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Classification and causes of jaundice or asymptomatic hyperbilirubinemia

Namita Roy-Chowdhury, PhD
Jayanta Roy-Chowdhury, MD, MRCP
Section Editors
Sanjiv Chopra, MD, MACP
Elizabeth B Rand, MD
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


The normal serum bilirubin concentration in children and adults is less than 1 mg/dL (17 micromol/liter), less than 5 percent of which is present in conjugated form. The measurement is usually made using diazo reagents and spectrophotometry. Conjugated bilirubin reacts rapidly ("directly") with the reagents. The measurement of unconjugated bilirubin requires the addition of an accelerator compound and is often referred to as the indirect bilirubin. (See "Clinical aspects of serum bilirubin determination".)

Jaundice is often used interchangeably with hyperbilirubinemia. However, a careful clinical examination cannot detect jaundice until the serum bilirubin is greater than 2 mg/dL (34 micromol/liter), twice the normal upper limit. The yellow discoloration is best seen in the periphery of the ocular conjunctivae and in the oral mucous membranes (under the tongue, hard palate). Icterus may be the first or only sign of liver disease; thus its evaluation is of critical importance.

For clinical purposes, the predominant type of bile pigments in the plasma can be used to classify hyperbilirubinemia into two major categories (table 1 and algorithm 1A-B).

Plasma elevation of predominantly unconjugated bilirubin due to the overproduction of bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation

Plasma elevation of both unconjugated and conjugated bilirubin due to hepatocellular diseases, impaired canalicular excretion, and biliary obstruction

