The patient presenting with isolated hyperbilirubinemia
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1 Available online at Digestive and Liver Disease 41 (2009) Review Article The patient presenting with isolated hyperbilirubinemia L. Fabris a,b, M. Cadamuro b, L. Okolicsanyi a, a Department of Surgical and Gastroenterological Sciences, University of Padova, UOC Gastroenterologia, Ospedale Cà Foncello, Treviso, Via Giustiniani, Padova, Italy b Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Italy Received 3 November 2008; accepted 11 November 2008 Available online 3 February 2009 Abstract Hyperbilirubinemia is a common laboratory finding in clinical practice, being found in several haematological and liver diseases as well as in familial conditions (5 10% in Western countries). Although most of the familial forms of hyperbilirubinemia are classically viewed as benign conditions, they have gained an increased interest in the last few years since recent data have indicated that subjects with an impaired bilirubin metabolism may have an increased susceptibility to drug toxicity. The authors briefly review the main steps of bilirubin metabolism, with a special emphasis on the emerging concepts on the molecular mechanisms of regulation by nuclear receptors (NRs) and genetic factors. Then the different forms of isolated hyperbilirubinemia occurring in both adults and paediatrics are systematically analysed, and a new categorisation is also proposed in light of the recent advances in bilirubin research. Finally, a diagnostic algorithm is discussed, along with a correct approach to its management, in order to avoid unnecessary medical investigations Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Bilirubin; Crigler-Najjar syndrome; Dubin-Johnson syndrome; Gilbert syndrome; MRP2; UDP-GT 1. Introduction Increased serum bilirubin concentration is a common finding in clinical practice. Hyperbilirubinemia may reflect an increased bilirubin production and/or an impaired hepatic handling, thus implying possible haematological and liver disorders, respectively. However, it is also found as isolated laboratory abnormality, without overt signs of haemolysis or any evidence of liver disease, a feature found in 5 10% or even more of general population in Western countries [1]. These forms are often familial, and comprise a wide clinical spectrum, ranging from mild hyperbilirubinemia of Gilbert syndrome (GS) in young adults to the severe Crigler-Najjar type I syndrome in infants, where hyperbilirubinemia is associated with kernicterus and severe brain damage. However, when dealing with hyperbilirubinemia some methodological clues have to be carefully considered before starting investigations. In fact, although the normal limit of serum bilirubin concentration is conventionally considered around 17.5 mol/l, epidemiological data show that sex differences are commonly present in serum bilirubin: in fact, mean values are about 10 mol/l in females and 13 mol/l in males [2]. However, these sex differences are not taken into account in the common clinical practice. Therefore, since serum bilirubin concentration is the result of a balance between pigment production and its elimination, we will first review the main step of bilirubin metabolism, and then we will analyse different clinical forms of isolated hyperbilirubinemia in both children and adults. A proposed categorisation of these conditions is given in Table 1. This work has been presented in part as invited lecture in the Session entitled Challenges in the interpretation of abnormal liver function tests at the United European Gastroenterology Week (UEGW) held in Paris, October Corresponding author. Tel.: ; fax: address: lajos.okolicsanyi@unipd.it (L. Okolicsanyi) Bilirubin metabolism (Fig. 1) Bilirubin is the end product of heme catabolism originating from haemoglobin and other haemoproteins in the reticuloendothelial system (RES), mostly in the spleen. From /$ Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi: /j.dld
2 376 L. Fabris et al. / Digestive and Liver Disease 41 (2009) Table 1 Isolated hyperbilirubinemia in adults and paediatrics. (A) Adults Congenital Gilbert syndrome Crigler-Najjar syndrome type II Dubin-Johnson syndrome Rotor syndrome Haemolysis Acquired Xenobiotics (i.e. cytosine arabinoside) Following OLTx (donors with GS) Fasting Haemolysis (B) Paediatrics Physiological jaundice Breast milk jaundice Crigler-Najjar syndromes (type I and type II) UDP-GT polymorphisms Gilbert syndrome with haemolytic diseases (i.e. associated with G6-PDH deficiency) this site, bilirubin is released into the blood, where it is tightly bound to albumin to be delivered to the liver, where it is taken up by the hepatocyte through an active process mediated by a sinusoidal membrane system, belonging to the family of organic anion transporter proteins (OATPs). This is a Na-independent transport