AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Increased production of bilirubin

Hemolysis generally induces a modest elevation in 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

• Congestive heart failure
• Surgical/naturally occurring shunts
• Drugs/contrast agents: Unconjugated hyperbilirubinemia due to drugs/contrast agent resolves within 48 hours of discontinuing the drug
• • Rifampicin
  • Rifamycin
  • Probenecid
  • Flavaspidic acid
  • Bunamiodyl (cholecystographic agent)

Neonatal jaundice

• Physiologic jaundice: All newborns have higher bilirubin levels (mainly unconjugated bilirubin) compared to adults.
• Nonphysiologic jaundice
• • Breast milk jaundice (maternal milk jaundice): Breastfed infants have higher mean bilirubin levels compared to formula-fed infants.
  • Lucey-Driscoll syndrome (maternal serum jaundice)
  • Hemolysis
  • Metabolic/endocrine disorders
  • Galactosemia
  • Fructosemia
  • Hypoglycemia
  • Hypoalbuminemia
  • Hypothyroidism
  • Sepsis
  • Hypoxia
  • Hypertrophic pyloric stenosis
• Increased bilirubin load
• ABO/Rh incompatibility
• • Inherited RBC disorders - Sickle cell disease, hereditary spherocytosis/elliptocytosis
  • Drug reactions
  • Ineffective erythropoiesis - Thalassemia, vitamin B-12 deficiency, congenital dyserythropoietic anemia

Impaired conjugation of bilirubin

Three degrees of inherited defects of bilirubin conjugation are known to exist in humans (ie, Crigler-Najjar syndrome type I and type II, Gilbert syndrome). Gilbert syndrome, also called constitutional hepatic dysfunction or familial nonhemolytic jaundice, is the mildest form of inherited nonhemolytic unconjugated hyperbilirubinemia.

Pathophysiology

Increased production of bilirubin

Ineffective erythropoiesis (ELB production): In a review of 11 such cases, evidence existed of rapid heme and hemoglobin turnover within the bone marrow, possibly due to 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

• Physiologic jaundice: Several 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 leading to an increased bilirubin load
  • Low levels of bilirubin uridine diphosphate (UDP)–glucuronosyltransferase (UGT) activity
  • Hydrolysis of conjugated bilirubin by intestinal beta-glucuronidase resulting in the release of unconjugated bilirubin in the intestine: In neonates, bacterial degradation of bilirubin is reduced because intestinal flora is not fully developed. This may lead to increased absorption of unconjugated bilirubin.
  • Epidemiology: Hyperbilirubinemia may reach or exceed 10 mg/dL in approximately 16% of newborns.
• Nonphysiologic jaundice
• • 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.
  • Maternal milk jaundice: An undefined substance, present in maternal milk, inhibits bilirubin UGT activity. This inhibitory effect of breast milk increases during storage but is destroyed by heating to 56°C.
  • Maternal serum jaundice (Lucey-Driscoll syndrome): This may result from the presence of an unidentified inhibitor of UGT, which enters the fetus through maternal serum.

Impaired conjugation of bilirubin

• Crigler-Najjar syndrome type I: Hepatic bilirubin UGT activity is undetectable.
• Crigler-Najjar syndrome type II (Arias syndrome): The reduction of hepatic bilirubin UGT activity is incomplete.
• Servedio et al reported patients with Crigler-Najjar types I and II may also possess mutations in the promoter region of the UGT1A1 gene.¹ This gene codes for the bilirubin-UGT enzyme that is impaired in Gilbert syndrome.
• 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, the principal gene encoding this enzyme. 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.
  • Investigators have discovered that Gilbert syndrome may coexist with other liver diseases, such as nonalcoholic steatohepatitis; unconjugated hyperbilirubinemia in these patients may be due to Gilbert syndrome and should not always be attributed to the underlying liver disease.
  • A case report from the Czech Republic also reported the simultaneous occurrence of mutations causing Gilbert syndrome and Dubin-Johnson syndrome in a 3-year-old boy.
• Huang et al reported that adults with certain haplotypes in UGT1A1, OATP2, and G6PD genes are at a higher risk of developing unconjugated hyperbilirubinemia.²

Frequency

United States

Regarding unconjugated hyperbilirubinemia caused by increased production of bilirubin, ineffective erythropoiesis (ELB production) is associated with a heterogeneous group of disorders that is frequently familial. Regarding unconjugated hyperbilirubinemia caused by impaired conjugation of bilirubin, Crigler-Najjar syndrome type I occurs in persons of all ethnic groups and is inherited as an autosomal recessive trait. Gilbert syndrome affects 4-13% of the population.

