Gilbert Syndrome and Unconjugated Hyperbilirubinemia Due To Bilirubin Overproduction - UpToDate

22/5/23, 17:54 Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction - UpToDate
Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Gilbert syndrome and unconjugated hyperbilirubinemia

due to bilirubin overproduction
AUTHORS: Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD, Namita Roy-Chowdhury, PhD, FAASLD, Xia Wang, MD, PhD
SECTION EDITOR: Keith D Lindor, MD
DEPUTY EDITOR: Shilpa Grover, MD, MPH, AGAF
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2023.

This topic last updated: Jul 28, 2022.
INTRODUCTION
The metabolism of bilirubin by the liver is comprised of four distinct but interrelated stages
(see "Bilirubin metabolism"):
● Uptake from the circulation

● Intracellular storage
● Conjugation with glucuronic acid
● Biliary excretion
Normally, approximately 96 percent of plasma bilirubin is unconjugated. Abnormalities in any

of the above steps can result in hyperbilirubinemia in which there is either an elevation in
unconjugated bilirubin alone or of both unconjugated (indirect) and conjugated (direct)
bilirubin. Complex clinical disorders such as hepatitis or cirrhosis can affect multiple
processes, resulting in the accumulation of both unconjugated and conjugated bilirubin. In
these settings, the proportion of conjugated bilirubin in plasma increases. By contrast, the
unconjugated fraction alone is increased when there is bilirubin overproduction (as with
hemolysis) without liver disease or in the setting of inherited or acquired disorders that
impair bilirubin uptake or glucuronidation. (See "Classification and causes of jaundice or
asymptomatic hyperbilirubinemia".)
The most common causes of unconjugated hyperbilirubinemia are bilirubin overproduction,

Gilbert syndrome, and neonatal jaundice. This topic will review the first two disorders with an
emphasis on Gilbert syndrome. Crigler-Najjar syndromes type I and II (rare inherited diseases
associated with unconjugated hyperbilirubinemia), neonatal jaundice, and the evaluation of
https://www.uptodate.com/contents/gilbert-syndrome-and-unconjugated-hyperbilirubinemia-due-to-bilirubin-overproduction/print?search=HIPER… 1/22
patients with jaundice are discussed separately. (See "Crigler-Najjar syndrome" and "Etiology
and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Diagnostic approach
to the adult with jaundice or asymptomatic hyperbilirubinemia" and "Evaluation of jaundice
caused by unconjugated hyperbilirubinemia in children".)
REFERENCE RANGES
Liver test reference ranges will vary from laboratory to laboratory. As an example, one
hospital's normal reference ranges for adults are as follows [1]:
● Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)
● Alkaline phosphatase:
• Male: 45 to 115 int. unit/L
• Female: 30 to 100 int. unit/L
● Alanine aminotransferase (ALT):
● Aspartate aminotransferase (AST):
● Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)
● Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)
● Gamma-glutamyl transpeptidase (GGT):
● Prothrombin time (PT): 11.0 to 13.7 seconds
BILIRUBIN OVERPRODUCTION
Most disorders associated with bilirubin overproduction cause hemolysis. Transient elevation
of the unconjugated form of bilirubin can also occur during absorption of large hematomas.
The breakdown of hemoglobin results in the production of bilirubin. In order to be excreted
in bile, bilirubin needs to be made water soluble, which is achieved by conjugating it to
glucuronic acid. In the setting of bilirubin overproduction, the liver’s ability to conjugate the
bilirubin is overwhelmed, leading to unconjugated hyperbilirubinemia. (See "Bilirubin
metabolism".)
In the setting of hemolysis, the plasma bilirubin concentration rarely exceeds 3 to 4 mg/dL.
Although a small amount of conjugated bilirubin can accumulate in the serum, the
proportion of the conjugated form stays within the normal limits (about 4 percent of total
bilirubin) [2-4]. Higher levels may be seen when coexisting abnormalities of hepatobiliary
function are present [2]. Of note, the laboratory techniques used to determine the "direct"
and "indirect" fractions of bilirubin overestimate the true proportion of conjugated bilirubin.
(See "Clinical aspects of serum bilirubin determination", section on 'Measurement of serum
bilirubin'.)
Examples of disorders associated with hemolysis include ( table 1):
● Diseases associated with abnormal red cell morphology leading to their premature
destruction (eg, sickle cell anemia and hereditary spherocytosis)
● Mechanical hemolysis (eg, thrombotic thrombocytopenic purpura/hemolytic-uremic

syndrome)
● Autoimmune hemolytic anemia due to warm or cold agglutinins
● Toxic or idiosyncratic disorders (eg, drug toxicity)
● Diseases associated with ineffective erythropoiesis leading to destruction of red cell

precursors in the bone marrow (eg, thalassemia minor)
● Rare inherited anemias termed "congenital dyserythropoietic anemias" that are

