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
    EMBO Molecular Medicine 09/2012; 4(9):882-95. DOI:10.1002/emmm.201201228 · 8.67 Impact Factor
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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.
    Annals of surgery 11/2012; 258(6). DOI:10.1097/SLA.0b013e31827905eb · 8.33 Impact Factor
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    ABSTRACT: Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types—PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.
    Journal of Clinical and Experimental Hepatology 01/2013; 4(1). DOI:10.1016/j.jceh.2013.10.005
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Tomohide Hori