INTRODUCTION	Section 2 of 9
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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.

Presently, 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:

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

• Internationally: 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 recent 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
Author Information Introduction Clinical Differentials Workup Treatment Follow-up Miscellaneous Bibliography

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