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Unconjugated
Hyperbilirubinemia
Updated: Feb 26, 2024
Author: Michael Nicholas Gianarakis, MBBS; Chief Editor: BS Anand, MD

Overview

Practice Essentials
Unconjugated hyperbilirubinemia can result from increased production, impaired conjugation, or impaired hepatic uptake of
bilirubin, a yellow bile pigment produced from hemoglobin during erythrocyte destruction.[1, 2] It can also occur naturally in
newborns. Unless treated vigorously, most patients with Crigler-Najjar syndrome type 1, a form of unconjugated
hyperbilirubinemia, die in early infancy.

The image below illustrates the production of bilirubin.

Unconjugated Hyperbilirubinemia. Production of bilirubin.

Signs and symptoms

Signs and symptoms of unconjugated hyperbilirubinemia include the following:

Ineffective erythropoiesis (early labeled bilirubin [ELB] production): Characterized by the onset of asymptomatic
jaundice

Crigler-Najjar (CN) syndrome type 1: Jaundice develops in the first few days of life and rapidly progresses by the
second week; patients may present with evidence of kernicterus, the clinical manifestations of which are hypotonia,
deafness, oculomotor palsy, lethargy and, ultimately, death

Crigler-Najjar syndrome type 2: Usually, no clinical symptoms are reported with this disease entity except for the
presence of jaundice

Gilbert syndrome: May manifest only as jaundice on clinical examination; at least 30% of patients with Gilbert
syndrome are asymptomatic, although nonspecific symptoms, such as abdominal cramps, fatigue, and malaise, are
common

Benign neonatal hyperbilirubinemia (also referred to as physiologic jaundice): Clinically obvious in 50% of neonates
during the first 5 days of life

Pathologic neonatal jaundice: Maternal serum jaundice, also known as Lucey-Driscoll syndrome, is an autosomal
recessive metabolic disorder affecting the enzymes involved in bilirubin metabolism; it causes a transient familial
neonatal unconjugated hyperbilirubinemia, and jaundice occurs during the first 4 days of life

See Presentation for more detail.

Diagnosis

Crigler-Najjar syndrome type 1

Except for the presence of high serum unconjugated bilirubin levels, the results of liver tests in Crigler-Najjar syndrome type
1 are normal. Serum bilirubin levels range from 20-50 mg/dL. Conjugated bilirubin is absent from serum, and bilirubin is not
present in urine. Definitive diagnosis of Crigler-Najjar syndrome requires high-performance liquid chromatography of bile or a
tissue enzyme assay of a liver biopsy sample.

Crigler-Najjar syndrome type 2

Crigler-Najjar syndrome type 2 results in lower bilirubin concentrations than does type I, with levels ranging from 7-20 mg/dL.

Gilbert syndrome

As a rule, Gilbert syndrome can be diagnosed by a thorough history and physical examination and confirmed by standard
blood tests. Laboratory results include the following:

Unconjugated hyperbilirubinemia (< 4 mg/dL) noted on several occasions

Normal results of complete blood count (CBC), reticulocyte count, and blood smear

Normal liver function test (LFT) results

An absence of other disease processes

Genetic testing can confirm, but is not required for a definitive diagnosis. Specialized tests that can support the diagnosis
have occasionally been used. There is no role for percutaneous liver biopsy in the diagnosis of Gilbert syndrome.

Benign neonatal hyperbilirubinemia

In this physiological phenomenon, the peak total serum bilirubin level is 5-6 mg/dL (86-103 µmol/L), occurs at 48-120 hours
of age, and does not exceed 17-18 mg/dL (291-308 µmol/L).

Breast milk jaundice

In breast milk jaundice, the bilirubin may increase to levels as high as 20 mg/dL, necessitating the need for phototherapy
and the discontinuation of breastfeeding.

Ineffective erythropoiesis

This is characterized by a marked increase in fecal urobilinogen excretion and a normal or near-normal red blood cell
lifespan.

See Workup for more detail.

Management

Crigler-Najjar syndrome type 1

Pharmacologic therapy: Administration of cholestyramine, calcium phosphate, oral agar, orlistat, and Sn-
protoporphyrin[3, 4]

Repeated exchange transfusions

Long-term phototherapy

Plasmapheresis

Hemoperfusion

Liver transplantation: The only guaranteed form of therapy

Hepatocyte transplantation

Crigler-Najjar syndrome type 2

Patients with this disease may not require any treatment or can be managed with phenobarbital.

Gilbert syndrome

In light of the benign and inconsequential nature of Gilbert syndrome, the use of medications to treat patients with this
condition is unjustified in clinical practice.

Neonatal jaundice

No treatment is needed for benign neonatal hyperbilirubinemia. For breast milk jaundice and other types of nonphysiologic
jaundice, phototherapy can be used.

See Treatment and Medication for more detail.

Background
Unconjugated hyperbilirubinemia can result from an increased production, impaired conjugation, or impaired hepatic uptake
of bilirubin, a yellow bile pigment produced from hemoglobin during erythrocyte destruction. It can also occur naturally in
newborns. (See Pathophysiology and Etiology.)

Biochemistry of bilirubin
Bilirubin is a potentially toxic catabolic product of heme metabolism. There are elaborate physiologic mechanisms for its
detoxification and disposition. Understanding these mechanisms is necessary for the interpretation of the clinical significance
of high serum bilirubin concentrations. (See Pathophysiology and Prognosis.)

In adults, 250-400 mg of bilirubin is produced daily. Approximately 70-80% of daily bilirubin is derived from the degradation
of the heme moiety of hemoglobin. The remaining 20-25% is derived from the hepatic turnover of heme proteins, such as
myoglobin, cytochromes, and catalase. A small portion of daily bilirubin is derived from the destruction of young or
developing erythroid cells.

Bilirubin is poorly soluble in water at physiologic pH because of the internal hydrogen bonding that engages all polar groups
and gives the molecule an involuted structure. The fully hydrogen-bonded structure of bilirubin is designated bilirubin IX-
alpha-ZZ. The intramolecular hydrogen bonding shields the hydrophilic sites of the bilirubin molecule, resulting in a
hydrophobic structure. Water-insoluble, unconjugated bilirubin is associated with all the known toxic effects of bilirubin. Thus,
the internal hydrogen bonding is critical in producing bilirubin toxicity and also prevents its elimination.

Conversion of bilirubin IX-alpha to a water-soluble form by disruption of the hydrogen bonds is essential for its elimination by
the liver and kidney. This is achieved by glucuronic acid conjugation of the propionic acid side chains of bilirubin. Bilirubin
glucuronides are water-soluble and are readily excreted in bile. Bilirubin is primarily excreted in normal human bile as
diglucuronide; unconjugated bilirubin accounts for only 1-4% of pigments in normal bile. See the images below.

Unconjugated Hyperbilirubinemia. Production of bilirubin.

Unconjugated Hyperbilirubinemia. Enterohepatic circulation of bilirubin.

Unconjugated Hyperbilirubinemia. Conjugation of bilirubin.

Increased production of bilirubin

Hemolysis generally induces a modest elevation in the plasma levels of unconjugated bilirubin (1-4 mg/dL). During acute
hemolytic crises, such as those occurring in sickle cell disease or paroxysmal nocturnal hemoglobinuria, bilirubin production
and plasma bilirubin may transiently exceed these levels. Although the plasma bilirubin level increases linearly in relation to
bilirubin production, the bilirubin concentration may still be near the reference range in patients with a 50% reduction in red
blood cell survival if hepatic bilirubin clearance is within the reference range.
Ineffective erythropoiesis (early labeled bilirubin [ELB] production) that is markedly increased is the basis of a rare disorder
known as primary shunt hyperbilirubinemia, or idiopathic dyserythropoietic jaundice.

Impaired hepatic bilirubin uptake

The hepatic uptake of bilirubin can be reduced by the following:

Congestive heart failure

Surgical/naturally occurring shunts

Drugs/contrast agents

Unconjugated hyperbilirubinemia due to drugs/contrast agents resolves within 48 hours of discontinuing the drug; agents
that can cause the condition include rifampicin, rifamycin, probenecid, flavaspidic acid, and bunamiodyl (cholecystographic
agent).

Impaired conjugation of bilirubin

The following inherited defects of bilirubin conjugation are known to exist in humans:

Crigler-Najjar syndrome types 1 and 2

Gilbert syndrome

Gilbert syndrome is believed to affect approximately 3-10% of the adult population.[5] Crigler-Najjar syndrome is a much
rarer disorder, with only a few hundred cases described in the literature. (See Epidemiology.)

Crigler-Najjar syndrome

First described by Crigler and Najjar in 1952, Crigler-Najjar syndrome is a congenital, familial, nonhemolytic jaundice
associated with high levels of unconjugated bilirubin. The original report described 6 infants from 3 related families with
severe unconjugated hyperbilirubinemia, which was recognized shortly after birth. (See Prognosis.)

Five of the children died by the age of 15 months of kernicterus, a potentially fatal disorder affecting the basal ganglia and
other parts of the central nervous system. The remaining patient died at age 15 years, several months after suffering a
devastating brain injury.[6] (Activation of astrocytes by unconjugated hyperbilirubinemia is believed to play a major part in
kernicterus via the production of inflammatory cytokines.[7] )

Crigler-Najjar syndrome is a rare disorder caused by an impairment of bilirubin metabolism resulting in a deficiency or
complete absence of hepatic microsomal bilirubin-uridine diphosphate glucuronosyltransferase (bilirubin-UGT) activity.[8]
(See Pathophysiology and Etiology.)

Two distinct forms of Crigler-Najjar syndrome are as follows:

Crigler-Najjar syndrome type 1: Associated with neonatal unconjugated hyperbilirubinemia (high levels) and
kernicterus

Crigler-Najjar syndrome type 2 (also called Arias syndrome): Presents with a lower serum bilirubin level; responds to
phenobarbital treatment

Type 1 is an autosomal recessive disorder, while the mode of inheritance for Crigler-Najjar syndrome type 2 is still not clear.
Autosomal dominant transmission with variable penetrance and autosomal recessive transmission have both been reported
for type 2.

