Gilbert Syndrome

Article Author:
Viveksandeep Thoguluva Chandrasekar
Article Editor:
Savio John
Updated:
10/27/2018 12:31:36 PM
PubMed Link:
Gilbert Syndrome

Introduction

Gilbert syndrome is the most common inherited disorder of bilirubin metabolism leading to decreased glucuronidation of bilirubin. Augustin Nicolas Gilbert first described the condition in 1901. It is also called Meulengracht disease or constitutional hepatic dysfunction or familial nonhemolytic jaundice. It is generally a benign condition characterized by recurrent episodes of jaundice. Patients are usually asymptomatic, except for the finding of icterus or jaundice. No treatment is usually necessary.

Etiology

The episodes of jaundice can be triggered by several factors such as fasting, dehydration, inter-current illnesses, overexertion, stress, hemolysis or menstruation. By reducing the total calorie intake to 400 Kcal per day or being on a normocaloric diet without lipids, these patients can have a rise in plasma bilirubin concentration up to three times normal within 48 hours. The plasma bilirubin returns to normal levels within 24 hours of having a normal diet. Several theories have been postulated for this, which include increased cycling of the bilirubin by enterohepatic circulation, decreased conjugation due to a decrease in the levels of UDP-glucuronic acid which is a co-substrate in glucuronidation and also an increased bilirubin load which is released from the adipocytes.

Epidemiology

It has been reported that the prevalence of Gilbert syndrome is between 4% and 16% in different populations. During adolescence, there is a change in the sex steroid concentration which affects the bilirubin metabolism which leads to increased bilirubin levels. Hence, most patients with Gilbert syndrome present during puberty. It is also more commonly seen in males due to a higher level of daily production of bilirubin.

Pathophysiology

Uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) is a group of enzymes which help with the glucuronidation of various chemicals in the body for metabolism and excretion. UGT1A1 is the enzyme which is responsible for the conjugation of glucuronic acid with bilirubin for the metabolism of bilirubin. UGT1A1 conjugates glucuronic acid to bilirubin and converts it into a water-soluble substance which can be excreted in bile. More than 100 mutations have been implicated in the causation of Gilbert syndrome, but the two most common genotype among Caucasians is the homozygous polymorphism of two extra bases (TA) in the TATAA box sequence of the promoter region of the UGT1A1 gene. The extra bases reduce the affinity of the binding protein to the TATAA box causing reduced gene expression. This results in a 10% to 35% reduction in the UGT1A1 enzyme activity. Patients manifest this syndrome only when they are generally homozygous for this mutation, and hence, it is typically inherited in an autosomal recessive pattern. It has been estimated that up to 9% to 10% of the general population of the Western world is homozygous to the variant promoter and up to 42% of the population is heterozygous.

Histopathology

The liver appears normal except for mild non-specific accumulation of lipofuscin pigment in the centrilobular zones. There are other mild abnormalities which can be seen in electron microscopy.

Toxicokinetics

Bilirubin-UGT is involved in the metabolism of estrogen and several other drugs through glucuronidation. Hence, individuals with Gilbert syndrome may be susceptible to toxicities from these substances that require glucuronidation for metabolism. Irinotecan is one of the well-known medications with increased toxicity in patients with Gilbert syndrome. The active metabolite SN-38 can get accumulated and lead to diarrhea in these patients. Atazanavir and Indinavir are an anti-retroviral medication (HIV protease inhibitors) which can increase bilirubin level by decreasing the activity of UGT. Acetaminophen and tolbutamide are two other medications which require glucuronidation although their clinical significance is unclear in these individuals. Accumulation of these drugs can lead to toxicities theoretically, but avoidance of these drugs is not recommended currently. Studies on acetaminophen in Gilbert syndrome individuals have shown that intravenous administration leads to decreased glucuronidation but not with oral administration.

History and Physical

Most patients with Gilbert syndrome are usually asymptomatic except for intermittent episodes of jaundice. They usually appear first during adolescence due to changes in the concentration of sex steroids. When Gilbert syndrome occurs in combination with other diseases like hereditary spherocytosis, glucose-6-phosphatase deficiency, breastfeeding, thalassemia or other conditions which can increase unconjugated bilirubin levels, they may potentiate the increase in the level of bilirubin. Although Gilbert syndrome can cause mild to moderate hyperbilirubinemia in neonates in the absence of any superimposed hemolytic disease, it does not cause significant elevation of unconjugated bilirubin in neonates to cause kernicterus. It has, however, been reported to cause worsening neonatal jaundice when associated with other hemolytic conditions which can lead to kernicterus. Some patients may have complaints like malaise, fatigue, nausea, anxiety, loss of appetite, and abdominal discomfort but studies have not shown any correlation with these symptoms and the bilirubin levels.

Evaluation

The only significant laboratory abnormality in patients with Gilbert syndrome is increased unconjugated bilirubin levels, and they are usually below 3 mg/dL with less than 20% of the bilirubin levels being conjugated. When associated with other pathological conditions which increase hemolysis, the level can be higher, but even then it is usually below 6 mg/dL. The diagnosis can be presumed with elevated unconjugated bilirubin levels on repeat testing with normal complete blood count, reticulocyte count, LDH, peripheral smear and normal levels of aminotransferases and alkaline phosphatase. Of note, fasting serum bile acids are normal. There is no role for any imaging modalities in the absence of any other laboratory abnormalities. Provocative tests such as 48-hour fast, observing a rise in bilirubin concentration after a low-lipid and low-calorie diet or after intravenous administration of nicotinic acid (which raises the osmotic fragility of red blood cells), observing a fall in serum bilirubin level on taking phenobarbitone (which induces the hepatic conjugating enzyme) can be considered but they are usually not performed.

Genetic testing can be used for confirmation when the diagnosis is difficult otherwise. They can be tested by using polymerase chain reaction or DNA-fragment sequencing for DNA mutations in UGT1A1 gene.

Treatment / Management

There is no specific treatment required for patients with Gilbert syndrome as they are usually asymptomatic. Recognition of the disorder and discussion of the mode of inheritance is more important to avoid unnecessary testing in the patient and family members. In patients with co-existing disorders with increased bilirubin levels, phenobarbital can be used to decrease the bilirubin level by inducing the UGTs.

Pearls and Other Issues

Bilirubin is known to exert an anti-oxidant effect, and in individuals with mildly increased bilirubin levels such as Gilbert syndrome, it may offer a protective effect due to that. Patients with Gilbert syndrome have a lower incidence of ischemic heart disease due to decreased production of advanced glycation end products which prevents endothelial dysfunction and reduces progression of atherosclerosis. Studies have also shown a reduction in the incidence of Hodgkin lymphoma, endometrial cancer, and cancer-related mortality when compared to the general population. In fact, the all-cause mortality rate is lower in individuals with mild hyperbilirubinemia due to Gilbert syndrome compared to the general population. In overweight children who develop the nonalcoholic fatty liver disease (NAFLD), the mean bilirubin levels were lower compared to those children who did not develop NAFLD. Gilbert syndrome patients are also at an increased risk of developing pigment gallstones (cholelithiasis), and especially in patients with other disorders of hemolysis like thalassemia, Sickle cell disease, and hereditary spherocytosis.