Mortality/Morbidity

Nonphysiological causes of unconjugated hyperbilirubinemia, such as Rhesus incompatibility, can lead to kernicterus, a potentially fatal disorder affecting the basal ganglia and other parts of the central nervous system if left untreated. Activation of astrocytes by unconjugated hyperbilirubinemia is believed to play a major part in brain toxicity via the production of inflammatory cytokines.

• Increased production of bilirubin, ineffective erythropoiesis (ELB production): Morbidity and mortality appear to be minimal. The disease is rare and is associated with an excellent prognosis.
• Neonatal jaundice, nonphysiologic: Morbidity and mortality appear to be relatively minimal. Regarding maternal milk jaundice, the jaundice may continue for 4 weeks but resolves promptly when breastfeeding is stopped. The prognosis is excellent. Regarding maternal serum jaundice (Lucey-Driscoll syndrome), jaundice can persist for several weeks, but the prognosis is good.
• Impaired conjugation of bilirubin: For Crigler-Najjar syndrome type I, unless treated vigorously (ie, orthotopic liver transplant, segmental transplantation), most affected patients die by 15 months of life. Fortunately, more patients are surviving to adulthood because of advances in the treatment of hyperbilirubinemia. For Crigler-Najjar syndrome type II (Arias syndrome), although type II runs a more benign clinical course than type I, several cases of bilirubin-induced brain damage have been reported. For Gilbert syndrome, once the diagnosis is established, only reassurance is necessary because of the excellent prognosis.

Sex

• Gilbert syndrome is diagnosed more commonly in boys after puberty than in girls. The apparent sex difference is due to the fact that daily bilirubin production is lower in women compared to men, and the residual bilirubin UGT activity may be sufficient for excreting the daily bilirubin load.

Age

• Increased production of bilirubin: Onset of ineffective erythropoiesis (ELB production) usually occurs at age 20-30 years.
• Impaired conjugation of bilirubin: Crigler-Najjar syndrome type I manifests during the first days of life.

CLINICAL

Section 3 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

• Increased production of bilirubin: Ineffective erythropoiesis (ELB production) is characterized by the onset of asymptomatic jaundice.
• Neonatal jaundice, physiologic: Physiologic jaundice is clinically obvious in 50% of neonates during the first 5 days of life.
• Neonatal jaundice, nonphysiologic
• • Maternal milk jaundice: Bilirubin levels in breastfed babies can occasionally reach 15-24 mg/dL by 10-19 days of life.
  • Maternal serum jaundice (Lucey-Driscoll syndrome): Jaundice occurs during the first 4 days of life, with serum bilirubin concentrations reported at 8.9-65 mg/dL and reached within 7 days of birth.
• Impaired conjugation of bilirubin
• • Crigler-Najjar syndrome type II (Arias syndrome): During surgery or intercurrent illnesses, the levels may increase to as much as 40 mg/dL.
  • Gilbert syndrome: Serum bilirubin fluctuates with time and increases during fasting, intercurrent illness, emotional stress, or menstruation. Apart from mild jaundice, physical examination findings in people with Gilbert syndrome are normal.

Physical

• Increased production of bilirubin
• • Ineffective erythropoiesis (ELB production): Patients with these diseases, which are characterized by abnormalities in heme biosynthesis within the developing normoblast, do not exhibit evidence of increased red blood cell destruction but they have significant increases in total bile pigment turnover. However, red blood cell destruction is increased, together with an absolute (but not relative) increase in erythroid ELB production in paroxysmal nocturnal hemoglobinuria and sickle cell anemia or following hemorrhage.
  • Hemolysis is characterized by unconjugated hyperbilirubinemia, although significant levels of conjugated bilirubin may be observed in the presence of underlying liver disease, sepsis, drugs, or when the amount of bilirubin generated and conjugated exceeds the biliary transport limit for conjugated bilirubin, as may occur in acute hemolytic crises or with multiple blood transfusions. Hemolysis due to hereditary abnormalities of erythrocytes (eg, hereditary spherocytosis/elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell disease) generally produces a milder degree of jaundice, which may manifest within a few days of birth or as recurrent episodes during later life, and frequently in association with febrile illnesses.

