• Esmaeil Salimi Faculty of Materials and Chemical Engineering, Shahrood University of Technology, P. O. Box: 3619995161, Semnan, Iran
  • Azadeh Ghaee Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, P.O. Box: 143951374, Tehran, Iran
  • Ahmad Fauzi Ismail Advanced Membrane Technology Research Center (AMTEC), Universiti Teknologi Malaysia, 81310 UTM Johor Bahru, Johor, Malaysia
  • Mohd Hafiz Dzarfan Othman Advanced Membrane Technology Research Center (AMTEC), Universiti Teknologi Malaysia, 81310 UTM Johor Bahru, Johor, Malaysia



Hyperbilirubinemia, Blood purification, Affinity chromatography, Overview, Therapy


Bilirubin removal from blood and curing patients suffering from hyperbilirubinemia by surgery, medication or interventional therapies was common, previously. Alternative bilirubin separation techniques such as plasma exchange, affinity chromatography and etc., are efficient in reducing high levels of bilirubin with fewer side effects. However, due to the various causes and complications associated with hyperbilirubinemia, different strategies are needed for the treatment. This article offers a historical overview on these strategies, challenges and also outlines the technological advantages and disadvantages associated with various bilirubin removal techniques.


Stange, J., T. I. Hassanein, R. Mehta, S. R. Mitzner and R. H. Bartlett. 2002. The Molecular Adsorbents Recycling System as a Liver Support System Based on Albumin Dialysis: A Summary of Preclinical Investigations, Prospective, Randomized, Controlled Clinical Trial, and Clinical Experience From 19 Centers. Artif Organs. 26: 103-110.

Daas, M., D. J. Plevak, E. F. Wijdicks, J. Rakela, R. H. Wiesner, D. G. Piepgras, W. F. Dunn and J. L. Steers. 1995. Acute Liver Failure: Results of a 5-Year Clinical Protocol. Liver Transpl Surg. 1: 210-219.

Karp, W. B. 1979. Biochemical Alterations in Neonatal Hyperbilirubinemia and Bilirubin Encephalopathy: A Review. Pediatrics. 64: 361-368.

Hauser, S. C., J. C. Ziurys and J. L. Gollan. 1986. Regulation of Bilirubin Glucuronide Synthesis in Primate (Macaca Fascicularis) Liver. Kinetic Analysis of Microsomal Bilirubin Uridine Diphosphate Glucuronyltransferase. Gastroenterology. 91: 287-296.

Schwesinger, W. H. and W. E. Kurtin.1983. Changes in Serum and Bile Bilirubin Induced by Acute hemolysis. J Surg Res. 35: 520-524.

Gourley, G. R. 1997. Bilirubin Metabolism and Kernicterus. Adv Pediatr. 44: 173-229.

Hansen, T. W. R. and D. Bratlid.1986. Bilirubin and Brain Toxicity. Acta Pædiatrica. 75: 513-522.

Ennever, J. F. 1988. Phototherapy for Neonatal Jaundice. Photochem Photobiol. 47: 871-876.

Meyer, T. W. 2012. The Removal of Protein-bound Solutes by Dialysis. Journal of Renal Nutrition. 22: 203-206.

Vienken, J. and H. Christmann. 2006. How Can Liver Toxins be Removed? Filtration and Adsorption with the Prometheus System. Therapeutic Apheresis and Dialysis. 10: 125-131.

Khurshid, I., L. Anderson, G. H. Downie and G. S. Pape. 2002. Sickle Cell Disease, Extreme Hyperbilirubinemia, and Pericardial Tamponade: Case Report and Review of the Literature. Crit Care Med. 30: 2363-2367.

Trey, C., D. G. Burns and S. J. Saunders. 1966. Treatment of Hepatic Coma by Exchange Blood Transfusion. N Engl J Med. 274: 473-481.

Lepore, M. J. and A. J. Martel. 1970. Plasmapheresis with Plasma Exchange in Hepatic Coma. Methods and Results in Five Patients with Acute Fulminant Hepatic Necrosis. Ann Intern Med. 72: 165-174.

Lepore, M. J., L. J. Stutman, C. A. Bonanno, E. F. Conklin, J. G. Robilotti, Jr. and P. J. McKenna. 1972. Plasmapheresis with Plasma Exchange in Hepatic Coma. II. Fulminant Viral Hepatitis as a Systemic Disease. Arch Intern Med. 129: 900-907.

