Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency

Daan B E van Wessel, Richard J Thompson, Emmanuel Gonzales, Irena Jankowska, Benjamin L Shneider, Etienne Sokal, Tassos Grammatikopoulos, Agustina Kadaristiana, Emmanuel Jacquemin, Anne Spraul, Patryk Lipiński, Piotr Czubkowski, Nathalie Rock, Mohammad Shagrani, Dieter Broering, Talal Algoufi, Nejat Mazhar, Emanuele Nicastro, Deirdre Kelly, Gabriella Nebbia, Henrik Arnell, Björn Fischler, Jan B F Hulscher, Daniele Serranti, Cigdem Arikan, Dominique Debray, Florence Lacaille, Cristina Goncalves, Loreto Hierro, Gema Muñoz Bartolo, Yael Mozer-Glassberg, Amer Azaz, Jernej Brecelj, Antal Dezsőfi, Pier Luigi Calvo, Dorothee Krebs-Schmitt, Steffen Hartleif, Wendy L van der Woerd, Jian-She Wang, Li-Ting Li, Özlem Durmaz, Nanda Kerkar, Marianne Hørby Jørgensen, Ryan Fischer, Carolina Jimenez-Rivera, Seema Alam, Mara Cananzi, Noémie Laverdure, Cristina Targa Ferreira, Felipe Ordonez, Heng Wang, Valerie Sency, Kyung Mo Kim, Huey-Ling Chen, Elisa Carvalho, Alexandre Fabre, Jesus Quintero Bernabeu, Estella M Alonso, Ronald J Sokol, Frederick J Suchy, Kathleen M Loomes, Patrick J McKiernan, Philip Rosenthal, Yumirle Turmelle, Girish S Rao, Simon Horslen, Binita M Kamath, Maria Rogalidou, Wikrom W Karnsakul, Bettina Hansen, Henkjan J Verkade, Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium, Daan B E van Wessel, Richard J Thompson, Emmanuel Gonzales, Irena Jankowska, Benjamin L Shneider, Etienne Sokal, Tassos Grammatikopoulos, Agustina Kadaristiana, Emmanuel Jacquemin, Anne Spraul, Patryk Lipiński, Piotr Czubkowski, Nathalie Rock, Mohammad Shagrani, Dieter Broering, Talal Algoufi, Nejat Mazhar, Emanuele Nicastro, Deirdre Kelly, Gabriella Nebbia, Henrik Arnell, Björn Fischler, Jan B F Hulscher, Daniele Serranti, Cigdem Arikan, Dominique Debray, Florence Lacaille, Cristina Goncalves, Loreto Hierro, Gema Muñoz Bartolo, Yael Mozer-Glassberg, Amer Azaz, Jernej Brecelj, Antal Dezsőfi, Pier Luigi Calvo, Dorothee Krebs-Schmitt, Steffen Hartleif, Wendy L van der Woerd, Jian-She Wang, Li-Ting Li, Özlem Durmaz, Nanda Kerkar, Marianne Hørby Jørgensen, Ryan Fischer, Carolina Jimenez-Rivera, Seema Alam, Mara Cananzi, Noémie Laverdure, Cristina Targa Ferreira, Felipe Ordonez, Heng Wang, Valerie Sency, Kyung Mo Kim, Huey-Ling Chen, Elisa Carvalho, Alexandre Fabre, Jesus Quintero Bernabeu, Estella M Alonso, Ronald J Sokol, Frederick J Suchy, Kathleen M Loomes, Patrick J McKiernan, Philip Rosenthal, Yumirle Turmelle, Girish S Rao, Simon Horslen, Binita M Kamath, Maria Rogalidou, Wikrom W Karnsakul, Bettina Hansen, Henkjan J Verkade, Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium

Abstract

Background and aims: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date.

Approach and results: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 μmol/L (P = 0.05) tended to be associated with improved NLS.