pathway, which is different from the bile acid uptake system, and acts in concert with the counter transport of glutathione (GSH). Once in the hepatocyte, bilirubin is bound to special cytosol storing proteins called ligandin and Z protein, and then carried to the microsomes of the smooth endoplasmic reticulum, where it is conjugated with glucuronic acid to form mono- and diglucuronides. This process is catalysed by the enzyme uridine diphosphoglucuronate-glucuronosyl transferase (UDP-GT) and represents the rate-limiting step of the entire bilirubin metabolism. After glucurono-conjugation, bilirubin is transformed into a hydrophilic compound amenable to be secreted into the bile mainly via an ATP-dependent conjugate export pump called multidrug resistance protein 2 (MRP2). This is a member of the ATP-binding cassette transporter family localised to the canalicular membrane (gene symbol ABCC2) Fig. 1. The main steps of bilirubin formation, hepatic metabolism and intestinal degradation are illustrated in this figure. Bilirubin (BR) is produced from erythrocytes and haemoproteins in the reticuloendothelial system (RES). From the RES bilirubin is released into the blood, where it is tightly bound to albumin. Once in the sinusoidal blood, bilirubin is taken up by the hepatocyte through a basolateral transporter, called OATP. In the hepatocyte, enzymes involved in bilirubin metabolism are finely regulated by nuclear receptors (see details in hepatocyte nucleus). Then, bilirubin is targeted to the rough endoplasmic reticulum, where it is conjugated with one or two molecules of glucuronic acid: this process, catalysed by the enzyme UDP-GT, is the rate-limiting step of the entire bilirubin metabolism. Once transformed in a water-soluble pigment, bilirubin can be excreted into the bile by the MRP2 carrier protein, located at the canalicular membrane of the hepatocyte. In the gastrointestinal tract bilirubin is degraded by the intestinal bacteria and then transformed to stercobilin and eliminated with the stool. The fraction of the pigment re-absorbed by the intestinal wall in the general circulation is eliminated in the urine as urobilirubin.
3 L. Fabris et al. / Digestive and Liver Disease 41 (2009) that transfers organic anions different from bile acids including bilirubin glucuronide, and other sulphate, glucuronide, and glutathione conjugates from the hepatocyte into bile [3,4]. ABC transporters are present in intracellular pools from which they are targeted to the apical membrane [5]. The correct apical localisation of this membrane transporter is crucial for its function and depends upon the interactions with membrane cytoskeletal proteins such as radixin, belonging to a family of proteins cross-linking actin filaments and integral membrane proteins [6]. In addition, a small fraction of conjugated bilirubin is also excreted by the hepatocyte straight to the plasma, by-passing the biliary system, through the multidrug resistance protein 3 (MRP3 or ABCC3 or CMOAT2), an ATP-dependent transporter located at the basolateral domain of the plasma membrane [7]. Once delivered to the gastrointestinal tract through the biliary tree, bilirubin is deconjugated by the -glucuronidase of gut bacteria and further oxidized to stercobilin which is a coloured pigment and eliminated as such in the stool. A fraction of stercobilin can be re-absorbed by the small intestinal mucosa and re-excreted by either the liver or the kidney as urobilirubin. Recent data indicate that once deconjugated in the intestinal lumen, free bilirubin may inactivate digestive proteases secreted by the pancreas, such as trypsin and chymotrypsin: this mechanism may provide a prompt and effective defence of the lower intestinal mucosa from proteolytic digestion [8] Regulation of membrane transporters and metabolising enzymes by NRs An emerging concept in liver physiology is that the metabolism of endobiotic and xenobiotic compounds, among which bilirubin and bile acids, shares hepatic transport and metabolic systems which are crucially regulated at a transcriptional level by a series of nuclear receptors (NRs), a family of pleotrophic transcription factors [9]. Their expression and function is finely regulated by tuned mechanisms operating in different organs, including liver, intestine and kidney. In general, after ligand binding, NRs undergo a conformational change that in a coordinated fashion dissociates corepressors on one side and facilitates recruitment of coactivator proteins to enable transcriptional activation of the gene encoding these systems on the other. By binding to biliary constituents, NRs orchestrate downstream responses aimed at regulating hepatic transport and metabolisation of these substances as an adaptive protective mechanism against biliary toxicity. This mechanism is clinically relevant as NRs may be selectively stimulated by therapeutic agents (rifampin) during