Abstract
Normal serum contains unconjugated bilirubin and small concentrations of bilirubin glucuronides (approximately 4% of total bilirubins). A second conjugated form of bilirubin, tentatively identified as bilirubin-protein conjugates, with pharmacokinetic properties that are clearly distinct from those of bilirubin glucuronides, occurs in serum of patients in whom hepatic elimination of bilirubin glucuronides is, or recently has been, impaired.
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References
Hymans van den Bergh AAH, Müller P (1916) Über eine direkte und eine indirekte Diazoreaktion auf Bilirubin. Biochem Z 77: 90
Fevery J, Blanckaert NN, Leroy P, Michiels R, Heirwegh KPM (1983) Analysis of bilirubins in biological fluids by extraction and thin-layer chromatography of the intact tetrapyrroles: application to bile of patients with Gilbert’s syndrome, hemolysis or cholelithiasis. Hepatology 3: 177
Muraca M, Blanckaert N (1983) Liquid chromatographic assay and identification of mono- and diester conjugates of bilirubin in normal serum. Clin Chem 29: 1767
Blanckaert N, Heirwegh KPM, Zaman Z (1977) Comparison of the biliary excretion of the four isomers of bilirubin-IX in Wistar and homozygous Gunn rats. Biochem J 164: 229
Berk PD, Martin JF, Blaschke TF, Scharschmidt BF, Plotz PH (1975) Unconjugated hyperbilirubinemia-physiologic evaluation and experimental approaches to therapy. Ann Int Med 82: 552
Shupeck M, Wolkoff AW, Scharschmidt BF, Waggoner JG, and Berk PD (1987) Studies of the kinetics of purified conjugated bilirubin-3H in the rat. Am J Gastroenterol 70: 259
Berk PD, Potter BJ, Stremmel W (1987) Role of plasma membrane ligand-binding proteins in the hepatocellular uptake of albumin-bound organic anions. Hepatology 7: 165
Wolkoff AW (1987) The role of an albumin receptor in hepatic organic anion uptake: The controversy continues. Hepatology 7: 777
Sorrentino D, Stremmel W, Berk BD (1987) The hepatocellular uptake of bilirubin: current concepts and controversies. Molec Aspects Med 9: 405
Wolkoff AW, Sosiak A, Greenblatt HC et al (1985) Immunological studies of an organic anion binding protein (OABP) isolated from rat liver cell plasma membranes. J Clin Invest 76: 454
Tiribelli C, Lunazzi GC, Sottocase GL (1986) Mechanisms of hepatic uptake of organic anions. Clin Sci 7: 1
Stremmel W, Berk PD (1986) Hepatocellular uptake of sulfobromophthalein (BSP) and bilirubin is selectively inhibited by an antibody to the liver plasma membrane BSP/bilirubin binding proteins. J Clin Invest 78: 822
Sottocasa GL, Baldini G, Sandri G, et al (1982) Reconstitution in vitro of sulfobromophthalein transport by bilitranslocase. Biochim Biophys Seta 685: 123
Gartner V, Stockert RJ, Levine WG et al (1982) Effect of nafenopin on the uptake of bilirubin and sulfobromophthalein by isolated perfused rat liver. Gastroeneterology 83: 1163
Meijer DKF, Vonk RJ, Keulemans K, et al (1977) Hepatic uptake and biliary excretion of dibromosulphthalein. Albumin dependence, influence of phenobarbital and nafenopin pretreatment and the role of Y and Z protein. J Pharmacol Exp Ther 202: 8