Buckner, C.D., R.A. Clift, W. Volwiler, D.M. Donohue, J.M. Burnell, F.C. Saunders and E.D. Thomas. 1973. Plasma Exchange in Patients with Fulminant Hepatic Failure. Arch Intern Med. 132: 487-492.

Guo, W., Z. Shang, Y. Yu and L. Zhou. 1994. Membrane Affinity Chromatography of Alkaline Phosphatase. Journal of Chromatography A. 685: 344-348.

Avramescu, M. E., W. F. Sager, Z. Borneman and M. Wessling. 2004. Adsorptive Membranes for Bilirubin Removal. J Chromatogr B Analyt Technol Biomed Life Sci. 803: 215-223.

Denizli, A. and E. PiÅŸkin. 2001. Dye-ligand Affinity Systems. Journal of Biochemical and Biophysical Methods. 49: 391-416.

Brodersen, R. 1979. Bilirubin. Solubility And Interaction with Albumin and Phospholipid. J Biol Chem. 254: 2364-2369.

Jin, G., Q. Yao, S. Zhang and L. Zhang. 2008. Surface Modifying of Microporous PTFE Capillary for Bilirubin Removing from Human Plasma and Its Blood Compatibility. Materials Science and Engineering: C. 28: 1480-1488.

Romagnoli, C., G. Polidori, M. Foschini, L. Cataldi, P. De Turris, G. Tortorolo and R. Mastrangelo. 1975. Agar in the Management of Hyperbilirubinaemia in the Premature Baby. Arch Dis Child. 50: 202-204.

Lauterburg, B. H., E. R. Dickson, A. A. Pineda, G. L. Carlson and H. F. Taswell. 1979. Removal of Bile Acids and Bilirubin by Plasmaperfusion of U.S.P. Charcoal-coated Glass Beads. J Lab Clin Med. 94: 585-592.

Chandy, T. and C. P. Sharma. 1992. Polylysine-immobilized Chitosan Beads as Adsorbents for Bilirubin. Artif Organs. 16: 568-576.

Xia, B., G. Zhang and F. Zhang. 2003. Bilirubin Removal by Cibacron Blue F3GA Attached Nylon-based Hydrophilic Affinity Membrane. Journal of Membrane Science. 226: 9-20.

Alvarez, C., M. Strumia and H. Bertorello. 2001. Synthesis and Characterization of a Biospecific Adsorbent Containing Bovine Serum Albumin as a Ligand and Its Use for Bilirubin Retention. J Biochem Biophys Methods. 49: 649-656.

Lopukhin, U. M., B. K. Shurkalin, U. A. Leykin, N. G. Evseev, M. N. Molodenkov, V. N. Kuznetzov, V. D. Gorchakov and A. S. Blagosklonov. 1975. Letter: Bilirubin Removal by Anion-Exchange Resin. Lancet. 2: 461.

Yu, Y. H. and B. L. He. 1996. A New Type of ALSS — The Preparation of Crosslinked Chitosan Resins and Its Adsorption Properties for Bilirubin. Reactive and Functional Polymers. 31: 195-200.

Si, S., L. Si, F. Ren, D. Zhu and Y. Fung. 2002. Study of Adsorption Behavior of Bilirubin on Human-Albumin Monolayer Using A Quartz Crystal Microbalance. J Colloid Interface Sci. 253: 47-52.

Davies, C. R., P. S. Malchesky and G. M. Saidel. 1990. Temperature and Albumin Effects on Adsorption of Bilirubin from Standard Solution Using Anion-exchange Resin. Artif Organs. 14: 14-19.

Komissarova, L. K., A. A. Kuznetsov, N. P. Gluchoedov, M. V. Kutushov and M. A. Pluzan. 2001. Absorptive Capacity of Iron-based Magnetic Carriers for Blood Detoxification. Journal of Magnetism and Magnetic Materials. 225: 197-201.

Syu, M.J., J.H. Deng and Y.M. Nian. 2004. Towards bilirubin imprinted poly(methacrylic acid-co-ethylene glycol dimethylacrylate) for the specific binding of α-bilirubin. Analytica Chimica Acta. 504: 167-177.

Wang, H., J. Ma, Y. Zhang and B. He. 1997. Adsorption of Bilirubin on the Polymeric Î’-Cyclodextrin Supported by Partially Aminated Polyacrylamide Gel. Reactive and Functional Polymers. 32: 1-7.

Wu, G. and G. Brown. 1991. Adsorption of Bilirubin by Amine-Containing Polyacrylamide Resins. Reactive Polymers. 14: 49-61.