Over the past decades, progress has been made in the diagnosis and treatment of Crigler-Najjar syndrome. Phototherapy
was long recognized as a form of treatment,[9] and in 1986, liver transplantation was shown to be curative.[10] In 1992, the
locus of the missing gene behind this disorder was identified. (See Presentation, Workup, Treatment, and Medication.)[11,
12]

Gilbert syndrome

Gilbert syndrome is a benign, familial disorder inherited in an autosomal recessive pattern characterized by intermittent
jaundice in the absence of hemolysis or an underlying liver disease. The condition is recognized to arise from a mutation in
the promoter region of the UGT1A1 gene, which results in reduced UGT production. (See Pathophysiology and Etiology.)

Also called constitutional hepatic dysfunction or familial nonhemolytic jaundice, Gilbert syndrome is the mildest form of
inherited, nonhemolytic unconjugated hyperbilirubinemia.[13] The most common inherited cause of unconjugated
hyperbilirubinemia, it occurs in 3-7% of the world’s population. (See Epidemiology.)

By definition, bilirubin levels in Gilbert syndrome are lower than 6 mg/dL, though most patients exhibit levels lower than 3
mg/dL. Considerable daily and seasonal variations are observed, and in as many as one third of patients, the bilirubin levels
may occasionally be normal.

Gilbert syndrome may be precipitated by dehydration, fasting, menstrual periods, or other causes of 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 typically resolve spontaneously without curative treatment.

As a rule, Gilbert syndrome can be diagnosed with a thorough history and physical examination and can be confirmed with
standard blood tests. Repeated investigations and invasive procedures are not usually justified for establishing a diagnosis.
(See Presentation and Workup.)

Once the diagnosis of Gilbert syndrome is established, the most important aspect of treatment is reassurance. In light of the
benign and inconsequential nature of the syndrome, the use of medications to treat patients with this condition is unjustified
in clinical practice. (See Treatment and Medication.)

Neonatal jaundice

Benign neonatal hyperbilirubinemia

All newborns have higher bilirubin levels (mainly unconjugated bilirubin) than do adults.

Pathologic jaundice

This includes breast milk jaundice, also known as maternal milk jaundice (breastfed infants have higher mean bilirubin levels
than do formula-fed infants),[14] and maternal serum jaundice, also known as Lucey-Driscoll syndrome.

ABO/Rh incompatibility

Neonatal jaundice can also result from an increased bilirubin load or from ABO/Rh incompatibility. ABO/Rh incompatibility
can have the following causes:

Inherited red blood cell disorders: Sickle cell disease and hereditary spherocytosis/elliptocytosis

Drug reactions

Ineffective erythropoiesis: Thalassemia, vitamin B-12 deficiency, and congenital dyserythropoietic anemia

Pathophysiology
Unconjugated bilirubin is transported in the plasma bound to albumin. At the sinusoidal surface of the liver, unconjugated
bilirubin detaches from albumin and is transported through the hepatocyte membrane by facilitated diffusion. Within the
hepatocyte, bilirubin is bound to two major intracellular proteins: cytosolic Y protein (ie, ligandin or glutathione S-transferase
B) and cytosolic Z protein (also known as fatty acid–binding protein [FABP]). The binding of bilirubin to these proteins
decreases the efflux of bilirubin back into the plasma and, therefore, increases net bilirubin uptake. (See the image below.)

Unconjugated Hyperbilirubinemia. Enterohepatic circulation of bilirubin.

In order for bilirubin to be excreted into bile and, therefore, eliminated from the body, it must be made more soluble. This
water-soluble, or conjugated, form of bilirubin is produced when glucuronic acid enzymatically is attached to one or both of
the propionic side chains of bilirubin IX-alpha (ZZ). Enzyme-catalyzed glucuronidation is one of the most important
detoxification mechanisms of the body. Of the various isoforms of the UGT family of enzymes, only one of them, bilirubin-
UGT1A1, is physiologically important in bilirubin glucuronidation.

UGT enzymes are normally concentrated in the lipid bilayer of the endoplasmic reticulum of the hepatocytes, intestinal cells,
kidneys, and other tissues.

Attachment of glucuronic acid to bilirubin occurs through an ester linkage and, therefore, is called esterification. This
esterification is catalyzed by bilirubin-UGT, which is located in the endoplasmic reticulum of the hepatocyte. This reaction
leads to the production of water-soluble bilirubin monoglucuronide and bilirubin diglucuronide. Other compounds, such as
xylose and glucose, also can undergo esterification with bilirubin.

Bilirubin diglucuronide is the predominant pigment in healthy adult human bile, representing over 80% of the pigment.
However, in subjects with reduced bilirubin-UGT activity, the proportion of bilirubin diglucuronide decreases, and bilirubin
monoglucuronide may constitute more than 30% of the conjugates excreted in bile.

Increased production of bilirubin

In a review of 11 cases of ineffective erythropoiesis (early labeled bilirubin [ELB] production), evidence existed of rapid heme
and hemoglobin turnover in the bone marrow, possibly due to the premature destruction of red blood cell precursors. These
patients also had erythroid hyperplasia of bone marrow, reticulocytosis, increased iron turnover with diminished red blood
cell incorporation, and hemosiderosis of hepatic parenchymal cells and Kupffer cells. The underlying defect responsible for
the high rate of heme turnover within the bone marrow remains unknown.

Neonatal jaundice
Hyperbilirubinemia may reach or exceed 10 mg/dL in approximately 16% of newborns. In a study of genetic risk factors in 35
breastfed term infants with prolonged unconjugated hyperbilirubinemia, Chang et al found that 29 of the infants had one or
more UGT1A1 mutations, with variation at nucleotide 211 being the most common.[15] Moreover, a significantly higher
percentage of these neonates possessed the variant nucleotide 211 than did the control group (n=90). The authors also
found that the risk of prolonged hyperbilirubinemia was higher in the male infants than in the female neonates.

In a study involving 126 Indian infants with hyperbilirubinemia, de Silva et al found an association between single-nucleotide
polymorphisms (SNPs) of both the UGT1A1 and OATP2 genes and altered bilirubin metabolism, suggesting these
polymorphisms may be possible risk factors for neonatal hyperbilirubinemia.[16]

Benign neonatal hyperbilirubinemia

Benign neonatal hyperbilirubinemia (physiologic jaundice) is a mild unconjugated hyperbilirubinemia that affects nearly all
newborns and resolves within the first several weeks after birth. It has been shown that bilirubin production in a term
newborn is 2-3 times higher than in adults. It is caused by increased bilirubin production, decreased bilirubin clearance, and
increased enterohepatic circulation. The following factors contribute to the development of physiologic jaundice:

Inefficient hepatic excretion of unconjugated bilirubin

Portal venous shunting through a patent ductus venosus

Shortened red blood cell survival

Immaturity of hepatic bilirubin clearance: Bilirubin-UGT activity is only 1% of normal adult levels at birth, regardless of
gestational age; enzyme activity increases to adult levels by the 14th week of life; the main precipitant factors are
decreased energy intake and delayed closure of the ductus venosus

Hydrolysis of conjugated bilirubin: The activity of beta-glucuronidase is increased in newborns, which leads to greater
hydrolysis of conjugated bilirubin to the unconjugated form; the unconjugated bilirubin is reabsorbed from the
intestine through the process of enterohepatic circulation

Low bacterial degradation of bilirubin: In neonates, the bacterial degradation of bilirubin is reduced because the
intestinal flora is not fully developed; this may lead to increased absorption of unconjugated bilirubin[17]

Bilirubin and drug metabolism in neonates can also be affected by the influences of ethnicity on UGT1A1 haplotype
mutations.[18] A cohort study of 241 consecutive term Asian infants reported that not only was there a variance in the
prevalence of hypomorphic haplotypes, but also that the frequency varied between the different races.[19] For example,
Indian neonates were more likely to have at least one hydromorphic haplotype (64%) than were Chinese (48%) and Malay
(31%) neonates. There was also a trend between the number of G71R mutations and the need for phototherapy.

The peak total serum bilirubin level in physiologic jaundice typically is 5-6 mg/dL (86-103 µmol/L), occurs 48-120 hours after
birth, and does not exceed 17-18 mg/dL (291-308 µmol/L). Higher levels of unconjugated hyperbilirubinemia are pathologic
and occur in various conditions.

Nonphysiologic jaundice

Breast milk (maternal milk) jaundice results from increased enterohepatic circulation. It is thought to result from an
unidentified component of human milk that enhances the intestinal absorption of bilirubin. One possible mechanism for
hyperbilirubinemia in breastfed infants is the increased concentration of beta-glucuronidase in breast milk. Beta-
glucuronidase deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing the enterohepatic
circulation).

Maternal serum jaundice (Lucey-Driscoll syndrome) may result from the presence of an unidentified inhibitor of UGT, which
enters the fetus through maternal serum.

Impaired conjugation of bilirubin

Deficiency of bilirubin-UGT leads to an ineffective esterification of bilirubin, which in turn results in an unconjugated
hyperbilirubinemia. Reduced bilirubin conjugation as a result of decreased or absent UGT activity is found in several
acquired conditions and inherited diseases, such as Crigler-Najjar syndrome (types I and II) and Gilbert syndrome. Bilirubin
conjugating activity is also very low in the neonatal liver. An illustration of bilirubin conjugation is shown in the image below.

Unconjugated Hyperbilirubinemia. Conjugation of bilirubin.

UGT activity toward bilirubin is modulated by various hormones. Excess thyroid hormone and ethinyl estradiol, but not other
oral contraceptives, inhibit bilirubin glucuronidation. In comparison, the combination of progestational and estrogenic steroids
results in increased enzyme activity.

Bilirubin glucuronidation can also be inhibited by certain antibiotics (eg, novobiocin or gentamicin at serum concentrations
exceeding therapeutic levels) and by chronic hepatitis,[20] advanced cirrhosis, and Wilson disease.[21]

Crigler-Najjar syndrome

One or more mutations in any one or more of the five exons of the gene that codes for UGT 1A1 can cause Crigler-Najjar
syndrome.[22, 23, 24, 25] More than 50 mutations that cause Gilbert syndrome and Crigler-Najjar syndrome have been
identified, most of which are missense or nonsense mutations.

Depending on the severity of a mutation’s effect on the enzymatic activity, Crigler-Najjar syndrome type 1 (a complete
absence of enzymatic activity) or Crigler-Najjar syndrome type 2 (UGT level < 10% of normal) may result. The differentiation
between type 1 and 2 is not always easy, and both types are quite possibly different expressions of a single disease.

