Exploration of Digestive Diseases

From: Etiopathogenesis and pathophysiology of cholestasis

Table 1. Plasma membrane transporters and channels involved in hepatobiliary function

Cells	Membrane	Protein	Gene	Substrates
Hepatocytes	Basolateral	NTCP	SLC10A1	Bile acids
		OATP1B1	SLCO1B1	Bile acids, organic anions
		OATP1B3	SLCO1B3	Bile acids, organic anions
		MRP3	ABCC3	Bile acids, organic anions
		MRP4	ABCC4	Bile acids, organic anions
		NBC4	SLC4A5	Na⁺/HCO₃^–symporter
		NHE1	SLC9A1	Na⁺/H⁺ antiporter
		SK2	KCNN2	K⁺ channel
		BSC	SLC12A2	Na⁺/Cl^– symporter
		AQP9	AQP9	Water channel
Hepatocytes	Canalicular	BSEP	ABCB11	Bile acids
		MRP2	ABCC2	Organic anions
		MDR1	ABCB1	Several
		BCRP	ABCG2	Bile acids, steroids
		MDR3	ABCB4	Phosphatidyl choline
		FIC1	ATP8B1	Phosphatidyl serine
		ABCG5/G8	ABCG5/G8	Cholesterol
		NHE3	SLC9A3	Na⁺/H⁺ antiporter
		AQP8	AQP8	Water channel
Cholangiocytes	Basolateral	OSTα/β	SLC51A/B	Bile acids, organic anions
		NHE1	SLC9A1	Na⁺/H⁺ antiporter
		NDCBE	SLC4A8	Cl^–/HCO₃^– antiporter
		SK2	KCNN2	K⁺ channel
		BSC	SLC12A2	Na⁺/Cl^– symporter
		MRP3	ABCC3	Bile acids, organic anions
		MRP4	ABCC4	Bile acids, organic anions
		AQP4	AQP4	Water channel
Cholangiocytes	Apical	ASBT	SLC10A2	Bile acids
		AE2	SLC4A2	Cl^–/HCO₃^– antiporter
		CFTR	ABCC7	Cl^– channel
		NBC4	SLC4A5	Na⁺/HCO₃^– symporter
		AQP1	AQP1	Water channel

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BCRP: breast cancer resistance protein; HCO₃^–: bicarbonate; KCNN2: potassium calcium-activated channel subfamily N member 2

Declarations

Author contributions

MA: writing – review & editing; SOR and AMC: writing – original draft; JJGM: supervision.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This study was funded by the CIBERehd (EHD15PI05/2016) and “Fondo de Investi-gaciones Sanitarias, Instituto de Salud Carlos III”, Spain (PI16/00598 and PI19/00819, co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”); Spanish Ministry of Economy, Industry and Competitiveness (SAF2016-75197-R); “Junta de Cas-tilla y Leon” (SA063P17); AECC Scientific Foundation (2017/2020), Spain; “Proyectos de Investigación Modalidad C2”, University of Salamanca (18.K137/463AC01 and 18.K140/463AC01); “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain and Fundación University of Salamanca, Spain (PC-TCUE18-20_051); Fundació Marato TV3 (Ref. 201916-31). SOR was supported by a postdoctoral contract (FPU) funded by the “Junta de Castilla y Leon” (SA074P20). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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References

Jüngst C, Berg T, Cheng J, Green RM, Jia J, Mason AL, et al. Intrahepatic cholestasis in common chronic liver diseases. Eur J Clin Invest. 2013;43:1069–83. [DOI] [PubMed]

Brauer RW. Mechanisms of bile secretion. J Am Med Assoc. 1959;169:1462–6. [DOI] [PubMed]

Sperber I. Secretion of organic anions in the formation of urine and bile. Pharmacol Rev. 1959;11:109–34. [PubMed]

Marin JJG. How we have learned about the complexity of physiology, pathobiology and pharmacology of bile acids and biliary secretion. World J Gastroenterol. 2008;14:5617–9. [DOI] [PubMed] [PMC]