Wolkoff AW, Goresky CA, Sellin J, et al (1979) Role of ligandin in transfer of bilirubin from plasma into liver. Am J Physiol 236: E638
Raymond GD, Galambos JT (1971) Hepatic storage and excretion of bilirubin in man. Am J Gastroenterol 55: 135
Wolkoff AW, Roy Chowdhury J, Arias IM (1983) Hereditary Jaundice and Disorders of Bilirubin Metabolism. In: Stanhury JB, Wijngaarden JB, Frederickson DS, Goldstein IL, Brown MS (eds) The metabolic basis of inherited disease. 5th Ed, McGraw-Hill, Inc, NY pp 1385–1420
Blanckaert N, Gollan J, Schmid R (1980) Mechanism of bilirubin diglucuronide formation in intact rats. Bilirubin diglucuronide formation in vivo. J Clin Invest 65: 1332
Sieg A, Heirwegh KPM (1988) Evidence against enzymic conversion in vitro of bilirubinmono- to bilirubindiglucuronide in preparations from Gunn rat liver (abstr). Gastroeneterol 80: 1349
Gordon ER, Meier PM, Goresky CA, Boyer JL (1984) Mechanism and subcellular site of bilirubin diglucuronide formation in rat liver. J Biol Chem 259: 5500
Vanstapel F, Blanckaert N (1987) On the binding of bilirubin and its structural analogs to hepatic microsomal UDP-glucuronyltransferase. Biochemistry 26: 6074
Vanstapel F, Licko V, Blanckaert N (1985) Kinetic evidence for bilirubin monoglucuronide (BMG) formation at a single substrate binding site of rat liver microsomal UDP-glucuronyltransferase (abstr.). Hepatology 5: 1010
Falany CN, Tephly TR (1983) Separation, purification and characterisation of three isenzymes of UDP-glucuronyltransferase from rat liver microsomes. Arch. Biochem Biophys 227: 248
Chowdhury RJ, Chowdhury RN, Falany CN, Tephly TR, Arias IM (1986) Isolation and characterization of multiple forms of rat liver UDP glucuronate glucuronosyltransferase. Biochemistry J 233: 827
Jackson R, Burchell B (1986) The full length coding sequence of rat liver UDP-glucuronyltransferase cDNA and comparison with other members of this gene family. Nucleic Acid Res 14: 779
Mackenzie PI (1986) Rat liver UDP-glucuronosyltransferase. Sequence and expression of a form of a cDNA encoding a phenobarbital-inducible form. J Biol Chem 261: 6119
Mackenzie PI (1986) Rat liver UDP-glucuronosyltransferase. cDNA sequence and expression of a form glucuronidating 3-hydroxyandrogens. J Biol Chem 261: 14112
Mackenzie PI (1987) Rat liver UDP-glucuronosyltransferase. Identification of cDNAs encoding two enzymes which glucuronidate testosterone, dihydrotestosterone, and β-estradiol. J Biol Chem 262: 9744
Iyanagi T, Haniu M, Sogawa K, Fujii-Kuriyanma Y, Watanabe S, Shively JE, Anan KF (1986) Cloning and characterization of cDNA encoding 3-methylcholanthrene inducible rat mRNA for UDP-glucuronosyltransferase. J Biol Chem 261: 15007
Hallinan T, de Brito AER (1981) Topology of endoplasmic reticular enzyme systems and its possible regulatory significance. In: Hormones and cell regulation, Dumont JE, Nunez J (eds) Vol 5, Elsevier North Holland, pp 73–95
Hayward D, Schiff D, Fedunec S, Chan G, Davis PJ, Poznansky MJ (1900) Bilirubin diffusion through lipid membranes
Nuwayhid N, Glaser JH, Johnson JC, Conrad HE, Hauser SC, Hirschberg CB (1986) Xylosylation and glucuronosylation reactions in rat liver Golgi apparatus and endoplasmic reticulum. J Biol Chem 261: 12936.