Gilbert syndrome

Hepatic bilirubin UGT activity is consistently decreased to approximately 30% of normal in individuals with Gilbert syndrome.
Decreased bilirubin-UGT activity has been attributed to an expansion of thymine-adenine (TA) repeats in the promoter region
of the UGT-1TA gene. Racial variations in the number of TA repeats and a correlation with enzyme activity suggest that
these polymorphisms contribute to the variations in bilirubin metabolism. An increased proportion of the bilirubin
monoconjugates in bile reflects reduced transferase activity.[15, 26, 27, 28]

Fasting, febrile illness, alcohol, or exercise can exacerbate jaundice in patients with Gilbert syndrome. Hemolysis and mild
icterus usually occur at times of stress, starvation, and infection.

Investigators have discovered that Gilbert syndrome may coexist with other liver diseases, such as nonalcoholic
steatohepatitis. Therefore, unconjugated hyperbilirubinemia in patients with these other conditions may be due to Gilbert
syndrome and should not always be attributed to the underlying liver disorder.
UGT mutations in Gilbert syndrome

Bilirubin-UGT, which is located primarily in the endoplasmic reticulum of hepatocytes, is responsible for conjugating bilirubin
into bilirubin monoglucuronides and diglucuronides. It is one of several UGT enzyme isoforms responsible for the
conjugation of a wide array of substrates, including carcinogens, drugs, hormones, and neurotransmitters.

Knowledge of these enzymes has been enhanced greatly by the characterization of the UGT1 gene locus in humans. The
gene that expresses bilirubin-UGT has a complex structure and is located on chromosome 2.[26, 29, 30, 31, 32, 33, 34]
There are five exons, of which exons 2-5, at the 3' end, are constant components of all isoforms of UGT, coding for the
uridine diphosphate (UDP)-glucuronic acid binding site. Exon 1 encodes for a unique region within each UGT and confers
substrate specificity; exon 1a encodes the variable region for bilirubin UGT1A1. Defects in the UGT1A1 enzyme are
responsible for Gilbert syndrome and for Crigler-Najjar syndrome.[35, 36]

Expression of UGT1A1 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) in the TATAA region interferes with the
binding of 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.[29, 37, 38, 39, 40]

Insertion of a homozygous TA dinucleotide in the regulatory TATA box in the UGT 1A1 gene promoter is the most common
genetic defect in Gilbert syndrome.[7]

In Gilbert syndrome, the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and
protease inhibitor side effects. In vivo research into the genotype, present in 76% of individuals with Gilbert syndrome,
suggests that transcription and transcriptional activation of glucuronidation genes responsible for conjugation and
detoxification are directly affected, leading to lower responsiveness.[34]

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 do patients with the wild-type allele.

Whether reduced bilirubin-UGT activity results from a reduced number of enzyme molecules or from a qualitative enzyme
defect is unknown. To compound this uncertainty, other factors (eg, occult hemolysis or hepatic transport abnormalities) may
be involved in the clinical expression of Gilbert syndrome. For example, many individuals who are homozygous for the
TATAA defect do not demonstrate unconjugated hyperbilirubinemia, and many 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 help to explain the finding of intermediate levels of hyperbilirubinemia in family members of
patients with Crigler-Najjar syndrome.

Gilbert syndrome can also frequently coexist with conditions associated with unconjugated hyperbilirubinemia, such as
thalassemia[41] and glucose-6-phosphate deficiency (G6PD).[42, 43] Much of the observed unconjugated
hyperbilirubinemia could be attributed to variation at the UGT 1A1 locus.[44]

Origa et al, in a study of 858 patients with transfusion-dependent thalassemia, found that in individuals with a combination of
thalassemia and the Gilbert syndrome genotype (TA)7/(TA)7 UGT1A1, the latter effected the prevalence of cholelithiasis and
influenced the age at which the condition arose.[45] The authors suggested that in patients with a combination of
thalassemia and Gilbert syndrome, biliary ultrasonography should be performed, starting in childhood.

A Greek study of 198 adult patients with cholelithiasis, along with 152 controls, also found evidence of an association
between Gilbert syndrome and the development of cholelithiasis.[46]
Etiology
Increased bilirubin production can result from the following:

Hemolysis

Dyserythropoiesis

Hematoma

Impaired hepatic bilirubin uptake can result from the following:

Congestive heart failure

Portosystemic shunts

Drugs: Rifamycin, rifampin, probenecid

Impaired bilirubin conjugation can result from the following:

Crigler-Najjar syndrome types I and II

Gilbert syndrome (decreased uptake and/or conjugation)

Benign neonatal hyperbilirubinemia (physiologic jaundice)

Breast milk jaundice

Maternal serum jaundice

Hypothyroidism/hyperthyroidism

Ethinyl estradiol

Liver diseases: Chronic hepatitis,[20] cirrhosis, and Wilson disease

Epidemiology
Occurrence in the United States

There have been fewer than 50 known cases of Crigler-Najjar syndrome in the United States, and only a few hundred cases
have been described in the world literature.[47] In the United States, the prevalence of Gilbert syndrome is 3-7%.

Breast milk jaundice affects approximately 0.5-2.4% of live births. There is a familial incidence of 13.9%, indicating that, in
some cases, a unique genetic factor may be expressed.

International occurrence

Crigler-Najjar syndrome is a rare disease. The estimated incidence is 1 case per 1,000,000 births, with only several hundred
people worldwide having been reported to have this disease. The syndrome is mostly encountered in communities where
high rates of consanguineous marriages prevail.

The prevalence of Gilbert syndrome varies considerably around the world, depending on which diagnostic criteria are used
(eg, number of bilirubin determinations, method of analysis, bilirubin levels used for diagnosis, whether the patient was
fasting). Estimates of prevalence may be complicated further by molecular genetic studies of polymorphisms in the TATAA
promoter region, which affect as many as 36% of Africans but only 3% of Asians.

Race-related demographics

In Gilbert syndrome, differences exist in the mutation of the UGT1A1 gene in certain ethnic groups; the TATAA element in the
promoter region is the most common mutation site in the white population. For example, a strong correlation has been found
between the UGT1A1*28 polymorphism and hyperbilirubinemia in Romanian patients with Gilbert syndrome.[5] In a study of
292 Romanian patients with Gilbert syndrome and 605 healthy counterparts, investigators used PCR gene amplification and
found that the highest frequency of polymorphism was UGT1A1*28 (7TA), occurring in nearly 62% of the entire study group,
followed by nearly 37% with the UGT1A1*1 (6TA) allele, and 0.61% and 0.72%, respectively, with the 5TA and 8TA variants.
[5] Nearly 58% of the study cohort had the (TA)6/7 heterozygous genotype, followed by 32% with the homozygous (TA)7/7
genotype.

A racial variation exists in the development of neonatal jaundice. A common mutation in the UGT gene (Gly71Arg) leads to
an increased incidence of severe neonatal hyperbilirubinemia (approximately 20%) in Asians.

Obstetric obesity appears to correspond with both maternal and neonatal hyperbilirubinemia, potentially via the inhibition of
hepatic UGT1A1 enzyme, with the highest prevalence in Native Hawaiian and Pacific Island women.[48] Investigators found
that increasing obesity and maternal obesity correlated with elevated maternal unconjugated bilirubin; maternal obesity was
also associated with neonatal hyperbilirubinemia, particularly in Native Hawaiian and Pacific Island women.[48]

Sex-related demographics

Gilbert syndrome is diagnosed more commonly in boys after puberty than in girls. The apparent sex difference is due to the
fact that the daily bilirubin production is lower in women than in men.[49] The male-to-female ratio for Gilbert syndrome
ranges from 2:1 to 7:1.

Crigler-Najjar syndrome occurs in both sexes equally, while neonatal physiologic jaundice occurs more frequently in males.
[49]

Age-related demographics

The age at which symptoms of unconjugated hyperbilirubinemia appear varies as follows:

Crigler-Najjar syndrome type 1: Symptoms appear within the first few days of life[50]

Crigler-Najjar syndrome type 2: Symptoms may present later than they do in type 1; patients have jaundice during the
first few years of life.

Gilbert syndrome: This is usually diagnosed around puberty, possibly because of the inhibition of bilirubin
glucuronidation by endogenous steroid hormones.

Benign neonatal hyperbilirubinemia affects nearly all newborns, occurs in the first 2-5 days following birth, and
resolves within the first several weeks after birth.

Breast milk jaundice typically begins after the first 3-5 days, peaks within 2 weeks after birth, and progressively
declines to normal levels over 3-12 weeks.

Ineffective erythropoiesis (ELB production): This condition usually emerges at age 20-30 years.

Prognosis
Neonatal jaundice

Breast milk jaundice

The prognosis in this condition is excellent. The jaundice may continue for 4 weeks but promptly resolves when
breastfeeding is discontinued. Even so, the bilirubin level needs to be closely monitored, with adjustments in care made
accordingly to prevent persistent hyperbilirubinemia and its potential complications (ie, kernicterus in the fragile neonatal
period).

However, late neurodevelopment or hearing defects have not been observed in neonates, thus enabling the pediatrician to
encourage continuation of breastfeeding in most cases of healthy infants with breast milk jaundice.

Maternal serum jaundice

The prognosis in maternal serum jaundice is good, but jaundice can persist for several weeks. This entity is occasionally
associated with kernicterus.

Impaired conjugation of bilirubin

Crigler-Najjar syndrome type 1

Kernicterus in infancy or later in life is the main cause of death in Crigler-Najjar syndrome type 1. This disease can also
result in permanent neurologic sequelae, due to bilirubin encephalopathy. Even with treatment, most, if not all, patients with
Crigler-Najjar (CN) syndrome type 1 eventually develop some neurologic deficit.

Unless treated vigorously (ie, orthotopic liver transplant, segmental transplantation), most patients with Crigler-Najjar
syndrome type 1 die by age 15 months. Fortunately, more patients are surviving to adulthood because of advances in the
treatment of hyperbilirubinemia.