Galman C, Angelin B, Rudling M. Pronounced variation in bile acid synthesis in humans is related to gender, hypertriglyceridaemia and circulating levels of fibroblast growth factor 19. J Intern Med. 2011;270:580–8. [DOI] [PubMed]

Fisher MM, Yousef IM. Sex differences in the bile acid composition of human bile: studies in patients with and without gallstones. Can Med Assoc J. 1973;109:190–3. [PubMed] [PMC]

Feldman AG, Sokol RJ. Recent developments in diagnostics and treatment of neonatal cholestasis. Semin Pediatr Surg. 2020;29:150945. [DOI] [PubMed] [PMC]

Hofmann AF. Biliary secretion and excretion in health and disease: current concepts. Ann Hepatol. 2007;6:15–27. [DOI] [PubMed]

Strazzabosco M, Fabris L. Functional anatomy of normal bile ducts. Anat Rec (Hoboken). 2008;291:653–60. [DOI] [PubMed] [PMC]

10.

Diamond JM. The reabsorptive function of the gall-bladder. J Physiol. 1962;161:442–73. [DOI] [PubMed] [PMC]

11.

Monte MJ, Marin JJ, Antelo A, Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol. 2009;15:804–16. [DOI] [PubMed] [PMC]

12.

Marin JJ, Macias RI, Briz O, Banales JM, Monte MJ. Bile acids in physiology, pathology and pharmacology. Curr Drug Metab. 2016;17:4–29. [DOI] [PubMed]

13.

Boyer JL. Bile formation and secretion. Compr Physiol. 2013;3:1035–78. [DOI] [PubMed] [PMC]

14.

Jones AL, Schmucker DL, Renston RH, Murakami T. The architecture of bile secretion. A morphological perspective of physiology. Dig Dis Sci. 1980;25:609–29. [DOI] [PubMed]

15.

Kullak-Ublick GA, Meier PJ. Mechanisms of cholestasis. Clin Liver Dis. 2000;4:357–85. [DOI] [PubMed]

16.

Erlinger S. Physiology of bile flow. Prog Liver Dis. 1972;4:63–82.

17.

Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na⁺/bile acid cotransporter. J Clin Invest. 1994;93:1326–31. [DOI] [PubMed] [PMC]

18.

Ananthanarayanan M, Ng OC, Boyer JL, Suchy FJ. Characterization of cloned rat liver Na⁺-bile acid cotransporter using peptide and fusion protein antibodies. Am J Physiol. 1994;267:G637–43. [DOI] [PubMed]

19.

Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003;1609:1–18. [DOI] [PubMed]

20.

Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet. 2006;368:230–9. [DOI] [PubMed]

21.

Schafmayer C, Hartleb J, Tepel J, Albers S, Freitag S, Volzke H, et al. Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany. BMC Gastroenterol. 2006;6:36. [DOI] [PubMed] [PMC]

22.

Sanders G, Kingsnorth AN. Gallstones. BMJ. 2007;335:295–9. [DOI] [PubMed] [PMC]

23.

Nakai Y, Isayama H, Wang HP, Rerknimitr R, Khor C, Yasuda I, et al. International consensus statements for endoscopic management of distal biliary stricture. J Gastroenterol Hepatol. 2020;35:967–79. [DOI] [PubMed] [PMC]

24.

Mezina A, Karpen SJ. Genetic contributors and modifiers of biliary atresia. Dig Dis. 2015;33:408–14. [DOI] [PubMed] [PMC]

25.

Bektas M, Dokmeci A, Cinar K, Halici I, Oztas E, Karayalcin S, et al. Endoscopic management of biliary parasitic diseases. Dig Dis Sci. 2010;55:1472–8. [DOI] [PubMed]

26.

Rana SS, Bhasin DK, Nanda M, Singh K. Parasitic infestations of the biliary tract. Curr Gastroenterol Rep. 2007;9:156–64. [DOI] [PubMed]

27.

Karrer FM, Hall RJ, Stewart BA, Lilly JR. Congenital biliary tract disease. Surg Clin North Am. 1990;70:1403–18. [DOI] [PubMed]

28.

Virgile J, Marathi R. Cholangitis. Treasure Island (FL): StatPearls Publishing; 2022.

29.