Causes

• Increased bilirubin production
• • Hemolysis
  • Dyserythropoiesis
  • Hematoma
• Impaired hepatic bilirubin uptake
• • Congestive heart failure
  • Portosystemic shunts
  • Drugs - Rifamycin, rifampin, probenecid, flavaspidic acid, bunamiodyl
• Impaired bilirubin conjugation
• • 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, cirrhosis, Wilson disease (decreased uptake and conjugation)
• Fasting hyperbilirubinemia - Contributed to by increased enterohepatic circulation of bilirubin and genetic factors

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Increased production of bilirubin

In ineffective erythropoiesis (ELB production), a marked increase in ELB formation has been documented in diseases associated with ineffective erythropoiesis such as iron deficiency anemia, pernicious anemia, thalassemia, erythropoietic porphyria, and lead poisoning.

Neonatal jaundice, physiologic

While no specific test exists for physiologic jaundice, other causes of jaundice should be considered in infants with one or more of the following: (1) jaundice occurring within 24 hours of birth, (2) serum concentrations of unconjugated bilirubin of 11-12 mg/dL in infants who are formula-fed or 14-15 mg/dL in infants who are breastfed, (3) increased levels of conjugated bilirubin (>2 mg/dL), or (4) jaundice persisting for more than 2 weeks.

For full-term infants with no evidence of hemolysis, the American Academy of Pediatrics recommends initiating phototherapy according to a threshold for serum bilirubin that depends on the infant's age, as follows: (1) 15 mg/dL at age 25-48 hours, (2) 18 mg/dL at age 49-72 hours, and (3) 20 mg/dL at age 72 hours or older. Unfortunately, these values are not based on large prospective studies, and they may not apply to all infants. These recommendations should not be extrapolated to preterm or ill infants because of a higher risk of toxic effects in these infants. Bilirubin concentration is merely a marker of possible neurotoxic effects and should be evaluated as part of the infant's overall condition.

The American Academy of Pediatrics has established guidelines for the diagnosis and treatment of hyperbilirubinemia in newborns. These guidelines are available through the American Academy of Pediatrics (see Management of Hyperbilirubinemia in the Healthy Term Newborn).

Neonatal jaundice, nonphysiologic

Regarding maternal serum jaundice (Lucey-Driscoll syndrome), jaundice begins earlier and is more severe compared to maternal milk jaundice.

WORKUP

Section 5 of 10  

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

Lab Studies

• Increased production of bilirubin, ineffective erythropoiesis (ELB production) - Marked increase in fecal urobilinogen excretion and a normal or near-normal red blood cell life span
• Impaired conjugation of bilirubin
• • Crigler-Najjar syndrome type I: Results of liver tests, except high serum unconjugated bilirubin levels, are normal. Serum bilirubin levels range from 20-50 mg/dL. Conjugated bilirubin is absent from serum, and bilirubin is not present in urine.
  • Crigler-Najjar syndrome type II (Arias syndrome): Serum bilirubin levels range from 7-20 mg/dL. This disorder may be distinguished definitively from type I by chromatographic analysis of pigments excreted in bile. In type II, bile contains significant amounts of conjugated bilirubin, although the proportion of bilirubin monoglucuronide in bile is increased.
  • Gilbert syndrome: Hyperbilirubinemia is the only serum biochemical abnormality. Serum bilirubin concentrations range from 1-5 mg/dL. Two provocative tests, energy deprivation and nicotinic acid administration, have been used. 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 assay has also been introduced to identify TA repeats and may be used as a screening test.