Henning, D. S., G. R. Brown and L. E. St-Pierre. 1986. Polymer Resins with Amino Acid Containing Pendants for Sorption of Bilirubin. II. Polyamide Resins with Various Basic Amino Acids. Int J Artif Organs. 9: 33-38.

Zhu, X. X., G. R. Brown and L. E. St-Pierre. 1990. Adsorption of Bilirubin with Polypeptide-coated Resins. Biomater Artif Cells Artif Organs. 18: 75-93.

Kocakulak, M., A. Denizli, A. Y. Rad and E. Piskin. 1997. New Sorbent for Bilirubin Removal from Human Plasma: Cibacron Blue F3GA-immobilized poly(EGDMA-HEMA) Microbeads. Journal Chromatogr B Biomed Sci Appl. 693: 271-276.

Ju, J., G. He, Z. Duan, W. Zhao, Y. Liu, L. Zhang and Y. Li. 2013. Improvement of Bilirubin Adsorption Capacity of Cellulose Acetate/Polyethyleneimine Membrane Using Sodium Deoxycholate. Biochemical Engineering Journal. 79: 144-152.

Brian, B. F., W. J. Dorson, V. B. Pizziconi, P. J. Ramseyer and J. E. Brooker. 1988. Augmented Hemoperfusion for Hyperbilirubinemia. ASAIO Trans. 34: 585-589.

Tang, T., X. Li, Y. Xu, D. Wu, Y. Sun, J. Xu and F. Deng. 2011. Bilirubin Adsorption on Amine/Methyl Bifunctionalized SBA-15 with Platelet Morphology. Colloids Surf B Biointerfaces. 84: 571-578.

Quaglia, M., E. De Lorenzi, C. Sulitzky, G. Caccialanza and B. Sellergren. 2003. Molecularly Imprinted Polymer Films Grafted from Porous or Nonporous Silica: Novel Affinity Stationary Phases in Capillary Electrochromatography. ELECTROPHORESIS. 24: 952-957.

Yang, Y., Y. Long, Q. Cao, K. Li and F. Liu. 2008. Molecularly Imprinted Polymer Using Beta-Cyclodextrin as Functional Monomer for the Efficient Recognition of Bilirubin. Anal Chim Acta. 606: 92-97.

Syu, M. J., Y. M. Nian, Y. S. Chang, X. Z. Lin, S. C. Shiesh and T. C. Chou. 2006. Ionic Effect on the Binding of Bilirubin to the Imprinted Poly(Methacrylic Acid-Co-Ethylene Glycol Dimethylacrylate). Journal of Chromatography A. 1122: 54-62.

Wu, A. H. and M. J. Syu. 2006. Synthesis of Bilirubin Imprinted Polymer Thin Film for the Continuous Detection of Bilirubin in an MIP/QCM/FIA System. Biosensors and Bioelectronics. 21: 2345-2353.

Baydemir, G., N. Bereli, M. Andac, R. Say, I.Y. Galaev and A. Denizli. 2009. Bilirubin Recognition Via Molecularly Imprinted Supermacroporous Cryogels. Colloids Surf B Biointerfaces. 68: 33-38.

Zimmerman, S. C. and N. G. Lemcoff. 2004. Synthetic Hosts Via Molecular Imprinting-Are Universal Synthetic Antibodies Realistically Possible? Chemical Communications. 5-14.

Song, C., A. Zhang, W. Shi, H. Jiang and D. Ge. 2011. Functionalized Silica Nanotubes As Affinity Matrices for Bilirubin Removal. Nanotechnology, IEEE Transactions on. 10: 626-631.

Zhang, L. and G. Jin. 2006. Novel Method for Bilirubin Removal from Human Plasma within Modified Polytetrafluoroethylene Capillary. Reactive and Functional Polymers. 66: 1106-1117.

Wei, H., L. Xu, J. Ren and L. Jia. 2012. Adsorption of Bilirubin to Magnetic Multi-walled Carbon Nanotubes as a Potential Application in Bound Solute Dialysis. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 405: 38-44.

Yang, Z., S. Si and Y. Fung. 2007. Bilirubin Adsorption on Nanocrystalline Titania Films. Thin Solid Films. 515: 3344-3351.

Syu, M. J., J. H. Deng, Y. M. Nian, T.C. Chiu and A.H. Wu. 2005. Binding specificity of α-bilirubin-imprinted poly (methacrylic acid-co-ethylene glycol dimethylacrylate) toward α-bilirubin. Biomaterials. 26: 4684-4692.