Vanstapel F, Blanckaert N (1986) Carrier-mediated translocation of intact UDP-glucose (UDPGlc) and related compounds into the lumen of rough endoplasmic reticulum (RER)-derived vesicles of rat liver (abstr.). Gastroenterology 90: 1778
Vanstapel F, Blanckaert N (1987) Endogenous esterification of bilirubin by liver microsomes. Evidence for an intramicrosomal pool of UDP-glucose and lumenal orientation of bilirubin UDP-glycosyltransferase. J Biol Chem 262: 4616
Wolkoff AW, Ketley JN, Waggoner JG et al (1978) Hepatic accumulation and intracellular binding of conjugated bilirubin. J Clin Invest 61: 142
Muraca M, Fevery J, Blanckaert N (1987) Relationships between serum bilirubins and production and conjugation of bilirubin: Studies in Gilbert’s syndrome, Crigler-Najjar disease, hemolytic disorders, and rat models. Gastroenterol 92: 309
Scharschmidt BF (1986) Biliary secretion of bile pigments. In: Bile Pigments and Jaundice: Molecular, Metabolic, and Medical Aspects, Ostrow JD (ed) Marcel Dekker Inc, NY, pp 243–253
Lauff JJ, Kasper HE, Ambrose RT (1981) Separation of bilirubin species in serum and bile by high performance liquid chromatography. J Chromatogr 226: 391
Lauff JJ, Kasper MB, Wu T-W, Ambrose RT (1982) Isolation and characterization of a fraction of bilirubin in serum that is firmly bound to protein. Clin Chem 28: 629
Blanckaert N, D’Argenio G (1982) Presence of bilirubins linked covalently to albumin in serum of patients with cholestasis. Gastroenterology 82: 1222 (A)
Blanckaert N, Servaes R, Leroy P (1986) Measurement of bilirubin-protein conjugates in serum and application to human and rats sera. J Lab Clin Med 108: 77
Compemolle F, Van Hees GP, Blanckaert N, Heirwegh KPM (1978) Glucuronic acid conjugates of bilirubin-IXa in normal bile compared with postobstructive bile — Transformation of the 1-O-acyl glucuronides into 2-, 3-, and 4-O-acyglucuronides. Biochemistry J 171: 185
Blanckaert N, Compemolle F, Leroy P, Van Houtte R, Fevery J, Heirwegh KPM (1978) The fate of bilirubin-IXa glucuronide in cholestasis and during storage in vitro. Intramolecular rearrangement to positional isomers of glucuronic acid. Biochemistry J 171: 203
McDonagh AF, Palma LA, Trull FR, Lightner DA (1982) Phototherapy for neonatal jaundice. Configuretional isomers of bilirubin. J Am Chem Soc 104: 6865
Lightner DA (1982) Structure, photochemistry, and organic chemistry of bilirubin. In: Heirwegh PM, Brown SB (eds) Bilirubin, Vol I, Chemistry, CRC Press, Boca Raton, Florida
Lightner DA, Linnane III WP, Ahlfors CE (1983) Photooxygenation products of bilirubin in the urine of jaundiced phototherapy neonates. In: Rubaltelli FF, Jori G (eds) Neonatal Jaundice, New Trends in Phototherapy, Plenum Press New York
Ostrow JD, Celic L (1984) Bilirubin chemistry, ionization and solubilization by bile salts. Hepatology 4: 38S
Bonnett R, Davies JE, Hursthouse MB (1976) Structure of bilirubin. Nature 262: 326
Brodersen R (1982) Physical chemistry of bilirubin: Binding to macromolecules and membranes. In: Heirwegh KPM, Brown SB (eds) Bilirubin, vol I, Chemistry, CRC Press, Boca Raton, Florida
McDonagh AF, Palma LA, Lauff JJ, Wu TW (1984) Origin of mammalian biliprotein and rearrangement of bilirubin glucuronides in vivo in the rat. J Clin Invest 74: 763
Jansen PLM (1981) ß-Glucuronidase-resistant bilirubin glucuronide isomers in cholestatic liver disease — determination of bilirubin metabolites in serum by means of high-pressure liquid chromatography. Clin Chim Acta 110: 309
