AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Bilirubin is the 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.

In adults, 250-400 mg of bilirubin is produced daily. Approximately 70-80% of daily bilirubin is derived from 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 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 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 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.

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 2 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.

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 isoform, bilirubin-UGT-1 (BUGT1), is physiologically important in bilirubin glucuronidation.

This attachment occurs through an ester linkage and, therefore, is called esterification. This esterification is catalyzed by the microsomal enzyme bilirubin uridine-diphosphate glucuronosyltransferase (ie, 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. Reduction of conjugating enzyme activity to approximately 30% of normal results in a mild but discernible increase in serum bilirubin concentrations. This conjugation reaction is essential for bilirubin excretion into bile.

Deficiency of bilirubin-UGT leads to ineffective esterification of bilirubin, which, in turn, results in an unconjugated hyperbilirubinemia. Reduced bilirubin conjugation as a result of a decreased or absent UDP-glucuronosyltransferase 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.

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, advanced cirrhosis, and Wilson disease.

Three primary diseases result from abnormal bilirubin-UGT production. The severity of the resulting illness depends on the degree of bilirubin-UGT deficiency.

Crigler-Najjar syndrome, also referred to as congenital nonhemolytic jaundice with glucuronosyltransferase deficiency, is a rare, autosomal recessive disorder of bilirubin metabolism. It has been divided into 2 distinct forms (types I and II) based upon the severity of the disease. The molecular defect in Crigler-Najjar syndrome can be caused by a variety of alterations in the coding sequences of the bilirubin-uridine diphosphate glucuronosyltransferase (UGT1A1) gene, and these mutations lead to the production of an abnormal protein, resulting in complete loss or very low levels of hepatic bilirubin-UGT (UGT1A1) activity.

In contrast, the defect in Gilbert syndrome is in the promoter region, the TATAA element, rather than in the gene itself; as a result, reduced amounts of the normal protein are produced.

The absence of bilirubin-UGT leads to Crigler-Najjar type I syndrome. Crigler-Najjar type I syndrome is a disease that causes kernicterus in infants, which usually leads to death. Crigler-Najjar type II syndrome results from decreased levels of bilirubin-UGT. Kernicterus usually does not develop in this disease; therefore, the long-term prognosis is better.

Gilbert syndrome results from decreased levels of bilirubin-UGT. Gilbert syndrome results in a mild hyperbilirubinemia without any clinical sequelae. The long-term prognosis is good.

Other disease states that are seen in the neonatal period consist of physiologic jaundice and breast milk jaundice.

Physiologic jaundice is a mild unconjugated hyperbilirubinemia that affects nearly all newborns and resolves within the first several weeks after birth. It is caused by increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation.

It has been shown that bilirubin production in a term newborn is 2-3 times higher than in adults. This increased production is due to the shorter life span and the greater turnover of neonatal red blood cells. Bilirubin clearance is decreased in newborns, mainly due to the deficiency of the enzyme UGT. UGT activity in term neonates is approximately 1% of that in adults. Also, newborns have fewer intestinal bacteria than adults, resulting in a decreased capacity to reduce bilirubin to urobilinogen and subsequent higher intestinal bilirubin concentrations. In addition, the activity of beta-glucuronidase also is increased, which leads to greater hydrolysis of conjugated to unconjugated bilirubin. The unconjugated bilirubin is reabsorbed from the intestine through the process of enterohepatic circulation, further increasing the bilirubin load in the infant.

The peak total serum bilirubin level in physiologic jaundice typically 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). Higher levels of unconjugated hyperbilirubinemia are pathologic and occur in various conditions, as previously mentioned.

Breast milk jaundice results from increased enterohepatic circulation. It is thought to result from an unidentified component of human milk that enhances intestinal absorption of bilirubin. One possible mechanism for hyperbilirubinemia in breast-fed infants compared to formula-fed infants is the increased concentration of beta-glucuronidase in breast milk. Beta-glucuronidase deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing enterohepatic circulation). Blocking the deconjugation of bilirubin through beta-glucuronidase inhibition may provide a mechanism to reduce intestinal absorption of bilirubin in breast-fed infants; however, this has yet to be proven.

Frequency

United States

The frequency of the various diseases resulting from impaired bilirubin conjugation is based on the disease process. Crigler-Najjar type I syndrome is rare in the US population; reported cases number only in the hundreds. Crigler-Najjar type II syndrome also is an uncommon disease.