Imaging Studies

• Impaired conjugation of bilirubin, Crigler-Najjar syndrome type I: The gallbladder is visualized using oral cholecystography despite very high serum bilirubin levels because excretion of nonglucuronidated organic anions is normal.
• Japanese researchers have reported that patients with schizophrenia associated with Gilbert syndrome have specific changes of signal intensities on fluid-attenuated inversion-recovery magnetic resonance images. This suggests that schizophrenia with associated Gilbert syndrome may produce changes in the fronto-temporal cortex, limbic system, and basal ganglia.

Other Tests

• Impaired conjugation of bilirubin, Crigler-Najjar syndrome type I: Bile collected through duodenal aspiration is light yellow because of small amounts of unconjugated bilirubin. Bilirubin conjugates are nearly absent from the bile.

Histologic Findings

In impaired conjugation of bilirubin, Crigler-Najjar syndrome type I, liver histology findings are normal.

TREATMENT

Section 6 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

• Crigler-Najjar syndrome type I
• • Treatment is aimed at reducing serum bilirubin concentrations.
  • Phototherapy is the measure that is used most commonly and results in the formation of bilirubin photoisomers that can be excreted in bile without conjugation. The effectiveness of phototherapy decreases after age 3-4 years because the ratio of skin surface area to body mass is reduced.
  • During a crisis, rapid bilirubin clearance may be achieved using plasmapheresis.
  • Although liver transplantation is the only definitive treatment, allogenic hepatocyte transplantation has been accomplished successfully in one patient.
• Crigler-Najjar syndrome type II (Arias syndrome)
• • Because patients with Crigler-Najjar syndrome type II are much less likely to develop neurologic consequences than those with type I disease, specific therapy for the hyperbilirubinemia may be unnecessary.
  • Occasionally, patients with symptomatic jaundice are treated to improve their quality of life. This can be accomplished through the administration of phenobarbital (60-180 mg qd 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 (500 mg PO qid), which is associated with fewer adverse effects (clofibrate is no longer on the US market).
  • Although the treatment of these conditions has not changed in several years, there is increasing interest in new therapies based on recent animal studies. Potential new therapies that have yet to be tried in humans include zinc salts, lipase inhibitors, such as orlistat, and injections of adenovirus vectors. Gene therapy may only be considered as an experimental intervention in patients with life-threatening diseases when standard therapy, such as liver transplantation, is not possible.

MEDICATION

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

Drug Category: Anticonvulsants

Used to reduce serum bilirubin levels.

Drug Category: Antihyperlipidemic agents

Clofibrate reduces serum bilirubin levels.

FOLLOW-UP

Section 8 of 10  

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

Complications

• Increased production of bilirubin
• • Hemolysis: Formation of pigment gallstones, reflecting precipitation of calcium bilirubinate, is the major complication of long-standing excessive bilirubin production.
  • Ineffective erythropoiesis (ELB production): Similar to other causes of enhanced bilirubin production, it predisposes to cholelithiasis.
• Neonatal jaundice, nonphysiologic
• • Maternal milk jaundice: Neurologic damage has not been reported.
  • Maternal serum jaundice (Lucey-Driscoll syndrome): This entity is occasionally associated with kernicterus.

Prognosis

• Increased production of bilirubin, ineffective erythropoiesis (ELB production): Prognosis for this rare form of ineffective erythropoiesis appears to be excellent.
• Neonatal jaundice, nonphysiologic
• • Maternal milk jaundice: Jaundice may continue for 4 weeks but promptly resolves when breastfeeding is discontinued. Prognosis is excellent.
  • Maternal serum jaundice (Lucey-Driscoll syndrome): Prognosis is good, but jaundice can persist for several weeks.
• Impaired conjugation of bilirubin
• • Crigler-Najjar syndrome type I: Unless treated vigorously (ie, orthotopic liver transplant, segmental transplantation), most affected patients die by 15 months of life. Fortunately, more patients are surviving to adulthood because of advances in the treatment of hyperbilirubinemia.
  • Crigler-Najjar syndrome type II (Arias syndrome): Although type II runs a more benign clinical course than type I, several cases of bilirubin-induced brain damage have been reported.
  • Gilbert syndrome: Once the diagnosis is established, only reassurance is necessary because of the excellent prognosis.

Patient Education

• For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education articles Cirrhosis and Newborn Jaundice.

