Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1969 Nov;48(11):2176–2190. doi: 10.1172/JCI106184

Studies of bilirubin kinetics in normal adults

Paul D Berk 1, Robert B Howe 1, Joseph R Bloomer 1, Nathaniel I Berlin 1
PMCID: PMC297471  PMID: 5824077

Abstract

This report describes studies of bilirubin kinetics in 13 healthy young adults. The plasma content of unconjugated bilirubin-14C was determined at frequent intervals for 24-30 hr after the intravenous injection of a tracer dose of unconjugated isotopic bilirubin. Fecal and urinary radioactivity were measured for 7 days. During this time cumulative recovery averaged 96% of the injected dose. The plasma curves were processed by digital computer. For the 30 hr experimental period, a sum of three exponentials, with average half-times of 18, 81, and 578 min, was required to describe the data. Using the plasma curve integral method, the hepatic bilirubin clearance (47 ±10 ml/min, mean ±SD), the bilirubin production rate (3.8 ±0.6 mg/kg per day), and the mean red blood cell life span (101 ±13 days) were calculated directly from the parameters of this function. To gain further insight into the metabolism of unconjugated bilirubin, the data were also used to determine the parameters of a multicompartmental model. In the model proposed, plasma unconjugated bilirubin exchanges with two additional pools one of which is thought to represent extrahepatic extravascular, and the other intrahepatic unconjugated bilirubin. Bilirubin is eliminated from the system via the proposed intrahepatic pool. From the data and the model, pool sizes and exchange rates between compartments were calculated, and the liver: plasma concentration gradient estimated. These studies provide a detailed analysis of the kinetics of unconjugated bilirubin in a healthy normal population and are intended to serve as a reference point for studies of abnormal states.

