infection, for example:
    • Viral hepatitis. See the CKS topics on Hepatitis A, Hepatitis B, and Hepatitis C for more information.
    • Cytomegalovirus.
    • Epstein-Barr virus.
  • Drugs, such as:
    • Paracetamol — a subset of people with Gilbert's syndrome may be more susceptible to liver damage after a paracetamol overdose. 
    • Erythromycin.
    • Oestrogens.
    • Corticosteroids. 
    • Chlorpromazine.
  • Metabolic causes, such as:
    • Ischaemic hepatitis.
    • Wilson's disease.
    • Haemochromatosis.
    • Alpha-1-antitrypsin deficiency.
  • Auto-immune causes, such as:
    • Primary biliary cirrhosis.
    • Primary sclerosing cholangitis.
    • Auto-immune hepatitis.
  • Malignancy and infiltrative diseases, such as:
    • Cholangiocarcinoma.
    • Extrinsic compression from other malignancy.
    • Tuberculosis. See the CKS topic on Tuberculosis for more information.
    • Lymphoma.
    • Amyloidosis.
    • Sarcoidosis.
    • Non-metastatic renal carcinoma.
    • Metastatic carcinoma.
• See the CKS topic on Jaundice in adults for more information on the causes of jaundice in adults.

Scenario: Management of Gilbert's syndrome

From birth onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on the primary care management of Gilbert's syndrome.

Search dates

February 2021 - October 2025.

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• Gilbert disease/
• gilbert disease.tw, or gilbert syndrome.tw, or gilbert's disease.tw, or gilbert's syndrome.tw,
• Unconjugated or isolated (hyperbilirubin?emia).ti,ab. + .kw.

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.