MULTIMEDIA

Section 9 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Unconjugated hyperbilirubinemia. Production of bilirubin.
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Media file 2:  Unconjugated hyperbilirubinemia. Enterohepatic circulation of bilirubin.
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Media file 3:  Unconjugated hyperbilirubinemia. Conjugation of bilirubin.
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Media type:  Graph

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
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• Differentials
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• Follow-up
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• References

1. Servedio V, d'Apolito M, Maiorano N, Minuti B, Torricelli F, Ronchi F, et al. Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation. Hum Mutat. Mar 2005;25(3):325. [Medline].
2. Huang CS, Huang MJ, Lin MS, Yang SS, Teng HC, Tang KS. Genetic factors related to unconjugated hyperbilirubinemia amongst adults. Pharmacogenet Genomics. Jan 2005;15(1):43-50. [Medline].
3. Alexandra Brito M, Silva RF, Brites D. Bilirubin toxicity to human erythrocytes: a review. Clin Chim Acta. Dec 2006;374(1-2):46-56. [Medline].
4. Basiglio CL, Arriaga SM, Pelusa HF, Almará AM, Roma MG, Mottino AD. Protective role of unconjugated bilirubin on complement-mediated hepatocytolysis. Biochim Biophys Acta. Jul 2007;1770(7):1003-10. [Medline].
5. Basiglio CL, Arriaga SM, Pelusa HF, Almará AM, Roma MG, Mottino AD. Protective role of unconjugated bilirubin on complement-mediated hepatocytolysis. Biochim Biophys Acta. Jul 2007;1770(7):1003-10. [Medline].
6. Bender GJ, Cashore WJ, Oh W. Ontogeny of bilirubin-binding capacity and the effect of clinical status in premature infants born at less than 1300 grams. Pediatrics. Nov 2007;120(5):1067-73. [Medline].
7. Bernhard V. Bilirubin, metabolism and jaundice. In: Brandt LJ, ed. Clinical Practice of Gastroenterology. New York, NY: Churchill Livingstone; 1999.
8. Borlak J, Thum T, Landt O, Erb K, Hermann R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology. Oct 2000;32(4 Pt 1):792-5. [Medline].
9. Carl L, Berg JM. Bilirubin metabolism and the pathophysiology of jaundice. In: Schiff ER, Gollan JL, eds. Schiff's Disease of the Liver. 8^th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999.
10. Cebecauerova D, Jirasek T, Budisova L, Mandys V, Volf V, Novotna Z. Dual hereditary jaundice: simultaneous occurrence of mutations causing Gilbert's and Dubin-Johnson syndrome. Gastroenterology. Jul 2005;129(1):315-20. [Medline].
11. Clementi M, Di Gianantonio E, Fabris L, Forabosco P, Strazzabosco M, Tenconi R. Inheritance of hyperbilirubinemia: evidence for a major autosomal recessive gene. Dig Liver Dis. Apr 2007;39(4):351-5. [Medline].
12. Colletti JE, Kothori S, Jackson DM, Kilgore KP, Barringer K. An emergency medicine approach to neonatal hyperbilirubinemia. Emerg Med Clin North Am. Nov 2007;25(4):1117-35, vii. [Medline].
13. Costa E. Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis. Jan-Feb 2006;36(1):77-80. [Medline].
14. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. Feb 22 2001;344(8):581-90. [Medline].
15. Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A. Unconjugated hyperbilirubinemia in nonalcoholic steatohepatitis--is it Gilbert's syndrome?. Trop Gastroenterol. Jul-Sep 2005;26(3):123-5. [Medline].
16. Ellis E, Wagner M, Lammert F, Nemeth A, Gumhold J, Strassburg CP, et al. Successful treatment of severe unconjugated hyperbilirubinemia via induction of UGT1A1 by rifampicin. J Hepatol. Jan 2006;44(1):243-5. [Medline].
17. Falcăo AS, Silva RF, Fernandes A, Brito MA, Brites D. Influence of hypoxia and ischemia preconditioning on bilirubin damage to astrocytes. Brain Res. May 29 2007;1149:191-9. [Medline].
18. Fernandes A, Falcao AS, Silva RF, Gordo AC, Gama MJ, Brito MA, et al. Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin. J Neurochem. Mar 2006;96(6):1667-79. [Medline].
19. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. May 14 1998;338(20):1422-6. [Medline].
20. Hafkamp AM, Havinga R, Ostrow JD, Tiribelli C, Pascolo L, Sinaasappel M, et al. Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: phototherapy and orlistat treatment in Gunn rats. Pediatr Res. Apr 2006;59(4 Pt 1):506-12. [Medline].
21. Hafkamp AM, Havinga R, Sinaasappel M, Verkade HJ. Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats. Hepatology. Mar 2005;41(3):526-34. [Medline].
22. Hafkamp AM, Nelisse-Haak R, Sinaasappel M, Oude Elferink RP, Verkade HJ. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial. Pediatr Res. Dec 2007;62(6):725-30. [Medline].
23. Huang CS. Molecular genetics of unconjugated hyperbilirubinemia in Taiwanese. J Biomed Sci. 2005;12(3):445-50. [Medline].
24. Kempf DJ, Waring JF, Morfitt DC, Werner P, Ebert B, Mitten M, et al. Practical preclinical model for assessing the potential for unconjugated hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors. Antimicrob Agents Chemother. Feb 2006;50(2):762-4. [Medline].
25. Lee HC, Fang SB, Yeung CY, Tsai JD. Urinary tract infections in infants: comparison between those with conjugated vs unconjugated hyperbilirubinaemia. Ann Trop Paediatr. Dec 2005;25(4):277-82. [Medline].
26. Manning D, Todd P, Maxwell M, Jane Platt M. Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed. Sep 2007;92(5):F342-6. [Medline].
27. Miyaoka T, Yasukawa R, Mihara T, Mizuno S, Yasuda H, Sukegawa T, et al. Fluid-attenuated inversion-recovery MR imaging in schizophrenia-associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). Eur Psychiatry. Jun 2005;20(4):327-31. [Medline].
28. Ostanek B, Furlan D, Mavec T, Lukac-Bajalo J. UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians. Blood Cells Mol Dis. Mar-Apr 2007;38(2):78-82. [Medline].
29. Pashapour N, Nikibahksh AA, Golmohammadlou S. Urinary tract infection in term neonates with prolonged jaundice. Urol J. 2007;4(2):91-4; discussion 94. [Medline].
30. Petit FM, Hébert M, Gajdos V, Mollet-Boudjemline A, Labrune P. Comments on seven novel mutations of the UGT1A1 gene in patients with unconjugated hyperbilirubinemia by D'Apolito et al. Haematologica. Jul 2007;92(7):e80. [Medline].
31. Robards C, Brull SJ. The anesthetic implications of Crigler-Najjar syndrome. Anesth Analg. Feb 2007;104(2):435-6. [Medline].
32. Smith JR, Donze A, Schuller L. An evidence-based review of hyperbilirubinemia in the late preterm infant, with implications for practice: management, follow-up, and breastfeeding support. Neonatal Netw. Nov-Dec 2007;26(6):395-405. [Medline].
33. Tiribelli C, Ostrow JD. New concepts in bilirubin and jaundice: report of the Third International Bilirubin Workshop, April 6-8, 1995, Trieste, Italy. Hepatology. Nov 1996;24(5):1296-311. [Medline].
34. Toietta G, Mane VP, Norona WS, Finegold MJ, Ng P, McDonagh AF, et al. Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A. Mar 15 2005;102(11):3930-5. [Medline].
35. Urawa N, Kobayashi Y, Araki J, Sugimoto R, Iwasa M, Kaito M. Linkage disequilibrium of UGT1A1 *6 and UGT1A1 *28 in relation to UGT1A6 and UGT1A7 polymorphisms. Oncol Rep. Oct 2006;16(4):801-6. [Medline].
36. Vítek L. Etiology of fasting hyperbilirubinemia: genetic factors versus enhanced enterohepatic cycling of bilirubin. Gastroenterology. Nov 1999;117(5):1255-6. [Medline].
37. Watchko JF. Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns. Neuromolecular Med. 2006;8(4):513-29. [Medline].

Article Last Updated: May 14, 2008