Full text

PDF
2190

Images in this article

2185Image
on p.2185
2186Image
on p.2186
2187Image
on p.2187

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ali M. A., Billing B. Plasma disappearance of conjugated and unconjugated C14 bilirubin in the rat with obstructive jaundice. Proc Soc Exp Biol Med. 1967 Feb;124(2):339–342. doi: 10.3181/00379727-124-31737. [DOI] [PubMed] [Google Scholar]
  2. Araki Y., Miyasaki T., Kashima M., Oomori S., Ogawa H. [Kinetics of bilirubin metabolism--an approach to a new procedure for diagnosing jaundice]. Nihon Rinsho. 1966 Jun;24(6):1002–1009. [PubMed] [Google Scholar]
  3. BERMAN M., SHAHN E., WEISS M. F. The routine fitting of kinetic data to models: a mathematical formalism for digital computers. Biophys J. 1962 May;2:275–287. doi: 10.1016/s0006-3495(62)86855-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. BERMAN M. The formulation and testing of models. Ann N Y Acad Sci. 1963 May 10;108:182–194. doi: 10.1111/j.1749-6632.1963.tb13373.x. [DOI] [PubMed] [Google Scholar]
  5. BERMAN M., WEISS M. F., SHAHN E. Some formal approaches to the analysis of kinetic data in terms of linear compartmental systems. Biophys J. 1962 May;2:289–316. doi: 10.1016/s0006-3495(62)86856-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. BERSON S. A., YALOW R. S. The use of K42 or P32 labeled erythrocytes and I131 tagged human serum albumin in simultaneous blood volume determinations. J Clin Invest. 1952 Jun;31(6):572–580. doi: 10.1172/JCI102643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. BILLING B. H., GRAY C. H., KULCZYCKA A., MANFIELD P., NICHOLSON D. C. THE METABOLISM OF (14C)-BILIRUBIN IN CONGENITAL NON-HAEMOLYTIC HYPERBILIRUBINAEMIA. Clin Sci. 1964 Aug;27:163–170. [PubMed] [Google Scholar]
  8. BILLING B. H., WILLIAMS R., RICHARDS T. G. DEFECTS IN HEPATIC TRANSPORT OF BILIRUBIN IN CONGENITAL HYPERBILIRUBINAEMIA: AN ANALYSIS OF PLASMA BILIRUBIN DISAPPEARANCE CURVES. Clin Sci. 1964 Oct;27:245–257. [PubMed] [Google Scholar]
  9. BROWN W. R., GRODSKY G. M., CARBONE J. V. INTRACELLULAR DISTRIBUTION OF TRITIATED BILIRUBIN DURING HEPATIC UPTAKE AND EXCRETION. Am J Physiol. 1964 Dec;207:1237–1241. doi: 10.1152/ajplegacy.1964.207.6.1237. [DOI] [PubMed] [Google Scholar]
  10. Barrett P. V., Mullins F. X., Berlin N. I. Studies on the biosynthesis production of bilirubin-C14: an improved method utilizing delta-aminolevulinic acid-4-C14 in dogs. J Lab Clin Med. 1966 Dec;68(6):905–912. [PubMed] [Google Scholar]
  11. Barrett V., Berk P. D., Menken M., Berlin N. I. Bilirubin turnover studies in normal and pathologic states using bilirubin-14C. Ann Intern Med. 1968 Feb;68(2):355–377. doi: 10.7326/0003-4819-68-2-355. [DOI] [PubMed] [Google Scholar]
  12. Berlin N. I., Berman M., Berk P. D., Phang J. M., Waldmann T. A. The application of multicompartmental analysis to problems of clinical medicine. Combined clinical staff conference at the National Institutes of Health. Ann Intern Med. 1968 Feb;68(2):423–448. doi: 10.7326/0003-4819-68-2-423. [DOI] [PubMed] [Google Scholar]
  13. Berman M. A postulate to aid in model building. J Theor Biol. 1963 May;4(3):229–236. doi: 10.1016/0022-5193(63)90001-8. [DOI] [PubMed] [Google Scholar]
  14. Bernstein L. H., Ezzer J. B., Gartner L., Arias I. M. Hepatic intracellular distribution of tritium-labeled unconjugated and conjugated bilirubin in normal and Gunn rats. J Clin Invest. 1966 Jul;45(7):1194–1201. doi: 10.1172/JCI105425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Bradley S. E., Ingelfinger F. J., Bradley G. P., Curry J. J. THE ESTIMATION OF HEPATIC BLOOD FLOW IN MAN. J Clin Invest. 1945 Nov;24(6):890–897. doi: 10.1172/JCI101676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. CHAPLIN H., Jr, MOLLISON P. L., VETTER H. The body/venous hematocrit ratio: its constancy over a wide hematocrit range. J Clin Invest. 1953 Dec;32(12):1309–1316. doi: 10.1172/JCI102859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. COBURN R. F., BLAKEMORE W. S., FORSTER R. E. Endogenous carbon monoxide production in man. J Clin Invest. 1963 Jul;42:1172–1178. doi: 10.1172/JCI104802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. COHEN S., FREEMAN T., McFARLANE A. S. Metabolism of I-131-labelled human albumin. Clin Sci. 1961 Apr;20:161–170. [PubMed] [Google Scholar]
  19. Cameron J. L., Filler R. M., Iber F. L., Abei T., Randolph J. G. Metabolism and excretion of C14-labeled bilirubin in children with biliary atresia. N Engl J Med. 1966 Feb 3;274(5):231–236. doi: 10.1056/NEJM196602032740501. [DOI] [PubMed] [Google Scholar]