Kruse EJ. Palliation in pancreatic cancer. Surg Clin North Am. 2010;90:355–64. [DOI] [PubMed]

30.

Anderson B, Doyle MBM. Surgical considerations of hilar cholangiocarcinoma. Surg Oncol Clin N Am. 2019;28:601–17. [DOI] [PubMed]

31.

Khan AS, Dageforde LA. Cholangiocarcinoma. Surg Clin North Am. 2019;99:315–35. [DOI] [PubMed]

32.

Zhang H, Yang T, Wu M, Shen F. Intrahepatic cholangiocarcinoma: epidemiology, risk factors, diagnosis and surgical management. Cancer Lett. 2016;379:198–205. [DOI] [PubMed]

33.

Khim G, Em S, Mo S, Townell N. Liver abscess: diagnostic and management issues found in the low resource setting. Br Med Bull. 2019;132:45–52. [DOI] [PubMed] [PMC]

34.

Lun ZR, Gasser RB, Lai DH, Li AX, Zhu XQ, Yu XB, et al. Clonorchiasis: a key foodborne zoonosis in China. Lancet Infect Dis. 2005;5:31–41. [DOI] [PubMed]

35.

Lazaridis KN, LaRusso NF. The cholangiopathies. Mayo Clin Proc. 2015;90:791–800. [DOI] [PubMed] [PMC]

36.

Hohenester S, de Buy Wenniger LM, Paulusma CC, van Vliet SJ, Jefferson DM, Elferink RPO, et al. A biliary HCO3– umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 2012;55:173–83. [DOI] [PubMed]

37.

Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet. 2018;391:2547–59. [DOI]

38.

Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology. 2013;145:521–36. [DOI] [PubMed] [PMC]

39.

Pena-Perez CA, Diaz-Ponce-Medrano JA. Secondary sclerosing cholangitis in critically ill patients. Cir Cir. 2019;86:49–55. [PubMed]

40.

Moyer K, Balistreri W. Hepatobiliary disease in patients with cystic fibrosis. Curr Opin Gastroenterol. 2009;25:272–8. [DOI] [PubMed]

41.

Spengler EKJ, Dunkelberg J, Schey R. Alcoholic hepatitis: current management. Dig Dis Sci. 2014;59:2357–66. [DOI] [PubMed]

42.

Teli MR, Day CP, James OFW, Burt AD, Bennett MK. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet. 1995;346:987–90. [DOI] [PubMed]

43.

Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360:2758–69. [DOI] [PubMed]

44.

Nissenbaum M, Chedid A, Mendenhall C, Gartside P; VA Cooperative Study Group #119. Prognostic significance of cholestatic alcoholic hepatitis. Dig Dis Sci. 1990;35:891–6. [DOI] [PubMed]

45.

Hoofnagle JH. Reactivation of hepatitis B. Hepatology. 2009;49:S156–65. [DOI] [PubMed]

46.

Mason AL, Wick M, White HM, Benner KG, Lee RG, Regenstein F, et al. Increased hepatocyte expression of hepatitis B virus transcription in patients with features of fibrosing cholestatic hepatitis. Gastroenterology. 1993;105:237–44. [DOI] [PubMed]

47.

Davies SE, Portmann BC, O’Grady JG, Aldis PM, Chaggar K, Alexander GJ, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology. 1991;13:150–7. [DOI] [PubMed]

48.

Miyake T, Michitaka K, Tokumoto Y, Furukawa S, Ueda T, Soga Y, et al. Fibrosing cholestatic hepatitis with hepatitis C virus treated by double filtration plasmapheresis and interferon plus ribavirin after liver transplantation. Clin J Gastroenterol. 2009;2:125–30. [DOI] [PubMed]

49.

Schluger LK, Sheiner PA, Thung SN, Lau JY, Min A, Wolf DC, et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology. 1996;23:971–6. [DOI] [PubMed]

50.

Lim HL, Lau GKK, Davis GL, Dolson DJ, Lau JYN. Cholestatic hepatitis leading to hepatic failure in a patient with organ-transmitted hepatitis C virus infection. Gastroenterology. 1994;106:248–51. [DOI] [PubMed]

51.

