GILBERT’S SYNDROME - SYMPTOMS, TRIGGERS, CAUSES, AND TREATMENT

Updated 16 November 2023

For people that get jaundice several times a year, they may have Gilbert’s Syndrome. Find out more about the symptoms and causes of Gilbert’s Syndrome below, as well as how to manage high bilirubin levels and when to seek treatment.

What is Gilbert’s Syndrome?

Gilbert’s Syndrome is a rare disorder in which the person’s liver does not metabolize bilirubin properly, resulting in slower clearance of bilirubin from the system. Bilirubin is a waste product derived from dead red blood cells and hemoglobin. It contributes towards the yellow-brown color of bile and, to a lesser degree, urine as well. The reduced bilirubin metabolism in Gilbert’s Syndrome promotes high bilirubin levels in the blood that cause intermittent episodes of jaundice, also known as hyperbilirubinemia.

Prevalence. This condition is thought to affect between 3-16% of the population, with males being more commonly affected than females. Studies suggest that female reproductive hormones, especially progesterone, increase the level of enzymes required to metabolize bilirubin[1]. Diagnosis is common during adolescence when hormones begin to peak, and during young adulthood. Population-based studies also reveal a lower prevalence of Gilbert Syndrome amongst Japanese individuals and a higher prevalence amongst those with type 1 diabetes and other rare genetic diseases.

Is Gilbert's Syndrome an autoimmune disease? Gilbert Syndrome is not an autoimmune disorder and is not related to excessive immune reactivity, autoimmunity, or inflammation. In fact, Gilbert Syndrome may lessen the risk of developing autoimmune diseases due to the antioxidant properties of bilirubin. Patients with other autoimmune diseases may be prone to episodes of hyperbilirubinemia[2].

What is the difference between Gilbert syndrome and Crigler-Najjar?

Crigler-Najjar syndrome is a similar condition to that of Gilbert’s syndrome, yet it is a lot rarer and more severe. In Crigler-Najjar syndrome, mutations in the UGT1A1 gene stop the enzyme from being produced entirely (type I) or cause a severe deficiency (type II). These result in more severe chronic hyperbilirubinemia as compared to that of Gilbert’s syndrome. Crigler-Najjar syndrome leads to a form of brain damage called kernicterus due to the high deposition of unconjugated bilirubin in the brain. This can be delayed till later in life with prompt treatment. While Gilbert’s syndrome is benign, Crigler-Najjar requires treatment and may even demand liver transplantation. [3] 

Gilbert’s Syndrome Symptoms

Generally, the elevated bilirubin levels seen in those with Gilbert Syndrome are not enough to cause symptoms other than intermittent episodes of jaundice. Jaundice can cause the skin and whites of the eyes to turn yellow. This is due to the color of bilirubin and often is not a cause of concern in those with Gilbert Syndrome.

Hyperbilirubinemia may also cause the following symptoms:

• Dark-coloured urine or red-clay colored stool
• Fatigue
• Difficulties concentrating
• Abdominal discomfort
• Nausea or diarrhea
• Appetite loss
• Flu-like symptoms
• Itching
• Dizziness

Severe jaundice can indicate the presence of liver disease, infections, or other problems. However, those with Gilbert Syndrome are likely to be at a reduced risk of contracting metabolic syndrome or liver disease. If jaundice occurs with intense or unusual symptoms, it is important to go see a doctor to rule out other health conditions.

Various Medication Sensitivities. Symptoms may become worse when those with the condition are exposed to triggers. This may predispose individuals with Gilbert’s Syndrome to being more sensitive toward medications and foods that make use of the liver glucuronidase enzyme pathway in order to be metabolized. Some of these include  general anesthetics, irinotecan, acetaminophen, menthol, estradiol benzoate, lamotrigine, and rifamycin SV. These compounds may cause worse jaundice and may heighten toxic side effects in those with Gilbert syndrome, yet these effects are often negligible if present, and patients are not often advised to avoid medication. If toxic side effects develop in response to any medication, contact your healthcare provider immediately.

Gallstone Risk. Chronic hyperbilirubinemia is a known risk factor for gallstone formation due to the way in which it combines with calcium to form calcium bilirubinate salts[4]. Studies reveal that people with Gilbert Syndrome have a higher prevalence of gallstones than people who are not affected.

Infantile Gilbert Syndrome and Neurotoxicity Risk. In infants, hyperbilirubinemia is considered neurotoxic and, if high enough, potentially fatal. However, most newborns with Gilbert Syndrome do not often get bilirubin levels high enough in order for them to be considered problematic, toxic, or fatal.

