Progressive familial intrahepatic cholestasis

Department of Neuroscience, Mayo Clinic in Florida, Jacksonville, FL 32224, USA.
Hepatobiliary & pancreatic diseases international: HBPD INT (Impact Factor: 1.17). 12/2010; 9(6):570-8.
Source: PubMed


Three types of progressive familial intrahepatic cholestasis (PFIC) have been identified, but their etiologies include unknown mechanisms.
A PubMed search on "progressive familial intrahepatic cholestasis" and "PFIC" was performed on the topic, and the relevant articles were reviewed.
The etiologies of the three PFIC types still include unknown mechanisms. Especially in PFIC type 1, enterohepatic circulation of bile acid should be considered. Ursodeoxycholic acid, partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course.
Since the etiologies and disease mechanisms of PFIC are still unclear, detailed studies are urgently required. Strategies for more advanced therapies are also needed. These developments in the future are indispensable, especially for PFIC type 1 patients.

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    • "From a mechanistic perspective, our data show that the phenotype is largely rescued by anti-miR-33 oligonucleotides. Authors suggested that a therapy that combines statins and anti-miR-33 oligonucleotides may be useful in hyperlipidemic patients by reversing statin-induced, miR-33-mediated repression of ABCA1, which ultimately would increase plasma HDL (Horie et al, 2010; Marquart et al, 2010; Najafi-Shoushtari et al, 2010; Rayner et al, 2010). Our new data show that miR-33 plays a key role in the hepatic response to statins by coordinating the expression of several sterol transporters, and that disruption of the miR-33 pathway prevents statin-induced hepatotoxicity. "
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    ABSTRACT: Bile secretion is essential for whole body sterol homeostasis. Loss-of-function mutations in specific canalicular transporters in the hepatocyte disrupt bile flow and result in cholestasis. We show that two of these transporters, ABCB11 and ATP8B1, are functional targets of miR-33, a micro-RNA that is expressed from within an intron of SREBP-2. Consequently, manipulation of miR-33 levels in vivo with adenovirus or with antisense oligonucleotides results in changes in bile secretion and bile recovery from the gallbladder. Using radiolabelled cholesterol, we show that systemic silencing of miR-33 leads to increased sterols in bile and enhanced reverse cholesterol transport in vivo. Finally, we report that simvastatin causes, in a dose-dependent manner, profound hepatotoxicity and lethality in mice fed a lithogenic diet. These latter results are reminiscent of the recurrent cholestasis found in some patients prescribed statins. Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins. →See accompanying article
    Full-text · Article · Sep 2012 · EMBO Molecular Medicine
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    ABSTRACT: Objective: Conventionally, liver transplantation, ileoileal bypass, and partial external or internal biliary diversion are used in the treatment of progressive familial intrahepatic cholestasis (PFIC). However, postoperative recurrence, chronic diarrhea, and permanent stoma are the major concerns. We present a novel approach of laparoscopic cholecystocolostomy with antireflux Y-loop for the management of children with PFIC. Methods: Between August 2003 and April 2011, 20 children with PFIC (median age: 1.47 years; range: 10.8 months to 5.11 years) successfully underwent laparoscopic cholecystocolostomies for bile diversions. Gallbladder was incised longitudinally for cholecystocolostomy. Transverse colon was divided proximal to splenic flexure. End-to-side anastomosis was established between distal transverse colon and mid-descending colon. The mobilized splenic flexure and proximal descending colon, that is, the stem of the Y-loop, was anastomosed to the gallbladder. Results: The mean operative time was 2.02 ± 0.18 hours (range: 2-2.5 hours). The mean postoperative hospital stay was 8 days (range: 5-10 days). Average time for full resumption of diet was 3 days (range: 2-4 days). Average Y-loop length was 17.65 cm (range: 15-20 cm). The median follow-up period was 54 months (range: 12-104 months). All patients were jaundice free after 7 to 20 days and pruritus subsided in 3 to 14 days. Liver function parameters significantly improved postoperatively. Success rate (normalization of serum bile acids at postoperative 12 months) was 85%. No mortality or morbidities associated with diarrhea, cholangitis, or intrahepatic reflux were observed. Conclusions: The novel approach of laparoscopic cholecystocolostomy offers a safe and effective treatment option for PFIC in children with good success rates and minimal morbidity.
    No preview · Article · Nov 2012 · Annals of surgery
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    ABSTRACT: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are two rare autosomal recessive disorders, characterized by cholestasis. They are related to mutations in hepatocellular transport system genes involved in bile formation. The differentiation between PFIC and BRIC is based on phenotypic presentation: PFIC is a progressive disease, with evolution to end-stage liver disease. BRIC is characterized by intermittent recurrent cholestatic episodes, with irresistible pruritus, mostly without evident liver damage. Between symptomatic periods, patients are completely asymptomatic. In this article, a short overview of the aetiology, the clinical and diagnostic characteristics and the therapy of both PFIC and BRIC are given.
    No preview · Article · Dec 2012 · Acta gastro-enterologica Belgica
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