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Literature review current through: Nov 2017. | This topic last updated: Nov 14, 2016.
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  1. Reisman Y, Gips CH, Lavelle SM, Wilson JH. Clinical presentation of (subclinical) jaundice--the Euricterus project in The Netherlands. United Dutch Hospitals and Euricterus Project Management Group. Hepatogastroenterology 1996; 43:1190.
  2. http://mghlabtest.partners.org/MGH_Reference_Intervals_August_2011.pdf (Accessed on March 29, 2013).
  3. ROBINSON S, VANIER T, DESFORGES JF, SCHMID R. Jaundice in thalassemia minor: a consequence of "ineffective erythropoiesis". N Engl J Med 1962; 267:523.
  4. Israels G, Zipursky A. Primary shunt hyperbilirubinemia due to an alternate path of bilirubin production. Am J Med 1959; 27:693.
  5. Berk PD, Wolkoff AW, Berlin NI. Inborn errors of bilirubin metabolism. Med Clin North Am 1975; 59:803.
  6. Snyder AL, Satterlee W, Robinson SH, Schmid R. Conjugated plasma bilirubin in jaundice caused by pigment overload. Nature 1967; 213:93.
  7. Donner MG, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology 2001; 34:351.
  8. Jansen PL, Roskams T. Why are patients with liver disease jaundiced? ATP-binding cassette transporter expression in human liver disease. J Hepatol 2001; 35:811.
  9. Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008; 48:1167.
  10. Dhawan A, Taylor RM, Cheeseman P, et al. Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl 2005; 11:441.
  11. WATSON CJ, WEIMER M. Composition of the urobilin group in urine bile, and feces and the significance of variations in health and disease. J Lab Clin Med 1959; 54:1.
  12. SCHAFFNER F, POPER H. Capillarization of hepatic sinusoids in man. Gastroenterology 1963; 44:239.
  13. Kenwright S, Levi AJ. Sites of competition in the selective hepatic uptake of rifamycin-SV, flavaspidic acid, bilirubin, and bromsulphthalein. Gut 1974; 15:220.
  14. Chowdhury JR, Chowdhury NR, Moscioni AD, et al. Differential regulation by triiodothyronine of substrate-specific uridinediphosphoglucuronate glucuronosyl transferases in rat liver. Biochim Biophys Acta 1983; 761:58.
  15. Rius M, Nies AT, Hummel-Eisenbeiss J, et al. Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology 2003; 38:374.
  16. Cello JP. Acquired immunodeficiency syndrome cholangiopathy: spectrum of disease. Am J Med 1989; 86:539.
  17. McCarty M, Choudhri AH, Helbert M, Crofton ME. Radiological features of AIDS related cholangitis. Clin Radiol 1989; 40:582.
  18. Mendenhall CL, Anderson S, Weesner RE, et al. Protein-calorie malnutrition associated with alcoholic hepatitis. Veterans Administration Cooperative Study Group on Alcoholic Hepatitis. Am J Med 1984; 76:211.
  19. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989; 20:594.
  20. Stricker BHCH. Drug-induced Hepatic Injury, Elsevier, Amsterdam 1993.
  21. Tandon BN, Tandon HD, Tandon RK, et al. An epidemic of veno-occlusive disease of liver in central India. Lancet 1976; 2:271.
  22. Tandon BN, Joshi YK, Sud R, et al. Follow-up of survivors of epidemic veno-occlusive disease in India. Lancet 1984; 1:730.
  23. Hall AJ, Harrington JM, Waterhouse JA. The Epping jaundice outbreak: a 24 year follow up. J Epidemiol Community Health 1992; 46:327.
  24. Bagla P, Kaiser J. India's spreading health crisis draws global arsenic experts. Science 1996; 274:174.
  25. Fuchs M, Sanyal AJ. Sepsis and cholestasis. Clin Liver Dis 2008; 12:151.
  26. Hojo M, Sano N, Takikawa H. Effects of lipopolysaccharide on the biliary excretion of bile acids and organic anions in rats. J Gastroenterol Hepatol 2003; 18:815.
  27. Bolder U, Ton-Nu HT, Schteingart CD, et al. Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion. Gastroenterology 1997; 112:214.
  28. Welsh FK, Ramsden CW, MacLennan K, et al. Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice. Ann Surg 1998; 227:205.
  29. Dourakis SP, Sinani C, Deutsch M, et al. Cholestatic jaundice as a paraneoplastic manifestation of renal cell carcinoma. Eur J Gastroenterol Hepatol 1997; 9:311.
  30. Walther MM, Johnson B, Culley D, et al. Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlates with paraneoplastic syndromes but not patient survival. J Urol 1998; 159:718.
  31. Karakolios A, Kasapis C, Kallinikidis T, et al. Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma. Clin Gastroenterol Hepatol 2003; 1:480.
  32. Allardyce DB. Cholestasis caused by lipid emulsions. Surg Gynecol Obstet 1982; 154:641.
  33. van Deventer SJ, ten Cate JW, Tytgat GN. Intestinal endotoxemia. Clinical significance. Gastroenterology 1988; 94:825.
  34. Zimmerman HJ, Fang M, Utili R, et al. Jaundice due to bacterial infection. Gastroenterology 1979; 77:367.
  35. Dale O, Brown BR Jr. Clinical pharmacokinetics of the inhalational anaesthetics. Clin Pharmacokinet 1987; 12:145.
  36. Faust TW, Reddy KR. Postoperative jaundice. Clin Liver Dis 2004; 8:151.
  37. Stratta RJ, Wood RP, Langnas AN, et al. Diagnosis and treatment of biliary tract complications after orthotopic liver transplantation. Surgery 1989; 106:675.
  38. Betrosian A, Balla M, Kafiri G, et al. Reversal of liver failure in sickle cell vaso-occlusive crisis. Am J Med Sci 1996; 311:292.
  39. Bond LR, Hatty SR, Horn ME, et al. Gall stones in sickle cell disease in the United Kingdom. Br Med J (Clin Res Ed) 1987; 295:234.
  40. Charlotte F, Bachir D, Nénert M, et al. Vascular lesions of the liver in sickle cell disease. A clinicopathological study in 26 living patients. Arch Pathol Lab Med 1995; 119:46.
  41. Reyes H. Review: intrahepatic cholestasis. A puzzling disorder of pregnancy. J Gastroenterol Hepatol 1997; 12:211.
  42. Shaw D, Frohlich J, Wittmann BA, Willms M. A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol 1982; 142:621.
  43. Leevy CB, Koneru B, Klein KM. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1997; 113:966.