Search

The article discusses the rare phenotypic recurrence of severe bile salt export pump (BSEP) deficiency among those patients having undergone liver transplant. The main recommendation after several studies indicates that children who are undergoing liver transplantation for BSEP deficiency should be checked for circulating anti-BSEP antibodies.

During cholestasis, bile acids are mainly excreted into the urine, but adaptive renal responses to cholestasis, especially molecular mechanisms for renal secretion of bile acids, have not been well understood. Organic anion transporters (OAT1 and OAT3) are responsible for membrane transport of anionic compounds at the renal basolateral membranes. In the present study, we investigated the pathophysiological roles of OAT1 and OAT3 in terms of renal handling of bile acids. The Eisai hyperbilirubinemic rats (EHBR), mutant rats without multidrug resistance-associated protein 2, showed higher serum and urinary concentrations of bile acids, compared with Sprague-Dawley (SD) rats (wild type). The protein expression level of rat OAT3 was significantly increased in EHBR compared with SD rats, whereas the expression of rat OAT1 was unchanged. The transport activities of rat and human OAT3, but not OAT1, were markedly inhibited by various bile acids such as chenodeoxycholic acid and cholic acid. Cholic acid, glycocholic acid, and taurocholic acid, which mainly increased during cholestasis, are transported by OAT3. The plasma concentration of [beta]-lactam antibiotic cefotiam, a specific substrate for OAT3, was more increased in EHBR than in SD rats despite upregulation of OAT3 protein. This may be due to the competitive inhibition of cefotiam transport by bile acids via OAT3. In conclusion, the present study clearly demonstrated that OAT3 is responsible for renal secretion of bile acids during cholestasis and that the pharmacokinetic profile of OAT3 substrates may be affected by cholestasis. Eisai hyperbilirubinemic rat; renal secretion; SLC22A8

Inverse acinar regulation of Mrp2 and 3 represents an adaptive response to hepatocellular cholestatic injury. We studied whether obstructive cholestasis (bile duct ligation) and LPS treatment affect the zonal expression of Bsep (Abcb11), Mrp4 (Abcc4), Ntcp (Slc10a1), and Oatp isoforms (Slcolal, Slcola4, and slco1b2) in rat liver, as analyzed by semiquantitative immunofluorescence. Contribution of TNF-[alpha] and IL-1[beta] to transporter zonation in obstructive cholestasis was studied by cytokine inactivation. In normal liver Bsep, Mrp4, Ntcp, and Oatp1a1 were homogeneously distributed in the acinus, whereas Oatp1a4 and Oatp1b2 expression increased from zone 1 to 3. Glutamine synthetase-positive pericentral hepatocytes exhibited markedly lower Oatp1a4 expression than the remaining zone 3 hepatocytes. In cholestatic liver Bsep and Ntcp immunofluorescence in periportal hepatocytes significantly decreased to 66 [+ or -] 4% (P < 0.01) and 67 [+ or -] 7% (P < 0.05), whereas it was not altered in pericentral hepatocytes. Oatp1a4 was significantly induced in hepatocytes with a primarily low expression, i.e., in periportal hepatocytes and in glutamine synthetase-positive pericentral hepatocytes, Likewise, Oatp1b2 was upregulated in periportal hepatocytes. Mrp4 zonal induction was homogeneous. Inactivation of TNF-[alpha] and IL-1[beta] prevented periportal downregulation of Bsep. Recruitment of neutrophils and polymorphonuclear cells mainly occurred in the periportal zone. Likewise, IL- 1[beta] induction was largely found periportally. No significant transporter zonation was seen following LPS treatment. In conclusion, zonal downregulation of Bsep in obstructive cholestasis is associated with portal inflammation and is mediated by TNF-[alpha] and IL-1[beta]. Periportal downregulation of Ntcp and induction of Oatp1a4 and Oatp1b2 may represent adaptive mechanisms to reduce cholestatic injury in hepatocytes with profound downregulation of Bsep and Mrp2. hepatobiliary transport; bile salts; cytokines; acinar regulation; organic anion transporters

OBJECTIVES. We sought to verify the association between maternal intrahepatic cholestasis of pregnancy (ICP) and neonatal respiratory distress syndrome (RDS) and to determine how bile acids levels alter the risk of developing neonatal RDS. METHODS. We extracted data from our divisional database about all of the newborns born during the years 2000-2004. We compared 77 neonates born from pregnancies complicated by ICP with 427 neonates in the same range of gestational age born from noncomplicated pregnancies. We studied maternal bile acids levels immediately before delivery in mothers with ICP and measured bile acid levels during the first 24 hours of life in their newborns. RESULTS. The incidence of RDS in newborns from cholestatic pregnancies was twice that the reference population (28.6% vs 14%). The multivariate analysis showed that the risk of RDS in these newborns was ~2.5 times higher than in control infants. Within the ICP group, maternal and neonatal bile acid levels of infants affected by RDS were not significantly higher than those of healthy infants. The multivariate analysis showed that a low gestational age was the most important risk factor, but the probability of respiratory distress syndrome also increased by 2%o for every additional micromole of the interaction term "neonatal by maternal bile acids level." CONCLUSIONS. Maternal ICP is significantly associated with the occurrence of RDS in the newborn. We hypothesize that bile acids can produce surfactant depletion in the alveoli reverting the reaction of phospholipase [A.sub.2]. This hypothesis could potentially be confirmed by bronchoalveolar lavage study. Key Words bile acid pneumonia, respiratory distress syndrome, pregnancy complications, Abbreviations ICP--intrahepatic cholestasis of pregnancy BA--bile acid RDS--respiratory distress syndrome INTRAHEPATIC CHOLESTASIS OF pregnancy (ICP) is a clinical syndrome of unknown pathophysiology, characterized by generalized pruritus and biochemical cholestasis, occurring [...]