Schiff ER. Atypical clinical manifestations of hepatitis A. Vaccine. 1992;10:S18–20. [DOI] [PubMed]

52.

Munoz-Martinez SG, Diaz-Hernandez HA, Suarez-Flores D, Sanchez-Avila JF, Gamboa-Dominguez A, Garcia-Juarez I, et al. Atypical manifestations of hepatitis A virus infection. Rev Gastroenterol Mex (Engl Ed). 2018;83:134–43. Spanish. [DOI]

53.

Jung YM, Park SJ, Kim JS, Jang JH, Lee SH, Kim JW, et al. Atypical manifestations of hepatitis A infection: a prospective, multicenter study in Korea. J Med Virol. 2010;82:1318–26. [DOI] [PubMed]

54.

Glikson M, Galun E, Oren R, Tur-Kaspa R, Shouval D. Relapsing hepatitis A review of 14 cases and literature survey. Medicine (Baltimore). 1992;71:14–23. [DOI] [PubMed]

55.

Lanford RE, Feng Z, Chavez D, Guerra B, Brasky KM, Zhou Y, et al. Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl Acad Sci U S A. 2011;108:11223–8. [DOI] [PubMed] [PMC]

56.

Czaja AJ. Diagnosis and management of autoimmune hepatitis. Clin Liver Dis. 2015;19:57–79. [DOI] [PubMed]

57.

Czaja AJ. Diagnosis and management of the overlap syndromes of autoimmune hepatitis. Can J Gastroenterol. 2013;27:417–23. [DOI] [PubMed] [PMC]

58.

Czaja AJ. The overlap syndromes of autoimmune hepatitis. Dig Dis Sci. 2013;58:326–43. [DOI] [PubMed]

59.

Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E; International Autoimmune Hepatitis Group. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54:374–85. [DOI] [PubMed]

60.

Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Autoimmune cholangitis within the spectrum of autoimmune liver disease. Hepatology. 2000;31:1231–8. [DOI] [PubMed]

61.

Xu ZW, Li YS. Pathogenesis and treatment of parenteral nutrition-associated liver disease. Hepatobiliary Pancreat Dis Int. 2012;11:586–93. [DOI] [PubMed]

62.

Nanji AA, Anderson FH. Sensitivity and specificity of liver function tests in the detection of parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr. 1985;9:307–8. [DOI] [PubMed]

63.

Beath SV, Kelly DA. Total parenteral nutrition-induced cholestasis: prevention and management. Clin Liver Dis. 2016;20:159–76. [DOI] [PubMed]

64.

Reimund JM, Duclos B, Arondel Y, Baumann R. Persistent inflammation and immune activation contribute to cholestasis in patients receiving home parenteral nutrition. Nutrition. 2001;17:300–4. [DOI] [PubMed]

65.

Guglielmi FW, Regano N, Mazzuoli S, Fregnan S, Leogrande G, Guglielmi A, et al. Cholestasis induced by total parenteral nutrition. Clin Liver Dis. 2008;12:97–110. [DOI] [PubMed]

66.

Bouchecareilh M. Alpha-1 antitrypsin deficiency-mediated liver toxicity: why do some patients do poorly? What do we know so far? Chronic Obstr Pulm Dis. 2020;7:172–81. [DOI] [PubMed] [PMC]

67.

Chappell S, Hadzic N, Stockley R, Guetta-Baranes T, Morgan K, Kalsheker N. A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology. 2008;47:127–32. [DOI] [PubMed]

68.

Lane E, Murray KF. Neonatal cholestasis. Pediatr Clin North Am. 2017;64:621–39. [DOI] [PubMed]

69.

Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. [DOI] [PubMed] [PMC]

70.

Schieferdecker A, Wendler P. Structural mapping of missense mutations in the Pex1/Pex6 complex. Int J Mol Sci. 2019;20:3756. [DOI] [PubMed] [PMC]

71.

Li Q, Sun Y, van IJzendoorn SCD. A link between intrahepatic cholestasis and genetic variations in intracellular trafficking regulators. Biology (Basel). 2021;10:119. [DOI] [PubMed] [PMC]

72.