Neonates of mothers with Crigler-Najjar syndrome type 1 develop adverse outcomes, including developmental delay,
hearing loss, and cerebellar syndrome.[51]

Crigler-Najjar syndrome type 2

Although the type 2 form of this disease runs a more benign clinical course than type 1, several cases of bilirubin-induced
brain damage have been reported. (Bilirubin encephalopathy occurs usually when patients experience a superimposed
infection or stress.) With proper treatment, however, neurologic sequelae can be avoided.

In neonates of mothers with Crigler-Najjar syndrome type 2, the use of phenobarbital in pregnancy appears to be safe, with
good fetal and maternal outcome.[51]

Gilbert syndrome

Gilbert syndrome is a common and benign condition. The bilirubin disposition may be regarded as falling within the range of
normal biologic variation. The syndrome has no deleterious associations and an excellent prognosis, and affected persons
can lead a normal lifestyle. As further confirmation of its benign nature, studies have reported excellent results in patients
undergoing living-donor liver transplantation from donors with Gilbert syndrome.[52, 53]

Epidemiologic studies have reported an association between Gilbert syndrome, hyperbilirubinemia, and a reduced risk of
cardiovascular disease.[54, 55, 56] The exact mechanism for this finding is unclear, but the antioxidant properties of bilirubin
may be contributory in conjunction with heme oxygenase.[57, 58, 59] (See the image below.) Moreover, mildly elevated
unconjugated bilirubin appears to be associated with reduced platelet activation-related thrombogenesis and inflammation in
patients with Gilbert syndrome, which may play a role in protecting these individuals from cardiovascular mortality.[56]
Unconjugated Hyperbilirubinemia. Production of bilirubin.

Clinicians need to be aware that patients with Gilbert syndrome may be at higher risk of developing toxicity from certain
medications (eg, irinotecan) and protease inhibitors (eg, atazanavir,[60, 61] indinavir) that can inhibit UGT metabolism.[62] A
study by Lankisch et al reported that the risk of severe hyperbilirubinemia with indinavir was associated with genetic variants
of UGT1A3 and UGT1A7 genes in addition to Gilbert syndrome (UGT1A1*28).[63]

Kweekel et al reported that patients who were more likely to develop the side effects of irinotecan toxicity, such as life-
threatening neutropenia and diarrhea, were more likely to have an underlying liver disease, hepatic conjugation disorders, or
UGT1A1*28 genotype.[64] However, due to a lack of prospective data, the relationship between the UGT1A1 genotype and
irinotecan toxicity remains unclear, although the irinotecan product label recommends reducing the irinotecan dose in
patients with this genotype.

Increased production of bilirubin

The prognosis for ineffective erythropoiesis (ELB production) appears to be excellent. Similar to other causes of enhanced
bilirubin production, however, it predisposes patients to cholelithiasis.

Patient Education
Educate patients and families about the chronicity of the disease and the need for lifelong treatment. Instruct them to
immediately report any change in the patient's mental or neurologic status.

Genetic counseling is recommended for prospective parents with a family history of Crigler-Najjar syndrome.

Presentation
History
Increased bilirubin production

Ineffective erythropoiesis (ELB production) is characterized by the onset of asymptomatic jaundice.

Impaired conjugation of bilirubin

Crigler-Najjar (CN) syndrome type 1

Apart from jaundice, the affected infant usually appears healthy at birth. Jaundice develops in the first few days of life and
rapidly progresses by the second week; therefore, exchange transfusion is warranted despite phototherapy. A family history
that includes consanguinity, relatives with severe jaundice without hemolysis, or relatives with evidence of liver disease and
a history of exchange transfusion further supports the diagnosis.

Because of its autosomal recessive transmission, consanguinity is a risk factor for Crigler-Najjar syndrome type 1.

Crigler-Najjar syndrome type 2

Usually, no clinical symptoms except for jaundice are reported with this disease entity. However, bilirubin encephalopathy
has been reported.

Gilbert syndrome

Diagnosis is made in patients who have no past history of liver disease and manifest only jaundice on clinical examination.

At least 30% of patients with Gilbert syndrome are asymptomatic, although nonspecific symptoms, such as abdominal
cramps, fatigue, and malaise, are common. No relationship exists between the abdominal symptoms and plasma bilirubin
levels.

Abdominal symptoms may be multifactorial, with underlying anxiety probably playing an important role. Although it is true
that not all patients with Gilbert syndrome and abdominal symptoms are anxious, they nonetheless appear to have organic-
type discomfort that is hard to characterize and frequently eludes diagnosis.

Neonatal jaundice

Benign neonatal hyperbilirubinemia

Benign neonatal hyperbilirubinemia (physiologic jaundice) is clinically obvious in 50% of neonates during the first 5 days of
life.

Nonphysiologic

In maternal serum jaundice (Lucey-Driscoll syndrome), jaundice occurs during the first 4 days of life.

Physical Examination
Crigler-Najjar syndrome

Type 1

Patients with Crigler-Najjar syndrome type 1 appear healthy at birth, with no signs of liver disease. Patients may present with
evidence of kernicterus, the clinical manifestations of which are hypotonia, deafness, oculomotor palsy, lethargy, and,
ultimately, death.

Type 2

Apart from jaundice, physical findings are usually normal in Crigler Najjar syndrome type 2, with no signs of hemolysis or
liver disease.

Gilbert syndrome

Apart from mild jaundice, physical examination findings in infants with Gilbert syndrome are normal.

DDx

Diagnostic Considerations
The American Academy of Pediatrics established guidelines for the diagnosis and treatment of hyperbilirubinemia in
newborns in 2022.[65] These are available through the American Academy of Pediatrics.

Ineffective erythropoiesis (ELB production)

A marked increase in early-labeled bilirubin (ELB) formation has been documented in diseases associated with ineffective
erythropoiesis, including the following:

Iron deficiency anemia

Pernicious anemia

Thalassemia

Erythropoietic porphyria

Lead poisoning

Although no specific test exists for physiologic jaundice, other causes of jaundice should be considered in infants with one or
more of the following:

Jaundice occurring within 24 hours of birth

Serum concentrations of unconjugated bilirubin of 11-12 mg/dL in infants who are formula-fed or 14-15 mg/dL in
infants who are breastfed

Increased levels of conjugated bilirubin (>2 mg/dL)

Jaundice persisting for more than 2 weeks

Gilbert syndrome
Gilbert syndrome has a broad differential diagnosis because numerous causes of unconjugated hyperbilirubinemia must be
considered. In particular, the possibility of biliary disease must be taken into account.

Other conditions
Other conditions to be considered include the following:

Physiologic neonatal jaundice

Hemolysis

Hematoma

Acute and chronic liver disease

Primary hyperbilirubinemia from ineffective erythropoiesis

Infections

Cardiac disease (eg, congestive heart failure or prosthetic heart valves)

Rhabdomyolysis

High-altitude living

Medications (eg, probenecid, rifampicin, or other antibiotics)

Thyrotoxicosis

Additional considerations in the diagnosis of impaired bilirubin conjugation include the following:

Dyserythropoiesis

Portosystemic shunts

Neonates

Hyperthyroidism

Ethinyl estradiol

Differential Diagnoses
Iron Deficiency Anemia

Pediatric Lead Toxicity

Pernicious Anemia

Workup

Workup

Approach Considerations
All patients with impaired bilirubin conjugation have an elevated total serum bilirubin level that is due primarily to the
unconjugated form; however, the level of elevation varies according to the underlying disease process.

Transient elevations of plasma bilirubin may be seen in healthy neonates. The plasma bilirubin usually returns to normal
within 10 days. For infants in whom the plasma bilirubin level remains elevated, search for the inherited disorders of bilirubin
metabolism.

In neonates, transcutaneous devices that use multiwavelength spectral reflectance can be used to estimate total serum
bilirubin levels and avoid blood sampling. At higher total serum bilirubin levels, the transcutaneous measurements may
underestimate the total serum bilirubin concentration; therefore, serum measurements should be obtained. Also, the
transcutaneous measurements are not reliable in infants undergoing phototherapy.

In a study, Cakmak et al suggested that by measuring haptoglobin levels from the cord blood, neonatologists and
pediatricians could stratify neonates into high- versus low-risk groups for developing jaundice, leading to earlier intervention.
Because haptoglobin levels decrease during hemolysis, which in turn plays a significant role in raising the serum bilirubin
levels in neonates, the investigators examined the relationship between decreasing haptoglobin levels and the risk of
jaundice in 84 term babies.[66]

The average gestational age of the mothers was 39.5 ±1.5 weeks. The authors noted a negative correlation between
haptoglobin levels drawn from the umbilical cord blood and bilirubin values on the fifth postpartum day.

Crigler-Najjar Syndrome
Although no simple, widely available clinical test is available to confirm the diagnosis of Crigler-Najjar syndrome,
unconjugated hyperbilirubinemia in the presence of normal liver function test findings is characteristic of the disease.

Direct bilirubin is less than 15% of the total serum bilirubin in Crigler-Najjar syndrome. High-performance liquid
chromatography analysis of duodenal bile reveals that, in Crigler-Najjar syndrome type 1, negligible bilirubin diglucuronides
or monoglucuronides are present; in the type 2 syndrome, these conjugates are present but in low concentrations. DNA
analysis can be very helpful in establishing the correct diagnosis.

Persistent unconjugated hyperbilirubinemia levels of more than 20 mg/dL after the first week of life in the absence of liver
disease or hemolysis strongly suggests UGT deficiency.

Findings on abdominal imaging studies, such as plain radiography, computed tomography (CT) scanning, and
ultrasonography, are normal in Crigler-Najjar syndrome.

Definitive diagnosis of Crigler-Najjar syndrome requires high-performance liquid chromatography of bile or a tissue enzyme
assay of a liver biopsy sample.

Crigler-Najjar syndrome type 1

Except for the presence of high serum unconjugated bilirubin levels, the results of liver tests in Crigler-Najjar syndrome type
1 are normal. Serum bilirubin levels range from 20-50 mg/dL. Conjugated bilirubin is absent from serum, and bilirubin is not
present in urine.

Bile collected through duodenal aspiration is light yellow because of small amounts of unconjugated bilirubin. Bilirubin
conjugates are nearly absent from the bile.

Crigler-Najjar syndrome type 2

Crigler-Najjar syndrome type 2 results in lower bilirubin concentrations than does type I, with levels ranging from 7-20 mg/dL.
Higher bilirubin levels may be seen if coexisting hemolysis or an intercurrent illness is present.