cholestasis. Among NRs, the pregnane X receptor (PXR; NR1I2) and the constitutive androstane receptor (CAR; NR1I3) have been shown to be involved in bilirubin metabolism by inducing MRP2 and UGT1A1, in addition to stimulating bile acid excretion. On the other hand, it has also been demonstrated that bilirubin is capable of activating CAR [10] Genetic regulation of bilirubin conjugation The gene encoding for the microsomal enzyme catalysing the conjugation of bilirubin to UDP-glucuronic acid has been identified in 1991 as UGT1A1 locus, which has been located to the region q37 of chromosome 2 [11]. This gene contains at least thirteen first exons in the amino-terminal region, which are unique and can splice to common exons 2 through 5 in the carboxy-terminal region, which are identical for all UDP-GT isoforms. Each first exon, which directs RNA polymerase II, is strictly regulated by its own promoter TATAA box. In physiological conditions the TATAA box is composed of six thymidine adenine repeats: (TA 6 )TAA. Once activated, exons 1A and 1D encode for the substrate-specific amino acid termini of the two specific isoforms known in humans, of which only GT1-A1 regulates bilirubin metabolism. Mutations in these different genetic components variably affect the bilirubin conjugating activity. If the encoding exon is mutated, the UDP-GT is structurally altered, and thus functionally ineffective, whilst if mutations affect the nonencoding TATAA promoter, they lead to a reduced expression of an otherwise structurally and functionally normal protein. Moreover, in addition to bilirubin, UGT1A1 is involved in the detoxifying processes of several other compounds, including some xenobiotics and hormones (rifamycin, tolbutamine, paracetamol, irinotecan and ethynylestadiol), and therefore, reduced expression of this enzyme can increase susceptibility to drug toxicity [12,13]. 2. Familial hyperbilirubinemias 2.1. Gilbert syndrome (GS) GS is characterised by a mild yellow colouration of the sclera with slightly fluctuating elevated serum concentrations of unconjugated bilirubin in otherwise healthy subjects, without overt signs of haemolysis and other abnormalities of hepatocellular function. In these subjects a genetic defect in the promoter region of the UGT1A1 gene has been described: instead of a TATAA element with six repeats, it contains two extra bases of thymidine adenine [14]. However, the UDP-GT gene complex is structurally unaltered, giving the normality of both the nucleotide sequences of all five exons encoding for the UDP-GT and the relative intron exon junctions. Although necessary, the promoter genetic defect is not sufficient by itself to lead to hyperbilirubinemia and subicterus. Using a complex segregation analysis, we have recently showed that unconjugated hyperbilirubinemia exhibits a precise mode of inheritance with a major recessive gene with a frequency of 0.45 as responsible for higher serum bilirubin values, but accounting for only a part of them [2]. This finding implies that additional factors, such as a generalized defect in the hepatocyte uptake or in the intracellular translocation of organic anions, a shortened erythrocyte life span, and sex hormones, are required
4 378 L. Fabris et al. / Digestive and Liver Disease 41 (2009) for the clinical evidence of GS. In particular, an impaired bilirubin uptake by hepatocytes seems to be relevant in a subgroup of patients with GS [15]. Although this condition is not considered a clinically relevant problem, recent evidences indicate that it may have important implications in some pharmacological treatments. In fact, UGT1A1 is involved in the detoxification processes of many xenobiotics, and when its activity is reduced, hepatocyte handling of these compounds may be affected, thereby predisposing to adverse toxic effects caused by prolonged serum levels of the intact drug, as reported with anticancer agents [12]. For instance, isolated hyperbilirubinemia has been found following standard dose cytosine arabinoside during the treatment of acute myeloid leukaemia [16]. Recently, acute cholestatic hepatitis has been described in a patient with GS taking flavoxate, a smooth muscle relaxant with antispasmodic properties, for urinary incontinence in association with tibolone, a synthetic steroid analogue for postmenopausal climacteric syndrome [17]. Given the metabolic pathway shared by different drugs at the glucuronosyl transferase activity level, great attention must be paid to patients with GS undergoing polytherapy [17]. Clinical relevance for GS has also been underlined in the transplantation setting. Hyperbilirubinemic living donors for liver transplantation with GS should not be discarded, but they may represent a cause of unconjugated hyperbilirubinemia following liver transplantation [18] Crigler-Najjar (CN) syndromes These are congenital forms of isolated unconjugated