Zhou Y, Zhang J. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features. Ital J Pediatr. 2014;40:77. [DOI] [PubMed] [PMC]

73.

Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction- cholestasis (ARC) syndrome. Nat Genet. 2004;36:400–4. [DOI] [PubMed]

74.

Cullinane AR, Straatman-Iwanowska A, Zaucker A, Wakabayashi Y, Bruce CK, Luo G, et al. Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet. 2010;42:303–12. [DOI] [PubMed] [PMC]

75.

Martinelli D, Travaglini L, Drouin CA, Ceballos-Picot I, Rizza T, Bertini E, et al. MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain. 2013;136:872–81. [DOI] [PubMed]

76.

Lenz D, McClean P, Kansu A, Bonnen PE, Ranucci G, Thiel C, et al. SCYL1 variants cause a syndrome with lowγ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). Genet Med. 2018;20:1255–65. [DOI] [PubMed] [PMC]

77.

Zhang J, Liu LL, Gong JY, Hao CZ, Qiu YL, Lu Y, et al. TJP2 hepatobiliary disorders: novel variants and clinical diversity. Hum Mutat. 2020;41:502–11. [DOI] [PubMed]

78.

Gonzales E, Taylor SA, Davit-Spraul A, Thebaut A, Thomassin N, Guettier C, et al. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology. 2017;65:164–73. [DOI] [PubMed]

79.

Qiu YL, Gong JY, Feng JY, Wang RX, Han J, Liu T, et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ-glutamyltransferase cholestasis. Hepatology. 2017;65:1655–69. [DOI] [PubMed] [PMC]

80.

Cutz E, Rhoads JM, Drumm B, Sherman PM, Durie PR, Forstner GG. Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation. N Engl J Med. 1989;320:646–51. [DOI] [PubMed]

81.

Girard M, Lacaille F, Verkarre V, Mategot R, Feldmann G, Grodet A, et al. MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. Hepatology. 2014;60:301–10. [DOI] [PubMed]

82.

Overeem AW, Li Q, Qiu YL, Carton-Garcia F, Leng C, Klappe K, et al. A molecular mechanism underlying genotype-specific intrahepatic cholestasis resulting from MYO5B mutations. Hepatology. 2020;72:213–29. [DOI] [PubMed] [PMC]

83.

Unlusoy Aksu A, Das SK, Nelson-Williams C, Jain D, Ozbay Hosnut F, Evirgen Sahin G, et al. Recessive mutations in KIF12 cause high gamma-glutamyltransferase cholestasis. Hepatol Commun. 2019;3:471–7. [DOI] [PubMed] [PMC]

84.

Zollner G, Trauner M. Mechanisms of cholestasis. Clin Liver Dis. 2008;12:1–26. [DOI] [PubMed]

85.

Roehlen N, Roca Suarez AA, El Saghire H, Saviano A, Schuster C, Lupberger J, et al. Tight junction proteins and the biology of hepatobiliary disease. Int J Mol Sci. 2020;21:825. [DOI] [PubMed] [PMC]

86.

Fallon MB, Brecher AR, Balda MS, Matter K, Anderson JM. Altered hepatic localization and expression of occludin after common bile duct ligation. Am J Physiol. 1995;269:C1057–62. [DOI] [PubMed]

87.

Fallon MB, Mennone A, Anderson JM. Altered expression and localization of the tight junction protein ZO-1 after common bile duct ligation. Am J Physiol. 1993;264:C1439–47. [DOI] [PubMed]

88.

Ge T, Zhang X, Xiao Y, Wang Y, Zhang T. Novel compound heterozygote mutations of TJP2 in a Chinese child with progressive cholestatic liver disease. BMC Med Genet. 2019;20:18. [DOI] [PubMed] [PMC]

89.

Xu J, Kausalya PJ, Van Hul N, Caldez MJ, Xu S, Ong AGM, et al. Protective functions of ZO-2/Tjp2 expressed in hepatocytes and cholangiocytes against liver injury and cholestasis. Gastroenterology. 2021;160:2103–18. [DOI] [PubMed]

90.

