Introduction

Named after the physician Doctor William Gilbert, Gilbert syndrome (GS) describes an inherited condition where there is an inability to process a by-product known as bilirubin.¹ Bilirubin is produced when red blood cells are broken down and is eventually processed by the liver and excreted by the body either through urine or stool.² Its pigment is what gives them their signature yellow colour. When there is a default in bilirubin processing like in GS, the buildup of bilirubin in the blood can cause the skin and whites of the eyes (sclera) to turn yellow, a symptom known as jaundice. 

It affects between 2% and 20% of people depending on ethnic origin, with 2% of East Asians and Europeans being affected and up to 20% of those with South Asian and Middle Eastern backgrounds being affected.¹ Here, we explain the relationship between GS and how the body processes the byproduct bilirubin. 

What is Bilirubin?

Bilirubin Synthesis 

As mentioned above, bilirubin is mainly produced during the breakdown of red blood cells by the liver.² The lifespan of a red blood cell is approximately 120 days, at which point white blood cells, known as macrophages, will engulf these cells so that their contents can be reused in the production of new red blood cells.³ For instance, the oxygen-carrying protein, haemoglobin, is made of iron-containing haem groups and globin, which are then processed by the spleen, liver and bone marrow. It is the breakdown of the haem groups that produces bilirubin. 

Unconjugated Versus Conjugated Bilirubin

Bilirubin exists in two forms: conjugated and unconjugated. This corresponds to its chemical structure. Unconjugated bilirubin is insoluble in water and lacks glucuronic acid, whereas conjugated bilirubin is soluble and has glucuronic acid bound to it.² When bilirubin is produced, it is unconjugated and needs to be bound to a protein known as albumin to travel through the blood and to the liver, due to its insolubility. When it reaches the liver, it is taken up by liver cells (hepatocytes) and is conjugated by enzymes. Once conjugated with glucuronic acid, it becomes soluble in water and can travel without being bound to albumin. 

Conjugated bilirubin is excreted in both urine and by the gastrointestinal tract (in faeces).² From the liver, it is excreted into the bile duct and gallbladder, which dispenses the bilirubin-containing bile into the small intestine. Bile is a green-yellow fluid that is essential for digestion: it allows for the function of digestive enzymes by lowering the pH of gut contents and aids absorption of fats through the small intestine.⁴

Once the conjugated bilirubin reaches the large intestine, it is broken down (deconjugated) by the gut bacteria to form urobilinogen, some of which is reabsorbed by the gut and excreted by the kidneys.² On its way to excretion, it oxidises, giving faeces and urine their colour. 

Causes of Gilbert Syndrome

GS is believed to be caused by a mutation in the UGT1A1 gene which codes for the UDP-glucuronosyltransferase 1A1 enzyme. This enzyme is responsible for conjugating unconjugated bilirubin by adding glucuronic acid.^1,5 Patients with GS inherit two faulty copies of this gene (one from each parent), defining GS as an autosomal recessive condition.

The prevalence of the types of mutations of the UGT1A1 gene varies in different ethnic ethnic groups, however, in patients with GS, they all cause the enzymes to be defective and prevent the conversion of bilirubin from its unconjugated form to its conjugated form.¹ As a result, the unconjugated bilirubin is unable to be excreted into bile and out of the body, causing a build-up of unconjugated bilirubin in the blood and rest of the body. 

Symptoms

Although some patients may present with recurrent symptoms, GS is described as a benign condition as it does not affect the patient’s long-term health including the risk of liver disease.¹ Symptoms usually begin to present in late teens and seem to affect mostly males.^1,6 These usually manifest as recurrent jaundice, with patients complaining of yellowing of skin and whites of eyes.⁷ There have also been correlations to an increased risk of pigmented gallstones, however, that is the limit to the severity of the condition.¹ The onset of symptoms can be linked to triggers which can include: 

• Stress 
• Dehydration 
• Menstruation 
• Fasting 
• Illness 

Diagnosis

Although GS is a genetically inherited condition, genetic testing as a tool for diagnosis is usually not recommended as there are over a hundred genetic mutations linked to GS, with patients presenting differently depending on the mutation.¹ Therefore, GS is mainly diagnosed clinically and ruling out other causes of jaundice. 

When a patient presents with jaundice, it is important to first rule out any other causes, with the usual, more severe culprit being liver disease. Examples of investigations and examinations include: 

• Blood bilirubin levels - GS patients usually have high levels of unconjugated bilirubin, usually around 3 mg/dL when symptomatic^1,9
• Liver enzymes in blood - to rule out liver diseases that may also cause jaundice, these are usually raised in such instances, but normal in GS patients 
• Medical histories - clinicians may ask about the history of alcohol use and possible abuse, along with the history of intravenous drug use to rule out alcoholic liver disease or hepatitis which is usually transmitted through the sharing of needles 
• Further investigations of the liver - rarely, if the clinician suspects other causes of jaundice they may request diagnostic imaging of the liver and gallbladder, such as ultrasound and computed tomography scans 

Differential Diagnosis 

As mentioned previously, jaundice is caused by an elevation of bilirubin in blood. In more sinister conditions this is usually caused by diseased or damaged liver cells as they are unable to process the bilirubin and effectively clear it.¹⁰ Another cause may be blockage of the bile duct and gallstones or an increase in bilirubin production through an increased breakdown in the number of red blood cells. Some of these causes may occur in the diseases listed below:

• Dubin-Johnson Syndrome⁷
• Haemolytic anaemia 
• Liver diseases e.g. cirrhosis, alcoholic hepatitis, viral hepatitis and Wilson’s disease 
• Biliary cholangitis 
• Medications e.g. combined oral contraceptives, corticosteroids and rifampicin 

Management and Prognosis

Generally, patients with GS do not require any treatment and have a very good prognosis¹ It is important to emphasise that GS is a benign condition, in which those affected may experience recurrent symptoms of jaundice that may be linked to certain triggers and may need to avoid such triggers. However, GS patients may need to make their clinicians aware of their condition as the UGT1A1 gene mutation may alter the activity of certain medications. 

Summary

• Gilbert Syndrome is a benign genetically inherited disease which causes an increase in bilirubin in the blood 
• Bilirubin is a byproduct of red blood cell breakdown and has unconjugated and conjugated forms 
• Raised bilirubin causes jaundice which causes the yellowing of the skin and whites of the eyes 
• It is more common in men and symptoms usually arise in adolescence 
• No treatment is necessary and patients have excellent prognosis, but jaundice can present in more serious conditions which need to be ruled out through further investigation