Conclusions: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

© The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Figures

Fig. 1
Fig. 1
Flowchart of patient inclusion from the NAPPED database and subsequent categorization based on genotype. *Either only one mutation in ATP8B1, ATP8B1 mutations of no (known) clinical consequence, mutations in ABCB11/TJP2, or participation in investigational drug trials. sEpisodic cholestasis and/or pruritus and transient hepatocellular damage. †Splice site, frameshift due to deletion or insertion, nonsense, or duplication.
Fig. 2
Fig. 2
Proportion of all patients alive with native liver with a surgical diversion over time (A) and proportion of patients alive with native liver (B) in all patients.
Fig. 3
Fig. 3
Proportion of patients with a surgical diversion (A) and proportion of patients alive with native liver (B) in patients without PPTMs (FIC1‐A), with one PPTM (FIC1‐B), or two PPTMs (FIC1‐C).
Fig. 4
Fig. 4
Pre‐SBD and post‐SBD biochemistry: sBAs (A), TSB (B), ALT (C), and AST (D) in patients with FIC1‐A (filled circles), FIC1‐B (open circles), and FIC1‐C (triangles) genotypes for whom paired data were available.
Fig. 5
Fig. 5
Observed native liver survival (x axis) in all patients with an FIC1 genotype, who underwent SBD (n = 62) or not (n = 68). The clock‐reset approach allows visualization of native liver survival up to SBD (solid line, all patients) and after SBD (dotted line, only patients who underwent SBD). The estimated HR is achieved by Cox regression, with SBD as a time‐dependent risk factor, adjusted for genotype, sex, and birth year.
Fig. 6
Fig. 6
NLS after SBD in patients with an FIC1‐A (no truncating mutations), an FIC1‐B (one truncating mutation), or an FIC1‐C (two truncating mutations) genotype.
Fig. 7
Fig. 7
NLS after SBD in patients with a sBA concentration of 
All figures (7)