This disorder may be distinguished definitively from type 1 by chromatographic analysis of pigments excreted in bile. In type
2, bile contains significant amounts of conjugated bilirubin, although the proportion of bilirubin monoglucuronide in bile is
increased.

Transferase activity measurements and the response to phenobarbital treatment can also distinguish Crigler-Najjar
syndrome type 1 from type 2. Phenobarbital has no effect in type 1 but causes an approximately 25% reduction in plasma
bilirubin level in most patients with type 2.

Liver function testing

Liver enzyme levels are usually within the reference range. Occasionally, however, these levels may be somewhat elevated,
as a result of intrahepatic cholestasis.

Percutaneous liver biopsy

Liver biopsy reveals normal histology other than the occasional bile plugs in the bile canaliculi. Bile is sometimes observed in
the portal triad, in dilated bile canaliculi, in hepatocytes, and in the Kupffer cells.

Enzymatic assay of liver tissue reveals absent UGT activity in Crigler-Najjar syndrome type 1 and diminished activity in
Crigler-Najjar syndrome type 2.

Gilbert Syndrome
As a rule, Gilbert syndrome can be diagnosed by a thorough history and physical examination and confirmed by standard
blood tests. Repeated investigations and invasive procedures are not usually justified for establishing a diagnosis.

Hyperbilirubinemia is the only biochemical serum abnormality in Gilbert syndrome. Serum bilirubin concentrations range
from 1-5 mg/dL. Two provocative tests, energy deprivation and nicotinic acid administration, have been used to diagnose the
condition. However, a significant number of false-positive and false-negative results limit the value of these tests in patients
with marginal elevation of serum bilirubin concentration.

A polymerase chain reaction (PCR) assay has also been introduced to identify TA repeats and may be used as a screening
test.

A complete blood count (CBC), including a reticulocyte count and a blood smear, is a useful screening test for excluding
hemolysis. Rarely, red blood cell abnormalities resembling variegate porphyria, possibly resulting from the increased
hepatocellular bilirubin concentration, have been described in persons with Gilbert syndrome.

Serum lactate dehydrogenase (LDH) levels are elevated in persons with hemolysis but are normal in those with Gilbert
syndrome.

A familial increase in serum alkaline phosphatase (ALP) levels has been reported in some persons with Gilbert syndrome.

Additional diagnostic tests are rarely required, because a diagnosis of Gilbert syndrome can generally be made on the basis
of the following findings:

Unconjugated hyperbilirubinemia noted on several occasions

Normal results from the CBC, reticulocyte count, and blood smear

Normal liver function test (LFT) results

An absence of other disease processes

Nevertheless, certain specialized tests (including some that are of historical interest, as well as the newer molecular genetic
techniques) are occasionally performed to confirm a diagnosis of Gilbert syndrome. These tests are described below to
introduce the clinician to the broad diagnostic armamentarium available for diagnosing Gilbert syndrome. Recourse to these
specialized tests should be rare and is usually difficult to justify in clinical practice, given that the diagnosis of Gilbert
syndrome is generally straightforward.
Fasting test

Within 48 hours of the start of a fast, there is usually a 2- to 3-fold rise in the plasma unconjugated bilirubin level, which
returns to normal levels within 24 hours after resumption of a normal diet. Although unconjugated bilirubin levels also rise
with fasting in patients with hemolysis or liver disease, the magnitude of the rise is less than that observed with Gilbert
syndrome. A similar rise in plasma bilirubin is also observed with normocaloric diets deficient in lipids and reverses promptly
with lipid replacement.

Nicotinic acid test

Intravenous (IV) administration of 50 mg of nicotinic acid results in a 2- to 3-fold rise in plasma unconjugated
hyperbilirubinemia within 3 hours. The mechanisms are multifactorial and probably related to the following:

Elevated osmotic fragility of red blood cells

Increase in splenic production of bilirubin

Transient inhibition of hepatic bilirubin-UGT activity

Increased splenic heme oxygenase activity

Because a similar, if less impressive, increase is observed in healthy individuals and those with hemolysis or liver disease,
the nicotinic test, like the fasting test, does not clearly distinguish patients with Gilbert syndrome from those who are healthy
or who have other disease processes.

Phenobarbital test

Phenobarbital and other enzyme inducers of the bilirubin-UGT system will normalize plasma bilirubin levels in patients with
Gilbert syndrome. This effect is predominantly due to the accelerated bilirubin clearance from enzyme induction, but it is also
due to reduced bilirubin turnover. Steroids can also reduce plasma bilirubin levels in Gilbert syndrome, by increasing the
hepatic uptake and storage of bilirubin.

Radiolabeled chromium test

The radiolabeled chromium test is used to measure red blood cell survival. As many as 60% of patients with Gilbert
syndrome have a mild and fully compensated state of hemolysis together with increased hepatic heme production. This
means that hyperbilirubinemia may develop due to reduced clearance, as well as increased production, of bilirubin, with
higher production resulting from increased erythroid or hepatic heme turnover.

Thin-layer chromatography

Thin-layer chromatography is diagnostic of Gilbert syndrome when it shows a significantly higher proportion of unconjugated
bilirubin than is seen in individuals with chronic hemolysis or liver disease or is found in healthy individuals. If confirmation of
the diagnosis is truly essential, chromatographic determination is of potential use. In Gilbert syndrome, this shows an
increased ratio of bilirubin monoglucuronide to diglucuronide, reflecting reduced bilirubin-UGT activity.

Drug clearance test

In approximately 30% of patients with unconjugated hyperbilirubinemia, there is impaired clearance of bromosulfophthalein,
indocyanine green, and free fatty acid, suggesting an abnormality in hepatic uptake, transport, or both. Metabolic clearance
of tolbutamide is also reduced in persons with Gilbert syndrome, but because the drug does not undergo glucuronidation,
hepatic uptake appears to be defective.

Plasma clearance of most drugs that undergo glucuronidation (eg, benzodiazepines) is unaffected. With regard to
acetaminophen, however, patients with Gilbert syndrome are a heterogeneous group, with some demonstrating normal
metabolism and others exhibiting marked reduction in glucuronidation and an increase in oxidation.[67, 68] These changes
suggest that people in this subgroup may be more susceptible to liver injury after an acetaminophen overdose, though no
such adverse events have been reported.

Polymerase chain reaction assay

PCR assay is a novel and rapid method of identifying genetic polymorphisms in the TATA box of the UGT1A1 gene by using
fluorescence resonance energy transfer. It is well recognized that genetic testing can confirm the diagnosis of Gilbert
Syndrome in settings where there is diagnostic confusion.

Imaging studies

Japanese researchers have reported that patients with schizophrenia associated with Gilbert syndrome have specific
changes in the signal intensities on fluid-attenuated inversion-recovery magnetic resonance imaging (FLAIR MRI) scans.
This suggests that schizophrenia with associated Gilbert syndrome may produce changes in the frontotemporal cortex,
limbic system, and basal ganglia.

Percutaneous liver biopsy

Liver biopsies are not performed routinely in Gilbert syndrome and are rarely necessary. Histologically, the liver is normal in
persons with this disorder, except for occasional accumulation of a lipofuscin-like pigment around the terminal hepatic
venules.

Neonatal Jaundice and Ineffective Erythropoiesis

Benign neonatal hyperbilirubinemia

In benign neonatal hyperbilirubinemia (physiologic jaundice), the peak total serum bilirubin level is 5-6 mg/dL (86-103
µmol/L), occurs at age 48-120 hours, and does not exceed 17-18 mg/dL (291-308 µmol/L).

Breast milk jaundice

In breast milk jaundice, bilirubin can increase to levels as high as 20 mg/dL, necessitating the need for phototherapy and the
discontinuation of breastfeeding.

Increased production of bilirubin

Ineffective erythropoiesis (ELB production) is characterized by a marked increase in fecal urobilinogen excretion and a
normal or near-normal red blood cell lifespan.

Treatment

Approach Considerations
Gilbert syndrome

Once the diagnosis of Gilbert syndrome is established, the most important aspect of treatment is reassurance. The clinician
must make it perfectly clear to the patient that the syndrome is essentially benign, is not associated with increased morbidity
(except for an increased incidence of side effects from certain drugs, such as the antitumor agent irinotecan), has an
excellent prognosis, and is associated with normal life expectancy. In light of the benign and inconsequential nature of
Gilbert syndrome, the use of medications to treat patients with this condition is unjustified in clinical practice.

Crigler-Najjar syndrome

Patients with Crigler-Najjar syndrome type 2 may not require any treatment or can be managed with phenobarbital. By
contrast, prompt treatment of kernicterus is required in patients with Crigler-Najjar syndrome type 1 to avoid the potentially
devastating neurologic sequelae.

Emergent management of bilirubin encephalopathy involves plasma exchange transfusion, which acts by removing the
bilirubin-saturated albumin and providing free protein, which draws bilirubin from the tissues.

Plasma exchange should be accompanied by long-term phototherapy, which helps in the conversion of bilirubin to more
soluble isoforms that can be excreted in the urine. Oral calcium phosphate may be a useful adjuvant to phototherapy in
Crigler-Najjar syndrome type 1. (It should be kept in mind, however, that phototherapy restricts the activities of the child and
his or her family. Phototherapy also causes insensible water loss, diarrhea, tanning of the skin, and problems in maintaining
body temperature.)

Inhibitors of heme oxygenase, such as tin protoporphyrin or tin-mesoporphyrin, may be helpful in reducing bilirubin levels
emergently, but the effect is short-lived.

Therapies based on gene and cell transfer techniques, although largely experimental at the present time, are likely to play
an important role in the management of Crigler-Najjar syndrome in the future.[69, 70]

Rescue phototherapy and phototherapy in transport for severe unconjugated hyperbilirubinemia

High-intensity light-emitting diode (LED) beds may be a safe rescue therapy for severe unconjugated neonatal
hyperbilirubinemia.[71] In a study of 200 jaundiced neonates at or over 35 weeks' gestation who were phototherapy
candidates, the use of a super LED bed achieved significantly higher success rates of intensive phototherapy (87%)
compared with conventional intensive phototherapy with triple fluorescent tube units (64%). There was also a significantly
greater reduction in bilirubin levels for both hemolytic and nonhemolytic subgroups in the super LED bed treatment group
than in similar subgroups that received standard intensive phototherapy.[71]

In a retrospective study over an 11-year period of 147 neonates with severe unconjugated hyperbilirubinemia at risk of
requiring exchange transfusion who were being transported for treatment, those who received phototherapy during transport
(n=104) were less likely to require exchange transfusion (19.2% vs. 34.9%) than neonates who did not receive phototherapy
during transport (n=43).[72] Moreover, although it did not reach statistical significance, the group that received phototherapy
during transport also had an increased reduction in serum bilirubin levels from before to after transport compared to the
group that did not receive phototherapy during transport.

