- Namita Roy-Chowdhury, PhD
Namita Roy-Chowdhury, PhD
- Professor of Medicine and Genetics
- Albert Einstein College of Medicine
- Jayanta Roy-Chowdhury, MD, MRCP
Jayanta Roy-Chowdhury, MD, MRCP
- Professor of Medicine and Genetics
- Albert Einstein College of Medicine
- Section Editors
- Sanjiv Chopra, MD, MACP
Sanjiv Chopra, MD, MACP
- Editor-in-Chief — Gastroenterology/Hepatology
- Section Editor — General Hepatology
- Section Editor — Gallbladder and Biliary Tract Disease
- Professor of Medicine
- Harvard Medical School
- Senior Consultant in Hepatology
- James Tullis Firm Chief
- Beth Israel Deaconess Medical Center
- Elizabeth B Rand, MD
Elizabeth B Rand, MD
- Section Editor — Pediatric Hepatology
- Professor of Pediatrics
- University of Pennsylvania School of Medicine
Bilirubin is the potentially toxic catabolic product of heme metabolism. Fortunately, 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. Furthermore, because bilirubin shares its metabolic pathway with various other sparingly water soluble substances that are excreted in bile, understanding bilirubin metabolism also provides insight into the mechanisms of transport, detoxification, and elimination of many other organic anions .
An overview of the major aspects of bilirubin formation and disposition will be reviewed here. The settings in which bilirubin disposition is impaired will also be discussed briefly. Clinical aspects of serum bilirubin determination, the evaluation of patients with hyperbilirubinemia, and the classification of causes of jaundice are presented separately. (See "Clinical aspects of serum bilirubin determination" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia" and "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)
FORMATION OF BILIRUBIN
Bilirubin is formed by breakdown of heme present in hemoglobin, myoglobin, cytochromes, catalase, peroxidase and tryptophan pyrrolase. Eighty percent of the daily bilirubin production (250 to 400 mg in adults) is derived from hemoglobin ; the remaining 20 percent being contributed by other hemoproteins and a rapidly turning-over small pool of free heme. Enhanced bilirubin formation is found in all conditions associated with increased red cell turnover such as intramedullary or intravascular hemolysis (eg, hemolytic, dyserythropoietic, and megaloblastic anemias).
Heme consists of a ring of four pyrroles joined by carbon bridges and a central iron atom (ferroprotoporphyrin IX). Bilirubin is generated by sequential catalytic degradation of heme mediated by two groups of enzymes:
- Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology 2014; 146:1625.
- Berk PD, Howe RB, Bloomer JR, Berlin NI. Studies of bilirubin kinetics in normal adults. J Clin Invest 1969; 48:2176.
- Berk PD, Rodkey FL, Blaschke TF, et al. Comparison of plasma bilirubin turnover and carbon monoxide production in man. J Lab Clin Med 1974; 83:29.
- Bissell DM, Hammaker L, Schmid R. Liver sinusoidal cells. Identification of a subpopulation for erythrocyte catabolism. J Cell Biol 1972; 54:107.
- Sassa S, Kappas A, Bernstein SE, Alvares AP. Heme biosynthesis and drug metabolism in mice with hereditary hemolytic anemia. Heme oxygenase induction as an adaptive response for maintaining cytochrome P-450 in chronic hemolysis. J Biol Chem 1979; 254:729.
- Drummond GS, Valaes T, Kappas A. Control of bilirubin production by synthetic heme analogs: pharmacologic and toxicologic considerations. J Perinatol 1996; 16:S72.
- Bonnet RJ, Davis E, Hursthouse MB. Structure of bilirubin. Nature 1976; 262:326.
- Itoh S, Onishi S. Kinetic study of the photochemical changes of (ZZ)-bilirubin IX alpha bound to human serum albumin. Demonstration of (EZ)-bilirubin IX alpha as an intermediate in photochemical changes from (ZZ)-bilirubin IX alpha to (EZ)-cyclobilirubin IX alpha. Biochem J 1985; 226:251.
- Van den Bergh AA, Muller P. Ueber eine direkte und eine indirekte Diazoreaktion auf Bilirubin. Biochem Z 1916; 77:90.
- Roy Chowdhury J, Arias IM. Disorders of bilirubin conjugation. In: Bile Pigments and Jaundice, Ostrow JD (Ed), Marcel Dekker, New York 1986. p.317.
- Chowdhury JR, Chowdhury NR, Wu G, et al. Bilirubin mono- and diglucuronide formation by human liver in vitro: assay by high-pressure liquid chromatography. Hepatology 1981; 1:622.