Sambrotta M, Strautnieks S, Papouli E, Rushton P, Clark BE, Parry DA, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet. 2014;46:326–8. [DOI] [PubMed] [PMC]

91.

Chen H, Huang X, Min J, Li W, Zhang R, Zhao W, et al. Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2. J Ethnopharmacol. 2016;179:197–207. [DOI] [PubMed]

92.

Hadj-Rabia S, Baala L, Vabres P, Hamel-Teillac D, Jacquemin E, Fabre M, et al. Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease. Gastroenterology. 2004;127:1386–90. [DOI] [PubMed]

93.

Balwani M, Bloomer J, Desnick R. Erythropoietic protoporphyria, autosomal recessive. Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH et al., editor. Seattle (WA): University of Washington, Seattle; 1993–2022.

94.

Bloomer JR. Hepatic protoporphyrin metabolism in patients with advanced protoporphyric liver disease. Yale J Biol Med. 1997;70:323–30. [PubMed] [PMC]

95.

Lee RG, Avner DL, Berenson MM. Structure-function relationships of protoporphyrin-induced liver injury. Arch Pathol Lab Med. 1984;108:744–6. [PubMed]

96.

Yamamoto S, Kitano Y, Eimoto T, Horie Y. Erythropoietic protoporphyria with severe cholestasis. Intern Med. 1994;33:802–5. [DOI] [PubMed]

97.

Nakanuma Y, Wada M, Kono N, Miyamura H, Ohta G. An autopsy case of erythropoietic protoporphyria with cholestatic jaundice and hepatic failure, and a review of literature. Virchows Arch A Pathol Anat Histol. 1981;393:123–32. [DOI] [PubMed]

98.

Balwani M, Naik H, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, et al. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked protoporphyria. JAMA Dermatol. 2017;153:789–96. [DOI] [PubMed] [PMC]

99.

Avner DL, Lee RG, Berenson MM. Protoporphyrin-induced cholestasis in the isolated in situ perfused rat liver. J Clin Invest. 1981;67:385–94. [DOI] [PubMed] [PMC]

100.

Perez-Barriocanal F, Redondo-Torres JG, Villanueva GR, Arteche E, Berenson MM, Marin JJG. Protoporphyrin IX-induced impairment of biliary lipid secretion in the rat. Clin Sci (Lond). 1989;77:473–8. [DOI] [PubMed]

101.

Berenson MM, Marin JJG, Larsen R, Avner D. Effect of bile acids on hepatic protoporphyrin metabolism in perfused rat liver. Gastroenterology. 1987;93:1086–93. [DOI] [PubMed]

102.

Hubscher SG, Lumley MA, Elias E. Vanishing bile duct syndrome: a possible mechanism for intrahepatic cholestasis in Hodgkin’s lymphoma. Hepatology. 1993;17:70–7. [DOI] [PubMed]

103.

Chen M, Suzuki A, Thakkar S, Yu K, Hu C, Tong W. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today. 2016;21:648–53. [DOI] [PubMed]

104.

Gijbels E, Vinken M. Mechanisms of drug-induced cholestasis. Methods Mol Biol. 2019;1981:1–14. [DOI] [PubMed]

105.

Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced cholestasis. Hepatology. 2011;53:1377–87. [DOI] [PubMed] [PMC]

106.

Bode KA, Donner MG, Leier I, Keppler D. Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem Pharmacol. 2002;64:151–8. [DOI] [PubMed]

107.

Fernandez-Murga ML, Petrov PD, Conde I, Castell JV, Gomez-Lechon MJ, Jover R. Advances in drug-induced cholestasis: clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol. 2018;120:196–212. [DOI] [PubMed]

108.

Zucchetti AE, Barosso IR, Boaglio A, Pellegrino JM, Ochoa EJ, Roma MG, et al. Prevention of estradiol 17β-d-glucuronide-induced canalicular transporter internalization by hormonal modulation of cAMP in rat hepatocytes. Mol Biol Cell. 2011;22:3902–15. [DOI] [PubMed] [PMC]

109.

Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJG. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol. 2006;44:1150–7. [DOI] [PubMed]

110.

