Recent advances in the pathogenesis and management of biliary atresia

Zagory, Jessica A.; Nguyen, Minh; Wang, Kasper S.

doi:10.1097/mop.0000000000000214

Cited by 44 publications

(37 citation statements)

References 83 publications

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“…Left untreated, BA is fatal; the only effective treatments are hepatic portoenterostomy (Kasai operation) and liver transplantation . In children, BA is the most common cause of end‐stage liver disease and the leading indication for liver transplantation . Ultimately, approximately 80% of children with BA will progress to need liver transplantation.…”

Section: Biliary Atresiamentioning

confidence: 99%

“…The Kasai operation involves excision of the extrahepatic biliary remnant with a high portal‐plate dissection to maximize exposure of residual bile ductules . Drainage of bile is re‐established from the portal plate into a 30–40 cm Roux limb of jejunum.…”

Section: Biliary Atresiamentioning

confidence: 99%

“…40 In children, BA is the most common cause of end-stage liver disease and the leading indication for liver transplantation. 41,42 Ultimately, approximately 80% of children with BA will progress to need liver transplantation.…”

Section: Biliary Atresiamentioning

confidence: 99%

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Transitional care for patients with surgical pediatric hepatobiliary disease: Choledochal cysts and biliary atresia

Aspelund

Mahdi

Rothstein

et al. 2019

J of Gastro and Hepatol

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Choledochal cysts (CDCs) and biliary atresia (BA) are rare pediatric hepatobiliary anomalies that require surgical intervention due to increased risk of malignancy and liver failure, respectively. The underlying disease and operative procedures place patients at risk for long‐term complications, which may continue to affect them into adulthood. Lack of a transitional care model in the health‐care system potentiates the challenges they will face following aging out of their pediatric providers' care. We sought to elucidate the long‐term complications and challenges patients with CDCs and BA face, review the current literature regarding transitioning care, and propose guidelines aiding adult providers in continued care and surveillance of these patients. A literature review was performed to assess short‐term and long‐term complications after surgery and the current standards for transitioning care in patients with a history of CDCs and BA. While transitional programs exist for patients with other gastrointestinal diseases, there are few that focus on CDCs or BA. Generally, authors encourage medical record transmission from pediatric to adult providers, ensuring accuracy of information and compliance with treatment plans. Patients with CDCs are at risk for developing biliary malignancies, cholangitis, and anastomotic strictures after resection. Patients with BA develop progressive liver failure, necessitating transplantation. There are no consensus guidelines regarding timing of follow up for these patients. Based on the best available evidence, we propose a schema for long‐term surveillance.

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Section: Biliary Atresiamentioning

confidence: 99%

Section: Biliary Atresiamentioning

confidence: 99%

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Transitional care for patients with surgical pediatric hepatobiliary disease: Choledochal cysts and biliary atresia

Aspelund

Mahdi

Rothstein

et al. 2019

J of Gastro and Hepatol

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“…While surgical bypass of the atretic extrahepatic biliary tree is essential for survival, the extent and progression of intrahepatic biliary fibrosis are key determinants of transplant-free survival [2]. Thus, characterizing the pathogenesis of biliary fibrosis associated with biliary atresia remains essential in efforts to impact survival for infants with BA.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Prominin-1 expression is associated with biliary fibrosis

Nguyen

Zagory

Dietz

et al. 2017

Surgery

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Background Intrahepatic biliary fibrosis, as seen with cholestatic liver injuries such as biliary atresia, is mechanistically distinct from fibrosis caused by hepatocyte toxicity. We previously demonstrated the expansion of cells expressing the stem/progenitor cell marker PROMININ-1 (PROM1), within regions of developing fibrosis in biliary atresia. Thus, we hypothesized that Prom1 expression is biliary fibrosis-specific. Methods Gene expression of Prom1 was analyzed in adult mice undergoing either cholestatic bile duct ligation (BDL) or hepatotoxic carbon tetrachloride (CCl4) administration by quantitative polymerase chair reaction. Lineage tracing of Prom1- expressing cells and Collagen-1α (Col1α)-expressing cells was performed after BDL in Prom1cre-ert2-lacz;Gfplsl and Col1αGfp transgenic mice, respectively. Results Prom1 expression increased significantly after BDL compared to sham (6.6±0.9 fold change at 2 weeks, p<0.05) but not with CCl4 (−0.7±0.5-fold change, NS). Upregulation of Prom1 was observed histologically throughout the liver as early as five days after BDL in Prom1cre-ert2-lacz mice by LacZ staining in non-hepatocyte cells. Lineage tracing of Prom1-expressing cells labeled prior to BDL in Prom1cre-ert2-lacz;Gfplsl mice, demonstrated increasing colocalization of GREEN FLUORESCENT PROTEIN (GFP) with biliary marker CYTOKERATIN-19 within ductular reactions up to 5 weeks after BDL consistent with biliary transdifferentiation. In contrast, rare colocalization of GFP with mesenchymal marker α-SMOOTH MUSCLE ACTIN in Prom1cre-ert2-lacz;Gfplsl mice and some colocalization of GFP with PROM1 in Col1αGfp mice, indicate minimal contribution of Prom1 progenitor cells to the pool of collagen-producing myofibroblasts. Conclusion During biliary fibrosis, Prom1-expressing progenitor cells transdifferentiate into cells within ductular reactions. This transdifferentiation may promote fibrosis.

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“…B iliary atresia (BA), a congenital fibro-obliterative cholangiopathy, is the most common cause of pediatric end-stage liver failure and the leading indication for liver transplant in children. (1)(2)(3)(4)(5)(6)(7)(8) The extent of intrahepatic biliary fibrosis at the time of Kasai hepatoportoenterostomy, an operation designed to bypass obstructed extrahepatic bile ducts, negatively correlates with successful surgical drainage, defined as serum total bilirubin levels <1.5 mg/dL within 3 months of operation, as well as transplant-free survival. (8) Even with successful surgical drainage, most patients experience progressive intrahepatic fibrosis and still progress to end-stage liver failure and cirrhosis.…”

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confidence: 99%

Prominin‐1 Promotes Biliary Fibrosis Associated With Biliary Atresia

Zagory¹,

Fenlon²,

Dietz³

et al. 2019

Hepatology

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In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant‐free survival. We recently linked the expansion of a population of prominin‐1 (Prom1)‐expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1‐expressing progenitor cells play a role in BA‐associated fibrosis. Rhesus rotavirus (RRV)‐mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre‐ert2‐nlacz, which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV‐induced BA, was absent in KO mice. RRV‐treated KO mice demonstrated significantly fewer cytokeratin‐19 (CK19)‐positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV‐treated KO mice expressed significantly less integrin‐β6, which encodes a key biliary‐specific subunit of a transforming growth factor (TGF) β activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant‐free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN‐1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin‐mediated TGF pathway activation.

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Recent advances in the pathogenesis and management of biliary atresia

Cited by 44 publications

References 83 publications

Transitional care for patients with surgical pediatric hepatobiliary disease: Choledochal cysts and biliary atresia

Transitional care for patients with surgical pediatric hepatobiliary disease: Choledochal cysts and biliary atresia

Hepatic Prominin-1 expression is associated with biliary fibrosis

Prominin‐1 Promotes Biliary Fibrosis Associated With Biliary Atresia

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