Wu TW (1983) Delta bilirubin: the fourth fraction of bile pigments in human serum. Isr J Chem 23: 241
Weiss JS, Gautam A, Lauff JJ et al (1983) The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia. N Engl J Med 309: 147
Gautam A, Seligson H, Gordon ER, Seligson D, Boyer JL (1984) Irreversible binding of conjugated bilirubin to albumin in cholestatic rats. J Clin Invest 73: 873
Wu TW, Sullivan SS (1982) Biliprotein in adult icteric serum — demonstrated by extension of the alkaline methanolysis procedure. Clin Chem 28: 2398
Jansen FH, Billing BH (1971) The identification of monoconjugates of bilirubin in bile as amide derivatives. Biochem J 125: 917
Blanckaert N, Heirwegh KPM (1986) Chap 3. Analysis and preparation of bilirubins and biliverdins. In: Bilirubin, Bile Pigments, and Jaundice, Ostrow JD (ed) Marcel Dekker, NY, pp 31–79
Salmon M, Fenselau C, Cukier JO et al (1974) Rapid transesterification of bilirubin glucuronides in methanol. Life Sci 15: 2069
Blanckaert N (1980) Analysis of bilirubin and bilirubin mono- and diconjugates. Determination of their relative amounts in biological fluids. Biochem J 185: 115
Berk PD, Jones EA, Howe RB, Berlin NI (1980) Disorders of bilirubin metabolism. In: Bondy BK, Rosenberg L (eds): Metabolic control and disease. WB Saunders, Philadelphia
Brodersen R (1966) Bilirubin diglucuronide in normal human blood serum. Scand J Clin Lab Invest 18: 361
Werner M, Tolls RE, Hultin JV, Mellecker J (1970) Influence of sex and age on the normal range of eleven serum constituents. Z Klin Chem Klin Bioch 8: 105
Owens D, Evans J (1975) Population studies in Gilbert’s syndrome. J Med Genet 12: 152
Rosenthal P, Pincus M, Fink D (1984) Sex-and age-related differences in bilirubin concentration in serum. Clin Chem 30: 1380
Bloomer JR, Berk PD, Howe RB, Waggoner JG, Berlin NI (1970) Comparison of fecal urobilinogen excretion with bilirubin production in normal volunteers and patients with increased bilirubin production. Clin Chim Acta 29: 463
Berk PD, Howe RB, Bloomer JR, Berlin NI (1969) Studies of bilirubin kinetics in normal adults. J Clin Invest 48: 2176
Muraca M, De Groote J, Fevery J (1983) Sex difference of hepatic conjugation of bilirubin determines its maximal biliary excretion in non-anaesthetized male and female rats. Clin Sci 64: 85
Muraca M, Fevery J (1984) Influence of sex and sex steroids on bilirubin uridine diphosphate-glucuronosyltransferase activity of rat liver. Gastroenterol 87: 308
Lester R, Schmid R (1963) Intestinal absorption of bile pigments. I. The enterohepatic circulation of bilirubin in the rat. J Clin Invest 42: 736
Muraca M, Fevery J, Blanckaert N, Strazzabosco M et al (1986) Different responses of serum bilirubin mono-and diconjugates to increasing bilirubin loads. J Hepatol 3: 559
Arias IM, Johnson L, Wolfson S (1961) Biliary excretion of injected conjugated and unconjugated bilirubin by normal and Gunn rats. Am J Physiol 200: 1091
Schalm L, Weber AP (1964) Jaundice with conjugated bilirubin in hyperhemolysis. Acta Med Scand 176: 549
Forker EL, Luxon BA (1985) Effects of unstirred Dissefluid, nonequilibrium binding, and surface-mediated dissociation on hepatic removal of albumin-bound organic anions. Am J Physiol 248: 6702
Van Hootegen P, Fevery J, Blanckaert N (1985) Serum bilirubins in hepatobiliary disease: Comparison with other liver function tests and changes in the post obstructive period. Hepatol 5: 112
