eMedicine Specialties > Gastroenterology > Systemic Disease

Hyperbilirubinemia, Unconjugated: Treatment & Medication

Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Coauthor(s): Nuri Ozden, MD, Assistant Professor, Department of Internal Medicine, Meharry Medical College
Contributor Information and Disclosures

Updated: Nov 19, 2009

Treatment

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.11
    • 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.12,13 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

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

Anticonvulsants

Used to reduce serum bilirubin levels.


Phenobarbital (Barbita, Luminal)

Increases conjugation and excretion of bilirubin. Reduces serum bilirubin levels by at least 25%.

Adult

60-180 mg/d PO in divided doses

Pediatric

Not established

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may also occur)

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; patients with nephritis

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in patients with fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Antihyperlipidemic agents

Clofibrate reduces serum bilirubin levels.


Clofibrate (Atromid-S)

No longer on the US market. Mechanism of action is unknown. Lowers serum triglycerides and very low-density lipoprotein levels. Serum cholesterol and low-density lipoprotein levels are lowered less predictably and less effectively.

Adult

500 mg PO qid

Pediatric

Not established

May potentiate effects of warfarin, insulin, and sulfonylureas; coadministration with dantrolene may decrease protein binding of dantrolene; coadministration with ursodiol may counteract effects of ursodiol; oral contraceptives may increase elimination; probenecid may increase effects (may need to decrease clofibrate dose)

Documented hypersensitivity; severe hepatic or renal dysfunction; primary biliary cirrhosis

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Possible increased risk of malignancy and cholelithiasis; monitor for abnormal elevation of ALT, AST, LDH, bilirubin, and alkaline phosphatase serum levels; caution in patients with peptic ulcer disease; cardiac arrhythmias have been reported; muscle aches, soreness, and cramping may occur

More on Hyperbilirubinemia, Unconjugated

Overview: Hyperbilirubinemia, Unconjugated
Differential Diagnoses & Workup: Hyperbilirubinemia, Unconjugated
Treatment & Medication: Hyperbilirubinemia, Unconjugated
Follow-up: Hyperbilirubinemia, Unconjugated
Multimedia: Hyperbilirubinemia, Unconjugated
References
Further Reading
[ CLOSE WINDOW ]

References

  1. 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].

  2. 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].

  3. 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].

  4. Chang PF, Lin YC, Liu K, Yeh SJ, Ni YH. Prolonged unconjugated hyperbilirubinemia in breast-fed male infants with a mutation of uridine diphosphate-glucuronosyl transferase. J Pediatr. Aug 13 2009;[Medline].

  5. 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].

  6. 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].

  7. Falcão 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].

  8. 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].

  9. 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].

  10. Brites D, Fernandes A, Falcão AS, Gordo AC, Silva RF, Brito MA. Biological risks for neurological abnormalities associated with hyperbilirubinemia. J Perinatol. Feb 2009;29 Suppl 1:S8-13. [Medline].

  11. Karakukcu C, Ustdal M, Ozturk A, Baskol G, Saraymen R. Assessment of DNA damage and plasma catalase activity in healthy term hyperbilirubinemic infants receiving phototherapy. Mutat Res. Aug 25 2009;[Medline].

  12. 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].

  13. Cuperus FJ, Hafkamp AM, Hulzebos CV, Verkade HJ. Pharmacological therapies for unconjugated hyperbilirubinemia. Curr Pharm Des. 2009;15(25):2927-38. [Medline].

  14. 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].

  15. Bernhard V. Bilirubin, metabolism and jaundice. In: Brandt LJ, ed. Clinical Practice of Gastroenterology. New York, NY: Churchill Livingstone; 1999.

  16. 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].

  17. Carl L, Berg JM. Bilirubin metabolism and the pathophysiology of jaundice. In: Schiff ER, Gollan JL, eds. Schiff's Disease of the Liver. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999.

  18. 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].

  19. 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].

  20. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. Feb 22 2001;344(8):581-90. [Medline].

  21. 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].

  22. 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].

  23. 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].

  24. 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].

  25. 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].

  26. 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].

  27. Huang CS. Molecular genetics of unconjugated hyperbilirubinemia in Taiwanese. J Biomed Sci. 2005;12(3):445-50. [Medline].

  28. 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].

  29. 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].

  30. 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].

  31. 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].

  32. 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].

  33. 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].

  34. 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].

  35. Vítek L. Etiology of fasting hyperbilirubinemia: genetic factors versus enhanced enterohepatic cycling of bilirubin. Gastroenterology. Nov 1999;117(5):1255-6. [Medline].

  36. Watchko JF. Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns. Neuromolecular Med. 2006;8(4):513-29. [Medline].

[ CLOSE WINDOW ]

Keywords

unconjugated hyperbilirubinemia, hemolysis, Gilbert syndrome, jaundice, bilirubin levels, high bilirubin, bilirubin level, elevated bilirubin, serum bilirubin, acute hemolytic crisis, paroxysmal nocturnal hemoglobinuria, unconjugated bilirubin, Crigler-Najjar syndrome, Gilbert syndrome, dyserythropoietic, physiologic jaundice, breast milk jaundice

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Coauthor(s)

Nuri Ozden, MD, Assistant Professor, Department of Internal Medicine, Meharry Medical College
Nuri Ozden, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Medical Editor

Ann Ouyang, MBBS, Professor, Department of Internal Medicine, Pennsylvania State University College of Medicine; Attending Physician, Division of Gastroenterology and Hepatology, Milton S Hershey Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.