associated with ineffective erythropoiesis, intramedullary normoblastic hyperplasia, and
secondary hemochromatosis
The approach to patients with hemolytic anemia is discussed in detail elsewhere.
GILBERT SYNDROME
The most common inherited disorder of bilirubin glucuronidation is Gilbert syndrome (also
known as Meulengracht disease). Gilbert syndrome is a benign condition that has also been
called "constitutional hepatic dysfunction" and "familial nonhemolytic jaundice" [5]. Although
many patients present as isolated cases, the condition can also run in families [6]. It is
characterized by recurrent episodes of jaundice and may be triggered by, among other
things, dehydration, fasting, intercurrent disease, menstruation, and overexertion [7]. Other
than jaundice, patients are typically asymptomatic. The hyperbilirubinemia in patients with
Gilbert syndrome is unconjugated. The diagnosis is made by excluding other causes of
unconjugated hyperbilirubinemia, though genetic testing is available. No treatment is
necessary, though it may be a risk factor for toxicity from some medications, such as
irinotecan.
Epidemiology — The prevalence of Gilbert syndrome has been reported to be between 4 and
16 percent in different populations [8-16]. Patients typically present during adolescence when
alterations in sex steroid concentrations affect bilirubin metabolism, leading to increased
plasma bilirubin concentrations [17]. 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 [17].
Pathogenesis — Gilbert syndrome is the result of a defect in the promotor of the gene that
encodes the enzyme uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1),
which is responsible for the conjugation of bilirubin with glucuronic acid.
Impaired bilirubin glucuronidation — Uridine diphosphoglucuronate (UDP)-

glucuronosyltransferases (UGTs) are a family of enzymes that mediate glucuronidation of
various endogenous and exogenous compounds ( figure 1). Bilirubin-UGT (UGT1A1)
conjugates bilirubin to glucuronic acid, converting the bilirubin into a water-soluble form that
is readily excreted in bile. Patients with Gilbert syndrome have a mutation in UGT1A1, the
gene that encodes bilirubin-UGT. (See "Bilirubin metabolism" and 'Genetic defect' below.)
Specialized tests can demonstrate a number of abnormalities in hepatic function including:
● A reduction in hepatic bilirubin-UGT activity, which is approximately 30 percent of

normal [18,19]
● A 14 to 34 percent increase in the proportion of monoconjugated bile pigments, which

normally represent only 7 to 10 percent of the total bile pigments [20]
Increased bilirubin production — Episodes of jaundice in patients with Gilbert syndrome

can be triggered by events that lead to increased bilirubin production, such as [7,21]:
● 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 [22,23]. A similar rise in bilirubin occurs in
patients with Gilbert syndrome who receive a normocaloric diet without lipids [24]. 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-
glycuronic acid (which serves as a cosubstrate in glucuronidation), and enhanced cycling of
bilirubin by the enterohepatic circulation [25-28].
Intercurrent febrile illnesses, physical exertion, and stress probably cause hyperbilirubinemia
by the same mechanisms as fasting [22].
Genetic defect — The genetic defect in patients with Gilbert syndrome involves the
promotor region of UGT1A1. Gilbert syndrome manifests only in people who are homozygous
for the variant promoter. As a result, its inheritance is most consistent with an autosomal
recessive trait ( table 2). However, heterozygotes for the Gilbert genotype have higher
average plasma bilirubin concentrations compared with those with two wild-type alleles [8]. It
is estimated that 9 percent of individuals of the general population in the Western world are
homozygous for the variant promoter, and up to 42 percent are heterozygous.
Characterization of the UGT1A gene locus has permitted an understanding of the molecular
defects responsible for Gilbert syndrome. The mutation responsible for Gilbert syndrome is in
the promoter region, upstream to exon 1 of UGT1A1 [8]. 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 [8]. Furthermore,
in the Japanese population, other mutations within the coding regions of UGT1A1 can cause
the Gilbert phenotype [29,30].
Because of the high frequency of the Gilbert type promoter, some heterozygous carriers of
structural mutations 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 [31,32]. 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".)
Histology — Histopathologically, the liver is normal except for nonspecific accumulation of

lipofuscin pigment in the centrilobular zones [33]. Minor abnormalities may be seen by
electron microscopy.
Clinical manifestations — With the exception of intermittent episodes of jaundice, most

patients with Gilbert syndrome are asymptomatic and have normal physical examination
findings. Laboratory testing reveals unconjugated hyperbilirubinemia, with total bilirubin
levels that are usually less than 3 mg/dL, though in the setting of increased bilirubin
production, the levels may be higher. (See 'Increased bilirubin production' above.)
Symptoms — Patients with Gilbert syndrome typically present with episodes of mild
intermittent jaundice due to predominantly unconjugated hyperbilirubinemia. Patients are
asymptomatic between episodes. Symptoms usually first appear during adolescence, when
alterations in sex steroid concentrations alter bilirubin metabolism, leading to increased
plasma bilirubin concentrations [17]. 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 [34].
Physical examination findings — 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 tests — Routine laboratory tests are usually normal in patients with Gilbert
syndrome, except for unconjugated hyperbilirubinemia ( table 2). Serum bilirubin levels
fluctuate; they are usually less than 3 mg/dL and can be normal. Certain associated
pathologic conditions or physiologic events can increase the plasma bilirubin concentrations
to higher values, but usually less than 6 mg/dL. (See 'Increased bilirubin production' above.)
Case reports have described patients with Gilbert syndrome who developed severe
unconjugated hyperbilirubinemia. Such patients typically have an additional mutation in the
UGT1A1 promoter, are heterozygous carriers of a Crigler-Najjar-type structural mutation, or
have a coexisting condition that predisposes to hyperbilirubinemia (eg, a disorder that causes
hemolysis) [35]. A report of two such patients (one with hereditary spherocytosis and another
with an additional mutation in UGT1A1) described successful treatment of the
hyperbilirubinemia with rifampicin, which acts by induction of UGT1A1 [35].
There are settings in which plasma bilirubin concentrations are reduced in patients with
Gilbert syndrome. These include the administration of corticosteroids, which increase hepatic
uptake of bilirubin, or administration of hepatic enzyme inducers (such as phenobarbital and
clofibrate), which normalize plasma bilirubin concentrations within one to two weeks [36-38].
Mild hemolysis without anemia has been detected in up to 40 percent of patients with Gilbert
syndrome when sensitive measures of red cell survival have been used [39,40]. This
observation is likely due to increased bilirubin production from hemolysis, which accentuates
the jaundice and brings Gilbert patients to medical attention.
Drug interactions — Since bilirubin-UGT is involved in the glucuronidation of estrogen and