hyperbilirubinemia, often severe (more than 30 mg/dl in CN type I, ranging 5 30 mg/dl in CN type II), caused by different genetic mutations in each of the five encoding exons resulting in different degrees of inactivation of the glucuronosyl transferase activity. As a functional consequence, glucuronoconjugation of bilirubin is markedly reduced or completely absent leading to serum retention and very high serum levels of unconjugated bilirubin in the neonatal period and therefore capable of crossing the blood-brain barrier. In the most severe cases, if untreated kernicterus and irreversible brain damage may develop. In both types of CN syndrome more than 35 mutations have been identified in each encoding exon; therefore, differences between type I and type II CN syndromes do not depend upon the mutation position, but rather on the number and/or the extension of the mutated gene area [19]. However, in contrast with CN type I, CN type II generally responds to enzyme inducers such as phenobarbitone, thus implying that some residual GT activity is still preserved in these patients. Recently, 12 novel mutated alleles of UGT1A1 have been identified in CN syndrome patients with a well-characterised genotype phenotype correlation [20]. Furthermore, an alternative splicing mechanism at the UGT1A locus which amplifies further the structural diversity of human UGT proteins has been recently described: it may act as an additional posttranscriptional regulatory mechanism of the glucurono-conjugation pathway [21]. From a genetic point of view, the milder type of GS and the most severe CN syndrome represent the two ends of a spectrum with increasing severity, where the same single locus is affected by different combinations of several mutations [22,23] Physiological jaundice of the newborn This is a physiologic condition occurring in neonates and characterised by serum levels of unconjugated bilirubin peaking at 5 6 mg/dl at days 3 4 after delivery and then gradually decreasing to adult levels by day 10. In some cases, jaundice may reach bilirubin levels up to 17 mg/dl. Its interest is mainly conceptual as it seems to be related to the immaturity of different factors involved in bilirubin metabolism, such as an increased load of bilirubin formation from disruption of erythrocytes with a shortened lifespan, a reduced hepatocyte uptake, intracellular transport and conjugation, and an increased entero-hepatic circulation caused by low bacterial conversion of conjugated bilirubin to urobilinogen and to high -glucuronidase activity Breast milk jaundice (BMJ) Originally described in 1963 [24], BMJ is characterised by prolonged unconjugated hyperbilirubinemia in otherwise healthy infants. In contrast with the physiological jaundice of the newborn, it is strictly related to the ingestion of breast milk, as bilirubin levels promptly normalise with cessation of breast-feeding. It is often characterised by serum levels of bilirubin up to 10 mg/dl, with potential risk for brain damage as seen in CN syndromes. The condition has been ascribed to different breast milk components such as pregnane-3,20 diol, nonesterified fatty acids, and glucuronidase, which variably affect UDP-GT activity [25]. Recently, a missense mutation in UGT1A1 identical to GS has been found in infants with BMJ, suggesting a genetic defect as the underlying cause triggered by environmental factors (breast milk components), analogously to GS Dubin-Johnson (DJ) syndrome This is a rare and benign condition, characterised by mixed with predominantly conjugated hyperbilirubinemia, usually found in adolescence, in the presence of otherwise normal liver function tests. It is caused by point mutation (missense and deletion mutations) in the gene encoding MRP2 (ABCC2), the canalicular transporter of multiple anionic conjugates different from bile acids, including bilirubin and oral cholecystographic agents. An animal model of DJ syndrome has been recently developed by affecting the function of radixin, a microtubule protein crucial for MRP2 canalicular targeting [6]. Along with hyperbilirubinemia, defining clinical features of DJ syndrome are increased urinary excretion of coproporphyrin type I (proportionally more than 80%) but with normal total urinary coproporphyrin excretion, and
