Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion

Emerick, Karan M.; Elías, Marc; Melín-Aldana, Héctor; Strautnieks, Sandra; Rj, Thompson; Bull, Laura N.; Knisely, A. S.; Whitington, Peter F.; Green, Richard M.

doi:10.1186/1471-230x-8-47

Cited by 26 publications

(33 citation statements)

References 37 publications

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“…Emerick et al demonstrated that ALGS patients at baseline had greater bile salt, cholesterol, phospholipid, and chenodeoxycholicto-cholic acid ratios than PFIC patients. (31) They also showed that following successful PEBD, ALGS patients have higher biliary lipid concentrations than PFIC patients, and that the FIC1 subtype of PFIC was associated with increased postoperative biliary phospholipic concentrations. Jericho et al studied the kinetics of bile acid turnover in 5 PFIC patients with successful PEBD compared to 5 PFIC patients who underwent LT (32) and observed comparable bile acid transport kinetics between the two groups.…”

Section: Discussionmentioning

confidence: 98%

“…The current study suggests that outcomes are much more complicated than one might glean from the existing published literature. Emerick et al demonstrated that ALGS patients at baseline had greater bile salt, cholesterol, phospholipid, and chenodeoxycholic‐to‐cholic acid ratios than PFIC patients . They also showed that following successful PEBD, ALGS patients have higher biliary lipid concentrations than PFIC patients, and that the FIC1 subtype of PFIC was associated with increased postoperative biliary phospholipic concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis

et al. 2017

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To evaluate the efficacy of non-transplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 Alagille syndrome (ALGS), 16 Familial Intrahepatic Cholestasis-1 (FIC1), 18 Bile Salt Export Pump (BSEP) disease, & 4 others with low γ-glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBD), 11 ileal exclusions (IE) and 7 gallbladder-to-colon diversion (GBC). Serum total bilirubin decreased after PEBD in FIC1 (8.1±4.0 vs. 2.9±4.1 mg/dL, preop vs. 12–24 months postop respectively, p=0.02) but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695±465 vs. 457±319 mg/dL; preop vs. 12–24 months postop respectively; p=0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182±70 vs. 260±73 IU/L, preop vs. 24 mos. p=0.03) but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS: 100% vs. 9% severe, FIC1: 64% vs. 10%; BSEP: 50% vs. 20%, preop vs. >24 mos. postop respectively, p<0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%, p=0.03. Overall, there were 15 major complications after surgery. 12 patients (3 ALGS, 3 FIC1, 6 BSEP) subsequently underwent liver transplantation. Conclusion This is the first multi-center analysis of non-transplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally although not uniformly result in improvement of pruritus and cholestasis.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis

et al. 2017

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“…The DKO mouse model develops cholestasis as early as 3 weeks of age and as such will be an excellent tool to study earlyonset cholestasis. Additionally, unlike that in diet-induced cholestasis (53), the DKO mice accumulate a range of both hydrophilic and hydrophobic BAs, similar to that in most clinical settings (54,55). Despite an early onset of liver damage, DKO mice remain viable for more than a year.…”

Section: Discussionmentioning

confidence: 99%

Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis

et al. 2011

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Bile acid homeostasis is tightly regulated via a feedback loop operated by the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP). Contrary to current models, which place FXR upstream of SHP in a linear regulatory pathway, here we show that the phenotypic consequences in mice of the combined loss of both receptors are much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. Fxr -/-Shp -/-mice exhibited cholestasis and liver injury as early as 3 weeks of age, and this was linked to the dysregulation of bile acid homeostatic genes, particularly cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1). In addition, double-knockout mice showed misregulation of genes in the C21 steroid biosynthesis pathway, with strong induction of cytochrome P450, family 17, subfamily a, polypeptide 1 (Cyp17a1), resulting in elevated serum levels of its enzymatic product 17-hydroxyprogesterone (17-OHP). Treatment of WT mice with 17-OHP was sufficient to induce liver injury that reproduced many of the histopathological features observed in the double-knockout mice. Therefore, our data indicate a pathologic role for increased production of 17-hydroxy steroid metabolites in liver injury and suggest that Fxr -/-Shp -/-mice could provide a model for juvenile onset cholestasis.

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“…Although in some reports serum transaminase levels and pruritus improved in about half of the patients upon UDCA [102,104,105], in most studies UDCA was not effective [106][107][108][109][110][111][112][113]. Even in patients with a mild phenotype (BRIC1, BRIC2), UDCA did not prevent or abort a cholestatic attack [19,24,31,39,40,[114][115][116] (Table 2A).…”

Section: Udcamentioning

confidence: 81%

“…This innovative technique was quickly adopted by other centres worldwide and so far sixteen additional casereports/series addressing the effect and technique of PEBD in the treatment of PFIC have been published (Table 3). Except for one small series of five patients in which PEBD did not have any effect [104], all others report normalization or improvement of liver function in 75-100% of the patients with low GGT-PFIC, indicated by at least improved liver tests and reduced pruritus [106,108,110,112,[136][137][138][139][140][141][142][143]. The response in patients with an undefined subtype of PFIC seems to be less [111,144].…”

Section: Biliary Diversionmentioning

confidence: 97%

Liver disease associated with canalicular transport defects: Current and future therapies

Stapelbroek

Erpecum

Klomp

et al. 2010

Journal of Hepatology

155

152

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Bile formation at the canalicular membrane is a delicate process. This is illustrated by inherited liver diseases due to mutations in ATP8B1, ABCB11, ABCB4, ABCC2 and ABCG5/8, all encoding hepatocanalicular transporters. Effective treatment of these canalicular transport defects is a clinical and scientific challenge that is still ongoing. Current evidence indicates that ursodeoxycholic acid (UDCA) can be effective in selected patients with PFIC3 (ABCB4 deficiency), while rifampicin reduces pruritus in patients with PFIC1 (ATP8B1 deficiency) and PFIC2 (ABCB11 deficiency), and might abort cholestatic episodes in BRIC (mild ATP8B1 or ABCB11 deficiency). Cholestyramine is essential in the treatment of sitosterolemia (ABCG5/8 deficiency). Most patients with PFIC1 and PFIC2 will benefit from partial biliary drainage. Nevertheless liver transplantation is needed in a substantial proportion of these patients, as it is in PFIC3 patients. New developments in the treatment of canalicular transport defects by using nuclear receptors as a target, enhancing the expression of the mutated transporter protein by employing chaperones, or by mutation specific therapy show substantial promise. This review will focus on the therapy that is currently available as well as on those developments that are likely to influence clinical practice in the near future.

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Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion

Cited by 26 publications

References 37 publications

Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis

Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis

Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis

Liver disease associated with canalicular transport defects: Current and future therapies

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