- Brown AK, Eisinger J, Blumberg WE, et al. A rapid fluorometric method for determining bilirubin levels and binding in the blood of neonates: comparisons with a diazo method and with 2-(4'-hydroxybenzene)azobenzoic acid dye binding. Pediatrics 1980; 65:767.
- Robertson A, Karp W, Brodersen R. Bilirubin displacing effect of drugs used in neonatology. Acta Paediatr Scand 1991; 80:1119.
- Rudman D, Bixler TJ 2nd, Del Rio AE. Effect of free fatty acids on binding of drugs by bovine serum albumin, by human serum albumin and by rabbit serum. J Pharmacol Exp Ther 1971; 176:261.
- Weiss JS, Gautam A, Lauff JJ, et al. The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia. N Engl J Med 1983; 309:147.
- Lauff JJ, Kasper ME, Ambrose RT. Quantitative liquid-chromatographic estimation of bilirubin species in pathological serum. Clin Chem 1983; 29:800.
- Wolkoff AW. Hepatocellular sinusoidal membrane organic anion transport and transporters. Semin Liver Dis 1996; 16:121.
- Kullak-Ublick GA, Hagenbuch B, Stieger B, et al. Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 1995; 109:1274.
- van de Steeg E, Stránecký V, Hartmannová H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122:519.
- Dutton GJ, Burchell B. Newer aspects of glucuronidation. Prog Drug Metab 1977; 2:1.
- Bosma PJ, Seppen J, Goldhoorn B, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994; 269:17960.
- Kobayashi T, Sleeman JE, Coughtrie MW, Burchell B. Molecular and functional characterization of microsomal UDP-glucuronic acid uptake by members of the nucleotide sugar transporter (NST) family. Biochem J 2006; 400:281.
- Arias IM, Che M, Gatmaitan Z, et al. The biology of the bile canaliculus, 1993. Hepatology 1993; 17:318.
- Jansen PL, Oude Elferink RP. Hereditary hyperbilirubinemias: a molecular and mechanistic approach. Semin Liver Dis 1988; 8:168.
- LESTER R, SCHMID R. Intestinal absorption of bile pigments. II. Bilirubin absorption in man. N Engl J Med 1963; 269:178.
- Stoll MS, Lim CD, Gray CH. Chemical variants of the uroblins. In: Bile Pigments, Chemistry and Physiology, Berk PD, Berlin NI (Eds), US Government Printing Office, Washington, DC 1977. p.483.
- Vítek L, Zelenka J, Zadinová M, Malina J. The impact of intestinal microflora on serum bilirubin levels. J Hepatol 2005; 42:238.
- Kapitulnik J, Bircher J, Hedorn HB. Chlorpromazine reduces plasma bilirubin levels in Crigler-Najjar syndrome type I (CNS-I). Hepatology 1989; 10:A708.
- Cameron JL, Pulaski EJ, Abei T, Iber FL. Metabolism and excretion of bilirubin-C14 in experimental obstructive jaundice. Ann Surg 1966; 163:330.
- Cameron JL, Filler RM, Iber FL, et al. Metabolism and excretion of C14-labeled bilirubin in children with biliary atresia. N Engl J Med 1966; 274:231.
- Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem 1995; 41:1504.
- Temme EH, Zhang J, Schouten EG, Kesteloot H. Serum bilirubin and 10-year mortality risk in a Belgian population. Cancer Causes Control 2001; 12:887.
- Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology 2004; 40:827.
- Zhu Z, Wilson AT, Mathahs MM, et al. Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury. Hepatology 2008; 48:1430.
- Shapiro SM, Bhutani VK, Johnson L. Hyperbilirubinemia and kernicterus. Clin Perinatol 2006; 33:387.
- Watchko JF, Tiribelli C. Bilirubin-induced neurologic damage--mechanisms and management approaches. N Engl J Med 2013; 369:2021.
- FORMATION OF BILIRUBIN
- Measurement of serum bilirubin
- METABOLISM OF BILIRUBIN
- Albumin binding of bilirubin in plasma
- Uptake and storage of bilirubin by hepatocytes
- Conjugation of bilirubin
- Excretion of conjugated bilirubin
- Degradation of bilirubin in the digestive tract
- Alternative pathways of bilirubin elimination
- BILIRUBIN IN DISEASE STATES
- Potential beneficial effects of bilirubin
- Bilirubin toxicity
- SUMMARY AND RECOMMENDATIONS