AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

Augustine Gilbert and Pierre Lereboullet first described Gilbert syndrome, the most common inherited cause of unconjugated hyperbilirubinemia, in 1901. This autosomal recessive condition is characterized by intermittent jaundice in the absence of hemolysis or underlying liver disease. The hyperbilirubinemia is mild and, by definition, less than 6 mg/dL. However, most patients exhibit levels of less than 3 mg/dL. Considerable daily and seasonal variations are observed, and bilirubin levels occasionally may be normal in as many as one third of patients.

Gilbert syndrome may be precipitated by dehydration, fasting, menstrual periods, or stress, such as an intercurrent illness or vigorous exercise. Patients may report vague abdominal discomfort and general fatigue for which no cause is found. These episodes resolve spontaneously, and no treatment is required, except supportive care.

Pathophysiology

Unconjugated hyperbilirubinemia in Gilbert syndrome has long been recognized as due to underactivity of the conjugating enzyme system bilirubin-uridine diphosphate glucuronyl transferase (bilirubin-UGT). Bilirubin-UGT is responsible for conjugating bilirubin into bilirubin monoglucuronides and diglucuronides and is located primarily in the endoplasmic reticulum of hepatocytes. Bilirubin-UGT is one of several UGT enzyme isoforms responsible for the conjugation of a wide array of substrates that include carcinogens, drugs, hormones, and neurotransmitters.

Knowledge of these enzymes has been enhanced greatly by characterization of the UGT1 gene locus in humans. The gene that expresses bilirubin-UGT has a complex structure and is located on chromosome 2. 

There are 5 exons, of which exons 2-5 at the 3' end are constant components of all isoforms of UGT, coding for the UDP-glucuronic acid–binding site. 

Exon 1 encodes for a unique region within each UGT and confers substrate specificity. However, multiple exon 1s (at least 13) exist, and, to complete the gene, one of these exons must be recruited. Exons 1a and 1d encode the variable region for bilirubin UGT1*1 (also known as UGT1A1) and UGT1*2, respectively, with UGT1*1 responsible for virtually all bilirubin conjugation and UGT1*2 playing little, if any, role. Expression of UGT1*1 depends on a promoter region in a 5' position relative to each exon 1 that contains a TATAA box. Impaired bilirubin glucuronidation therefore may result from mutations in exon 1a, its promoter, or the common exons.

A breakthrough in understanding the genetic basis of Gilbert syndrome was achieved in 1995, when abnormalities in the TATAA region of the promoter were identified. The addition of 2 extra bases (TA) to the TATAA region interferes with binding of the transcription factor IID and results in reduced expression of bilirubin-UGT1 (30% of normal). In the homozygous state, diminished bilirubin glucuronidation is observed, with bile containing an excess of bilirubin monoglucuronide over diglucuronide. Additional mutations have since been identified. For example, some healthy Asian patients with Gilbert syndrome do not have mutations at the promoter level but are heterozygotes for missense mutations (Gly71Arg, Tyr486Asp, Pro364Leu) in the coding region. These individuals also have significantly higher bilirubin levels than those with the wild-type allele.

Whether reduced bilirubin-UGT activity results from a reduced number of enzyme molecules or from a qualitative enzyme defect is unknown. To compound this further, other factors, such as occult hemolysis or hepatic transport abnormalities, may be involved in the clinical expression of Gilbert syndrome. For example, many individuals homozygous for the TATAA defect do not demonstrate unconjugated hyperbilirubinemia, and patients with reduced levels of bilirubin-UGT, as observed in some granulomatous liver diseases, do not develop hyperbilirubinemia.

Because of the high frequency of mutations in the Gilbert promoter, heterozygous carriers of Crigler-Najjar syndromes types 1 and 2 can also carry the elongated Gilbert TATAA sequence on their normal allele. Such combined defects can lead to severe hyperbilirubinemia and also help explain the finding of intermediate levels of hyperbilirubinemia in family members of patients with Crigler-Najjar syndrome. Gilbert syndrome can also frequently coexist with the conditions associated with unconjugated hyperbilirubinemia, such as thalassemia and glucose-6-phosphate deficiency.

Frequency

United States

The rate of Gilbert syndrome in the United States is 3-7% of the population.

International

The worldwide prevalence of Gilbert syndrome varies considerably depending on which diagnostic criteria are used, such as number of bilirubin determinations, method of analysis, bilirubin levels used for diagnosis, and whether the patient was fasting. This may be complicated further by molecular genetic studies of polymorphisms in the TATAA promoter region, which affects as many as 36% of Africans but only 3% of Asians. The clinical phenotype may not be as apparent as the determined genotype because of environmental influences, such as alcohol-induced bilirubin glucuronidation, which can reduce bilirubin levels.

Mortality/Morbidity

Gilbert syndrome is a benign condition with no associated morbidity or mortality.

Race

Gilbert syndrome is not restricted to any ethnic group and occurs in persons of all races.