Gilbert syndrome affects approximately 3-7% of the population.

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

Mortality/Morbidity

The various diseases resulting from impaired bilirubin conjugation have differing prognoses.

• The Crigler-Najjar type I syndrome usually results in death during infancy, with only a few patients surviving to adolescence. The cause of death is encephalopathy from kernicterus.
• Crigler-Najjar type II syndrome results in elevated unconjugated bilirubin levels, but patients with Crigler-Najjar type II syndrome tend to live into old age and are not at risk for kernicterus. The morbidity associated with the disease is low. Many patients with Crigler-Najjar type II syndrome are unaffected by this condition.
• Gilbert syndrome is a benign disorder associated with no increase in mortality or morbidity. Patients who are affected are anicteric, with a normal life expectancy. Patients usually do not experience complications from their hyperbilirubinemia. 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.
• Physiologic jaundice is a benign disorder as well.
• Breast milk jaundice is also a benign disorder. The bilirubin levels need to be checked to avoid complications of hyperbilirubinemia. 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.

Race

In Gilbert syndrome, differences exist in the mutation of the UGT1A1 gene in certain ethnic groups. As mentioned previously, the TATAA element in the promoter region is the most common site of mutation in the Caucasian population.

No racial predilection exists for Crigler-Najjar syndrome.

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.

Sex

No sexual predilection exists in Crigler-Najjar type I and II syndromes. In Gilbert syndrome, males are affected more frequently than females. Neonatal physiologic jaundice is increased in males. Breast milk jaundice is seen equally in males and females.

Age

All of the diseases are inherited and, therefore, are present from birth. The age at which symptoms appear may vary.

• In Crigler-Najjar type I syndrome, symptoms appear within the first few days of life, and most patients die in infancy. A few patients have survived into adolescence.
• In Crigler-Najjar type II syndrome, patients have jaundice during the first few years of life.
• Patients with Gilbert syndrome usually are diagnosed when aged 10-30 years.
• Physiologic jaundice affects nearly all newborns, occurs in the first 2-5 days, 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Crigler-Najjar type I disease: The disease process appears at birth. Because the population affected by this disease overwhelmingly consists of infants, no clinical symptoms are reported.
• Crigler-Najjar type II disease: Usually, no clinical symptoms are reported with this disease entity; however, bilirubin encephalopathy has been reported.
• Gilbert syndrome: Patients may present with nonspecific symptoms such as fatigue and abdominal discomfort; however, most patients are asymptomatic.

Physical

• Crigler-Najjar type I: Physical examination findings are normal, except for jaundice. Patients may present with evidence of kernicterus. Kernicterus (the chronic and permanent sequela of bilirubin toxicity) develops during the first year after birth. The 3 major features are movement disorders (eg, chorea, ballismus, tremor), gaze abnormalities, and auditory abnormalities.
• Crigler-Najjar type II: Physical examination findings are normal, except for jaundice.
• Gilbert syndrome: Patients may present with jaundice; however, most patients are asymptomatic.

Causes

All of the diseases of impaired conjugation of bilirubin are inherited syndromes caused by abnormalities in the level of the enzyme bilirubin-UGT activity.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Extravascular hemolysis
Hematoma (extravasation of blood into tissues)
Intravascular hemolysis
Dyserythropoiesis
Congestive heart failure
Portosystemic shunts
Neonates
Hyperthyroidism
Ethinyl estradiol
Liver diseases (eg, chronic hepatitis, advanced cirrhosis, Wilson disease)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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.
• • Crigler-Najjar type I syndrome results in very high elevations in bilirubin concentrations (20-50 mg/dL).
  • Crigler-Najjar type II syndrome results in lower bilirubin concentrations than type I, with levels usually in the range of 6-22 mg/dL.
  • Gilbert syndrome results in bilirubin levels of 1-7 mg/dL.
  • 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).
  • 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.

Other Tests

• 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.