Prevention

Use drugs that displace bilirubin, such as sulfa, salicylates, furosemide, ampicillin, and ceftriaxone, with caution (or
completely avoid).

The bilirubin level may rapidly rise to dangerous levels under certain conditions, such as fasting, infections, trauma, fever,
and poor compliance with therapy.

Nonsurgical Correction of Bilirubin Levels

Crigler-Najjar syndrome type 1

Therapeutic response varies according to the type of Crigler-Najjar syndrome being treated. Crigler-Najjar syndrome type 1
does not respond to phenobarbital therapy, and patients may require repeated exchange transfusions followed by long-term
phototherapy to prevent neurologic complications.

Other therapies include plasmapheresis, hemoperfusion, and the administration of cholestyramine, calcium phosphate, oral
agar, and orlistat.[3] An approach to therapy using Sn-protoporphyrin, a heme oxygenase inhibitor, was introduced to
prevent an increase in serum bilirubin levels.[4] In patients with Crigler-Najjar syndrome type 1, however, liver transplantation
remains the only guaranteed form of therapy. This surgery should occur prior to the onset of kernicterus.

Phototherapy

Phototherapy causes the formation of water-soluble bilirubin isomers that can be secreted in bile without conjugation.

Patients with Crigler-Najjar syndrome type 1 generally need 10-16 hours of treatment per day. Monitor the intensity of light to
keep it at a level of at least 4-10 µW/cm2/nm. The appropriate wavelength is in the blue-green spectrum at 425-475 nm.

The efficacy of phototherapy is dose dependent; therefore, the response to phototherapy increases when the dose is
increased. Efficacy of phototherapy can be increased by increasing the intensity of light, by increasing exposure of the body
surface, and by using reflecting surfaces (eg, mirrors). Double-surface phototherapy has also been used in some cases to
improve the outcome. Oral calcium phosphate may be a useful adjuvant to phototherapy in Crigler-Najjar syndrome type 1.

The effectiveness of phototherapy decreases after age 3-4 years, because the ratio of skin surface area to body mass is
reduced.[73]

Problems associated with phototherapy include restriction of activity and play, poor compliance, inability of the patient to
travel or take vacations, irritation from the eye shades, difficulties in temperature maintenance, tanning of the skin,
embarrassment from the need to be nearly nude during phototherapy, and difficulty in procuring phototherapy lamps. Long-
term phototherapy may lead to developmental delay, impaired weight gain, and possible psychological disturbances.

More recent studies indicate that conventional and intensive phototherapy are also associated with DNA damage in term
infants with hyperbilirubinemia.[74]

Newer methods of delivering phototherapy, such as sit-up phototherapy units, may reduce phototherapy time by 50% while
maintaining its effectiveness and, thus, may allow a child to attend school.

Exchange transfusion

As previously mentioned, emergent management of bilirubin encephalopathy involves plasma exchange transfusion, which
acts by removing bilirubin-saturated albumin and providing free protein, which draws bilirubin from the tissues. Plasma
exchange should be accompanied by long-term phototherapy. Treatment with exchange transfusions and phototherapy
should be initiated early.

Gene therapy

Gene therapy offers the greatest potential for cure for patients with Crigler-Najjar syndrome. Successful cloning of the gene
responsible for bilirubin glucuronosyltransferase activity offers the hope of future gene therapy to correct this deficiency.[69]

Clinically significant improvement can be achieved even with partial enzyme replacement. About 5% of normal UGT 1A1 can
significantly lower the plasma bilirubin concentration and decrease the need for phototherapy.

Long-term monitoring

Despite medical treatment, patients are at risk for sudden increases in serum bilirubin levels. Parents and physicians should
be alert to such bilirubin crises. The child usually presents with altered sensorium, incoordination, slurring of speech, and
weakness. Coma may eventually occur.

Treatment of severe episodes of hyperbilirubinemia includes intense phototherapy, exchange transfusion, plasmapheresis,
and tin-mesoporphyrin. During periods of illness, kernicterus may occur at a low level of bilirubin.
Crigler-Najjar syndrome type 2

Phenobarbital therapy has been shown to be effective in reducing plasma bilirubin levels in patients with Crigler-Najjar
syndrome type 2. Administration of 60-180 mg/day of the drug (in divided doses) can reduce serum bilirubin levels by at
least 25%. A response should be expected within 2-3 weeks. A similar benefit can be observed with clofibrate, which is
associated with fewer adverse effects. (Clofibrate is no longer on the US market.) However, patients with the type 2
syndrome often do well even without therapy.

In rare cases, however, patients with Crigler-Najjar syndrome type 2 require exchange transfusions or long-term
phototherapy.

Gilbert syndrome

No therapy is necessary for patients with Gilbert syndrome. However, many therapeutic approaches have been used. As
with Crigler-Najjar type II syndrome, phenobarbital has been shown to decrease bilirubin production. The most important
aspect in the care of patients with Gilbert syndrome, however, is recognition of the disorder and its inconsequential nature.

Toxicity

Irinotecan toxicity in Gilbert syndrome is of some concern, however. As a result of a mutation in the UGT1A1 gene promoter,
affected patients show reduced inactivation of the active topoisomerase inhibitor 7-ethyl-10-hydroxycampothecin (SN-38).
Glucuronidation rates of the active metabolite SN-38 are significantly lower in people who are homozygous and
heterozygous for the TA-TATAA variant allele than in those with the wild-type genotype (TATAA).

In patients with Gilbert or Crigler-Najjar syndrome, reduced glucuronidation of SN-38 leads to SN-38 toxicity and causes
symptoms such as diarrhea. Preliminary results from clinical trials suggest that screening cancer patients for the UGT1A1
promoter polymorphism may reduce the prevalence of irinotecan toxicity. Until this evidence is available, caution is
warranted before irinotecan is prescribed to this subset of patients.

Pharmacogenetics

The clinical relevance of pharmacogenetics in Gilbert syndrome has yet to be determined. Although impaired glucuronidation
and excretion of certain drugs have been reported, such impairment has not resulted in any adverse clinical events, and the
risk probably remains more theoretical than real.[62, 63]

Neonatal jaundice

No treatment is needed for benign neonatal hyperbilirubinemia (physiologic jaundice). For breast milk jaundice and other
types of nonphysiologic jaundice, phototherapy can be used.

Phototherapy, which consists of exposing the infant's skin to light, is a safe and efficient method to reduce the toxicity of
bilirubin and to increase its elimination. The use of phototherapy decreases the risk that the total serum bilirubin
concentration will reach the level at which exchange transfusion is recommended.[75]

Maintaining adequate hydration and urine output is important during phototherapy to prevent dehydration.

An uncommon complication of phototherapy is the so-called bronze baby syndrome. This occurs in some infants with
cholestatic jaundice and is manifested by a dark, grayish brown discoloration of the skin, serum, and urine. The condition
gradually resolves without sequelae within several weeks after discontinuation of therapy.

Liver and Hepatocyte Transplantation

Liver transplantation
Liver transplantation remains the sole definitive treatment for Crigler-Najjar syndrome type 1.[76, 77] Cadaveric orthotopic
and auxiliary and living related liver transplantation have resulted in excellent survival rates and prognoses.

Early liver transplantation in patients with Crigler-Najjar syndrome type 1 decreases the incidence of neurologic deficits,
especially for patients in whom reliable administration of phototherapy cannot be guaranteed.[78, 79]

Hepatocyte transplantation

Hepatocyte transplantation has become an effective therapy for patients with inborn metabolic errors. It involves
catheterization of the portal vein and an infusion of donor hepatocytes.[78, 80, 81, 82]

The immunosuppression regimen is similar to that administered to patients receiving whole-organ transplantation and
currently includes tacrolimus and prednisolone.

Stem cells and stem cell–derived hepatocytes should offer the potential to overcome the current limitations on the supply of
hepatocytes and on the extent of repopulation of the liver after transplantation.[83]

Hepatocyte transplantation has been reported to decrease the need for phototherapy and to increase the activity of UGT to
5.5% of normal.

In a report, hepatocyte transplantation resulted in bilirubin levels decreasing to and maintaining the long-term stabilization at
about 50% of the values found prior to cell infusion.[84]

Guidelines

Guidelines Summary
Updated guidelines on the management of hyperbilirubinemia in newborn infants of 35 or more weeks of gestation were
published in August 2022 by the American Academy of Pediatrics (AAP) in Pediatrics.[65] Neonatal hyperbilirubinemia is
common, and complications are rare; early identification of potential severe and devastating neurologic effects such as acute
encephalopathy and kernicterus is crucial. Select strong or moderate recommendations are summarized below.

Prevention

Infants of mothers with unknown (due to no prenatal antibody screening) or positive maternal antibody screening should
undergo direct antiglobulin testing (DAT) as well as blood typing via cord or peripheral blood.

Avoid oral supplementation with water or dextrose water for prevention of hyperbilirubinemia or for reducing bilirubin
concentrations (strong recommendation).

Assessment and Monitoring

Total serum bilirubin (TSB) should be the definitive test for guiding phototherapy and escalating care, including exchange
transfusion.

Visually assess all infants for jaundice a minimum of every 12 hours post delivery until discharge. Measure levels of TSB or
transcutaneous bilirubin (TcB) as soon as possible for infants observed to be jaundiced less than 24 hours after birth (strong
recommendation).

For identification of potential pathologic stasis, measure total and direct-reacting (or conjugated) levels of bilirubin in
breastfed infants still jaundiced at age 3-4 weeks, as well as formula-fed infants still jaundiced at age 2 weeks.