References

    1. Elferink RO, Groen AK. Genetic defects in hepatobiliary transport. Biochim Biophys Acta 2002;1586:129‐145.
    1. Bull LN, Thompson RJ. Progressive familial intrahepatic cholestasis. Clin Liver Dis 2018;22:657‐669.
    1. Noe J, Kullak‐Ublick GA, Jochum W, Stieger B, Kerb R, Haberl M, et al. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 2005;43:536‐543.
    1. Bull LN, Van Eijk MJT, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, et al. A gene encoding a P‐type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998;18:219‐224.
    1. Andersen JP, Vestergaard AL, Mikkelsen SA, Mogensen LS, Chalat M, Molday RS. P4‐ATPases as phospholipid flippases: structure, function, and enigmas. Front Physiol 2016;7:275.
    1. Paulusma CC, de Waart DR, Kunne C, Mok KS, Elferink RP. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem 2009;284:9947‐9954.
    1. Folmer DE, van der Mark VA, Ho‐Mok KS, Oude Elferink RP, Paulusma CC. Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1. Hepatology 2009;50:1597‐1605.
    1. Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology 2009;136:1060‐1069.
    1. Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, et al. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology 2004;126:756‐764.
    1. Frankenberg T, Miloh T, Chen FY, Ananthanarayanan M, Sun AQ, Balasubramaniyan N, et al. The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 2008;48:1896‐1905.
    1. Demeilliers C, Jacquemin E, Barbu V, Mergey M, Paye F, Fouassier L, et al. Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation. Hepatology 2006;43:1125‐1134.
    1. Koh S, Takada T, Kukuu I, Suzuki H. FIC1‐mediated stimulation of FXR activity is decreased with PFIC1 mutations in HepG2 cells. J Gastroenterol 2009;44:592‐600.
    1. Davit‐Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma‐glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology 2010;51:1645‐1655.
    1. Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol 2010;53:170‐178.
    1. Tygstrup N, Steig BA, Juijn JA, Bull LN, Houwen RH. Recurrent familial intrahepatic cholestasis in the Faeroe Islands: phenotypic heterogeneity but genetic homogeneity. Hepatology 1999;29:506‐508.
    1. Stapelbroek JM, Peters TA, van Beurden DH, Curfs JH, Joosten A, Beynon AJ, et al. ATP8B1 is essential for maintaining normal hearing. Proc Natl Acad Sci U S A 2009;106:9709‐9714.
    1. Ray NB, Durairaj L, Chen BB, McVerry BJ, Ryan AJ, Donahoe M, et al. Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. Nat Med 2010;16:1120‐1127.
    1. Folvik G, Hilde O, Helge GO. Benign recurrent intrahepatic cholestasis: review and long‐term follow‐up of five cases. Scand J Gastroenterol 2012;47:482‐488.
    1. Nagasaka H, Yorifuji T, Kosugiyama K, Egawa H, Kawai M, Murayama K, et al. Resistance to parathyroid hormone in two patients with familial intrahepatic cholestasis: possible involvement of the ATP8B1 gene in calcium regulation via parathyroid hormone. J Pediatr Gastroenterol Nutr 2004;39:404‐409.
    1. Verhulst PM, van der Velden LM, Oorschot V, van Faassen EE, Klumperman J, Houwen RH, et al. A flippase‐independent function of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1, is required for apical protein expression and microvillus formation in polarized epithelial cells. Hepatology 2010;51:2049‐2060.
    1. Walkowiak J, Jankowska I, Pawlowska J, Bull L, Herzig KH, Socha J. Normal pancreatic secretion in children with progressive familial intrahepatic cholestasis type 1. Scand J Gastroenterol 2006;41:1480‐1483.
    1. Li L, Deheragoda M, Lu Y, Gong J, Wang J. Hypothyroidism associated with ATP8B1 deficiency. J Pediatr 2015;167:1334‐1339.e1.
    1. Bull LN, Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Dodge JL, et al. Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. Hepatol Commun 2018;2:515‐528.
    1. Ismail H, Kalicinski P, Markiewicz M, Jankowska I, Pawlowska J, Kluge P, et al. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion. Pediatr Transplant 1999;3:219‐224.
    1. Hollands CM, Rivera‐Pedrogo FJ, Gonzalez‐Vallina R, Loret‐de‐Mola O, Nahmad M, Burnweit CA. Ileal exclusion for Byler’s disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg 1998;33:220‐224.
    1. Arnell H, Bergdahl S, Papadogiannakis N, Nemeth A, Fischler B. Preoperative observations and short‐term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis. J Pediatr Surg 2008;43:1312‐1320.
    1. Nicastro E, Stephenne X, Smets F, Fusaro F, de Magnee C, Reding R, et al. Recovery of graft steatosis and protein‐losing enteropathy after biliary diversion in a PFIC 1 liver transplanted child. Pediatr Transplant 2012;16:E177‐E182.
    1. van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Sokal E, Grammatikopoulos T, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol 2020;73:84‐93.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap): a metadata‐driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377‐381.
    1. Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004;40:27‐38.
    1. Takatsu H, Tanaka G, Segawa K, Suzuki J, Nagata S, Nakayama K, et al. Phospholipid flippase activities and substrate specificities of human type IV P‐type ATPases localized to the plasma membrane. J Biol Chem 2014;289:33543‐33556.
    1. van der Woerd WL, Mulder J, Pagani F, Beuers U, Houwen RHJ, van de Graaf SFJ. Analysis of aberrant pre‐messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA. Hepatology 2015;61:1382‐1391.
    1. Bourke B, Goggin N, Walsh D, Kennedy S, Setchell KD, Drumm B. Byler‐like familial cholestasis in an extended kindred. Arch Dis Child 1996;75:223‐227.
    1. Bull LN, Juijn JA, Liao M, van Eijk MJ, Sinke RJ, Stricker NL, et al. Fine‐resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Hum Genet 1999;104:241‐248.
    1. van Ooteghem NA, Klomp LW, van Berge‐Henegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol 2002;36:439‐443.
    1. Clayton RJ, Iber FL, Ruebner BH, McKusick VA. Byler disease: fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969;117:112‐124.
    1. Klomp LW, Bull LN, Knisely AS, van Der Doelen MA, Juijn JA, Berger R, et al. A missense mutation in FIC1 is associated with Greenland familial cholestasis. Hepatology 2000;32:1337‐1341.
    1. Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 2006;44:478‐486.
    1. Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008;134:1203‐1214.
    1. Iannelli F, Collino A, Sinha S, Radaelli E, Nicoli P, D’Antiga L, et al. Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency. Nat Commun 2014;5:3850.
    1. Miyagawa‐Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, et al. Allograft steatohepatitis in progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation. Liver Transpl 2009;15:610‐618.
    1. Aydogdu S, Cakir M, Arikan C, Tumgor G, Yuksekkaya HA, Yilmaz F, et al. Liver transplantation for progressive familial intrahepatic cholestasis: clinical and histopathological findings, outcome and impact on growth. Pediatr Transplant 2007;11:634‐640.

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