5 L. Fabris et al. / Digestive and Liver Disease 41 (2009) Fig. 2. Diagnostic algorithm of isolated hyperbilirubinemia. When liver function is normal, familial unconjugated hyperbilirubinemias must be considered along with haemolytic disorders. When haemolysis has been ruled out, the entity of increased levels and age are important factors to be considered for the correct diagnosis. In young adults or adolescent individuals with mild hyperbilirubinemia (less than 5 mg/100 ml), Gilbert syndrome is likely present. In contrast, in newborns with markedly increased serum bilirubin concentrations (often reaching mg/dl, or even more) Crigler-Najjar syndromes should be suspected. Although the diagnosis of unconjugated hyperbilirubinemias is basically clinical, genetic tests to detect UDPG1 and TATAA box mutations can be further considered. However, if the conjugated fraction is prevalent, Dubin-Johnson and Rotor syndromes should be suspected: liver biopsy and urinary coproporphyrin excretion are useful to address the differential diagnosis. Recently, tests for MRP2 genotyping have become available in some skilled laboratories. absent or delayed gallbladder and biliary tree visualisation at 99mTc-HIDA cholescintigraphy. Furthermore, this condition is associated with typical morphologic features: the liver is macroscopically black coloured, and at liver histology hepatocytes contain a grossly granular pigmentation in close vicinity to bile canaliculi, with a spontaneous fluorescence likely indicating the presence of lipofuscin. However, the mechanisms leading to the formation of these histological changes remain hitherto unclear Rotor syndrome This condition is similar to but even rarer than DJ syndrome (only limited cases have been sporadically reported so far) and is clinically characterised by mixed, mostly, conjugated hyperbilirubinemia, lack of biliary tree visualisation at cholescintigraphy, and increased total urinary coproporphyrin excretion but at higher levels than DJ syndrome, and with a lower urinary coproporphyrin type I/type III ratio. In contrast with DJ syndrome, MRP2 is regularly expressed on hepatocyte canaliculi and liver cells are not pigmented. Recent evidence suggest that hepatocyte GSH-S-transferase activity is reduced in subjects with Rotor syndrome [26] Hyperbilirubinemias caused by drug interference with bilirubin metabolism A number of drugs may interfere with different steps of the bilirubin metabolism, causing isolated jaundice in the absence of a fully developed cholestatic syndrome. Since
6 380 L. Fabris et al. / Digestive and Liver Disease 41 (2009) UGT1A1 is involved in the detoxification process of a variety of exogenous compounds, as stated before, a reduced glucuronidation may be responsible for a reduced drug clearance and therefore lead to toxic effects due to prolonged plasma concentration of these drugs, as shown for irinotecan [13,27]. In contrast, UGT1A1 activity may also be activated by some enzyme inducers, such as phenobarbitone and its derivates [28]: this favourable effect may be therapeutically exploited in cases with very high serum levels of unconjugated bilirubin, as seen in CN syndromes. Notably, in addition to glucuronidation, all the other steps regulating bilirubin metabolism may be impaired by drugs, such as the bilirubin binding to albumin during its transport in the blood (sulphonamides) [29], the bilirubin uptake by the hepatocyte at the sinusoidal pole (the oral antidiabetic tolbutamide) [29], the intracellular transport of bilirubin to the microsomes to be conjugated (the uricosuric drug probenecid) [30], and, finally, once conjugated the bilirubin excretion into bile by the canalicular transporter MRP2 (the antibiotic fusidate) [31] Differential diagnosis of isolated hyperbilirubinemias The algorithm of the diagnostic approach to isolated hyperbilirubinemia is reported in Fig. 2. Diagnosis of the different forms of isolated hyperbilirubinemia is basically performed by exclusion, once normal liver function has been confirmed by the normality of routine liver enzymes and of serum bile acids. If the unconjugated fraction is prevalent, familial hyperbilirubinemias must be considered along with haemolytic disorders, even though it must be underlined that GS is not rarely associated with haemolytic diseases, such as G6-PDH deficiency, particularly in paediatrics. In this step, to rule out the possibility of haemolysis it is crucial to evaluate haemoglobin concentration, mean corpuscular value, serum LDH and aptoglobin levels, Coomb s tests, and the reticulocyte count. When haemolysis has been excluded, serum bilirubin levels should be determined at least three times with 1-month interval each, before confirming isolated hyperbilirubinemia, as serum bilirubin concentrations may often fluctuate. During this period, drugs potentially capable of interfering with the bilirubin metabolism must be suspended. If hyperbilirubinemia is confirmed, the entity of increased levels and age are important factors to be considered to address the correct diagnosis. When hyperbilirubinemia is mild, generally less than 5 mg/100 ml, and is found in adolescents or young adults, GS is likely present. Given the benignity of this condition, patient reassurance is mandatory. When deep, prolonged jaundice is seen in newborns with marked increase in serum bilirubin concentrations, often reaching mg/dl, CN type II should be suspected in the absence of neurological signs. In more severe cases, with serum bilirubin concentrations greater than 25 mg/dl