Treatment
The AAP provides new TSB thresholds for intensive phototherapy on the basis of infants’ gestational age, risk factors for
hyperbilirubinemia neurotoxicity, and age in hours. (However, infants may be treated at lower levels, based on individual
circumstances, family preferences, and shared decision-making with clinicians.)

In the setting of inpatient phototherapy, measure TSB within 12 hours of initiation. Guide the timing of the first
postphototherapy TSB measurement and the frequency of TSB monitoring during phototherapy based on infants’ age, the
presence of risk factors for hyperbilirubinemia neurotoxicity, and TSB level and trajectory.

In the setting of home phototherapy, measure TSB daily. Admit the infant for inpatient phototherapy with elevations of TSB,
narrowing of the difference between the TSB and phototherapy threshold, or when the TSB level is at least 1 mg/dL above
the phototherapy threshold.

To evaluate for anemia or obtain a baseline in case anemia develops in infants requiring phototherapy, measure hemoglobin
concentration, hematocrit, or complete blood count (CBC). For assessing the underlying cause(s) of hyperbilirubinemia in
infants requiring phototherapy, obtain a DAT in infants of mothers with a positive antibody screen, a maternal O blood group
regardless of Rh(D) status, or mothers who are Rh(D)-.

Measure glucose-6-phosphate dehydrogenase (G6PD) activity in any infant with jaundice of unknown cause in the setting of
TSB elevations despite intensive phototherapy, sudden TSB increases or increases after an initial decline, or escalation of
care.

Base repeat postphototherapy bilirubin measurement on the risk of rebound hyperbilirubinemia. Measuring TcB instead of
TSB is an option if at least 24 hours have passed since the cessation of phototherapy.

Escalate care when an infant’s TSB reaches or exceeds the escalation-of-care threshold (2 mg/dL below the exchange
transfusion threshold) for infants without known risk factors for hyperbilirubinemia neurotoxicity, or for infants with rising TSB
despite phototherapy or infants with at least one recognized risk factor for hyperbilirubinemia.

When escalation of care is required, obtain STAT levels of total and direct-reacting serum bilirubin, CBC, serum albumin and
chemistries, as well as type and crossmatch.

Measure TSB at least every 2 hours from the initiation of escalation of care until the end of such escalation of care. When
the TSB is below the threshold of escalation of care, follow the recommendations for monitoring infants on phototherapy.

Predischarge, provide all families with written and verbal education about neonatal jaundice. Provide written information for
ease of postdischarge care (eg, date, time, place of follow-up appointment; a prescription and follow-up appointment for TcB
or TSB, as needed). Provide the infant’s primary care provider with the birth hospitalization information (eg, last TcB or TSB
and the age at measurement, any DAT results). If it is unclear who will provide the infant’s follow-up care, provide such
information to the families. (Strong recommendation).

Medication

Medication Summary
In Crigler-Najjar syndrome type 2, patients with symptomatic jaundice are occasionally treated to improve their quality of life.

In patients with Crigler-Najjar syndrome type 1, phenobarbital, ursodeoxycholic acid, calcium (infusions), metalloporphyrins,
cholestyramine, chlorpromazine, and clofibrate (no longer on the US market), as well as alkalinization of urine, have all been
considered as potential therapies. Problems associated with the use of cholestyramine include taste and concern about bile
salt depletion and fat malabsorption. The exact roles and adverse effects of many of these drugs are not yet defined.

Metalloporphyrins have been used as a synthetic analogue of heme to inhibit the heme oxygenase enzyme, the rate-limiting
step in heme catabolism to bilirubin. Tin mesoporphyrin (SnMp) is the drug of choice (DOC) for clinical use because of its
increased potency, stability, and photophysical properties.
For Gilbert syndrome, no medical therapy is needed. As with Crigler-Najjar syndrome type 2, phenobarbital has been shown
to decrease bilirubin production.

Anticonvulsants

Class Summary
These drugs induce hepatic-enzyme metabolism, decreasing serum bilirubin levels. They are used to avoid potentially
devastating neurologic sequelae in Crigler-Najjar syndrome type 1 and for the management of neurologic symptoms in
Crigler-Najjar syndrome type 2.

Phenobarbital
Phenobarbital increases the conjugation and excretion of bilirubin. It reduces serum bilirubin levels by at least 25%.

The drug functions by means of phenobarbital-responsive enhancer module that stimulates the gene for UGT 1A1 to induce
production of bilirubin-conjugating enzyme. It does not, however, directly act on the UGT enzyme, as previously thought.

Phenobarbital is used to treat Crigler-Najjar syndrome type 2 and as an adjunct to phototherapy in some cases of Crigler-
Najjar syndrome type 1. In addition, it has been shown to be effective in the treatment and prevention of neonatal
hyperbilirubinemia.

Lipid-Lowering Agents

Class Summary
Agents in this class reduce serum bilirubin levels. They have been used for their effects in lowering bilirubin levels in
newborns.

Fenofibrate (TriCor, Triglide, Antara)

Fenofibrate lowers serum triglycerides and very low-density lipoprotein (VLDL) levels. However, in addition to its
hypolipidemic action, it also has the ability to induce bilirubin conjugation.

Calcium Salts

Class Summary
These agents bind bilirubin in the gut, enhancing bilirubin’s fecal excretion.
Calcium phosphate (Posture)
Calcium phosphate may reduce plasma bilirubin concentration in Crigler-Najjar syndrome type 1 and may be a useful
adjunct to phototherapy in reducing serum bilirubin levels.

Gallstone-Solubilizing Agents

Class Summary
Ursodeoxycholic acid (or ursodiol) partially replaces the circulating pool of endogenous bile acids. Because it is highly
hydrophilic, it replaces toxic detergent bile acids (eg, chenodeoxycholic acid, lithocholic acid). This effect may enhance the
biliary excretion of the toxic bile acids and may protect cells against liver-cell toxicity induced by detergent bile acids.

Ursodeoxycholic acid (Actigall, Urso)

This agent decreases liver enzymes (by decreasing liver-cell toxicity) and is therefore recommended in chronic liver disease.
Routine administration in Crigler-Najjar syndrome has not been universally adopted.

Antipsychotics, Phenothiazine

Class Summary
These drugs are used in therapy for acute intermittent porphyria, psychotic disorders, nausea, and vomiting.

Chlorpromazine
This agent is usually employed to treat acute intermittent porphyria, psychotic disorders, nausea, and vomiting. It is
recommended as an adjunct to phototherapy in the treatment of Crigler-Najjar syndrome type 1.

Questions & Answers

Overview

What causes unconjugated hyperbilirubinemia?

What are the signs and symptoms of unconjugated hyperbilirubinemia?

How is Crigler-Najjar syndrome type 1 diagnosed?

How is Crigler-Najjar syndrome type 2 diagnosed?

How is Gilbert syndrome diagnosed?

How are total serum bilirubin levels used to diagnose physiologic neonatal jaundice?

How are total serum bilirubin levels used to diagnose breast milk jaundice?

How is ineffective erythropoiesis characterized?

What are the treatment options for Crigler-Najjar syndrome type 1?

What are the treatment options for Crigler-Najjar syndrome type 2?

Which medications are used in the treatment of Gilbert syndrome?

When is phototherapy indicated for the treatment of unconjugated hyperbilirubinemia?

What is unconjugated hyperbilirubinemia?

What is Gilbert syndrome?

What is the biochemistry of bilirubin relative to unconjugated hyperbilirubinemia?

What leads to an increased production of bilirubin in unconjugated hyperbilirubinemia?

What causes impaired hepatic bilirubin uptake in unconjugated hyperbilirubinemia?

How is physiologic jaundice characterized in newborns?

What are the types of nonphysiologic jaundice in unconjugated hyperbilirubinemia?

What causes ABO/Rh incompatibility leading to neonatal jaundice?

What are the inherited defects of bilirubin conjugation in unconjugated hyperbilirubinemia?

What is Crigler-Najjar syndrome?

What are the forms of Crigler-Najjar syndrome?

What is the pathophysiology of unconjugated hyperbilirubinemia?

What is the pathophysiology of ineffective erythropoiesis in unconjugated hyperbilirubinemia?

What is pathophysiology of neonatal jaundice in unconjugated hyperbilirubinemia?

Which factors contribute to the development of physiologic jaundice in unconjugated hyperbilirubinemia?

What is the pathophysiology of nonphysiologic jaundice in unconjugated hyperbilirubinemia?

What is the pathophysiology of impaired conjugation of bilirubin in unconjugated hyperbilirubinemia?

What is the pathophysiology of Gilbert syndrome?

What is the role of UGT mutations in the pathophysiology of Gilbert syndrome?

What causes increased bilirubin production in unconjugated hyperbilirubinemia?

What causes impaired hepatic bilirubin uptake in unconjugated hyperbilirubinemia?

What causes impaired bilirubin conjugation in unconjugated hyperbilirubinemia?

What is the incidence of unconjugated hyperbilirubinemia in the US?

What is the global incidence of unconjugated hyperbilirubinemia?

What are the racial predilections of unconjugated hyperbilirubinemia?

How does the incidence of unconjugated hyperbilirubinemia vary by sex?

At what age do the symptoms of unconjugated hyperbilirubinemia first appear?

What is the prognosis of breast milk jaundice in unconjugated hyperbilirubinemia?

What is the prognosis of maternal serum jaundice in unconjugated hyperbilirubinemia?

What is the prognosis of Crigler-Najjar syndrome type 1?

What is the prognosis of Crigler-Najjar syndrome type 2?

What is the prognosis of Gilbert syndrome?

What is the prognosis of ineffective erythropoiesis (ELB production)?

What should be included in patient education about unconjugated hyperbilirubinemia?

Presentation

What is the clinical history of ineffective erythropoiesis (ELB production)?

What is the clinical history of Crigler-Najjar (CN) syndrome type 1?

What is the clinical history of Crigler-Najjar (CN) syndrome type 2?

What is the clinical history of Gilbert syndrome?

What is the clinical history of physiologic and nonphysiologic neonatal jaundice in unconjugated hyperbilirubinemia?

Which physical findings suggest Crigler-Najjar syndrome?

Which physical exam findings are characteristic of Gilbert syndrome?

DDX

What guidelines have been published for the diagnosis and treatment of unconjugated hyperbilirubinemia?

Which diseases are associated with ineffective erythropoiesis?