Baydemir, G., M. Andaç, N. Bereli, R. Say and A. Denizli. 2007. Selective Removal of Bilirubin from Human Plasma with Bilirubin-Imprinted Particles. Industrial & Engineering Chemistry Research. 46: 2843-2852.

Baydemir, G., N. Bereli, M. Andaç, R. Say, I. Y. Galaev and A. Denizli. 2009. Supermacroporous Poly (Hydroxyethyl Methacrylate) based Cryogel with Embedded Bilirubin Imprinted Particles. Reactive and Functional Polymers. 69: 36-42.

Åženel, S., F. Denizli, H. Yavuz ad A. Denizli. 2002. Bilirubin Removal from Human Plasma by Dye Affinity Microporous Hollow Fibers. Separation Science and Technology. 37: 1989-2006.

Altıntaş, E. B., D. Türkmen, V. Karakoç and A. Denizli. 2011. Efficient Removal of Bilirubin from Human Serum by Monosize Dye Affinity Beads. Journal of Biomaterials Science, Polymer Edition. 22: 957-971.

Yamazaki, K., K. Shinke and T. Ogino. 2013. Selective Adsorption of Bilirubin Against Albumin to Oxidized Single-Wall Carbon Nanohorns. Colloids and Surfaces B: Biointerfaces. 112: 103-107.

Gao, B., H. Lei, L. Jiang and Y. Zhu. 2007. Studies on Preparing and Adsorption Property of Grafting Terpolymer Microbeads of PEI-GMA/AM/MBA for Bilirubin. Journal of Chromatography B. 853: 62-69.

Timin, A., E. Rumyantsev and A. Solomonov. 2014. Synthesis and Application of Amino-Modified Silicas Containing Albumin as Hemoadsorbents for Bilirubin Adsorption. Journal of Non-Crystalline Solids. 385: 81-88.

Timin, A. S., A. V. Solomonov and E. V. Rumyantsev. 2014. Polyacrylate Guanidine and Polymethacrylate Guanidine as Novel Cationic Polymers for Effective Bilirubin Binding. Journal of Polymer Research. 21: 1-9.

Ma, Z., M. Kotaki and S. Ramakrishna. 2005. Electrospun Cellulose Nanofiber as Affinity Membrane. Journal of Membrane Science. 265: 115-123.

Guo, L., L. Zhang, J. Zhang, J. Zhou, Q. He, S. Zeng, X. Cui and J. Shi. 2009. Hollow Mesoporous Carbon Spheres—An Excellent Bilirubin Adsorbent. Chemical Communications. 6071-6073.

Timin, A. S., E. V. Rumyantsev, A. V. Solomonov, I. I. Musabirov, S. N. Sergeev, S. P. Ivanov, G. Berlier and E. Balantseva. 2015. Preparation and Characterization of Organo-Functionalized Silicas for Bilirubin Removal. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 464: 65-77.

Timin, A., E. Rumyantsev, S. N. Lanin, S.A. Rychkova, S. S. Guseynov, A. V. Solomonov and E. V. Antina. 2014. Preparation and Surface Properties of Mesoporous Silica Particles Modified with Poly (N-vinyl-2-pyrrolidone) as a Potential Adsorbent for Bilirubin Removal. Materials Chemistry and Physics. 147: 673-683.

Denizli, A., M. Kocakulak and E. PiÅŸkin. 1998. Bilirubin Removal from Human Plasma in a Packed-Bed Column System with Dye-Affinity Microbeads. Journal of Chromatography B: Biomedical Sciences and Applications. 707: 25-31.

Rad, A. Y., H. Yavuz, M. Kocakulak and A. Denizli. 2003. Bilirubin Removal from Human Plasma with Albumin Immobilised Magnetic Poly (2â€hydroxyethyl methacrylate) Beads. Macromolecular Bioscience. 3: 471-476.

Uzun, L. and A. Denizli. 2006. Bilirubin Removal Performance of Immobilized Albumin in a Magnetically Stabilized Fluidized Bed. Journal of Biomaterials Science, Polymer Edition. 17: 791-806.

Weber, V., I. Linsberger, M. Hauner, A. Leistner, A. Leistner and D. Falkenhagen. 2008. Neutral Styrene Divinylbenzene Copolymers for Adsorption of Toxins in Liver Failure. Biomacromolecules. 9: 1322-1328.