Abu-Hayyeh S, Papacleovoulou G, Lovgren-Sandblom A, Tahir M, Oduwole O, Jamaludin NA, et al. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology. 2013;57:716–26. [DOI] [PubMed] [PMC]

111.

Garzel B, Yang H, Zhang L, Huang SM, Polli JE, Wang H. The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity. Drug Metab Dispos. 2014;42:318–22. [DOI] [PubMed] [PMC]

112.

Smith DD, Rood KM. Intrahepatic cholestasis of pregnancy. Clin Obstet Gynecol. 2020;63:134–51. [DOI] [PubMed]

113.

Clayton RJ, Iber FL, Ruebner BH, McKusick VA. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child. 1969;117:112–24. [DOI] [PubMed]

114.

Paulusma CC, de Waart DR, Kunne C, Mok KS, Elferink RPJO. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem. 2009;284:9947–54. [DOI] [PubMed] [PMC]

115.

Bull LN, Thompson RJ. Progressive familial intrahepatic cholestasis. Clin Liver Dis. 2018;22:657–69. [DOI] [PubMed]

116.

de Vree JML, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A. 1998;95:282–7. [DOI] [PubMed] [PMC]

117.

Vitale G, Gitto S, Vukotic R, Raimondi F, Andreone P. Familial intrahepatic cholestasis: new and wide perspectives. Dig Liver Dis. 2019;51:922–33. [DOI] [PubMed]

118.

Alonso-Pena M, Espinosa-Escudero R, Herraez E, Briz O, Cagigal ML, Gonzalez-Santiago JM, et al. Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia. Hepatology. 2022;[Epub ahead of print]. [DOI] [PubMed]

119.

Monte MJ, Alonso-Pena M, Briz O, Herraez E, Berasain C, Argemi J, et al. ACOX2 deficiency: an inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia. J Hepatol. 2017;66:581–8. [DOI] [PubMed]

120.

Chen HL, Li HY, Wu JF, Wu SH, Chen HL, Yang YH, et al. Panel-based next-generation sequencing for the diagnosis of cholestatic genetic liver diseases: clinical utility and challenges. J Pediatr. 2019;205:153–9.E6. [DOI] [PubMed]

121.

Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun. 2016;7:10713. [DOI] [PubMed] [PMC]

122.

Henkel SA, Squires JH, Ayers M, Ganoza A, McKiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol. 2019;11:450–63. [DOI] [PubMed] [PMC]

123.

Junge N, Goldschmidt I, Wiegandt J, Leiskau C, Mutschler F, Laue T, et al. Dubin-Johnson syndrome as differential diagnosis for neonatal cholestasis. J Pediatr Gastroenterol Nutr. 2021;72:e105–11. [DOI] [PubMed]

124.

Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, Ohashi K, et al. Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing. J Pediatr. 2016;171:171–7.E4. [DOI] [PubMed]

125.

Togawa T, Mizuochi T, Sugiura T, Kusano H, Tanikawa K, Sasaki T, et al. Clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome: a multicenter study in Japan. J Pediatr. 2018;196:161–7.E1. [DOI] [PubMed]

126.

Dixon PH, Sambrotta M, Chambers J, Taylor-Harris P, Syngelaki A, Nicolaides K, et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep. 2017;7:11823. [DOI] [PubMed] [PMC]

127.

Chai J, Cai SY, Liu X, Lian W, Chen S, Zhang L, et al. Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis. J Hepatol. 2015;63:1440–8. [DOI] [PubMed] [PMC]

128.

Mariotti V, Cadamuro M, Spirli C, Fiorotto R, Strazzabosco M, Fabris L. Animal models of cholestasis: an update on inflammatory cholangiopathies. Biochim Biophys Acta Mol Basis Dis. 2019;1865:954–64. [DOI] [PubMed]

129.

Cameron GR, Oakley CL. Ligation of the common bile duct. J Pathol Bacteriol. 1932;35:769–98. [DOI]

130.

Halilbasic E, Fiorotto R, Fickert P, Marschall HU, Moustafa T, Spirli C, et al. Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2^–/– mice. Hepatology. 2009;49:1972–81. [DOI] [PubMed] [PMC]