Triggers of Jaundice

As a result of having elevated bilirubin as a baseline, other factors that serve to increase blood bilirubin levels can cause episodes of mild jaundice in those with Gilbert Syndrome.

Known triggers for jaundice in Gilbert Syndrome include:

• Fasting or daily caloric intake of 400 kcal or less
• Consuming a high-carb diet
• Dehydration
• Physical overexertion
• Stress
• Illness or infection
• Surgery
• Menstruation
• Sleep deprivation or disruption
• Alcohol consumption
• Medications that interfere with glucuronidation

Additionally, genetic comorbidities such as Thalassemia, Spherocytosis, Cystic Fibrosis, and other liver enzyme disorders may predispose those with Gilbert Syndrome to severe hyperbilirubinemia.

Possible Benefits of Hyperbilirubinemia

Those with Gilbert Syndrome and other conditions of hyperbilirubinemia may be predisposed towards a lower risk for various chronic lifestyle diseases, such as cardiovascular disease, type 2 diabetes, autoimmune diseases, neurodegenerative diseases, and some types of cancer[5]. Additionally, Gilbert Syndrome is linked to a reduced risk of cardiovascular and all-cause mortality. These benefits are ascribed to the antioxidant, anti-thrombotic, and anticarcinogenic effects of bilirubin.[6] Recent research revealed that those with Gilbert Syndrome might also have better than average respiratory function, a lower risk for respiratory disease[7], and better outcomes for those with COVID-19, including protection from its negative metabolic effects.

Small amounts of bilirubin are known to stimulate optimal red blood cell and heme production, suggesting that those with Gilbert Syndrome may also suffer less from anemia. On the other hand, hyperbilirubinemia may promote the weakening of red blood cells, which can increase the risk as well.

Causes

Gilbert Syndrome is caused by the combination of inherited genetics and factors that trigger jaundice.

Bilirubin Conjugation and Disposal. Genetic underpinnings for Gilbert Syndrome interfere with the metabolism of bilirubin, which is a by-product of red blood cell turnover. Bilirubin may be conjugated or unconjugated, with the former being water-insoluble and the latter being water-soluble. In the bloodstream, unconjugated bilirubin binds to albumin until it reaches the liver for conjugation prior to disposal. When absorbed by liver cells, bilirubin is conjugated by enzymes of the UGT (uridine diphosphate-glucuronosyltransferase) family prior to disposal. These enzymes form part of a major liver detoxification pathway known as glucuronidation. Conjugated bilirubin leaves the liver through the gallbladder in bile and can easily make its way to the colon without being reabsorbed. In the colon, it gets deconjugated again by gut bacteria and transformed into metabolites that are even less absorbable and easily excreted.[8]

Genetic Conjugation Defects in Gilbert Syndrome. Most cases of Gilbert’s Syndrome are caused by a mutation onthe gene coding for the glucuronidation enzyme UGT1A1. The mutation affects the UGT1A1 promoter, referred to as A(TA)7TAA, and the mutated enzyme is known as UGT1A1*28. Those with UGT1A1*28 have a 70% reduction in the activity of the UGT1A1 enzyme, resulting in a lower conjugation rate.[9] Hyperbilirubinemia in those with Gilbert Syndrome reduces intestinal motility and increases gut permeability by 1.5-2 times, resulting in a higher uptake of unconjugated bilirubin and slower bilirubin disposal.

Reduced Liver Cell Uptake of Bilirubin. Studies hint at a second genetic defect that reduces the ability of liver cells to absorb bilirubin. However, scientists are still uncertain as to how liver cells absorb unconjugated bilirubin. The combination of reduced liver uptake and limited conjugation predisposes those with Gilbert Syndrome to have higher than average blood bilirubin levels.[10]

Heightened Bilirubin Production and Slower Clearance. As bilirubin is a by-product of red blood cell breakdown, higher levels can increase red blood cell production. If the levels are too high, as seen in jaundice, it may cause red blood cells to become weaker and can potentially lend itself towards a catch-22 cycle of increased bilirubin production, reduced liver uptake and conjugation, and higher reabsorption from the gut. Fortunately, this cycle only means a slower clearance rate for those with Gilbert Syndrome, who characteristically experience mild jaundice from time to time that typically resolves within a few days to weeks. The condition is not life-threatening and may even be asymptomatic for up to 33% of patients.