Han, X.y. and Z.p. Zhang. 2009. Preparation of Grafted Polytetrafluoroethylene Fibers and Adsorption of Bilirubin. Polymer International. 58: 1126-1133.

Ando, K., K. Shinke, S. Yamada, T. Koyama, T. Takai, S. Nakaji and T. Ogino. 2009. Fabrication of Carbon Nanotube Sheets and Their Bilirubin Adsorption Capacity. Colloids and Surfaces B: Biointerfaces. 71: 255-259.

Ko, Y. M., C. I. Chen, C. J. Shieh and Y. C. Liu. 2012. Simultaneous Purification and Immobilization of D-Hydantoinase on the Immobilized Metal Affinity Membrane Via Coordination Bonds. Biochemical Engineering Journal. 61: 20-27.

Klein, E. 2000. Affinity Membranes: A 10-Year Review. Journal of Membrane Science. 179: 1-27.

Shi, W., Y. Shen, D. Ge, M. Xue, H. Cao, S. Huang, J. Wang, G. Zhang and F. Zhang. 2008. Functionalized Anodic Aluminum Oxide (AAO) Membranes for Affinity Protein Separation. Journal of Membrane Science. 325: 801-808.

Ge, D., W. Shi, L. Ren, F. Zhang, G. Zhang, X. Zhang and Q. Zhang. 2006. Variation Analysis of Affinity-Membrane Model Based on Freundlich Adsorption. Journal of Chromatography A. 1114: 40-44.

Shi, W., H. Cao, C. Song, H. Jiang, J. Wang, S. Jiang, J. Tu and D. Ge. 2010. Poly (pyrrole-3-carboxylic acid)-alumina Composite Membrane for Affinity Adsorption of Bilirubin. Journal of Membrane Science. 353: 151-158.

Shi, W., F. Zhang and G. Zhang. 2005. Mathematical Analysis of Affinity Membrane Chromatography. Journal of Chromatography A. 1081: 156-162.

Shi, W., F. Zhang and G. Zhang. 2005. Adsorption of Bilirubin with Polylysine Carrying Chitosan-Coated Nylon Affinity Membranes. Journal of Chromatography B. 819: 301-306.

Shi, W., F. Zhang, G. Zhang, L. Jiang, Y. Zhao and S. Wang. 2003. Polylysine-immobilized Affinity Nylon Membrane Used for Bilirubin Adsorption. Molecular Simulation. 29: 787-790.

Shi, W., F. Zhang, G. Zhang, D. Ge and Q. Zhang. 2005. Adsorption of Bilirubin on Polyâ€Lâ€Lysineâ€Containing Nylon Membranes: Applications in Affinity Chromatography. Polymer International. 54: 790-795.

Bayramoğlu, G., E. Yalçın and M. Y. Arıca. 2005. Characterization of Polyethylenimine Grafted and Cibacron Blue F3GA Immobilized Poly (hydroxyethylmethacrylate-co-glycydylmethacrylate) Membranes and Application to Bilirubin Removal from Human Serum. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 264: 195-202.

Shi, W., Y. Shen, H. Jiang, C. Song, Y. Ma, J. Mu, B. Yang and D. Ge. 2010. Lysine-attached Anodic Aluminum Oxide (AAO)–silica Affinity Membrane for Bilirubin Removal. Journal of Membrane Science. 349: 333-340.

Xue, M., Y. Ling, G. Wu, X. Liu, D. Ge and W. Shi. 2013. Surface-modified Anodic Aluminum Oxide Membrane with Hydroxyethyl Celluloses as a Matrix for Bilirubin Removal. Journal of Chromatography B. 912: 1-7.

Zhang, L. and G. Jin. 2005. Bilirubin Removal from Human Plasma by Cibacron Blue F3GA using Immobilized Microporous Affinity Membranous Capillary Method. Journal of Chromatography B. 821: 112-121.

Chernova, I. and K.Y. Gurevich. 1996. Structure and Sorption Characteristics of Bioaffinity membranes. Journal of Membrane Science. 113: 161-167.

Winchester, J. F., J. M. MacKay, C. D. Forbes, J. M. Courtney, T. Gilchrist and C. R. Prentice. 1978. Hemostatic Changes Induced in Vitro by Hemoperfusion Over Activated Charcoal. Artificial Organs. 2: 293-300.

Malchesky, P. S. 1994. Nonbiological Liver Support: Historic Overview. Artificial Organs. 18: 342-347.






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