INTRODUCTION — Gilbert syndrome (Meulengracht disease, constitutional hepatic dysfunction, and familial nonhemolytic jaundice) is a benign condition characterized by recurrent episodes of jaundice [1,2]. Other than jaundice, patients are typically asymptomatic. The hyperbilirubinemia in patients with Gilbert syndrome is unconjugated. Many patients present as isolated cases but the condition can also run in families. Exacerbations may be triggered by dehydration, fasting, intercurrent disease, menstruation, and overexertion [3]. No treatment is necessary, but it can increase the risk of toxicity from some medications, such as irinotecan.
This topic will review the epidemiology, clinical manifestations, diagnosis and management of Gilbert syndrome. Crigler-Najjar syndromes type I and II, neonatal jaundice, and the evaluation of patients with jaundice are discussed separately. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis", section on 'Gilbert syndrome' and "Crigler-Najjar syndrome" and "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia" and "Evaluation of jaundice caused by unconjugated hyperbilirubinemia in children".)
EPIDEMIOLOGY — Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation, with an estimated prevalence of 6 to 14 percent [4-8]. Patients typically present during adolescence when alterations in sex steroid concentrations affect bilirubin metabolism, leading to increased plasma bilirubin concentrations [9]. As a result, it is rarely diagnosed prior to puberty. The disorder is more commonly diagnosed in males, possibly due to a relatively higher level of daily bilirubin production [9].
GENETICS — The genetic defect in patients with Gilbert syndrome involves the promotor region of uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene. Uridine diphosphoglucuronate-glucuronosyltransferases (UGTs) are a family of enzymes that mediate glucuronidation of various endogenous and exogenous compounds. The UGT1A gene that encodes the enzyme UGT1A1 is responsible for the conjugation of bilirubin with glucuronic acid, converting the bilirubin into a water-soluble form that is readily excreted in bile (figure 1). (See "Bilirubin metabolism".)
Gilbert syndrome is an autosomal recessive disorder and manifests in people who are homozygous for the variant promoter (table 1). However, heterozygotes for the Gilbert genotype have higher average plasma bilirubin concentrations compared with those with two wild-type alleles [10].
Characterization of the UGT1A1 gene locus has permitted an understanding of the molecular defects responsible for Gilbert syndrome. The pathogenic variant responsible for Gilbert syndrome is in the promoter region, upstream to exon 1 of UGT1A1 [10]. The normal sequence of the TATAA element within the promoter is A[TA]6TAA. Patients with Gilbert syndrome are homozygous for a longer version of the TATAA sequence, A[TA]7TAA, which causes reduced production of bilirubin-UGT (figure 2). This variant is termed UGT1A1*28. The defect in Gilbert syndrome is different from that in the Crigler-Najjar syndromes, in which bilirubin-UGT is either absent or produced in an abnormal form with reduced or no activity. (See "Crigler-Najjar syndrome".)
The longer TATAA element has been found in all subjects with Gilbert syndrome studied in the United States, Europe, and countries of the Middle East and South Asia. However, other factors are probably involved in the expression of the Gilbert phenotype since not all patients who are homozygous for the variant promoter develop hyperbilirubinemia [10]. Furthermore, in the Japanese population, other variants within the coding regions of UGT1A1 can cause the Gilbert phenotype [11,12].
Because of the high frequency of the Gilbert type promoter, some heterozygous carriers of pathogenic variants that cause Crigler-Najjar syndrome type also carry the Gilbert type of TATAA element on their normal allele. Such combined defects can lead to severe hyperbilirubinemia, occasionally causing kernicterus [13,14]. This also explains the frequent finding of intermediate levels of hyperbilirubinemia in the family members of patients with Crigler-Najjar syndrome. (See "Crigler-Najjar syndrome".)
CLINICAL MANIFESTATIONS
Clinical presentation — Patients with Gilbert syndrome typically present with episodes of mild intermittent jaundice due to predominantly unconjugated hyperbilirubinemia. Symptoms usually first appear during adolescence, when alterations in sex steroid concentrations alter bilirubin metabolism, leading to increased plasma bilirubin concentrations [9]. Other than intermittent episodes of mild jaundice, patients are typically asymptomatic, though some will have nonspecific complaints, such as malaise, abdominal discomfort, or fatigue, of uncertain relation to the elevated plasma bilirubin concentration [15].
The physical examination in a patient with Gilbert syndrome is often normal because bilirubin levels are often below the levels needed to result in jaundice. During an episode of jaundice, the examination will be notable for scleral icterus.
Laboratory findings — Routine laboratory tests are usually normal in patients with Gilbert syndrome, except for unconjugated hyperbilirubinemia (table 1). Serum bilirubin levels fluctuate; they are usually less than 4 mg/dL and can be normal. The conjugated bilirubin is typically less than 20 percent of the total bilirubin fraction.