Diagnosis

A diagnosis of Gilbert Syndrome is usually sought out after receiving a blood test for an unrelated complaint that reveals high unconjugated bilirubin levels. Bilirubin levels are often tested to assess overall liver function alongside several other blood markers. A physician will first rule out other causes of hyperbilirubinemia before diagnosing Gilbert Syndrome, some of which include liver infections, liver disease, cancer, and other rare disorders of bilirubin metabolism.[11]

Gilbert Syndrome may be suspected if the patient’s other liver blood markers are normal, including red blood cell count, liver transaminases, and biliary damage markers. Confirmation of a Gilbert Syndrome diagnosis may require genetic testing to see if the person has a specific mutation on the UGT1A1 gene (UGT1A1*28). It is important to have a history of hyperbilirubinemia prior to genetic testing, as not all individuals with UGT1A1*28 develop Gilbert Syndrome.

When to Seek Treatment

As the condition is genetic and considered to be benign in most cases, Gilbert Syndrome treatment is unnecessary. Episodes of jaundice usually give rise to harmless symptoms and are able to resolve on their own with bed rest and adequate hydration. Up to 33% of those with Gilbert Syndrome do not ever have noticeable symptoms.[12]

Watching for Other Health Concerns. It is advisable to seek treatment if jaundice persists for longer than a few days, coupled with severe or unusual symptoms. This could be a sign of an infection or another health concern that can be treated.

Communicating About Gilbert Syndrome with a Doctor or Surgeon. While the condition is considered benign, it may be beneficial to discuss Gilbert Syndrome with your healthcare practitioner before agreeing to take medications for other conditions or prior to receiving an  anesthetic for surgery. The practitioner may adjust the dose of anesthetic to minimize recovery time (which may be extended with jaundice) and of medication if the side effects are severe enough.

Gilbert Syndrome Diet

A diet for Gilbert Syndrome is not recommended by healthcare providers. Those with Gilbert Syndrome are advised to consume a healthy balanced diet, keep well hydrated, and not overexert themselves with exercise. Avoiding highly processed foods, foods high in sugar or carbs, and alcohol may help reduce jaundice severity.

Evidence Supports Moderate Fat and Low Carb Intake for Gilbert Syndrome. There is evidence to suggest that those with Gilbert Syndrome would do better on a diet low in carbohydrates, with a fat intake of at least 9% or more. One study on 29 patients with the syndrome revealed that a high-carb diet increased symptom severity and bilirubin levels while lowering glucose intake and increasing fat intake helped to normalize bilirubin. The study concluded that a high-carb diet and fasting might contribute towards hyperbilirubinemia similarly by lowering fat intake.[13] It is possible that dietary fats may reduce the reabsorption of unconjugated bilirubin and promote faster excretion.

Paleo-Keto Diet May Resolve Symptoms for Some. Some online references suggest going on a modified paleo-keto diet due to one case study in which a woman with Gilbert Syndrome managed to normalize her bilirubin levels after being on a diet for over a year.[14] Despite the good results, the diagnosis was never confirmed through genetic testing, and there are no studies to confirm its efficacy for other individuals with chronically high bilirubinemia in the range of Gilbert Syndrome.

Prognosis

Gilbert’s syndrome is not known to cause mortality or long-term health problems and often has an extremely favorable prognosis. While prone to occasional symptoms pertaining to jaundice and an elevated gallstone risk, those with the syndrome can lead long, healthy lives.

Conclusion

Gilbert’s Syndrome is a genetic condition that affects the liver’s ability to process bilirubin, resulting in a slower clearance rate, higher than average blood bilirubin levels, and episodes of jaundice. Those with Gilbert Syndrome may experience symptoms related to jaundice, such as fatigue and abdominal discomfort. Intermittent jaundice tends to resolve within a few days from onset and may be triggered by various factors such as dehydration, medications, or fasting. Due to the antioxidant effects of bilirubin, Gilbert Syndrome may reduce the risk of several chronic lifestyle diseases yet can increase the risk of gallstone formation. No treatment is prescribed for Gilbert Syndrome. However, those with the condition are advised to keep hydrated and consume a healthy diet low in refined, high-carb foods.

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Sources:

• [1] https://pubmed.ncbi.nlm.nih.gov/6428963/
• [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507055/
• [3] https://www.ncbi.nlm.nih.gov/books/NBK562171/
• [4] https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1710092
• [5] https://pubmed.ncbi.nlm.nih.gov/37390966/
• [6] https://pubmed.ncbi.nlm.nih.gov/34814402/
• [7] https://patient.info/doctor/gilberts-syndrome-pro
• [8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159128/
• [9] https://pubmed.ncbi.nlm.nih.gov/22160004/
• [10] https://pubmed.ncbi.nlm.nih.gov/11230743/
• [11] https://pubmed.ncbi.nlm.nih.gov/29390925/
• [12] https://my.clevelandclinic.org/health/diseases/17661-gilberts-syndrome
• [13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1411132/
• [14] http://pubs.sciepub.com/ajmcr/3/4/9/ajmcr-3-4-9.pdf

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