What other causes of jaundice should be included in the differential diagnoses for infants with unconjugated
hyperbilirubinemia?

What are diagnostic considerations in Gilbert syndrome?

Which conditions should be considered in the differential diagnoses of unconjugated hyperbilirubinemia?

What are the differential diagnoses for Unconjugated Hyperbilirubinemia?

Workup

What is the significance of elevated total serum bilirubin level in the evaluation of unconjugated hyperbilirubinemia?

How is Crigler-Najjar syndrome diagnosed?

Which lab results suggest Crigler-Najjar syndrome type 1 syndrome?

Which lab results suggest Crigler-Najjar syndrome type 2 syndrome?

Which liver function testing results are characteristic of Crigler-Najjar syndrome?

What is the role of percutaneous liver biopsy in the diagnosis of Crigler-Najjar syndrome?

How is Gilbert syndrome diagnosed?

Which findings are diagnostic of Gilbert syndrome?

What is the role of a fasting test in the workup of Gilbert syndrome?

What is the role of a nicotinic acid test in the workup of Gilbert syndrome?

What is the role of a phenobarbital test in the workup of Gilbert syndrome?

What is the role of a radiolabeled chromium test in the workup of Gilbert syndrome?

What is the role of thin-layer chromatography in the workup of Gilbert syndrome?

What is the role of a drug-clearance test in the workup of Gilbert syndrome?

What is the role of polymerase chain reaction (PCR) assay in the workup of Gilbert syndrome?

What is the role of imaging studies in the workup of Gilbert syndrome?

What is the role of percutaneous liver biopsy in the workup of Gilbert syndrome?

What peak total serum bilirubin level is diagnostic of physiologic jaundice in unconjugated hyperbilirubinemia?

At what bilirubin level is phototherapy indicated for breast milk jaundice in unconjugated hyperbilirubinemia?

Which lab results are characteristic of ineffective erythropoiesis (ELB production) in unconjugated hyperbilirubinemia?

Treatment

What are treatment options for Gilbert syndrome?

What are the treatment options for Crigler-Najjar syndrome?

What is the role of phototherapy in the treatment of severe unconjugated neonatal hyperbilirubinemia?

How is unconjugated hyperbilirubinemia prevented?

What is the therapeutic response to nonsurgical correction of bilirubin levels in Crigler-Najjar syndrome type 1?

What is the efficacy of phototherapy for the treatment of Crigler-Najjar syndrome type 1?

What is the role of plasma exchange transfusion in the treatment of Crigler-Najjar syndrome type 1?

What is the role of gene therapy in the treatment of Crigler-Najjar syndrome type 1?

Why is long-term monitoring required in the management of Crigler-Najjar syndrome type 1?

What are the nonsurgical options for Crigler-Najjar syndrome type 2?

What are the nonsurgical options for Gilbert syndrome?

How is phototherapy administered in the treatment of nonphysiologic jaundice in unconjugated hyperbilirubinemia?

When is liver transplantation indicated in the treatment of unconjugated hyperbilirubinemia?

What is the efficacy of hepatocyte transplantation for the treatment of unconjugated hyperbilirubinemia?
Medications

Which medications are indicated in the treatment of unconjugated hyperbilirubinemia?

Which medications in the drug class Antipsychotics, Phenothiazine are used in the treatment of Unconjugated
Hyperbilirubinemia?

Which medications in the drug class Gallstone-Solubilizing Agents are used in the treatment of Unconjugated
Hyperbilirubinemia?

Which medications in the drug class Calcium Salts are used in the treatment of Unconjugated Hyperbilirubinemia?

Which medications in the drug class Lipid-Lowering Agents are used in the treatment of Unconjugated Hyperbilirubinemia?

Which medications in the drug class Anticonvulsants are used in the treatment of Unconjugated Hyperbilirubinemia?

Contributor Information and Disclosures

Author

Michael Nicholas Gianarakis, MBBS Resident Physician, Department of Internal Medicine, University of Illinois at Chicago
College of Medicine

Michael Nicholas Gianarakis, MBBS is a member of the following medical societies: American Association for the Study of
Liver Diseases, American College of Physicians, American Gastroenterological Association, American Society of Nephrology

Disclosure: Nothing to disclose.

Coauthor(s)

Elie M Ghoulam, MD, MS Gastroenterologist and Hepatologist, Quincy Medical Group

Elie M Ghoulam, MD, MS is a member of the following medical societies: American Association for the Study of Liver
Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for
Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases,
American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal
Endoscopy

Disclosure: Nothing to disclose.

Additional Contributors
Hisham Nazer, MBBCh, FRCP, DTM&H Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and
Clinical Nutrition, University of Jordan Faculty of Medicine, Jordan

Hisham Nazer, MBBCh, FRCP, DTM&H is a member of the following medical societies: American Association for Physician
Leadership, Royal College of Paediatrics and Child Health, Royal College of Surgeons in Ireland, Royal Society of Tropical
Medicine and Hygiene, Royal College of Physicians and Surgeons of the United Kingdom

Disclosure: Nothing to disclose.

Praveen K Roy, MD, MSc Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine

Praveen K Roy, MD, MSc is a member of the following medical societies: Alaska State Medical Association, American
Gastroenterological Association

Disclosure: Nothing to disclose.

Acknowledgements

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases,
American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal
Endoscopy

Disclosure: Nothing to disclose.

Showkat Bashir, MD Assistant Professor, Department of Medicine, Division of Gastroenterology, George Washington
University, Washington, DC

Showkat Bashir, MD is a member of the following medical societies: American College of Gastroenterology, American
College of Physicians, American Gastroenterological Association, and American Medical Association

Disclosure: Nothing to disclose.

David Eric Bernstein, MD Director of Hepatology, North Shore University Hospital; Professor of Clinical Medicine, Albert
Einstein College of Medicine

David Eric Bernstein, MD is a member of the following medical societies: American Association for the Study of Liver
Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological
Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Manoop S Bhutani, MD Professor, Co-Director, Center for Endoscopic Research, Training and Innovation (CERTAIN),
Director, Center for Endoscopic Ultrasound, Department of Medicine, Division of Gastroenterology, University of Texas
Medical Branch; Director, Endoscopic Research and Development, The University of Texas MD Anderson Cancer Center

Manoop S Bhutani, MD is a member of the following medical societies: American Association for the Advancement of
Science, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association,
American Institute of Ultrasound in Medicine, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Jack Bragg, DO Associate Professor, Department of Clinical Medicine, University of Missouri School of Medicine

Jack Bragg, DO is a member of the following medical societies: American College of Osteopathic Internists and American
Osteopathic Association

Disclosure: Nothing to disclose.

Annie T Chemmanur, MD Attending Physician, Metrowest Medical Center and University of Massachusetts Memorial
Hospital, Marlborough Campus

Annie T Chemmanur, MD is a member of the following medical societies: American College of Physicians-American Society
of Internal Medicine, American Gastroenterological Association, American Medical Association, and Massachusetts Medical
Society

Disclosure: Nothing to disclose.

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins
University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American
Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and
Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Gautam Dehadrai, MD Department Chair, Section Chief, Department of Interventional Radiology, Norman Regional Hospital

Gautam Dehadrai, MD is a member of the following medical societies: American College of Radiology, Medical Council of
India, and Radiological Society of North America

Disclosure: Nothing to disclose.

Jayant Deodhar, MD Associate Professor in Pediatrics, BJ Medical College, India; Honorary Consultant, Departments of
Pediatrics and Neonatology, King Edward Memorial Hospital, India

Disclosure: Nothing to disclose.

Shirley Donelson, MD Program Director, Assistant Professor, Department of Internal Medicine, Division of Digestive
Diseases, University of Mississippi Medical School

Shirley Donelson, MD is a member of the following medical societies: American College of Gastroenterology, American
College of Physicians, American Gastroenterological Association, American Medical Association, and Mississippi State
Medical Association

Disclosure: Nothing to disclose.

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of
Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and
Hepatology, Veteran Affairs Medical Center

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Dena Nazer, MD Medical Director, Child Protection Center, Children's Hospital of Michigan; Assistant Professor, Wayne
State University

Dena Nazer, MD is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of
Pediatrics, American Professional Society on the Abuse of Children, and Helfer Society

Disclosure: Nothing to disclose.

Mohamed Othman, MD Resident Physician, Department of Internal Medicine, University of New Mexico School of Medicine

Disclosure: Nothing to disclose.

Nuri Ozden, MD Assistant Professor, Department of Internal Medicine, Meharry Medical College

Nuri Ozden, MD is a member of the following medical societies: American College of Gastroenterology, American College of
Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Tushar Patel, MB, ChB Professor of Medicine, Ohio State University Medical Center

Tushar Patel, MB, ChB is a member of the following medical societies: American Association for the Study of Liver Diseases
and American Gastroenterological Association

Disclosure: Nothing to disclose.

David A Piccoli, MD Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia;
Professor, University of Pennsylvania School of Medicine

David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases,
American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Alessio Pigazzi, MD PhD, Head, Minimally Invasive Surgery Program, Division of Surgery, Department of General Oncologic
Surgery, City of Hope National Medical Center

Disclosure: Nothing to disclose.

Praveen K Roy, MD, AGAF Gastroenterologist, Ochsner Clinic Foundation; Adjunct Associate Research Scientist, Lovelace
Respiratory Research Institute; Editor-in-Chief, The Internet Journal of Gasteroenterology; Editorial Board, Signal
Transduction Insights; Editorial Board, The Internet Journal of Epidemiology; Editorial Board, Gastrointestinal Endoscopy
Review Letter

Praveen K Roy, MD, AGAF is a member of the following medical societies: American College of Gastroenterology, American
Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Jeanette G Smith, MD Fellow, Department of Gastroenterology-Hepatology, University of Connecticut School of Medicine

Jeanette G Smith, MD is a member of the following medical societies: American College of Physicians, American
Gastroenterological Association, and American Public Health Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-
Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis
Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver
Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical
Investigation, and Association of American Physicians

Disclosure: Springer Consulting fee Consulting; Gilead Consulting fee Review panel membership; Vertex Honoraria
Speaking and teaching; Bristol-Myers Squibb Honoraria Speaking and teaching; Springer Royalty Review panel
membership; Merck Honoraria Speaking and teaching

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