Analysis of mutations of MDR3 exons 9 and 23 in infants with parenteral nutrition-associated cholestasis

Abstract

Abstract. The aim of this study was to investigate mutations of multidrug resistance 3 (MDR3) exons 9 and 23 in infants with parenteral nutrition-associated cholestasis (PNAC). A total of 41 infants with PNAC were enrolled in the study. Genomic DNA was extracted from the peripheral venous blood leukocytes of each patient and MDR3 exons 9 and 23 were amplified by polymerase chain reaction. One patient was identified who carried a frameshift mutation in MDR3 exon 23 (C.2793) that was caused by the insertion of a single adenine residue, while mutations were not found in MDR3 exon 23 in the other 40 patients. The clinical features of the patient with the MDR3 exon 23 frameshift mutation included high serum γ-glutamyl transferase levels, the absence of biliary dilatation and deformity in magnetic resonance cholangiopancreatography, and abnormal electrical capacitance tomography imaging of the liver. No mutations in MDR3 exon 9 were identified in any of the patients. All 41 PNAC patients recovered following oral ursodeoxycholic acid treatment. The C.2793 frameshift mutation in MDR3 exon 23 is potentially associated with the development of PNAC in infants. IntroductionSince Dudrick et al first reported the application of parenteral nutrition (PN) in newborns in 1968 (1), the prognosis of preterm infants has markedly improved. However, in 1971, Peden et al reported the case of a premature infant who developed severe liver function damage owing to the application of total parenteral nutrition (TPN) (2). The autopsy of this patient revealed the presence of intrahepatic cholestasis, bile duct dilatation and cirrhosis. Since then, parenteral nutrition-associated cholestasis (PNAC) in preterm infants has garnered increasing attention.The pathogenesis of PNAC has not been elucidated until recently. PNAC is considered to be caused by a variety of factors, including premature birth, low birth weight, long PN duration, a lack of fasting, gastrointestinal irritation, infection, intestinal bacterial overgrowth, bacterial translocation, TPN solution nutrient imbalances, lack of trace elements and toxic ingredients in PN (3,4). These factors cause liver damage, degeneration, and fat deposition in the liver (5,6). In recent years, a number of studies have shown that MDR3 mutations or the decreased expression or dysfunction of MDR3 causes bile phospholipid deficiency, bile stone formation and the obstruction of small bile ducts, and may affect bile metabolism, thereby causing cholestasis (7,8). The purpose of the present study was to investigate whether mutations of MDR3 exons 9 and 23 were present in infants with PNAC. Materials and methods Subjects.A total of 41 infants with PNAC were enrolled in the study between June 2011 and December 2013. PNAC diagnostic criteria included: PN for >14 days, jaundice, a direct bilirubin level of >1.5 mg/dl, discolored stools, elevated liver enzymes, and the exclusion of biliary atresia, choledochal cysts, bile duct dilatation, surgery-induced disease, viral infection (hepatitis A, B or C and cytom...

Bile Acids as Metabolic Regulators and Nutrient Sensors

“…Total parenteral nutrition is used to treat infants with gastrointestinal abnormalities, short bowel syndrome, malnutrition, inflammatory bowel disease, and idiopathic diarrhea. Parenteral nutrition-associated cholestasis is associated with mutations in ABCB4 (MDR3) in preterm infants (142). UDCA can be used as bile acid replacement therapy to improve lipid absorption in patients with parenteral nutrition-associated cholestasis.…”

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

“…Most cases improve on withdrawing the drug and adding UDCA. Recent studies have demonstrated, that ABCB4 mutations (c.504C>T and c.485T>Ain exon 6 and c.2793 frameshift mutation in exon 23) are possibly involved in the development of parenteral nutrition-associated liver disease in premature infants[ 36 ].…”