Gilbert's syndrome

Synonyms: familial non-haemolytic hyperbilirubinaemia, constitutional hepatic dysfunction, Gilbert-Meulengracht syndrome, benign constitutional unconjugated hyperbilirubinaemia.

What is Gilbert's syndrome?

Gilbert's syndrome is characterised by a mild and intermittent unconjugated hyperbilirubinaemia, with no evidence of haemolysis or liver disease, and with normal liver function tests. It is usually an autosomal recessive disorder and is a common cause of unconjugated hyperbilirubinaemia. There have been some reports of autosomal dominant cases, mainly within Asian populations.

It was first described in 1901 by Nicolas Augustin Gilbert and Dominique Lereboullet.

How common is Gilbert's syndrome? (Epidemiology)

Homozygous Gilbert's syndrome affects 2-10% of the Caucasian population in the West.¹ . The worldwide prevalence of Gilbert's syndrome varies considerably depending on which diagnostic criteria are used. Men are more commonly affected than women.

However, many cases remain undiagnosed so its true prevalence is unknown.

Genetics

People with Gilbert's syndrome have a defect in the gene that encodes for the conjugating enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which results in a 60-70% reduction in the liver's ability to conjugate bilirubin. More than 100 different mutations have been identified in the UGT1A1 gene and their frequencies differ amongst different ethnic groups.^{2 3}

As it is a benign condition and is not associated with liver disease or reduced life expectancy, genetic counselling is not necessary.

Gilbert's syndrome symptoms and presentation

Gilbert's syndrome is usually diagnosed around puberty, when an increase in serum concentration of unconjugated bilirubin can lead to intermittent episodes of non-pruritic jaundice precipitated by:^{4 1}

• Intercurrent illness.

• Stress.

• Menstruation.

• Fasting.

• Dehydration.

• Physical exertion.

• Lack of sleep.

• Alcohol ingestion.

• Surgery.⁵

• Administration of certain drugs - eg, after chemotherapy and antiretroviral drugs.⁶

Symptoms, including tiredness, that may occur during an episode of jaundice are caused by the precipitating factor and do not result directly from Gilbert's syndrome.

Gilbert's syndrome may present in the newborn, especially if there is concurrent haemolysis such as ABO incompatibility; it has also been associated with breast milk jaundice.³

Associated conditions

Gilbert's syndrome can co-exist with the following conditions:

• Hereditary spherocytosis.⁷

• Congenital dyserythropoietic anaemia type 2.

• Thalassaemia.

• Type 1 diabetes.

Differential diagnosis

Other causes of unconjugated hyperbilirubinaemia

• Haemolysis.

• Autoimmune haemolytic anaemia.

• Glucose-6-phosphate dehydrogenase deficiency.

• Sickle cell disease.

• Thalassaemia.

• Hereditary spherocytosis.

• Excessive haemoglobin breakdown (eg, large haematoma reabsorption).

• Prosthetic heart valve.¹

• Crigler-Najjar syndrome types I or II.

Drugs causing elevated bilirubin levels

• Rifampicin (elevates conjugated levels).

• Paracetamol poisoning.

• Oestrogens.

• Erythromycin.

• Sulfasalazine and methyldopa can cause haemolysis.

Other

• Breast milk jaundice.

• Thyrotoxicosis (can lead to decreased glucuronosyltransferase activity).

Investigations¹

• Unconjugated bilirubin is elevated.

• Conjugated bilirubin is <20% of total bilirubin.

• Total serum bilirubin levels are >17 μmol/L and, although they can fluctuate, rarely exceed 85 μmol/L.

• Hb, reticulocyte count and blood film are normal (to distinguish from haemolysis).

• LFTs (including lactate dehydrogenase) and albumin are normal.

• Clotting is normal.

• There is no bilirubin, and subnormal amounts of urobilinogen, in the urine.

These investigations are diagnostic in the context of a patient showing:

• Recurrent episodes of self-resolving jaundice (especially ones that occur in response to the triggers described above); AND

• No clinical evidence of hepatobiliary disease or acute symptoms warranting admission.

Mild hyperbilirubinaemia can be mistaken for a sign of occult, chronic, or progressive liver disease, and precise diagnosis is important to avoid unnecessary invasive investigations. If there is clinical concern or uncertainty then discussion with a gastroenterologist or hepatologist is advisable. Very rarely, genetic testing may be available to confirm Gilbert's syndrome if there is any doubt.

Gilbert's syndrome prognosis

This is excellent. No treatment is required, it cannot progress to chronic liver disease, and life expectancy is normal.

The following drugs should be avoided or used with caution in people who have Gilbert's syndrome; testing for UGT1A1 gene variants may be indicated:^{2 8}

• Atazanavir and indinavir (used for the treatment of HIV infection).

• Gemfibrozil, particularly when combined with statins when there is an increased risk of toxicity including myositis.⁴

• Statins - there may be an increased risk of statin intolerance, so these patients should be closely monitored.

• Irinotecan (used for the treatment of advanced bowel cancer).

• Nilotinib and imatinib - used, for example, in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs).⁹

Bilirubin may have protective effects. It is an endogenous antioxidant.¹⁰ Having Gilbert's syndrome appears to reduce the risk of various age-related diseases, particularly cancer. A population-based cohort study found that overall mortality rates observed for people with Gilbert's syndrome in the UK population were almost half those of people without evidence of Gilbert's syndrome.¹¹ One theory to explain this is that the antioxidant properties of bilirubin have an anti-thrombotic effect via reducing platelet activation.¹² A large cohort study showed that having the UGT1A1 gene variant was significantly associated with better respiratory function and reduced odds of respiratory disease , with the strongest association being found in smokers, suggesting a protective effect of bilirubin.¹³