Sex

Population studies show that Gilbert syndrome occurs predominately in men, with a male-to-female ratio ranging from 2-7:1.

Age

Gilbert syndrome is usually diagnosed around puberty, possibly because of the inhibition of bilirubin glucuronidation by endogenous steroid hormones. In older persons, the diagnosis is usually made when unconjugated hyperbilirubinemia is noted on routine blood test results or unmasked by an intercurrent illness or stress.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

At least 30% of patients are asymptomatic, although nonspecific symptoms, such as abdominal cramps, fatigue, and malaise, are common. Abdominal symptoms in these patients are a poorly defined entity and may be secondary to underlying anxiety. However, not all patients with Gilbert syndrome and abdominal symptoms are anxious; nevertheless, they appear to have organic-type discomfort that is hard to characterize and frequently eludes diagnosis. No relationship exists between these abdominal symptoms and plasma bilirubin levels. Abdominal symptoms apparently may be multifactorial, with underlying anxiety probably playing an important role.

Physical

Mild jaundice is present intermittently in some individuals, but no other abnormal physical examination findings are evident. Infants homozygous for Gilbert syndrome may have a greater increase in neonatal jaundice when breastfed or when other disorders of heme metabolism are coinherited.

Causes

• Dehydration
• Fasting: This produces an increase in the plasma unconjugated bilirubin level.
• Intercurrent illness, such as a viral infection
• Menstrual periods
• Stress, such as trauma and overexertion

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hemolysis
Hematoma
Acute and chronic liver disease
Primary hyperbilirubinemia from ineffective erythropoiesis
Glucuronyl transferase deficiency
Infections
Cardiac disease (eg, congestive heart failure, prosthetic heart valves)
Rhabdomyolysis
High-altitude living
Medications (eg, probenecid, rifamycin, other antibiotics)
Thyrotoxicosis

As can be inferred from the above list, Gilbert syndrome has a broad differential diagnosis because causes of unconjugated hyperbilirubinemia must be considered.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count (including reticulocyte count and blood smear): This is a useful screening test to exclude hemolysis. Rarely, red blood cell abnormalities resembling variegate porphyria have been described in persons with Gilbert syndrome, possibly due to the increased hepatocellular bilirubin concentration.
• Lactate dehydrogenase: Levels are elevated in persons with hemolysis but are normal in those with Gilbert syndrome.
• Liver function tests: With the exception of unconjugated hyperbilirubinemia, standard liver function test results are normal. However, a familial increase in serum alkaline phosphatase levels has been reported in persons with Gilbert syndrome.

Imaging Studies

• Imaging studies are not required to confirm a diagnosis of Gilbert syndrome.

Other Tests

• Additional tests are rarely required because a diagnosis of Gilbert syndrome can be made in the presence of (1) unconjugated hyperbilirubinemia noted on several occasions; (2) normal results from CBC count, reticulocyte count, and blood smear; (3) normal liver function test results; and (4) an absence of other disease processes.
• The following investigations are occasionally performed to confirm a diagnosis of Gilbert syndrome. Those of historical interest, as well as the newer molecular genetic techniques, are included. They are described to introduce the clinician to the broad diagnostic armamentarium available for diagnosing Gilbert syndrome. Recourse to these specialized tests should be rare and is usually difficult to justify in clinical practice because the diagnosis of Gilbert syndrome is usually straightforward.
• • Fasting: This usually results in a 2- to 3-fold rise in the plasma unconjugated bilirubin level within 48 hours of a fast that returns to normal levels within 24 hours of resuming a normal diet. Although unconjugated bilirubin levels also rise with fasting in patients with hemolysis or liver disease, the magnitude of the rise is less than that observed with Gilbert syndrome. A similar rise in plasma bilirubin is also observed with normocaloric diets deficient in lipids and reverses promptly with lipid replacement. The precise mechanism of fasting and dietary-induced hyperbilirubinemia remains unclear. The fasting test remains of historic interest and has limited usefulness in the diagnosis of Gilbert syndrome.
  • Nicotinic acid: Intravenous administration of 50 mg of nicotinic acid results in a 2- to 3-fold rise in plasma unconjugated hyperbilirubinemia within 3 hours. The mechanisms are multifactorial and probably related to (1) elevated osmotic fragility of red blood cells, (2) increase in splenic production of bilirubin, (3) transient inhibition of hepatic bilirubin-UGT activity, and (4) increased splenic heme oxygenase activity. Although a similar but less impressive increase is observed in healthy individuals and those with hemolysis or liver disease, the nicotinic test, similar to fasting, does not clearly distinguish patients with Gilbert syndrome from those who are healthy or who have other disease processes.
  • Phenobarbital: Phenobarbital and other enzyme inducers of the bilirubin-UGT system will normalize plasma bilirubin in patients with Gilbert syndrome. This is predominantly due to accelerated bilirubin clearance from enzyme induction but is also due to reduced bilirubin turnover. Steroids can also reduce plasma bilirubin levels in Gilbert syndrome by increasing hepatic uptake and storage of bilirubin.
  • Radioactive-labeled chromium: This is used to measure red blood cell survival. As many as 60% of patients with Gilbert syndrome have a mild and fully compensated state of hemolysis together with increased hepatic heme production. As a result, hyperbilirubinemia may be due to reduced bilirubin clearance and increased production, the latter from increased erythroid or hepatic heme turnover.
  • Thin-layer chromatography: This test is diagnostic for Gilbert syndrome when it shows a significantly higher proportion of unconjugated bilirubin compared with individuals with chronic hemolysis or liver disease or those who are healthy. If confirmation of the diagnosis is truly essential, chromatographic determination is of potential use. This shows an increased ratio of bilirubin monoglucuronide to diglucuronide, reflecting reduced bilirubin-UGT activity.
  • Drug clearance: Approximately 30% of patients have impaired clearance of bromosulfophthalein, indocyanine green, and free fatty acid, suggesting an abnormality in hepatic uptake, transport, or both. The metabolic clearance of tolbutamide is also reduced in persons with Gilbert syndrome, but, because it does not undergo glucuronidation, hepatic uptake appears to be defective. Plasma clearance of most drugs that undergo glucuronidation (eg, benzodiazepines) is unaffected. However, with regard to acetaminophen, patients with Gilbert syndrome are a heterogeneous group, with some demonstrating normal metabolism and others exhibiting marked reduction in glucuronidation and an increase in oxidation. These changes could mean that people in this subgroup could be more susceptible to liver injury after an acetaminophen overdose, although no such adverse events have been reported.
  • Polymerase chain reaction: Polymerase chain reaction is a novel and rapid method of identifying genetic polymorphisms in the TATA box of the UGT1*1 gene using fluorescence resonance energy transfer.