Cholestasis is associated with accumulation of bile acids and lipids, and liver injury. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors that coordinate protective hepatic responses to potentially toxic stimuli, including bile acids. We investigated the role of these receptors in the regulation of bile acid and lipid metabolism in a bile duct ligation (BDL) model of cholestasis applied to receptor knockout mice. Hepatic damage from bile acid accumulation was increased in both CAR knockout (CARKO) and PXR knockout mice, but bile acid concentrations were lower in CARKO mice. High-density lipoprotein (HDL) cholesterol was elevated in CARKO mice, and serum total cholesterol increased less in CARKO or PXR knockout mice than WT mice after BDL. Gene expression analysis of the BDL knockout animals demonstrated that, in response to cholestasis, PXR and CAR both repressed and induced the specific hepatic membrane transporters Oatp-c (organic anion transporting polypeptide C) and Oatp2 ([Na.sup.+]-dependent organic anion transporter 2), respectively. Induction of the xenobiotic transporter multidrug resistance protein 1 in cholestasis was independent of either PXR or CAR, in contrast to the known pattern of induction of multidrug resistance protein 1 by xenobiotics. These results demonstrate that CAR and PXR influence cholesterol metabolism and bile acid synthesis, as well as multiple detoxification pathways, and suggest their potential role as therapeutic targets for the treatment of cholestasis and lipid disorders. bile acid | cholestasis | high-density lipoprotein | cholesterol

Background: Endoscopic balloon dilatation (EBD) of the sphincter of Oddi has been proposed as an alternative therapy with possible advantages, as compared with endoscopic sphincterotomy (ES), for removal of bile [...]

Abstract Aim--To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis. Methods--The medical records for six patients with ARC syndrome were [...]

Cystic fibrosis (CF) is an incurable inherited disease characterized by chronic respiratory infection and an inability of the pancreas to produce sufficient enzymes to properly digest food. With improvements in therapies directed against the respiratory infections, patients suffering from CF now survive into their twenties (compared with an average life span of only 14 years in 1969). As more patients live longer, liver and biliary tract problems are seen more frequently. In particular, cholestasis, or impaired bile flow, can produce nutritional deficits. In other conditions involving cholestasis, administration of the bile salt ursodeoxycholic acid (UDC) has been shown to stimulate bile flow and improve nutrition. To determine whether these beneficial effects would also be seen in CF patients, eight patients (aged 10 to 25) were given a six-month course of treatment with UDC. Following the treatment, bile flow was significantly improved. Liver function improved significantly on most indices in all patients; there was a slight deterioration of functional liver cell mass as measured by the galactose elimination test. Nutritional status of the patients increased, and they gained an average of four pounds, with a corresponding increase in muscle mass. Steatorrhea (the passing of fatty stools) was not affected by UDC treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)

Byline: Hideki Shima (1), Atsuyuki Yamataka (1), Toshihiro Yanai (1), Hiroyuki Kobayashi (1), Takeshi Miyano (1) Keywords: Choledochal cyst; Intrahepatic bile duct; Stones; Electrohydraulic lithotripsy Abstract: An 18-year-old girl who had undergone excision of a choledochal cyst and Roux-en-Y hepatico-jejunostomy at another hospital when 23 months old was referred to our department because of recurrent cholangitis. Radiological investigations showed stones lying in minimally dilated, right posterior intrahepatic bile ducts (IHBD). At laparotomy, the hepatico-jejunostomy site was incised, and a flexible endoscope inserted into the IHBD. Multiple stones packed in the IHBD were easily fragmented using an electro-hydraulic lithotripsy (EHL) device inserted through the endoscope, and removed. There were no EHL-related complications, and her postoperative progress was uneventful. She is currently well with no episodes of cholangitis after a follow-up period of 3 years. EHL is a simple, effective alternative method for removing IHBD stones after choledochal cyst excision. To the best of our knowledge, this is the first report of EHL being used to remove stones that developed in the IHBD after choledochal cyst excision. Author Affiliation: (1) Department of Pediatric Surgery, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, 113-8421, Tokyo , Japan Article History: Registration Date: 01/01/2003 Online Date: 01/02/2004

Roongpraiwan R, Suthutvoravut U, Feungpean B, Phuapradit P. J Med Assoc Thai 2002;85:S1199-S1205. OBJECTIVE: Malabsorption and deficiency of vitamin E are common consequences of chronic cholestasis. The objective of this [...]