Hymans van den Bergh AAH, Snapper I (1913) Deut Arch Klin Med 11: 540
Talafant E (1956) Properties and composition of the bile pigment giving a direct diazoreaction. Nature 178: 312
Billing BH, Cole PG, Lathe GH (1957) The excretion of bilirubin as a diglucuronide giving the direct Van den Bergh reaction. Biochem J 65: 774
Schmid R (1957) The identification of “direct-reacting” bilirubin as bilirubin glucuronide. J Biol Chem 229: 881
Doumas BT, Perry BW, Sasse EA, Straumfjord JV (1973) Standardization in bilirubin assays: Evaluation of selected methods and stability of bilirubin solutions. Clin Chem 19: 984
Jendrassik L, Grof P (1938) Vereinfachte photometrische Methoden zur Bestimmung des Blutbilirubins. Biochem Z 297: 81
Nosslin B (1960) The direct reaction of bile pigments in serum. Experimental and clinical studies. Scand J Clin Lab Invest 12; Suppl 49
Lo DH, Wu TW (1983) Assessment of the fundamental accuracy of the Jendrassik-Grof total and direct bilirubin assays. Clin Chem 29: 31
Tisdale WA, Kinsella ED (1959) The significance of the direct-reacting fraction of serum bilirubin in haemolytic jaundice. Am J Med 26: 214
Levine RA, Klatskin G (1964) Unconjugated hyperbilirubinemia in the absence of overt hemolysis, importance of acquired diseases as an etiologic factor in 366 adolescent and adult subjects. Am J Med 36: 541
Fevery J, Claes J, Heirwegh K, De Groote J (1967) Hyperbilirubinemia: significance of the ratio between direct-reacting and total bilirubin. Clin Chim Acta 17: 73
Dappen GM, Sundberg MW, Wu T-W, Babb BE, Schaeffer JR (1983) A diazo-based dry film for determination of total bilirubin in serum. Clin Chem 29: 37
Killenberg PG, Stevens RD, Wildermann RF, Wildermann NM (1980) The laboratory method as a variable in the interpretation of serum bilirubin fractionation. Gastroenterology 78: 1011
Garber GC (1981) Jendrassik-Grof analysis of total and direct bilirubin in serum with a centrifugal analyser. Clin Chem 27: 1410
Doumas BT, Perry BW, Jendrzejczak B, Katona V (1982) Pitfalls in the american monitor Kit methods for determination of total and “direct” bilirubin. Clin Chem 28: 2305
Wu T-W, Dappen GM, Spayd RW, Sundberg MW, Powers DM (1984) The Ektachem Clinical Chemistry slide for simultaneous determination of unconjugated and sugar-conjugated bilirubin. Clin Chem 30: 1304
Arvan D, Shirey TL (1985) Conjugated bilirubin: a better indicator of impaired hepatobiliary excretion than direct bilirubin. Ann Clin Lab Sci 15: 252
Weber AP, Schalm L (1962) Quantitative separation and determination of unconjugated bilirubin and conjugated bilirubin in human serum. Clin Chim Acta 7: 805
Heirwegh KPM, Blanckaert N (1982) Analytical chemistry of rubins. In: Bilirubin. Heirwegh KPM, Brown SB (eds) vol I, Chemistry, CRC Press, Boca Raton, Florida
Onishi S, Itoh S, Kawade N, Isobe K, Sugiyama S (1980) An accurate and sensitive analysis by high-pressure liquid chromatography of conjugated and unconjugated bilirubin IXa in various biological fluids. Biochem J 185: 281
Spivak W, Carey MC (1985) Reverse-phase HPLC separation, quantification and preparation of bilirubin and its conjugates from relative bile. Biochem J 225: 787
Blanckaert N, Kabra PM, Farina FA, Stafford BE et al (1980) Measurement of bilirubin and its monoconjugates and diconjugates in human serum by alkaline methanolysis and high-performance liquid chromatography. J Lab Clin Med 96: 198
