Progressive familial intrahepatic cholestasis: a single‐center experience of living‐donor liver transplantation during two decades in Japan

Hori, Tomohide; Egawa, Hiroto; Takada, Yasutsugu; Ueda, Mikiko; Oike, Fumitaka; Ogura, Yasuhiro; Sakamoto, Seisuke; Kasahara, Mureo; Ogawa, Kohei; Miyagawa‐Hayashino, Aya; Yonekawa, Yukihide; Yorifuji, Tohru; Watanabe, Ken; Doi, Hiraku; Nguyen, Justin H.; Chen, Feng; Baine, Ann Marie T.; Gardner, Lindsay B.; Üemoto, Shinji

doi:10.1111/j.1399-0012.2010.01368.x

Cited by 47 publications

(63 citation statements)

References 40 publications

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“… † Hori et al74 and Miyagawa‐Hayashino et al75 reported the same cohort of patients. Miyagawa‐Hayashino et al reported only the 8 PFIC1 patients with steatosis.…”

Section: Resultsmentioning

confidence: 87%

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Posttransplant metabolic syndrome in children and adolescents after liver transplantation: A systematic review

et al. 2012

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In long-term follow-up, 18-67% of pediatric liver transplant recipients are overweight or obese— with rates varying by age and pre-transplant weight status. Similar prevalence of post-transplant obesity is seen in adults. Adults also develop post-transplant metabolic syndrome, with consequent cardiovascular disease, at rates that exceed age and gender-matched populations. Post-transplant metabolic syndrome has never been studied in pediatric liver transplant recipients—a growing population as transplant outcomes continue to improve. This paper systematically reviews the literature on each component of metabolic syndrome—obesity, hypertension, dyslipidemia, and glucose intolerance—in pediatric liver transplant recipients. Rates of obesity are similar to that of the general U.S. population of children. But hypertension, dyslipidemia, and diabetes are more common than expected for age, gender, and obesity severity in transplant recipients. Immunosuppressive medications are major contributors. Limitations of prior studies—including heterogeneous methods of diagnosis, follow-up times, and immunosuppressive regimen—hinder the analysis of risk factors. Importantly, no studies report on graft or patient outcomes associated with metabolic syndrome components after pediatric liver transplant. However, if trends in children are similar to those seen in adults, these conditions may lead to significant long-term morbidity. Further research on the prevalence, causes, and consequences of post-transplant metabolic syndrome in pediatric liver transplant is needed and ultimately will help improve long-term outcomes.

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“… † Hori et al74 and Miyagawa‐Hayashino et al75 reported the same cohort of patients. Miyagawa‐Hayashino et al reported only the 8 PFIC1 patients with steatosis.…”

Section: Resultsmentioning

confidence: 87%

“…Posttransplant NAFLD in pediatric liver transplant recipients has been documented only in case series and reports69‐77 (Table 5). Four of the 19 children reported in these studies underwent transplantation for cirrhosis associated with nonalcoholic steatohepatitis (NASH) 69‐71.…”

Section: Resultsmentioning

confidence: 99%

Posttransplant metabolic syndrome in children and adolescents after liver transplantation: A systematic review

et al. 2012

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“…However, after restoration of bile flow, i.e. after LTx, high concentrations of bile salts enter the lumen of the intestine, which in combination with bile salt malabsorption may result in spillover of bile salts to the colon and in exacerbation of diarrhea that can be ameliorated by application of bile salt-binding resins [15][16][17][18][19]. This favors the hypothesis that intestinal bile salt malabsorption may be the underlying cause of diarrhea.…”

Section: Discussionmentioning

confidence: 75%

“…Extrahepatic symptoms such as diarrhea and hearing loss are common in PFIC1 and BRIC1 patients [10,13,14]. After LTx, PFIC1 patients have a high risk (~85%) of developing an exacerbated form of diarrhea, possibly as a consequence of restored bile flow [15][16][17][18][19]. Diarrhea is ameliorated upon treatment with bile salt-absorptive resins such as cholesevelam and cholestyramine [20].…”

Section: Introductionmentioning

confidence: 97%

The lipid flippase heterodimer ATP8B1–CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells

Mark

Waart

Ho-Mok

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1-CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.

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“…No effective medical therapy for this disease is currently available [3]. Even liver transplantation is insufficient to improve the clinical course and outcomes of patients with PFIC1 because of steatosis and fibrosis [4]. …”

Section: Introductionmentioning

confidence: 99%

Intractable itch relieved by 4-phenylbutyrate therapy in patients with progressive familial intrahepatic cholestasis type 1

Hasegawa

Hayashi

Naoi

et al. 2014

Orphanet J Rare Dis

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BackgroundProgressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1.MethodsThe therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected.Results4PB therapy had no beneficial effect on the patients’ liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy.Conclusions4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families.

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Progressive familial intrahepatic cholestasis: a single‐center experience of living‐donor liver transplantation during two decades in Japan

Cited by 47 publications

References 40 publications

Posttransplant metabolic syndrome in children and adolescents after liver transplantation: A systematic review

Posttransplant metabolic syndrome in children and adolescents after liver transplantation: A systematic review

The lipid flippase heterodimer ATP8B1–CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells

Intractable itch relieved by 4-phenylbutyrate therapy in patients with progressive familial intrahepatic cholestasis type 1

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