Histologic Findings

Liver histologic findings are normal in all 3 disease states.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Crigler-Najjar type I syndrome: The therapeutic goal is to produce a sustained reduction in plasma bilirubin concentration. Many different therapies have been tried in experimental protocols. No medical therapy has been found to be effective in patients with Crigler-Najjar type I syndrome; therefore, the treatment of choice for Crigler-Najjar type I syndrome is liver transplantation. Performance of liver transplantation should occur prior to the onset of kernicterus.
• • Medical therapies consist of phototherapy, plasmapheresis, calcium phosphate supplementation, calcium phosphate, and orlistat.
  • Hepatocyte transplantation is being studied as an alternative to liver transplantation.
  • Introduction of a normal bilirubin-UGT gene (UGT1A1) has the potential for curing the genetic defect leading to Crigler-Najjar syndrome.
• Crigler-Najjar type II syndrome: Phenobarbital therapy has been shown to be effective in reducing plasma bilirubin levels in patients with Crigler-Najjar type II syndrome. This can be accomplished by the administration of phenobarbital (60-180 mg/d in divided doses), which reduces 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. However, patients often do well, even in the absence of therapy.
• Gilbert syndrome: No therapy is necessary; however, many therapeutic approaches have been used. As with Crigler-Najjar type II syndrome, phenobarbital has been shown to decrease bilirubin production. The prognosis is excellent. The most important aspect in the care of these patients is recognition of the disorder and its inconsequential nature.
• Physiologic jaundice: No treatment is needed.
• Breast milk jaundice and other pathologic causes of jaundice in the neonate: Phototherapy can be used.
• • Phototherapy consists of exposing the infant's skin to light. It 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.
  • Phototherapy converts bilirubin into lumirubin in a process of structural isomerization that is not reversible. Lumirubin is a more soluble substance than bilirubin and is excreted without conjugation into bile and urine.
  • 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.

Surgical Care

Liver transplantation has been performed for the treatment of Crigler-Najjar type I syndrome.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

For Crigler-Najjar type I, no medications are effective. Combined phototherapy and exchange transfusions are beneficial in infants to prevent kernicterus. Liver transplantation is the treatment of choice.

For Crigler-Najjar type II, phenobarbital produces a fall in plasma bilirubin levels. Therapy only benefits patients cosmetically.

For Gilbert syndrome, no medical therapy is needed. As with Crigler-Najjar type II syndrome, phenobarbital has been shown to decrease bilirubin production.

Drug Category: Barbiturates

Presumably works through trophic action on the endoplasmic reticulum by increasing bilirubin-UGT activity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Most patients with Crigler-Najjar type I syndrome die in infancy.
• Patients with Crigler-Najjar type II often do well, even in the absence of therapy.
• The prognosis for Gilbert syndrome is excellent.
• The prognosis for physiologic jaundice is excellent.
• In breast milk jaundice, the prognosis is good; however, the bilirubin level needs to be closely monitored, with adjustments in care accordingly, to prevent persistent hyperbilirubinemia and its potential complications (ie, kernicterus in the fragile neonatal period).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• 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.
• Gilbert syndrome has a variable mode of inheritance and usually does not manifest until later in life.
• Consider and rule out disorders associated with hepatic, biliary, and/or pancreatic diseases prior to making the diagnosis of Gilbert syndrome.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Aono S, Adachi Y, Uyama E. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Lancet. Apr 15 1995;345(8955):958-9. [Medline].
• Bosma PJ, Chowdhury JR, Bakker C. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. Nov 2 1995;333(18):1171-5. [Medline].
• Chopra S. Disorders of the Liver. Lea & Febiger;1988: 23-37.
• Chopra S, May RJ. Pathophysiology of Gastrointestinal Diseases. Little Brown & Company;1989: 312-317.
• Gabilan JC, Benattar C, Lindenbaum A. Clofibrate treatment of neonatal jaundice. Pediatrics. Oct 1990;86(4):647-8.
• Kadakol A, Ghosh SS, Sappal BS. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat. Oct 2000;16(4):297-306.
• Schiff ER, Sorrell MF. Schiff's Diseases of the Liver. 8th ed. Lippincott Williams & Wilkins;1999: 151-174.
• Seppen J, Bosma PJ, Goldhoorn BG. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest. Dec 1994;94(6):2385-91.
• Tada K, Roy-Chowdhury N, Prasad V. Long-term amelioration of bilirubin glucuronidation defect in Gunn rats by transplanting genetically modified immortalized autologous hepatocytes. Cell Transplant. Nov-Dec 1998;7(6):607-16.
• Vroemen JP, Blanckaert N, Buurman WA. Treatment of enzyme deficiency by hepatocyte transplantation in rats. J Surg Res. Sep 1985;39(3):267-75.

Article Last Updated: Jul 24, 2006