Rosenthal P, Blanckaert N, Kabra PM, Thaler MM (1981) Liquid-chromatographic determination of bilirubin and its conjugates in rat serum and human amniotic fluid. Clin Chem 27: 1704
Jansen PLM, Cuypers HT, Peters WHM (1984) Quantitation of bilirubin conjugates with high-performance liquid chromatography in patients with low total serum bilirubin levels. Eur J Clin Invest 14: 295
Muraca M, Blanckaert N, Fevery J, Rubaltelli FF et al (1984) Serum bilirubin mono- and diconjugates in human newborns. In Rubaltelli FF, Jori G (eds): Neonatal Jaundice. Plenum Press, New York—London
Scharschmidt BF, Blanckaert N, Farina FA, Kabra PM et al (1982) Measurement of serum bilirubin and its mono- and diconjugates: application to patients with hepatobiliary disease. Gut 23:643
Sundberg MW, Lauff JJ, Weiss JS, Dappen GM et al (1984) Estimation of unconjugated, conjugated and “d” bilirubin fractions in serum by use of two coated thin films. Clin Chem 30: 1314
McKavanagh SM, Billing BH (1987) The use of Band-Elut for the estimation of serum bile pigments bonded covalently to albumin. Biomed Chromatogr 2: 62
Seligson D, Seligson H, Wu TW (1985) An anion-exchange chromatographic method for measuring bilirubin covalently bound to albumin. Clin Chem 31: 1317
Okolicsanyi L, Fevery J, Billing B, Berthelot P et al (1983) How should mild, isolated unconjugated hyperbilirubinemia be investigated? Sem Liver Dis 3: 36
Mesa A, Fevery J, Heirwegh KPM, De Groote J (1985) Effects of ioglycamide on the hepatic transport of bilirubin and its mono- and diconjugates in the rat. Hepatology 5: 600
Wulkan RW, Leijnse B (1986) Alkaline phosphatase and cholestasis. Ann Clin Biochem 23: 405
Hardy JB, Peeples MO (1971) Serum bilirubin levels in newborn infants. Distributions and associations with neurological abnormalities during the first year of life. Johns Hopkins Med J 128: 265
Bakken AF, Fog J (1967) Bilirubin conjugation in the newborn. Lancet 1: 1280
Jacobsen J, Brodersen R, Troll D (1967) Patterns of bilirubin conjugation in the newborn. Scand J Clin Lab Invest 120: 249
Jansen FH, Heirwegh KPM, Devriendt A (1969) Foetal bilirubin conjugation. Lancet 1: 702
Winsens A, Bratlid D (1972) Unconjugated and conjugated bilirubin in plasma from patients with erythroblastosis and neonatal hyperbilirubinemia. Acta Paediat Scand 61: 405
Lester R (1980) Physiologic cholestasis. Gastroenterology 78: 864
Barbara L, Lassari R, Roda A, Aldini R et al (1980) Serum bile acids in newborns and children. Pediatr Res 14: 1222
Suchy FJ, Balistrieri WF, Heubi JE, Searcy JE, Pevin RS (1981) Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants. Gastroenterology 80: 1037
Muraca M, Blanckaert N, Rubaltelli FF, Fevery J (1986) Unconjugated and conjugated bilirubin pigments during perinatal development. I. Studies on rat serum and intestine. Biol Neonate 49: 90
De Wolf-Peeters C, De Vos R, Desmet V (1971) Histochemical evidence of a cholestatic period in neonatal rats. Pediatr Res 5: 704
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Blanckaert, N., Fevery, J., Vanstapel, F., Muraca, M. (1989). Clinical Significance of Recent Developments in Serum Bilirubins. In: Salvatore, F., Roda, A., Sacchetti, L. (eds) Clinical Biochemistry in Hepatobiliary Diseases. Progress in Clinical Biochemistry and Medicine, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74394-8_7
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