several important drugs and carcinogens, individuals with Gilbert syndrome may be more
susceptible to the toxic effect of substances that require bilirubin-UGT-mediated hepatic
glucuronidation prior to excretion. Gilbert syndrome is known to increase the risk of toxicity
with irinotecan. The effect of Gilbert syndrome on other drugs that require bilirubin-UGT-
mediated hepatic glucuronidation is less clear.
The active metabolite of irinotecan, SN-38, is glucuronidated in the liver mainly by bilirubin-
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 [41,42]. (See "Systemic therapy for
nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section
on 'Treatment-related toxicity'.)
Two other drugs that require bilirubin-UGT-mediated hepatic glucuronidation are

acetaminophen and tolbutamide, although it is unclear if alterations in glucuronidation of
these drugs has clinical significance, and avoiding these drugs in patients with Gilbert
syndrome is not currently recommended [43,44]. 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 [43], but no such correlation was found after oral
administration [45,46].
Some drugs may induce hyperbilirubinemia in patients with Gilbert syndrome. Atazanavir, an
antiretroviral medication, is an inhibitor of bilirubin-UGT activity and is associated with
hyperbilirubinemia [47]. Isolated hyperbilirubinemia has also been reported during the
treatment of hepatitis C with peginterferon and ribavirin [48] and in patients receiving
pazopanib [49]. In such cases, it is not necessary to discontinue the therapy.
Cholelithiasis — Gilbert syndrome has been associated with an increased risk of

cholelithiasis in adults and children. This may be particularly important in patients with other
disorders that predispose to hemolysis such as hereditary spherocytosis, thalassemia major,
and sickle cell disease [50-52]. (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'.)
Neonatal jaundice — Breast milk jaundice during the second week after birth may be due
to the concurrent neonatal manifestation of Gilbert syndrome. (See "Etiology and
pathogenesis of neonatal unconjugated hyperbilirubinemia", section on 'Gilbert syndrome'.)
Diagnosis — The most important aspect of the diagnosis of Gilbert syndrome is recognizing
the disorder without subjecting patients to invasive and unnecessary testing. The diagnosis
has traditionally been established based on mild unconjugated hyperbilirubinemia (possibly
provoked by factors such as dehydration, fasting, intercurrent disease, menstruation, or
overexertion) in patients with no apparent liver disease or hemolysis.
A presumptive diagnosis can be made in patients with the following features [53-56]:
● Unconjugated hyperbilirubinemia 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.
The diagnosis is supported by observing a rise in the plasma bilirubin concentration following
a low lipid, 400 kcal diet. Another provocative test is to administer intravenous nicotinic acid,
which causes hyperbilirubinemia within three hours (possibly because of an increase in
bilirubin formation in the spleen and enhanced uptake by the liver) [26,57-59]. However,
these provocative tests are seldom necessary in clinical practice.
Genetic testing can confirm the diagnosis in settings where there is diagnostic confusion [9].
It is currently available at some clinical laboratories.
Treatment — No specific therapy is required for patients with Gilbert syndrome. The most
important aspect of the care of these patients is recognition of the disorder and its
inconsequential nature, except for an increased incidence of side effects from certain drugs
such as irinotecan. Its mode of inheritance should also be discussed to prevent unnecessary
testing in family members.
Prognosis — Long-term outcomes in patients with Gilbert syndrome are similar to those in
the general population. However, the Gilbert genotype is associated with increased severity
and duration of neonatal jaundice [16,60]. (See "Etiology and pathogenesis of neonatal
unconjugated hyperbilirubinemia", section on 'Gilbert syndrome'.)
Several studies have suggested that mildly increased serum bilirubin levels, such as those
associated with Gilbert syndrome, may be beneficial because of the antioxidative,
antiinflammatory, and metabolic effects of bilirubin. Patients with Gilbert syndrome may
have a lower incidence of atherosclerotic heart disease, endometrial cancer, Hodgkin
lymphoma, and cancer-related mortality [7,43,45]. Furthermore, overweight children
developing nonalcoholic fatty liver disease (NAFLD) were found to have lower mean serum
bilirubin levels than those who did not develop NAFLD [61]. In patients with diabetes mellitus
type 2, visceral fat and insulin resistance was inversely related to serum bilirubin levels [62].
The beneficial effect is not specific for the UGT1A1*28 genotype but is related directly to
serum bilirubin levels [63]. A report of increased breast cancer risk in subjects with Gilbert
syndrome [64] was not confirmed in larger studies [65]. Interestingly, risk of death from all
causes was found to be markedly reduced in subjects with mild hyperbilirubinemia and a
clinical diagnosis of Gilbert syndrome [66].
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 topics (see "Patient education: Gilbert syndrome (The Basics)")
● Beyond the Basics topics (see "Patient education: Gilbert syndrome (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● Bilirubin metabolism – Normally, approximately 96 percent of plasma bilirubin is

