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Hepatic expression of multidrug resistance protein 2 in biliary atresia

Authors:
Keita Terui at Chiba University
Keita Terui
Takeshi Saito
Takeshi Saito
Takeshi Saito
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Tomoro Hishiki
Tomoro Hishiki
Tomoro Hishiki
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Yoshiharu Sato
Yoshiharu Sato
Yoshiharu Sato
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Abstract and Figures

Biliary atresia (BA) is an idiopathic inflammatory obliterative cholangiopathy of neonates, leading to progressive biliary cirrhosis. Hepatoportoenterostomy (Kasai procedure) can cure jaundice in 30% to 80% of patients. Postoperative clearance of jaundice is one of the most important factors influencing long-term outcomes of BA patients. Multidrug resistance protein 2 (MRP2) is one of the canalicular export pumps located in hepatocytes; it exports organic anions and their conjugates (e.g., bilirubin) into bile canaliculus. Although MRP2 is an essential transporter for the excretion of bilirubin, its role in the clinical course of BA patients is unclear. The present study investigated the relationship between hepatic MRP2 expression and clinical course in BA patients, with particular emphasis in curing jaundice after hepatoportoenterostomy. No significant differences in hepatic MRP2 expression level were observed between BA and controls groups. There was no correlation between MRP2 expression and age at time of surgery in BA and control groups. In BA patients, MRP2 expression level in the jaundice and jaundice-free group did not differ significantly (2.0 × 10-4 vs 3.1 × 10-4, p = 0.094). Although the serum level of total bilirubin just before surgery did not correlate with MRP2 expression level (rs = 0.031, p = 0.914), the serum level of total bilirubin measured at 2 weeks (rs = -0.569, p = 0.034) and 4 weeks after surgery (rs = -0.620, p = 0.018) were significantly correlated with MRP2 expression level. Furthermore, MRP2 expression level was inversely correlated with ratio of change in serum total bilirubin level over 4 weeks (rs = -0.676, p = 0.008), which represents the serum bilirubin level measured at 4 weeks after surgery divided by value just before surgery. There was no correlation between expression level of MRP2 and nuclear receptors, such as retinoid × receptor α, farnesoid × receptor, pregnane × receptor, or constitutive androstane receptor. Hepatic MRP2 expression level was associated with postoperative clearance of jaundice in BA patients, at least within 1 month after hepatoportoenterostomy. This finding suggests that not only morphological appearance of the liver tissue but also the biological status of hepatocytes is important for BA pathophysiology.
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... Mrp2 impairment can affect the hepatic clearance of endogenous compounds, such as steroids, leukotrienes and many clinically important drugs (Gerk and Vore, 2002). The clinical importance of Mrp2-inhibition has been demonstrated by Mrp2 gene mutations (Kartenbeck et al., 1996) as well as by the down-regulation of its expression (Terui et al., 2011;Yamada et al., 2005) and its association with the occurrence of hyperbilirubinemia. Hence, it is of importance to dispose of an assay to avoid drug inhibition of Mrp2. ...
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BILIARY ATRESIA
Article
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Treatment of extrahepatic bile duct atresia: Results and long-term prognosis after hepatic portoenterostomy
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Unlabelled: A number of features (eg, age at time of surgery, size of microscopic biliary ductules) have been suggested to be useful predictors of the efficacy of portoenterostomy in the treatment of biliary atresia. However, no previous study has attempted to quantify the macroscopic appearance of the degree of hepatobiliary damage found during initial surgery. Methods: A macroscopic appearance at portoenterostomy (MAP) score was calculated for 30 infants treated consecutively at King's College Hospital, London. The MAP score was summated from four features (liver consistency, size of portal remnants, degree of portal hypertension, and associated extrahepatic anomalies), with the possible range being from 0 to 6. The infants had follow-up prospectively for a median of 32 months. Results: Twenty infants were anicteric at the time of analysis; their median time to clear jaundice was 48 days (Success group; n = 20). Of the remaining infants, eight had undergone transplantation, one had died awaiting transplantation, and one was still jaundiced (Failure group; n = 10). There was a significant correlation between the MAP score and the age at time of surgery (rB = .57, P = .0005), but only the MAP score was significantly different between the Success and Failure groups (P = .02). Component analysis showed that the portal-remnant subscore contributed most to discrimination (P = .007). The time until clearance of jaundice for the Success group was related to liver consistency (P = .01) and portal remnants (P = .02). Conclusion: Simple observation by an experienced surgeon (quantified as the MAP score) was a useful indicator of the success of this procedure and may be as valuable as the more sophisticated histological or biochemical tests.
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Nuclear receptors as therapeutic targets in cholestatic liver diseases
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Cholestasis results in intrahepatic accumulation of cytotoxic bile acids, which cause liver damage ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver injury is counteracted by a variety of adaptive hepatoprotective mechanisms including alterations in bile acid transport, synthesis and detoxification. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors including the farnesoid X receptor, pregnane X receptor, vitamin D receptor and constitutive androstane receptor, which target overlapping, although not identical, sets of genes. Because the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis, therapeutic targeting of these receptors via specific and potent agonists may further enhance the hepatic defence against toxic bile acids. Activation of these receptors results in repression of bile acid synthesis, induction of phases I and II bile acid hydroxylation and conjugation and stimulation of alternative bile acid export while limiting hepatocellular bile acid import. Furthermore, the use of nuclear receptor ligands may not only influence bile acid transport and metabolism but may also directly target hepatic fibrogenesis and inflammation. Many drugs already used to treat cholestasis and its complications such as pruritus (e.g. ursodeoxycholic acid, rifampicin, fibrates) may act via activation of nuclear receptors. More specific and potent nuclear receptor ligands are currently being developed. This article will review the current knowledge on nuclear receptors and their potential role in the treatment of cholestatic liver diseases.
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Determinants of survival after Kasai's operation in biliary atresia using actuarial analysis
Article
  • Jul 1979
Survival after Kasai's operation for "noncorrectable" biliary atresia is influenced by (1) age, (2) large bile ducts, and (3) concentration of the bile bilirubin. Critical values are: age less than 10.5 wk, any evidence of a large bile duct, and a bile bilirubin concentration greater than 8.8 mg/100 ml. Using these 3 factors, a predictive model is able to identify a favorable group with an 89% expected 4 yr survival.
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Histologic study of biliary fibrous remnants in 48 cases of extrahepatic biliary atresia: Correlation with postoperative bile flow restoration
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The fibrous remnants of bile ducts that were removed at surgery for extrahepatic biliary atresia were studied by serial section. Forty-eight specimens were classified into three types on the basis of histopathologic changes in the proximal portions of the speciments from the vicinity of the porta hepatis: (1) connective tissue without glands or other epithelial structures (15 cases); (2) connective tissue containing glands lined with cuboidal epithelium (15 cases); (3) connective tissue containing central biliary ducts and peripheral glands (18 cases). Histopathologic changes in sections from distal portions of the specimens did not conform to this classification. A precise correlation of prognostic significance could not be established between these histologic data and postoperative restoration of bile flow, although failure to restore flow was encountered most frequently in cases without demonstrable ducts or glands (TYPE 1).
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