and often accompanied by signs of neurological damage, CN type I must be considered. Given the risk of neurotoxicity in both conditions, hyperbilirubinemia must be treated urgently. Although the diagnosis of these conditions of unconjugated hyperbilirubinemia is basically clinical, recent advances in the technology of genomics have made a genetic test available in specialized centres to confirm the diagnosis. In particular, genetic analysis of the TATA box of the UGT1A1 gene has been recently proposed before starting a combination therapy with drugs metabolised through glucurono-conjugation [17]. In contrast with GS, familial conjugated hyperbilirubinemias are very rare conditions. The differential diagnosis between DJ and Rotor syndromes is based on the absence of hepatocyte pigmentation at liver biopsy, and on the increased total coproporphyrin urinary excretion with abnormal isomers ratio, as previously stated. Alternatively, a 99mTc-HIDA may also be useful to differentiate the two forms and therefore, to avoid liver biopsy. Recently, tests for MRP2 genotyping have become available in some skilled laboratories [32,33]. Since serum bilirubin levels are often higher than 5 mg/dl with an overt jaundice, reassuring patients on the benignity of hyperbilirubinemia is relevant also for these forms Management of hyperbilirubinemia CN type I and type II syndromes are the only conditions requiring a specific therapeutic intervention given the risk of neurotoxicity, whilst in the other benign forms of hyperbilirubinemia reassurance is the most reasonable approach, but a therapeutic intervention may be requested by the patient for cosmetical reasons. Before considering specific therapeutic options, assumption of putative harmful drugs must be investigated and suspended if any. As a general approach, phenobarbitone is a good inducer of UDP-GT activity, given at the daily dosage of mg/kg, but its clinical use is limited by behavioural side effects, particularly in young subjects. In addition, glutethimide, a hypnotic sedative alternative to barbiturates, may offer a similar enzyme inducing capability. Phototherapy is a well-established effective tool in the management of the severe forms of unconjugated hyperbilirubinemia, when given daily, at least every 12 h, starting early from the first days of life. It is based on the ability to convert unconjugated hyperbilirubinemia in harmless, water-soluble products, which can be easily eliminated from the urine [34]. However, its effectiveness fades with time, and compliance of young patients may be difficult to achieve. If phototherapy has become ineffective or it is not feasible, or early signs of neurological damage are developing, orthotopic liver transplantation (OLTx) must be strongly considered. It is the only effective treatment of severe hyperbilirubinemias, and assures long-term survival of these children. In the world registry of CN type I syndrome, 21 out of 57 patients undergoing OLTx were healthy, with better results when OLTx was performed early in the course of the disease [35]. Hepatocyte transplantation may represent an alternative to OLTx, and it has been performed in one patient with CN type I syndrome [36]: expression of UDP-GT
7 L. Fabris et al. / Digestive and Liver Disease 41 (2009) activity remained stable during a 9-month follow-up period, ensuring a marked reduction in serum bilirubin levels. Conflict of interest None declared. References [1] Okolicsanyi L, Nassuato G, Muraca M, Orlando R, Iemmolo RM, Lirussi F, et al. Epidemiology of unconjugated hyperbilirubinemia: revisited. Semin Liver Dis 1988;8: [2] Clementi M, Di Gianantonio E, Fabris L, Forabosco P, Strazzabosco M, Tenconi R, et al. Inheritance of hyperbilirubinemia: evidence for a major autosomal recessive gene. Dig Liver Dis 2007;39: [3] Keppler D, Arias IM. Hepatic canalicular membrane. Introduction: transport across the hepatocyte canalicular membrane. FASEB J 1997;11:15 8. [4] Keppler D, Konig J. Hepatic canalicular membrane 5: expression and localization of the conjugate export pump encoded by the MRP2 (cmrp/cmoat) gene in liver. FASEB J 1997;11: [5] Kipp H, Pichetshote N, Arias IM. 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Cancer Treat Rev 2008;34: [28] Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 2001;33: [29] Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354: [30] Herber R, Magdalou J, Haumont M, Bidault R, van Es H, Siest G. Glucuronidation of 3 -azido-3 -deoxythymidine in human liver microsomes: enzyme inhibition by drugs and steroid hormones. Biochem Biophys Acta 1992;1139:20 4. [31] Bode KA, Donner MG, Leier I, Keppler D. Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem Pharmacol 2002;64: [32] Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology 2006;130: [33] Tsujii H, König J, Rost D, Stöckel B, Leuschner U, Keppler D. 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