unconjugated. Abnormalities in any of the steps involved with bilirubin metabolism can
result in hyperbilirubinemia. The metabolism of bilirubin by the liver is comprised of
four distinct but interrelated stages (see "Bilirubin metabolism"):
• Uptake from the circulation
• Intracellular storage
• Conjugation with glucuronic acid
• Biliary excretion
● Bilirubin overproduction – Most disorders associated with bilirubin overproduction

cause hemolysis ( table 1). The breakdown of hemoglobin results in the production of
bilirubin. In order to be excreted in bile, bilirubin needs to be made water soluble, which
is achieved by conjugating it to glucuronic acid. In the setting of bilirubin
overproduction, the liver's ability to conjugate the bilirubin is overwhelmed, leading to
unconjugated hyperbilirubinemia. (See 'Bilirubin overproduction' above.)
● Gilbert syndrome
• Pathogenesis – Gilbert syndrome is the most common inherited disorder of bilirubin

glucuronidation and is characterized by recurrent episodes of jaundice due to
unconjugated hyperbilirubinemia ( table 2). 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. (See 'Gilbert syndrome' above and
'Pathogenesis' 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 – Laboratory testing reveals unconjugated hyperbilirubinemia,

with total bilirubin levels that are usually less than 3 mg/dL, though in the setting of
increased bilirubin production the levels may be higher. (See 'Laboratory tests' above
and 'Increased bilirubin production' above.)
• Diagnosis – A presumptive diagnosis of Gilbert syndrome may be made in patients

with unconjugated hyperbilirubinemia on repeated testing who have a normal
https://www.uptodate.com/contents/gilbert-syndrome-and-unconjugated-hyperbilirubinemia-due-to-bilirubin-overproduction/print?search=HIPE… 10/22
complete blood count, blood smear, reticulocyte count, plasma aminotransferase

concentrations, and alkaline phosphatase concentration. 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 'Diagnosis' above.)
• Management – No specific therapy is required for patients with Gilbert syndrome.

The most important aspect of the care of these patients is recognition of the disorder
and its benign nature. Its mode of inheritance should also be discussed to prevent
unnecessary testing in family members. (See 'Treatment' above and 'Drug
interactions' above and 'Genetic defect' above.)
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. http://mghlabtest.partners.org/MGH_Reference_Intervals_August_2011.pdf (Accessed on
March 29, 2013).
2. Berk PD, Jones EA, Howe RB, et al. Disorders of bilirubin metabolism. In: Metabolic Contr
ol and Disease, 8th ed, Bondy PK, Rosenberg LE (Eds), Saunders, Philadelphia 1980. p.100
9.
3. Muraca M, Fevery J, Blanckaert N. Relationships between serum bilirubins and

production and conjugation of bilirubin. Studies in Gilbert's syndrome, Crigler-Najjar
disease, hemolytic disorders, and rat models. Gastroenterology 1987; 92:309.
4. Muraca M, Blanckaert N. Liquid-chromatographic assay and identification of mono- and

diester conjugates of bilirubin in normal serum. Clin Chem 1983; 29:1767.
5. Gilbert A, Lereboullet P. La cholamae simple familiale. Sem Med 1901; 21:241.

6. Thompson RP. Genetic transmission of Gilbert's syndrome. In: Familial Hyperbilirubinemi
a, Okolicsanyi L (Ed), Wiley, New York 1981. p.91.
7. Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr 2012;

171:11.
8. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of
bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995;
333:1171.
9. Borlak J, Thum T, Landt O, et al. Molecular diagnosis of a familial nonhemolytic
hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 2000; 32:792.
10. Sieg A, Arab L, Schlierf G, et al. [Prevalence of Gilbert's syndrome in Germany]. Dtsch
Med Wochenschr 1987; 112:1206.
11. Monaghan G, Ryan M, Seddon R, et al. Genetic variation in bilirubin UPD-

glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996; 347:578.
12. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1

(UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?
Proc Natl Acad Sci U S A 1998; 95:8170.
13. Biondi ML, Turri O, Dilillo D, et al. Contribution of the TATA-box genotype (Gilbert
syndrome) to serum bilirubin concentrations in the Italian population. Clin Chem 1999;
45:897.
14. Lampe JW, Bigler J, Horner NK, Potter JD. UDP-glucuronosyltransferase (UGT1A1*28 and
UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin
concentrations. Pharmacogenetics 1999; 9:341.
15. Raijmakers MT, Jansen PL, Steegers EA, Peters WH. Association of human liver bilirubin
UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the
UGT1A1 gene. J Hepatol 2000; 33:348.
16. Roy-Chowdhury N, Deocharan B, Bejjanki HR, et al. Presence of the genetic marker for
Gilbert syndrome is associated with increased level and duration of neonatal jaundice.
Acta Paediatr 2002; 91:100.
17. Muraca M, Fevery J. Influence of sex and sex steroids on bilirubin uridine diphosphate-
glucuronosyltransferase activity of rat liver. Gastroenterology 1984; 87:308.
18. Black M, Billing BH. Hepatic bilirubin udp-glucuronyl transferase activity in liver disease
and gilbert's syndrome. N Engl J Med 1969; 280:1266.
19. Auclair C, Hakim J, Boivin P, et al. Bilirubin and paranitrophenol glucuronyl transferase
activities of the liver in patients with Gilbert's syndrome An attempt at a biochemical
breakdown of the Gilbert's syndrome. Enzyme 1976; 21:97.
20. Fevery J, Blanckaert N, Heirwegh KP, et al. Unconjugated bilirubin and an increased
proportion of bilirubin monoconjugates in the bile of patients with Gilbert's syndrome
and Crigler-Najjar disease. J Clin Invest 1977; 60:970.
21. Cobelli C, Ruggeri A, Toffolo G. BSP vs bilirubin kinetics in Gilbert's syndrome. In: Familial
Hyperbilirubinemia, Okolicsanyi L (Ed), Wiley, New York 1981. p.121.
22. Felsher BF, Rickard D, Redeker AG. The reciprocal relation between caloric intake and the
degree of hyperbilirubinemia in Gilbert's syndrome. N Engl J Med 1970; 283:170.
23. Barrett PV. Hyperbilirubinemia of fasting. JAMA 1971; 217:1349.
24. Gollan JL, Bateman C, Billing BH. Effect of dietary composition on the unconjugated
hyperbilirubinaemia of Gilbert's syndrome. Gut 1976; 17:335.
25. Cowan RE, Thompson RP, Kaye JP, Clark GM. The association between fasting
hyperbilirubinaemia and serum non-esterified fatty acids in man. Clin Sci Mol Med 1977;
53:155.
26. Felsher BF, Carpio NM, VanCouvering K. Effect of fasting and phenobarbital on hepatic
UDP-glucuronic acid formation in the rat. J Lab Clin Med 1979; 93:414.
27. Kotal P, Vítek L, Fevery J. Fasting-related hyperbilirubinemia in rats: the effect of
decreased intestinal motility. Gastroenterology 1996; 111:217.
28. Brink MA, Méndez-Sánchez N, Carey MC. Bilirubin cycles enterohepatically after ileal
resection in the rat. Gastroenterology 1996; 110:1945.
29. Aono S, Adachi Y, Uyama E, et al. Analysis of genes for bilirubin UDP-
glucuronosyltransferase in Gilbert's syndrome. Lancet 1995; 345:958.
30. Koiwai O, Nishizawa M, Hasada K, et al. Gilbert's syndrome is caused by a heterozygous

missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol
Genet 1995; 4:1183.
31. Chalasani N, Chowdhury NR, Chowdhury JR, Boyer TD. Kernicterus in an adult who is
heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic
defect. Gastroenterology 1997; 112:2099.
32. Kadakol A, Sappal BS, Ghosh SS, et al. Interaction of coding region mutations and the
Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of
unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet
2001; 38:244.
33. SAGILD U, DALGAARD OZ, TYGSTRUP N. Constitutional hyperbilirubinemia with

unconjugated bilirubin in the serum and lipochrome-like pigment granules in the liver.
Ann Intern Med 1962; 56:308.
34. Powell LW, Hemingway E, Billing BH, Sherlock S. Idiopathic unconjugated
hyperbilirubinemia (Gilbert's syndrome). A study of 42 families. N Engl J Med 1967;
277:1108.
35. Ellis E, Wagner M, Lammert F, et al. Successful treatment of severe unconjugated

hyperbilirubinemia via induction of UGT1A1 by rifampicin. J Hepatol 2006; 44:243.
36. Ohkubo H, Okuda K, Iida S. Effects of corticosteroids on bilirubin metabolism in patients
with Gilbert's syndrome. Hepatology 1981; 1:168.
37. Black M, Sherlock S. Treatment of Gilbert's syndrome with phenobarbitone. Lancet 1970;
1:1359.
38. Kutz K, Kandler H, Gugler R, Fevery J. Effect of clofibrate on the metabolism of bilirubin,
bromosulphophthalein and indocyanine green and on the biliary lipid composition in
Gilbert's syndrome. Clin Sci (Lond) 1984; 66:389.
39. Powell LW, Billing BH, Williams HS. An assessment of red cell survival in idiopathic
unconjugated hyperbilirubinaemia (Gilbert's syndrome) by the use of radioactive
diisopropylfluorophosphate and chromium. Australas Ann Med 1967; 16:221.
40. Blueger AF, Krupnikova EZ, Sondore VY, Semushina EP. Study of the etiology and
pathogenesis of low grade nonhemolytic unconjugated hyperbilirubinemia (Gilbert's
disease). Acta Hepatogastroenterol (Stuttg) 1977; 24:140.
41. Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of
irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in
the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin
Invest 1998; 101:847.
42. Burchell B, Soars M, Monaghan G, et al. Drug-mediated toxicity caused by genetic

deficiency of UDP-glucuronosyltransferases. Toxicol Lett 2000; 112-113:333.
43. de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased
bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology 1992; 102:577.
44. Carulli N, Ponz de Leon M, Mauro E, et al. Alteration of drug metabolism in Gilbert's
syndrome. Gut 1976; 17:581.
45. Ullrich D, Sieg A, Blume R, et al. Normal pathways for glucuronidation, sulphation and
oxidation of paracetamol in Gilbert's syndrome. Eur J Clin Invest 1987; 17:237.
46. Rauchschwalbe SK, Zühlsdorf MT, Wensing G, Kuhlmann J. Glucuronidation of

