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ILLUMINATIONS

How Does Conjugated Bilirubin Appear in the Bloodstream?

School of MedicineFaculty of Medical and Health Sciences
Asian Institute of Medicine, Science and Technology
Bedong 08100, Kedah Darul Aman, Malaysia
E-mail: dresprakash{at}gmail.com

In our university, undergraduate medical students (in the Bachelor of Medicine and Bachelor of Surgery Programme) are required to prepare "special study modules" as part of course requirements. This exercise provides students with an opportunity for an indepth study of areas not covered in the core curriculum. They are assigned a facilitator who guides the student in selecting the topic, selecting learning resources, and in preparing a written document (3,000 words) that is submitted for evaluation. This manuscript, which is presented as a dialogue, summarizes what happened between the facilitator, E. S. Prakash (ESP), and his student, Yugaseelan Taramalingam (YT), in one of the special study modules. In this instance, YT, a second-year undergraduate medical student, had a specific question: How does conjugated bilirubin leave the hepatocytes in Dubin-Johnson syndrome? This question first occurred to him during a problem based learning tutorial on jaundice. After answering this question, we were motivated to write this short article to Advances in Physiology Education once we verified that information about the actual mechanism of secretion of conjugated bilirubin into the bloodstream has still not been incorporated into commonly used textbooks of physiology.

YT: How does conjugated bilirubin leave the hepatocytes in Dubin-Johnson syndrome?

ESP: Bilirubin diglucuronide, a water-soluble molecule, is secreted by hepatocytes into bile canaliculi (2). However, even normally, a small fraction of bilirubin in blood is conjugated, but it does not normally exceed 0.4 mg/dl (2). Resorption of conjugated bilirubin from the intestine is negligible (3). How does conjugated bilirubin ever appear in the bloodstream in normal individuals, let alone those with Dubin-Johnson syndrome? Is turnover of liver cells responsible for causing some conjugated bilirubin to leak into blood? Obstruction to flow of bile is characterized by a predominance of conjugated bilirubin in blood (2). My understanding of this is shown in Fig. 1, i.e., a rise in intrabiliary pressures as a result of intra-/extrahepatic obstruction to bile flow will eventually overcome the resistance of tight junctions between the apical ends of hepatocytes, which is the only barrier that normally prevents bile from mixing with blood. If this happens, conjugated bilirubin will appear in the bloodstream. Furthermore, the conjugated hyperbilirubinemia of obstructive jaundice is accompanied by raised blood levels of alkaline phosphatase (2), an enzyme from bile duct epithelial cells, indicating that the above explanation is correct.

View larger version (13K): [in this window] [in a new window]   Fig. 1. Diagram depicting the relationship between bile canaliculi, hepatocytes, and perisinusoidal space of Disse. The bile canaliculi are oriented perpendicular to a plate of hepatocytes. MRP2, multidrug resistance protein 2 [also called multispecific organic anion transporter (MOAT)]. Yugaseelan's literature review indicated that multidrug resistance protein 3 (MRP3) is located in the basolateral membrane of the hepatocyte and enables secretion of conjugated bilirubin into the bloodstream. For details, please see the text.

ESP: Probably it makes homeostatic sense to have conjugated bilirubin and xenobiotics also transported via the hepatocyte basolateral membrane into the circulation so that they may be excreted in the urine.

YT: Review of a recent report by Belinsky et al. (1) indicates that multidrug resistance protein (MRP)3 located in the basolateral membrane of hepatocytes transports conjugated bilirubin into circulation. Normally, the secretion of conjugated bilirubin into bile is mediated by MRP2 located in the apical membrane of hepatocytes. Under conditions of hereditary (Dubin-Johnson syndrome) or acquired MRP2 deficiency, the isoform MRP3 is upregulated in the sinusoidal membrane of hepatocytes. MRP3-null mice have significantly reduced serum levels of bilirubin diglucuronide after bile duct ligation compared with wild-type mice. MRP3 may serve as an alternate route of elimination of bile acids and bilirubin glucuronides when MRP2 function is defective, such as under cholestatic conditions (1).

ESP: Well done Yugaseelan! This "discovery" has come about specifically because you insisted on reviewing bilirubin dynamics in the liver in Dubin-Johnson syndrome.

	REFERENCES

TOP REFERENCES

 

1. Belinsky MG, Dawson PA, Shchaveleva I, Bain LJ, Wang R, Ling V, Chen Grinberg A Z, Westphal H, Klein-Szanto A, Lerro A, Kruh GD. Analysis of the in vivo functions of Mrp 3. Mol Pharmacol 68: 160–168, 2005.[Abstract/Free Full Text]
2. Feldman M, Scharschmidt BF, Sleisenger MH (editors). Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, 1998.
3. Lester R, Schmid R. Intestinal absorption of bile pigments. I. The enterohepatic circulation of bilirubin in the rat. J Clin Invest 42: 736–746, 1963.[Web of Science][Medline]
4. Sobaniec-Lotowska ME, Lebensztejn DM. Ultrastructure of Kupffer cells and hepatocytes in the Dubin-Johnson syndrome: a case report. World J Gastroenterol 14: 987–989, 2006.
5. Wada M, Toh S, Taniguchi K, Nakamura T, Uchiumi T, Kohno K, Yoshida I, Kimura A, Sakisaka S, Adachi Y, Kuwano M. Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. Hum Mol Genet 7: 203–207, 1998.[Abstract/Free Full Text]

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