Unconjugated Hyperbilirubinemia

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.

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Production of bilirubin.

Signs and symptoms

Signs/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
• 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
• Physiologic neonatal jaundice - Clinically obvious in 50% of neonates during the first 5 days of life
• Nonphysiologic 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 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

Specialized tests that have occasionally been used to confirm a diagnosis of Gilbert syndrome include the following:

• Fasting test
• Nicotinic acid test
• Phenobarbital test
• Radiolabeled chromium test
• Thin-layer chromatography
• Drug clearance test
• Polymerase chain reaction (PCR) assay
• Percutaneous liver biopsy - Very rarely performed

Physiologic neonatal jaundice

In physiologic jaundice, 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 physiologic jaundice. For breast milk jaundice and other types of nonphysiologic jaundice, phototherapy can be used.

See Treatment and Medication for more detail.

• References

Background

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. 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 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.)

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Production of bilirubin.

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Enterohepatic circulation of bilirubin.

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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).

Neonatal jaundice

Physiologic jaundice

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

Nonphysiologic jaundice

This includes breast milk jaundice, also known as maternal milk jaundice (breastfed infants have higher mean bilirubin levels than do formula-fed infants),^[5] 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. With regard to the latter, 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

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.^[6] 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.^[7] (Activation of astrocytes by unconjugated hyperbilirubinemia is believed to play a major part in kernicterus via the production of inflammatory cytokines.^[8] )

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. (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 occasionally may 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.)

• References

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.)

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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 1 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 1 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 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 1 or more UGT1A1 mutations, with variation at nucleotide 211 being the most common.^[14] 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.^[15]

Physiologic jaundice

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^[16]

Bilirubin and drug metabolism in neonates can also be affected by the influences of ethnicity on UGT1A1 haplotype mutations.^[17] 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.^[18] For example, Indian neonates were more likely to have at least 1 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.

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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,^[19] advanced cirrhosis, and Wilson disease.^[20]

Crigler-Najjar syndrome

One or more mutations in any 1 or more of the 5 exons of the gene that codes for UGT 1A1 can cause Crigler-Najjar syndrome.^{[21, 22, 23, 24]} 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 variation in the number of TA repeats and a correlation with enzyme activity suggest that these polymorphisms contribute to variations in bilirubin metabolism. An increased proportion of the bilirubin monoconjugates in bile reflects reduced transferase activity.^{[14, 25, 26, 27]}

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.^{[25, 28, 29, 30, 31, 32, 33]} There are 5 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.^{[34, 35]}

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.^{[28, 36, 37, 38, 39]}

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.^[8]

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.^[33]

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^[40] and glucose-6-phosphate deficiency (G6PD).^{[41, 42]} Much of the observed unconjugated hyperbilirubinemia could be attributed to variation at the UGT 1A1 locus.^[43]

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.^[44] 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.^[45]

• References

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)
• Neonatal physiologic jaundice
• Breast milk jaundice
• Maternal serum jaundice
• Hypothyroidism/hyperthyroidism
• Ethinyl estradiol
• Liver diseases - Chronic hepatitis,^[19] cirrhosis, and Wilson disease

• References

Epidemiology

Occurrence in the United States

There have been less 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.^[46] 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.^[6] 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 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.^[6] 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.^[47] 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.^[47]

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. 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.

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^[48]
• 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
• Physiologic jaundice 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

• References

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.^[49]

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.^[49]

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.^{[50, 51]}

Epidemiologic studies have reported an association between Gilbert syndrome, hyperbilirubinemia, and a reduced risk of cardiovascular disease.^{[52, 53, 54]} The exact mechanism for this finding is unclear, but the antioxidant properties of bilirubin may be contributory in conjunction with heme oxygenase. (See the image below.)^{[55, 56, 57]} 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.^[54]

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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,^{[58, 59]} indinavir) that can inhibit UGT metabolism.^[60] 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).^[61]

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.^[62] 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.

• References

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.

For patient education information, see the Digestive Disorders Center and the Infections Center, as well as Cirrhosis and Newborn Jaundice.

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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 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

Physiologic

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.

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Physical Examination

Crigler-Najjar syndrome

Type 1

Apart from jaundice, physical findings are usually normal in Crigler Najjar syndrome type 1, with no signs of hemolysis or liver disease.

Type 2

Patients with Crigler-Najjar syndrome type 2 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.

Gilbert syndrome

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

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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 elevation 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 bilirubin levels in neonates, the investigators examined the relationship between decreasing haptoglobin levels and the risk of jaundice in 84 term babies.^[64]

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.

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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.

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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.^{[65, 66]} 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.

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Neonatal Jaundice and Ineffective Erythropoiesis

Physiologic jaundice

In 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, the 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.

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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 life 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.^{[67, 68]}

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.^[69] 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.^[69]

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).^[70] 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.

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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 wave length 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.^[71]

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.^[72]

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.^[67]

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.^{[60, 61]}

Neonatal jaundice

No treatment is needed for 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.^[73]

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.

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Liver and Hepatocyte Transplantation

Liver transplantation

Liver transplantation remains the sole definitive treatment for Crigler-Najjar syndrome type 1.^{[74, 75]} 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.^{[76, 77]}

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.^{[76, 78, 79, 80]}

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.^[81]

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.^[82]

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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.

• References

Phenobarbital

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Fenofibrate (TriCor, Triglide, Antara)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

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

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Calcium phosphate (Posture)

Clinical Context:  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.

• References

Class Summary

These agents bind bilirubin in the gut, enhancing bilirubin’s fecal excretion.

• References

Ursodeoxycholic acid (Actigall, Urso)

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Chlorpromazine

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

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

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