acetaminophen is independent of UGT1A1 promotor genotype. Int J Clin Pharmacol Ther
2004; 42:73.
47. Lankisch TO, Moebius U, Wehmeier M, et al. Gilbert's disease and atazanavir: from
phenotype to UDP-glucuronosyltransferase haplotype. Hepatology 2006; 44:1324.
48. Deterding K, Grüngreiff K, Lankisch TO, et al. Gilbert's syndrome and antiviral therapy of
hepatitis C. Ann Hepatol 2009; 8:246.
49. Xu CF, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with
Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer 2010; 102:1371.
50. del Giudice EM, Perrotta S, Nobili B, et al. Coinheritance of Gilbert syndrome increases
the risk for developing gallstones in patients with hereditary spherocytosis. Blood 1999;
94:2259.
51. Origa R, Galanello R, Perseu L, et al. Cholelithiasis in thalassemia major. Eur J Haematol
2009; 82:22.
52. Haverfield EV, McKenzie CA, Forrester T, et al. UGT1A1 variation and gallstone formation
in sickle cell disease. Blood 2005; 105:968.
53. Roda A, Roda E, Sama C, et al. Serum primary bile acids in Gilbert's syndrome.
Gastroenterology 1982; 82:77.
54. Vierling JM, Berk PD, Hofmann AF, et al. Normal fasting-state levels of serum cholyl-
conjugated bile acids in Gilbert's syndrome: an aid to the diagnosis. Hepatology 1982;
2:340.
55. Douglas JG, Beckett GJ, Nimmo IA, et al. Bile salt measurements in Gilbert's syndrome.
Eur J Clin Invest 1981; 11:421.
56. Okolicsanyi L, Fevery J, Billing B, et al. How should mild, isolated unconjugated
hyperbilirubinemia be investigated? Semin Liver Dis 1983; 3:36.
57. Fromke VL, Miller D. Constitutional hepatic dysfunction (CHD; Gilbert's disease); a review
with special reference to a characteristic increase and prolongation of the
hyperbilirubinemic response to nicotinic acid. Medicine (Baltimore) 1972; 51:451.
58. GYDELL K. Nicotinic acid induced hyperbilirubinemia and hypersideremia. I.

Observations in hemolytic disease and allied conditions. Acta Med Scand 1959; 164:305.
59. Gentile S, Tiribelli C, Persico M, et al. Dose dependence of nicotinic acid-induced
hyperbilirubinemia and its dissociation from hemolysis in Gilbert's syndrome. J Lab Clin
Med 1986; 107:166.
60. Monaghan G, McLellan A, McGeehan A, et al. Gilbert's syndrome is a contributory factor

in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr 1999; 134:441.
61. Lin YC, Chang PF, Hu FC, et al. Variants in the UGT1A1 gene and the risk of pediatric
nonalcoholic fatty liver disease. Pediatrics 2009; 124:e1221.
62. Liu J, Dong H, Zhang Y, et al. Bilirubin Increases Insulin Sensitivity by Regulating
Cholesterol Metabolism, Adipokines and PPARγ Levels. Sci Rep 2015; 5:9886.
63. Gordon DM, Neifer KL, Hamoud AA, et al. Bilirubin remodels murine white adipose tissue
by reshaping mitochondrial activity and the coregulator profile of peroxisome
proliferator-activated receptor α. J Biol Chem 2020; 295:9804.
64. Guillemette C, Millikan RC, Newman B, Housman DE. Genetic polymorphisms in uridine
diphospho-glucuronosyltransferase 1A1 and association with breast cancer among
African Americans. Cancer Res 2000; 60:950.
65. Guillemette C, De Vivo I, Hankinson SE, et al. Association of genetic polymorphisms in

UGT1A1 with breast cancer and plasma hormone levels. Cancer Epidemiol Biomarkers
Prev 2001; 10:711.
66. Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert's syndrome and the risk of death: a
population-based cohort study. J Gastroenterol Hepatol 2013; 28:1643.
Topic 3578 Version 26.0
GRAPHICS
Common causes of hemolysis and hemolytic anemia in adults
Nonimmune causes
Hereditary
Enzyme deficiencies (deficiencies of G6PD, pyruvate kinase, glucose-phosphate isomerase, 5'

nucleotidase)
Hemoglobinopathies (sickle cell disease, thalassemias, unstable hemoglobins)
Membrane disorders (hereditary spherocytosis, hereditary elliptocytosis, hereditary

stomatocytosis)
Acquired
Liver disease
Hypersplenism
Infections (Bartonella, clostridial sepsis, malaria, babesiosis)
Oxidant agents (dapsone, nitrites, aniline dyes)
Toxins (lead, copper, snake and spider bites)
Infusion of a hypotonic solution
Microangiopathic hemolytic anemia (TTP, HUS, complement-mediated TMA, drug-induced

