DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20184452

Approach and management considerations in low phospholipid associated cholelithiasis (LPAC) syndrome

Indrajit Suresh, Lokesh E., Amrit Nanaiah, Soumya Ganesh Nanaiah, Suhas C., Chandrababu D.

Abstract


Low phospholipid associated cholelithiasis (LPAC) syndrome, first described in 2001, could be the causality in a significant number of young patients with cholelithiasis, who have a recurrence of symptoms despite cholecystectomy. A mutation of the ABCB4/MDR3 gene, causes a disruption in the translocation of phosphatidylcholine, resulting in bile acid mediated biliary tract injury. The ABCB4 gene is also implicated in other diseases such as progressive familial intrahepatic cholestasis type 3, which is greater in severity and tools like genotyping can aid the physician in prognostication, as well as determining the response to medical therapy. A few symptomatic patients develop features of biliary obstruction due to intrahepatic calculi, and they require interventions-which may be endoscopic or surgical in nature. Although a majority of patients with LPAC syndrome respond well to ursodeoxycholic acid (UDCA) therapy, close monitoring is warranted to keep a check on disease progression.


Keywords


Cholelithiasis, Gallstones, intrahepatic calculi, LPAC, UDCA

Full Text:

PDF

References


Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology. 2001;120(6):1459-67.

Erlinger S. Low phospholipid-associated cholestasis and cholelithiasis. Clin Res Hepatol Gastroenterol. 2012;36 Suppl 1:S36-40.

Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterol. 2003;125(2):452-9.

Lagace TA. Phosphatidylcholine: greasing the cholesterol transport machinery. Lipid Insights. 2015;8(Suppl 1):65-73.

Elferink RP, Tytgat GN, Groen AK. Hepatic canalicular membrane 1: The role of MDR2 P-glycoprotein in hepatobiliary lipid transport. FASEB J. 1997;11(1):19-28.

Smith AJ, De vree JM, Ottenhoff R, Oude elferink RP, Schinkel AH, Borst P. Hepatocyte-specific expression of the human MDR3 P-glycoprotein gene restores the biliary phosphatidylcholine excretion absent in Mdr2 (-/-) mice. Hepatology. 1998;28(2):530-6.

Ruetz S, Gros P. Phosphatidylcholine translocase: a physiological role for the MDR2 gene. Cell. 1994;77(7):1071-81.

Venneman NG, Portincasa P, Vanberge-henegouwen GP, Van erpecum KJ. Cholesterol saturation rather than phospholipid/bile salt ratio or protein content affects crystallization sequences in human gallbladder bile. Eur J Clin Invest. 2004;34(10):656-63.

Lincke CR, Smit JJ, Van der velde-koerts T, Borst P. Structure of the human MDR3 gene and physical mapping of the human MDR locus. J Biol Chem. 1991;266(8):5303-10.

Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis. 2007;2:29.

Pasmant E, Goussard P, Baranes L, Laurendeau I, Quentin S, Ponsot P, et al. First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. Euro J Human Genetics. 2012 Mar;20(3):277-82.

Jung C, Driancourt C, Baussan C, Zater M, Hadchouel M, Meunier-Rotival M, et al. Prenatal molecular diagnosis of inherited cholestatic diseases. J Pedia Gastroenterol Nutrition. 2007 Apr 1;44(4):453-8.

Jacquemin E, De Vree M, Cresteil D, Sokal E, Sturm E, Dumont M, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001;120:1448-58.

Oude Elferink RP, Paulusma CC. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Eur J Physiol. 2007;453:601-10.

Lucena JF, Herrero JI, Quiroga J, Sangro B, Garcia-Foncillas J, Zabalegui N, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. Gastroenterol. 2003;124(4):1037-42.

Maggiore G, Bernard O, Hadchouel M, Lemonnier A, Alagille D. Diagnostic value of serum gamma-glutamyl transpeptidase activity in liver diseases in children. J Pediatr Gastroenterol Nutr. 1991;12:21-6.

Wang HH, Li T, Portincasa P, Ford DA, Neuschwander-Tetri BA, Tso P, et al. New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile. Liver Res. 2017 Jun 1;1(1):42-53.

Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man. J Clin Invest. 1978;61:998-1026.

Carey MC. Critical tables for calculating the cholesterol saturation of native bile. J Lipid Res. 1978;19(8):945-55.

Kassem MI, Sorour MA, Ghazal AH, El-Haddad HM, El-Riwini MT, El-Bahrawy HA. Management of intrahepatic stones: the role of subcutaneous hepaticojejunal access loop. A prospective cohort study. Inter J Surg. 2014 Sep 1;12(9):886-92.

Benzimra J, Derhy S, Rosmorduc O, Menu Y, Poupon R, Arrivé L. Hepatobiliary anomalies associated with ABCB4/MDR3 deficiency in adults: a pictorial essay. Insights Imaging. 2013;4(3):331-8.

Kim TK, Kim BS, Kim JH, Ha HK, Kim PN, Kim AY, et al. Diagnosis of intrahepatic stones: superiority of MR cholangiopancreatography over endoscopic retrograde cholangiopancreatography. Am J Roentgenol. 2002 Aug;179(2):429-34.

Poupon R, Arrive L, Rosmorduc O. The cholangiographic features of severe forms of ABCB4/MDR3 deficiency associated cholangiopathy in adults. Gastroenterol Clin Biol. 2010;34(6-7):380-7.

Trikudanathan G, Navaneethan U, Parsi MA. Endoscopic management of difficult common bile duct stones. World J Gastroenterol. 2013;19(2):165-73.

Jarufe N, Figueroa E, Muñoz C, Moisan F, Varas J, Valbuena JR, et al. Anatomic hepatectomy as a definitive treatment for hepatolithiasis: a cohort study. HPB. 2012 Sep 1;14(9):604-10.

Balandraud P, Gregoire E, Cazeres C, Le treut YP. Right hepatolithiasis and abnormal hepatic duct confluence: more than a casual relation?. Am J Surg. 2011;201(4):514-8.

Mchenry L, Lehman G. Difficult bile duct stones. Curr Treat Options Gastroenterol. 2006;9(2):123-32.

Hochberger J, Bayer J, May A, Mühldorfer S, Maiss J, Hahn EG, Ell C. Laser lithotripsy of difficult bile duct stones: results in 60 patients using a rhodamine 6G dye laser with optical stone tissue detection system. Gut. 1998 Dec 1;43(6):823-9.

Chen YK. Preclinical characterization of the Spyglass peroral cholangiopancreatoscopy system for direct access, visualization, and biopsy. Gastrointest Endo. 2007;65(2):303-11.

Rodrigues CM, Fan G, Wong PY, Kren BT, Steer CJ. Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med. 1998;4(3):165-78.

Duane WC, Hunninghake DB, Freeman ML, Pooler PA, Schlasner LA, Gebhard RL. Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile. Hepatology. 1988;8(5):1147-50.

Smith JL, Roach PD, Wittenberg LN, Riottot M, Pillay SP, Nestel PJ, et al. Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones. J Gastroenterol Hepatol. 2000;15(8):871-9.

Cheng S, Zou M, Liu Q, Kuang J, Shen J, Pu S, et al. Activation of constitutive androstane receptor prevents cholesterol gallstone formation. Am J Pathology. 2017 Apr 1;187(4):808-18.

Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. New Eng J Med. 2015;372(25):2387-97.