Genotype correlates with the natural history of severe bile salt export pump deficiency

Wessel, Daan B E van; Thompson, Richard J.; Gonzalès, Emmanuel; Jankowska, Irena; Sokal, Étienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipiński, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Bröering, Dieter C.; Algoufi, Talal; Mazhar, Nejat; Nicastro, Emanuele; Kelly, Déirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B F; Serranti, Daniele; Arıkan, Çiğdem; Polat, Esra; Debray, Dominique; Lacaille, Florence; Gonçalves, Ana Cristina; Hierro, Loreto; Bartolo, Gema Muñoz; Mozer‐Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezsőfi, Antal; Calvo, Pier Luigi; Grabhorn, Enke; Sturm, Ekkehard; Woerd, Wendy L. van der; Kamath, Binita M.; Wang, Jianshe; Li, Liting; Durmaz, Özlem; Önal, Zerrin; Bunt, Ton M.G.; Hansen, Bettina E.; Verkade, Henkjan J.

doi:10.1016/j.jhep.2020.02.007

Cited by 78 publications

(107 citation statements)

References 45 publications

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“…Notes: Case numbers in boldface indicate subjects of previous reports. 7,[9][10][11][12][13][14][15] Variants in boldface are novel.…”

Section: Discussionmentioning

confidence: 99%

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ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

Yong

et al. 2020

Liver International

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Background & Aims: ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal cholestasis (TNC). Methods: Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. Results: The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. Conclusions: Neonatal cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.

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“…Notes: Case numbers in boldface indicate subjects of previous reports. 7,[9][10][11][12][13][14][15] Variants in boldface are novel.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6] The genotype of patients with severe ABCB11 deficiency is associated with clinical outcomes. 7 TNC refers specifically to a status limited to infancy. Whether a patient with TNC will later prove to have BRIC, or even PFIC, cannot at present be predicted.…”

Section: Introductionmentioning

confidence: 99%

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

Yong

et al. 2020

Liver International

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“…35 Furthermore, a significant association was identified between lower post-SBD serum bile acids and long-term native liver survival: patients whose serum bile acids were <102 μmol/L after SBD survived up to 15 years with their native liver intact vs patients whose serum bile acids were ≥102 μmol/L, for whom less than half had this outcome. 35 Similarly, in a systematic review and meta-analysis evaluating studies with pre-and post-PEBD liver biochemistry values, patients with PFIC with reduced serum bile acids post-PEBD were more likely to have favourable clinical responses (ie, improved pruritus, decreased need for liver transplant). 59 Thus, the reduction in bile acids and improvement in clinical outcomes observed with SBD provide a strong rationale that disrupting enterohepatic circulation holds promise for treating patients with cholestatic liver disease.…”

Section: Interrup Ti On Of the Enterohepati C Circul Ati On A S A Tmentioning

confidence: 98%

“…Data from the NAPPED consortium also indicated that patient genotype, at least in the case of ABCB11-deficient PFIC for which data are available, may influence long-term outcomes following SBD; these data hint at a possibility for personalized medicine approaches in the future. 35 Inhibition of IBAT represents a pharmacologic approach for achieving the same ends as SBD: that is, interruption of the enterohepatic circulation of bile acids. IBAT is an integral brush border membrane glycoprotein that co-transports sodium and bile acids and is a major regulator of the bile acid pool size in animals and humans.…”

Section: Interrup Ti On Of the Enterohepati C Circul Ati On A S A Tmentioning

confidence: 99%

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Kamath

Stein²,

Houwen

et al. 2020

Liver International

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“…This change corresponded with a reduction in mean serum bile acids (from 363 μmol/L to 48 μmol/L, respectively). 13 Overall, a greater proportion of patients with lower serum bile acids after surgery survived with their native liver intact for up to 15 years versus those who had elevated serum bile acids post-surgery. 13 In addition, a systematic review and meta-analysis evaluating studies with pre-PEBD and post-PEBD liver biochemistry values found that patients with PFIC with reduced serum bile acids post-PEBD were more likely to have favourable clinical responses such as improved pruritus and decreased need for liver transplant.…”

Section: Introductionmentioning

confidence: 95%

Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis

Slavetinsky

Sturm

2020

BMJ Case Rep

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Untreated progressive familial intrahepatic cholestasis (PFIC) type 2, or bile salt exporter protein deficiency, frequently leads to severe pruritus, impaired growth and progressive liver fibrosis with risk of organ failure. We describe a 15-month-old male patient with severe pruritus diagnosed with PFIC type 2 enrolled in an open-label phase 2 study who received 4 weeks of treatment with odevixibat, an ileal bile acid transporter inhibitor under development for cholestatic liver disease treatment. The patient experienced reductions in serum bile acids and improvement in itching and sleep scores, and odevixibat was well tolerated. After the odevixibat study, symptoms returned and the patient underwent partial external biliary diversion (PEBD). Odevixibat treatment and PEBD produced similar normalisation of serum bile acid levels and improvements in pruritus and sleep disruptions. Thus, odevixibat appeared to be as effective as invasive PEBD in treating serum bile acids and cholestatic pruritus in this patient.

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Genotype correlates with the natural history of severe bile salt export pump deficiency

Cited by 78 publications

References 45 publications

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis

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