TMA, aortic stenosis, prosthetic valve leak)
Immune causes
Warm autoimmune hemolytic anemia (warm AIHA)
Drug-induced immune hemolysis
Hemolytic transfusion reactions (ABO incompatibility, alloantibodies)
Paroxysmal cold hemoglobinuria (PCH)
Paroxysmal nocturnal hemoglobinuria (PNH)
Cold agglutinin disease
Intravenous immune globulin (IVIG) or anti-RhD immune globulin
Nonimmune causes generally have a negative Coombs test (negative direct antiglobulin test
[DAT]); immune causes are typically DAT-positive. Refer to UpToDate for an approach to the
evaluation. Any hemolytic anemia can lead to an underestimation of the hemoglobin A1C
(HbA1C).
G6PD: glucose-6-phosphate dehydrogenase; TTP: thrombotic thrombocytopenic purpura; HUS:

hemolytic uremic syndrome; TMA: thrombotic microangiopathy.
Graphic 72394 Version 18.0
Bilirubin throughput in hepatocytes
Schematic representation of the steps involved in bilirubin (B)

throughput in hepatocytes: transport to the liver (primarily as
albumin-bound bilirubin), uptake at the sinusoidal membrane,
intracellular binding, conjugation (glucuronidation), and canalicular
excretion. Sinusoidal bilirubin uptake requires inorganic anions such
as chloride and is thought to be mediated by carrier proteins. Within
the hepatocyte, bilirubin binds to glutathione S-transferases (GSTs).
GST-binding reduces the efflux of the internalized bilirubin, thereby
increasing the net uptake. GSTs also bind bilirubin glucuronides (BG)
prior to excretion. Bilirubin also enters hepatocytes by passive
diffusion. Glucuronidation of bilirubin is mediated by a family of
enzymes, termed uridine diphosphoglucuronosyltransferase (UGT),
the most important of which is bilirubin-UGT-1 (UGT1A1). Conjugated
bilirubin is secreted actively across the bile canalicular membrane of
the hepatocyte against a concentration gradient that may reach
1:1000. The canalicular multidrug resistance protein 2 (MRP2) appears
to be the most important for the canalicular secretion of bilirubin. A
portion of the conjugated bilirubin is transported into the sinusoidal
blood via the ATP hydrolysis-couple pump, ABCC3, to undergo
reuptake via OATP1B1 and OATP1B3 by hepatocytes downstream to
the sinusoidal blood flow.
UDP: uridine diphosphate; UDPGA: uridine 5'-diphosphoglucuronic

acid; ABCC3: ATP-binding cassette subfamily C number 3; OATP1B1:
organic anion-transporting polypeptide 1B1; OATP1B3: organic anion-
transporting polypeptide 1B3.
Principal differential characteristics of inherited unconjugated

hyperbilirubinemia
Crigler-Najjar Crigler-Najjar
Gilbert syndrome
syndrome type I syndrome type II
Epidemiology and natural history
Mode of Autosomal recessive Autosomal recessive Autosomal recessive

inheritance
Prevalence Rare Rare Common

(approximately 9% of
White people are
homozygous for a
variant TATAA box; 4 to
5% have
hyperbilirubinemia)
Prognosis Kernicterus, unless Usually benign, Benign

vigorously treated kernicterus occurs
rarely
Routine clinical evaluation
Serum bilirubin 20 to 50 mg/dL Usually 8 to 20 mg/dL Usually <3 mg/dL

concentration* (340 to 850 (136 to 340 (<51 micromol/L)
micromol/L) micromol/L)
Routine liver Normal Normal Normal

function tests
Effect of None Reduction Reduction

phenobarbital on
serum bilirubin
Tests not routinely performed
Bilirubin Usually pale; contains Bilirubin glucuronides Bilirubin glucuronides

glucuronides ¶ small amounts of present: Increased present: Increased
unconjugated bilirubin proportion of bilirubin proportion of bilirubin
monoglucuronide monoglucuronide
Liver histology Normal, but fibrosis is Normal Normal

present in
approximately 40% of
cases [1]
Hepatic bilirubin Absent Markedly reduced Reduced (30% of

UGT activity (10% of normal) normal)
45-minute plasma Normal Normal Usually normal; may

BSP retention Δ be prolonged
UGT: uridine diphosphate glucuronosyltransferase; BSP: bromosulfophthalein.

* Serum bilirubin concentrations depend on age and optimal medical management. In each of
these disorders, further acute elevations may occur, triggered by fasting or intercurrent illnesses.
The risk of severe acute exacerbations (eg, bilirubin >20 mg/dL) and resulting kernicterus is high
for Crigler-Najjar syndrome type I, low for Crigler-Najjar syndrome type II, and absent for Gilbert
syndrome.
¶ Bilirubin glucuronides are measured by high-pressure liquid chromatography of bile collected

from the duodenum.
Δ Plasma BSP retention is prolonged in Dubin-Johnson and Rotor syndromes and in hepatobiliary
cholestatic disorders.
Reference:
1. Mitchell E, Ranganathan S, McKiernan P, et al. Hepatic Parenchymal Injury in Crigler-Najjar Type I. J Pediatr
Gastroenterol Nutr 2018; 66:588.
Genetic lesions in bilirubin-UGT deficiency syndromes
Organization of the UGT1A gene. The organization of the UGT1A locus is depicted in
the top panel. Four common exons (exons 2, 3, 4, and 5) are used in several UGT
isoforms expressed from this locus. Upstream from these exons are a series of
"unique" exons, only 1 of which is used in a given isoform. Each unique exon is
preceded by a separate promoter (solid arrows). Splicing of exon 1A1 to the common
region exons (2 to 5) generates the mRNA for bilirubin UGT (also termed UGT1A1).
Genetic lesions in any of the 5 exons constituting the bilirubin UGT mRNA can abolish
(Crigler-Najjar type I) or reduce (Crigler-Najjar type II) bilirubin-UGT activity. With type
I, the genetic lesions may result in a premature stop codon or a single amino acid
substitution. The sequence abnormalities can be located in the region encoding the
signal peptide or other domains of the enzyme, or even in the introns at the splice
donor or splice acceptor sites. Type II is caused by point mutations that result in
substitution of a single amino acid. In contrast with Crigler-Najjar syndrome types I
or II, Gilbert syndrome is caused by a promoter abnormality. Normally, the TATAA
element within the promoter upstream to exon 1A1 consists of A(TA)6TAA. In Gilbert
syndrome, 2 additional nucleotide residues (TA) are present in this element. Alleles
containing the Gilbert-type promoter are termed UGT1A1*28. In addition, Japanese
investigators have reported sequence abnormalities in the coding region of the gene
that cause mild elevations of serum bilirubin concentrations, consistent with Gilbert
syndrome.
UGT: uridine diphosphate glucuronosyltransferase; mRNA: messenger ribonucleic