Exacerbating factors — Certain associated pathologic conditions or physiologic events can increase the plasma bilirubin concentrations to higher values, but usually less than 6 mg/dL.
Episodes of jaundice in patients with Gilbert syndrome can be triggered by events that lead to increased bilirubin production, such as [3,16]:
●Fasting
●Hemolysis
●Intercurrent febrile illnesses
●Physical exertion
●Stress
●Menses
Reducing total daily caloric intake to 400 kcal results in a two- to threefold increase in the plasma bilirubin concentration within 48 hours [17,18]. A similar rise in bilirubin occurs in patients with Gilbert syndrome who receive a normocaloric diet without lipids [19]. The bilirubin concentration returns to baseline within 12 to 24 hours after resuming a normal diet. The cause of hyperbilirubinemia during fasting is probably multifactorial. Several causes have been hypothesized to contribute, including an increased bilirubin load due to the release of bilirubin contained within adipocytes, decreased conjugation due to depletion of UDP-glucuronic acid (which serves as a co-substrate in glucuronidation), and enhanced cycling of bilirubin by the enterohepatic circulation [20-23]. Intercurrent febrile illnesses, physical exertion, and stress probably cause hyperbilirubinemia by the same mechanisms as fasting [17].
DIAGNOSTIC EVALUATION
Diagnosis — Gilbert syndrome should be suspected in individuals with mild unconjugated hyperbilirubinemia possibly provoked by factors such as dehydration, fasting, intercurrent disease, menstruation, or overexertion, and no apparent liver disease or hemolysis. A presumptive diagnosis can be made in patients with the following features [24-27]:
●Unconjugated hyperbilirubinemia (<4 mg/dL) on repeated testing
●A normal complete blood count, blood smear, and reticulocyte count
●Normal plasma aminotransferases and alkaline phosphatase concentrations
The diagnosis is definitive in patients who continue to have normal laboratory studies (other than the elevation in plasma bilirubin) during the next 12 to 18 months. Genetic testing can confirm the diagnosis in settings where there is diagnostic confusion [4]. It is available at some clinical laboratories.
There is no role for liver biopsy in the diagnosis of Gilbert syndrome. Histopathologically, the liver is normal except for nonspecific accumulation of lipofuscin pigment in the centrilobular zones [28]. Minor abnormalities may be seen by electron microscopy.
Provocative tests are not performed in clinical practice. Examples of provocative tests that can support the diagnosis of Gilbert syndrome include a rise in the plasma bilirubin concentration following a low lipid, 400 kcal diet or within three hours of administration of intravenous nicotinic acid [21,29-31].
Differential diagnosis — The differential diagnosis of Gilbert syndrome includes disorders associated with an isolated increase in unconjugated bilirubin alone. The initial evaluation of a patient with isolated unconjugated hyperbilirubinemia includes an assessment for hemolytic anemia and discontinuation of medications (eg, rifampin and probenecid) that impair hepatic uptake of bilirubin. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)
Patients with Gilbert syndrome may also have coexisting conditions that may cause higher levels of unconjugated hyperbilirubinemia (eg, Crigler-Najjar-type structural mutation, a disorder that causes hemolysis) [32-34]. However, these patients have higher levels of hyperbilirubinemia (>4 mg/dL).
Complex clinical disorders such as hepatitis or cirrhosis can affect multiple processes, resulting in elevation of liver tests and the accumulation of both unconjugated and conjugated bilirubin. In these settings, the proportion of conjugated bilirubin in plasma increases. In contrast, the unconjugated fraction alone is increased in patients with Gilbert syndrome.
MANAGEMENT
Patient education and reassurance — No specific therapy is required for patients with Gilbert syndrome. Patients should be educated about avoiding exacerbating conditions and an increased risk of toxicity with specific medications. As Gilbert syndrome is a hereditary condition with incomplete penetrance, patients should inform family members to prevent unnecessary diagnostic testing. (See 'Genetics' above.)
Important considerations with medications — Administration of corticosteroids, which increase hepatic uptake of bilirubin, or administration of hepatic enzyme inducers (such as phenobarbital and clofibrate), normalize plasma bilirubin concentrations within one to two weeks [35-37].
●Medications requiring bilirubin-UGT mediated glucuronidation
•Irinotecan toxicity – Gilbert syndrome is known to increase the risk of toxicity with irinotecan. The active metabolite of irinotecan, SN-38, is glucuronidated in the liver mainly by bilirubin-uridine diphosphoglucuronate-glucuronosyltransferase (UGT). The major dose-limiting toxicity is diarrhea, and in patients who inherit certain UGT1A1 polymorphisms, reduced glucuronidation of SN-38 leads to an increased incidence of diarrhea and neutropenia, which may be severe [38,39]. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Treatment-related toxicity'.)