  20. Crigler J. F., Jr, Gold N. I. Effect of sodium phenobarbital on bilirubin metabolism in an infant with congenital, nonhemolytic, unconjugated hyperbilirubinemia, and kernicterus. J Clin Invest. 1969 Jan;48(1):42–55. doi: 10.1172/JCI105973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. EADIE G. S., BROWN I. W., Jr The potential life span and ultimate survival of fresh red blood cells in normal healthy recipients as studied by simultaneous Cr51 tagging and differential hemolysis. J Clin Invest. 1955 Apr;34(4):629–636. doi: 10.1172/JCI103112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. EVANS R. L. Short-lived red cells in normal individuals. Nature. 1954 Jan 16;173(4394):129–130. doi: 10.1038/173129a0. [DOI] [PubMed] [Google Scholar]
  23. GORESKY C. A. THE HEPATIC UPTAKE AND EXCRETION OF SULFOBROMOPHTHALEIN AND BILIRUBIN. Can Med Assoc J. 1965 Apr 17;92:851–857. [PMC free article] [PubMed] [Google Scholar]
  24. GRAY C. H., NEUBERGER A., SNEATH P. H. A. Studies in congenital porphyria. 2. Incorporation of 15N in the stercobilin in the normal and in the porphyric. Biochem J. 1950 Jun-Jul;47(1):87–92. doi: 10.1042/bj0470087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hammaker L., Schmid R. Interference with bile pigment uptake in the liver by flavaspidic acid. Gastroenterology. 1967 Jul;53(1):31–37. [PubMed] [Google Scholar]
  26. LONDON I. M., WEST R., SHEMIN D., RITTENBERG D. On the origin of bile pigment in normal man. J Biol Chem. 1950 May;184(1):351–358. [PubMed] [Google Scholar]
  27. LUTWAK L., BURTON B. T. FECAL DYE MARKERS IN METABOLIC BALANCE STUDIES. THE USE OF BRILLIANT BLUE AND METHYLCELLULOSE FOR ACCURATE SEPARATION OF STOOL PERIODS. Am J Clin Nutr. 1964 Feb;14:109–111. doi: 10.1093/ajcn/14.2.109. [DOI] [PubMed] [Google Scholar]
  28. Levitt M., Schacter B. A., Zipursky A., Israels L. G. The nonerythropoietic component of early bilirubin. J Clin Invest. 1968 Jun;47(6):1281–1294. doi: 10.1172/JCI105820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. OLIVERIO V. T., DENHAM C., DAVIDSON J. D. Oxygen flask combustion in determination of C-14 and H3 in biological materials. Anal Biochem. 1962 Aug;4:188–189. doi: 10.1016/0003-2697(62)90035-0. [DOI] [PubMed] [Google Scholar]
  30. OSTROW J. D., HAMMAKER L., SCHMID R. The preparation of crystalline bilirubin-C14. J Clin Invest. 1961 Aug;40:1442–1452. doi: 10.1172/JCI104375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. OSTROW J. D., SCHMID R. THE PROTEIN-BINDING OF C14-BILIRUBIN IN HUMAN AND MURINE SERUM. J Clin Invest. 1963 Aug;42:1286–1299. doi: 10.1172/JCI104813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. READ R. C. Studies of red-cell volume and turnover using radiochromium; description of a new closed method of red-cell volume measurement. N Engl J Med. 1954 Jun 17;250(24):1021–1027. doi: 10.1056/NEJM195406172502402. [DOI] [PubMed] [Google Scholar]
  33. Robinson S. H., Lester R., Crigler J. F., Jr, Tsong M. Early-labeled peak of bile pigment in man. Studies with glycine-14C and delta-aminolevulinic acid-3H. N Engl J Med. 1967 Dec 21;277(25):1323–1329. doi: 10.1056/NEJM196712212772501. [DOI] [PubMed] [Google Scholar]
  34. Robinson S. H., Owen C. A., Jr, Flock E. V., Schmid R. Bilirubin formation in the liver from nonhemoglobin sources. Experiments with isolated, perfused rat liver. Blood. 1965 Dec;26(6):823–829. [PubMed] [Google Scholar]
  35. SCHMID R., HAMMAKER L. METABOLISM AND DISPOSITION OF C14-BILIRUBIN IN CONGENITAL NONHEMOLYTIC JAUNDICE. J Clin Invest. 1963 Nov;42:1720–1734. doi: 10.1172/JCI104858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. SKINNER S. M., CLARK R. E., BAKER N., SHIPLEY R. A. Complete solution of the three-compartment model in steady state after single injection of radioactive tracer. Am J Physiol. 1959 Feb;196(2):238–244. doi: 10.1152/ajplegacy.1959.196.2.238. [DOI] [PubMed] [Google Scholar]
  37. STERLING K., GRAY S. J. Determination of the circulating red cell volume in man by radioactive chromium. J Clin Invest. 1950 Dec;29(12):1614–1619. doi: 10.1172/JCI102404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. WEBER A. P., SCHALM L. Quantitative separation and determination of bilirubin and conjugated bilirubin in human serum. Clin Chim Acta. 1962 Nov;7:805–810. doi: 10.1016/0009-8981(62)90063-3. [DOI] [PubMed] [Google Scholar]
  39. Watson C. J. The continuing challenge of hemoglobin and bile pigment metabolism. Ann Intern Med. 1965 Dec;63(6):931–944. doi: 10.7326/0003-4819-63-6-931. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES