INTRODUCTION — The metabolism of bilirubin by the liver is comprised of four distinct but interrelated stages (see "Bilirubin metabolism"):
●Uptake from the circulation
●Conjugation with glucuronic acid
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 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 :
●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
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 . 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" . Although many patients present as isolated cases, the condition can also run in families . It is characterized by recurrent episodes of jaundice and may be triggered by, among other things, dehydration, fasting, intercurrent disease, menstruation, and overexertion . 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 . 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 .
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 
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]:
●Intercurrent febrile illnesses
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 . 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 .
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 . 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 . 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 . 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 . 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 . 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 .
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) . 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 .
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 , 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 . Isolated hyperbilirubinemia has also been reported during the treatment of hepatitis C with peginterferon and ribavirin  and in patients receiving pazopanib . 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.
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 . In patients with diabetes mellitus type 2, visceral fat and insulin resistance was inversely related to serum bilirubin levels . The beneficial effect is not specific for the UGT1A1*28 genotype but is related directly to serum bilirubin levels . A report of increased breast cancer risk in subjects with Gilbert syndrome  was not confirmed in larger studies . 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 .
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
•Conjugation with glucuronic acid
●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.)
•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 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.)