Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

Geuken, E; Visser, Dorien S.; Kuipers, Folkert; Blokzijl, Hans; Leuvenink, Henri G. D.; Jong, Koert P. de; Peeters, Paul; Jansen, Petér L. M.; Slooff, Maarten J. H.; Gouw, Annette S.H.; Porte, Robert J.

doi:10.1016/j.jhep.2004.08.023

Cited by 98 publications

(83 citation statements)

References 37 publications

(53 reference statements)

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“…Analysis of bile collected 1 day after transplantation confirmed that the bile salt/phospholipid ratio in bile produced by Mdr2ϩ/Ϫ liver grafts remained abnormally high (Table 3). In accordance with observations in humans, 17 an increase in bile salt/phospholipid ratio was observed in recipients of wild-type livers, although ratios remained significant lower than in recipients of Mdr2ϩ/Ϫ livers. At 14 days after transplantation, biliary bile salt and phospholipid concentrations had returned to pre-transplantation values in the wild-type group.…”

Section: Resultssupporting

confidence: 91%

“…patic bile duct injury. 17 However, formal evidence for a cause-effect relationship between toxic bile formation and bile duct injury after OLT could not be established by this observational study. In fact, the possibility that toxic bile composition and bile duct injury both result from the same underlying factor could not be ruled out.…”

Section: Discussionmentioning

confidence: 78%

“…17 Whether bile salt toxicity actively contributes to hepatic injury or is an epiphenomenon could not be identified in this clinical study. Therefore, we designed a study using a model of arterialized OLT in mice heterozygous for the disruption of Mdr2 gene (Mdr2ϩ/Ϫ) to determine the impact of bile contents on biliary injury after OLT.…”

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confidence: 94%

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Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

et al. 2006

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Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2؉/؊) were transplanted into wild-type recipient mice. Mdr2؉/؊ mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2 ؊/؊ mice, the Mdr2؉/؊ mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2؉/؊ donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2؉/؊ livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2؉/؊ grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation. (HEPATOLOGY 2006;43:1022-1031

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 78%

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Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

et al. 2006

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“…Additionally, after liver transplantation, the bile flow rate is initially low and recovers with time. This recovery of bile flow rate is paralleled by an increased expression of BSEP mRNA in liver biopsies from transplanted livers [34].…”

Section: Pathophysiological Consequences Of Altered Bsep Function Andmentioning

confidence: 87%

The bile salt export pump

Stieger

Meier

2006

Pflugers Arch - Eur J Physiol

209

137

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“…In contrast to hydrophilic bile salts, hydrophobic compounds are cytotoxic [29,63]. Prolonged warm ischemia is associated with the formation of an unfavorable bile salt-to-phospholipid ratio subsequently contributing to bile duct injury [51].…”

Section: Toxicity Of the Bilementioning

confidence: 99%