acid.
Contributor Disclosures
Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD No relevant financial relationship(s) with
ineligible companies to disclose. Namita Roy-Chowdhury, PhD, FAASLD Consultant/Advisory Boards:
Johnson & Johnson [Radiation injury]. All of the relevant financial relationships listed have been
mitigated. Xia Wang, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Keith D Lindor, MD Consultant/Advisory Boards: Pliant [DSMB member]. All of the relevant
financial relationships listed have been mitigated. Shilpa Grover, MD, MPH, AGAF No relevant financial
relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for references
to be provided to support the content. Appropriately referenced content is required of all authors and
must conform to UpToDate standards of evidence.
Conflict of interest policy

Gilbert Syndrome and Unconjugated Hyperbilirubinemia Due To Bilirubin Overproduction - UpToDate

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Gilbert Syndrome and Unconjugated Hyperbilirubinemia Due To Bilirubin Overproduction - UpToDate

Uploaded by

Copyright:

Available Formats

22/5/23, 17:54 Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction - UpToDate

Official reprint from UpToDate®

Gilbert syndrome and unconjugated hyperbilirubinemia

Literature review current through: Apr 2023.

● Uptake from the circulation

Normally, approximately 96 percent of plasma bilirubin is unconjugated. Abnormalities in any

The most common causes of unconjugated hyperbilirubinemia are bilirubin overproduction,

● Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)

• Male: 45 to 115 int. unit/L

• Female: 30 to 100 int. unit/L

● Alanine aminotransferase (ALT):

• Male: 10 to 55 int. unit/L

• Female: 7 to 30 int. unit/L

● Aspartate aminotransferase (AST):

• Male: 10 to 40 int. unit/L

• Female: 9 to 32 int. unit/L

● Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)

● Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)

● Gamma-glutamyl transpeptidase (GGT):

• Male: 8 to 61 int. unit/L

• Female: 5 to 36 int. unit/L

● Prothrombin time (PT): 11.0 to 13.7 seconds

Examples of disorders associated with hemolysis include ( table 1):

● Mechanical hemolysis (eg, thrombotic thrombocytopenic purpura/hemolytic-uremic

● Autoimmune hemolytic anemia due to warm or cold agglutinins

● Toxic or idiosyncratic disorders (eg, drug toxicity)

● Diseases associated with ineffective erythropoiesis leading to destruction of red cell

● Rare inherited anemias termed "congenital dyserythropoietic anemias" that are

The approach to patients with hemolytic anemia is discussed in detail elsewhere.

Impaired bilirubin glucuronidation — Uridine diphosphoglucuronate (UDP)-

Specialized tests can demonstrate a number of abnormalities in hepatic function including:

● A reduction in hepatic bilirubin-UGT activity, which is approximately 30 percent of

● A 14 to 34 percent increase in the proportion of monoconjugated bile pigments, which

Increased bilirubin production — Episodes of jaundice in patients with Gilbert syndrome

Histology — Histopathologically, the liver is normal except for nonspecific accumulation of

Clinical manifestations — With the exception of intermittent episodes of jaundice, most

Physical examination findings — The physical examination in a patient with Gilbert

Drug interactions — Since bilirubin-UGT is involved in the glucuronidation of estrogen and

Two other drugs that require bilirubin-UGT-mediated hepatic glucuronidation are

Cholelithiasis — Gilbert syndrome has been associated with an increased risk of

● Unconjugated hyperbilirubinemia on repeated testing

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Gilbert syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Bilirubin metabolism – Normally, approximately 96 percent of plasma bilirubin is

• Uptake from the circulation

• Conjugation with glucuronic acid

● Bilirubin overproduction – Most disorders associated with bilirubin overproduction

• Pathogenesis – Gilbert syndrome is the most common inherited disorder of bilirubin

• Clinical manifestations – With the exception of intermittent episode of jaundice,

• Laboratory findings – Laboratory testing reveals unconjugated hyperbilirubinemia,

• Diagnosis – A presumptive diagnosis of Gilbert syndrome may be made in patients

complete blood count, blood smear, reticulocyte count, plasma aminotransferase

• Management – No specific therapy is required for patients with Gilbert syndrome.

Use of UpToDate is subject to the Terms of Use.

3. Muraca M, Fevery J, Blanckaert N. Relationships between serum bilirubins and

4. Muraca M, Blanckaert N. Liquid-chromatographic assay and identification of mono- and

5. Gilbert A, Lereboullet P. La cholamae simple familiale. Sem Med 1901; 21:241.

7. Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr 2012;

11. Monaghan G, Ryan M, Seddon R, et al. Genetic variation in bilirubin UPD-

12. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1

30. Koiwai O, Nishizawa M, Hasada K, et al. Gilbert's syndrome is caused by a heterozygous