•Other medications – The effect of Gilbert syndrome on other drugs that require bilirubin-UGT-mediated hepatic glucuronidation is less clear. As an example, acetaminophen and tolbutamide require bilirubin-UGT-mediated hepatic glucuronidation, but it is unclear if alterations in glucuronidation of these drugs has clinical significance, and avoiding these drugs in patients with Gilbert syndrome is not recommended [40,41]. Theoretically, diminished excretion of these drugs could potentially cause their accumulation and increase toxic effects. Studies based on intravenous administration of acetaminophen found reduced glucuronidation of the drug in subjects with Gilbert syndrome [40]. However, no such correlation was found after oral administration [42,43].
●Isolated hyperbilirubinemia with drugs that inhibit bilirubin-UGT activity – Several medications can induce hyperbilirubinemia in patients with Gilbert syndrome by inhibiting bilirubin-UGT activity. Hyperbilirubinemia resolves rapidly once therapy is stopped, however, discontinuation of treatment is not necessary [44]. Examples include atazanavir, an antiretroviral medication [45], ribavirin [46], pazopanib, sunitinib [47,48], and lenalidomide [49].
NATURAL HISTORY
Long-term complications — Gilbert syndrome has been associated with an increased risk of cholelithiasis in adults and children [50,51]. Coinheritance of disorders that predispose to hemolysis, such as hereditary spherocytosis, thalassemia major, and sickle cell disease, may further increase that risk [52-54]. (See "Hepatic manifestations of sickle cell disease", section on 'Cholelithiasis' and "Diagnosis of thalassemia (adults and children)", section on 'Jaundice and pigment gallstones' and "Hereditary spherocytosis", section on 'Pigment gallstones'.)
Prognosis — Several studies have suggested that mildly increased serum bilirubin levels, such as those associated with Gilbert syndrome, may be beneficial because of the antioxidative, anti-inflammatory, and metabolic effects of bilirubin. Patients with Gilbert syndrome may have a lower incidence of atherosclerotic heart disease, lung and colon cancer [3,40,42,55,56].
In patients with diabetes mellitus type 2, visceral fat and insulin resistance was inversely related to serum bilirubin levels [57]. The beneficial effect is not specific for the UGT1A1*28 genotype but is related directly to serum bilirubin levels [58]. In one population-based cohort study, all all-cause mortality was markedly reduced in individuals with hyperbilirubinemia with Gilbert syndrome as compared with individuals without Gilbert syndrome [59].
A report of increased breast cancer risk in subjects with Gilbert syndrome [60] has not been confirmed in larger studies [61].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited liver disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Gilbert syndrome (The Basics)")
●Beyond the Basics topic (see "Patient education: Gilbert syndrome (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation, with a prevalence of up to14 percent. (See 'Epidemiology' above.)
●Genetics – Gilbert syndrome is the result of a defect in the promotor of the gene that encodes the enzyme uridine diphosphoglucuronate-glucuronosyltransferase 1A1, which is responsible for the conjugation of bilirubin with glucuronic acid, converting bilirubin into a water-soluble form that is readily excreted in bile. (See 'Genetics' above.)
●Clinical manifestations – With the exception of intermittent episode of jaundice, most patients with Gilbert syndrome are asymptomatic and have normal physical examination findings. (See 'Clinical manifestations' above.)
●Laboratory findings and exacerbating factors – Laboratory testing reveals unconjugated hyperbilirubinemia, with total bilirubin levels that are usually less than 4 mg/dL, though in the setting of exacerbating factors, the levels may be higher but are usually <6 mg/dL. (See 'Laboratory findings' above and 'Exacerbating factors' above.)
●Diagnosis – A presumptive diagnosis of Gilbert syndrome may be made in patients with the following features:
•Unconjugated hyperbilirubinemia (<4 mg/dL) on repeated testing
•A normal complete blood count, blood smear, and reticulocyte count
•Normal plasma aminotransferases and alkaline phosphatase concentrations
The diagnosis is definitive in patients who continue to have normal laboratory studies (other than the elevation in plasma bilirubin) during the next 12 to 18 months. (See 'Diagnostic evaluation' above.)
●Management – No specific therapy is required for patients with Gilbert syndrome. Patients should be educated about avoiding exacerbating conditions and an increased risk of toxicity with specific medications. Patients should also inform family members to prevent unnecessary diagnostic testing. (See 'Management' above and 'Important considerations with medications' above and 'Genetics' above.)
●Natural history – Patients with Gilbert syndrome are at increased risk for gallstones, although the magnitude of this risk is unclear. Patients with Gilbert syndrome may have a lower risk of atherosclerotic heart disease, colon and lung cancer, and low mortality rates as compared with the general population. (See 'Natural history' above.)
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