Procedures

• Liver biopsies are not performed routinely and are rarely necessary.

Histologic Findings

The liver is normal histologically, except for occasional accumulation of a lipofuscinlike pigment around the terminal hepatic venules.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

The most important aspect of treatment once the diagnosis is established is reassurance. Patients with Gilbert syndrome should be informed of its benign nature and that hyperbilirubinemia is not associated with increased morbidity. It has an excellent prognosis and is associated with normal life expectancy, which must be made perfectly clear to the patient.

Diet

Diet is normal.

Activity

No activity restrictions are necessary.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care is not required.

In/Out Patient Meds

• Various medications have been used experimentally to reduce the hyperbilirubinemia of Gilbert syndrome. For example, phenobarbital and glutethimide activate hepatic bilirubin-UGT activity, while tin-protoporphyrin inhibits heme oxygenase to reduce bilirubin levels.
• In light of the benign and inconsequential nature of this condition, the use of medications in patients with Gilbert syndrome is unjustified in clinical practice.

Deterrence/Prevention

• Avoid known risk factors for precipitating hyperbilirubinemia (eg, dehydration, fasting).

Prognosis

• Gilbert syndrome is a common and benign condition. The bilirubin disposition may be regarded as falling within the range of normal biological variation. It has no deleterious associations and an excellent prognosis, and those who have it can lead a normal lifestyle. This is further confirmed by studies that report excellent results in patients undergoing living donor liver transplantation from donors with Gilbert syndrome.

Patient Education

• Patients should be warned that they might develop jaundice if they miss meals, become dehydrated, develop an infection (eg, viral infection), or undergo stress.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Gilbert syndrome can be diagnosed by a thorough history and physical examination and confirmed by standard blood tests. Repeated investigations and invasive procedures are not usually justified for establishing a diagnosis. Studies can be conducted within the realms of an institutional review board–approved study.
• The clinical relevance of pharmacogenetics in Gilbert syndrome is yet to be determined. Although impaired glucuronidation and excretion of certain drugs has been reported, this has not resulted in any adverse clinical events, and the risk probably remains more theoretical than real.
• Irinotecan toxicity in Gilbert syndrome is of some concern. Affected patients have reduced inactivation of the active topoisomerase inhibitor 7-ethyl-10-hydroxycampothecin (SN-38) caused by a mutation in the UDT-1*1 gene promoter. Glucuronidation rates of the active metabolite SN-38 are significantly lower in people who are homozygous and heterozygous for the TA-TATAA variant allele compared with the wild-type genotype (TATAA). In Gunn rats (an animal model of Crigler-Najjar syndrome) and in people with Gilbert or Crigler-Najjar syndrome, reduced glucuronidation of SN-38 leads to SN-38 toxicity and causes symptoms such as diarrhea. Preliminary results from clinical trials suggest that screening cancer patients for the UGT1*1 promoter polymorphism may reduce the prevalence of irinotecan toxicity, and, until this evidence is available, caution is warranted before prescribing irinotecan in this subset of patients.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 15, 2008