Predicting native liver injury and survival in biliary atresia

Hukkinen, Maria; Pihlajoki, Marjut; Pakarinen, Mikko P.

doi:10.1016/j.sempedsurg.2020.150943

Cited by 21 publications

(30 citation statements)

References 78 publications

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“…To better elucidate SOX9-positive LPLCs, multiple immunofluorescence staining was used to determine SOX9 and HNF4A double-positive LPLCs in our study. We previously indicated that BA-related prognosis predictors such as TBA, RDCs, and fibrosis [ 5 , 6 , 42 ] are associated with the emergence of LPLCs. LPLCs correlated with atypical RDC, which agrees with previous literature that LPLCs could be a possible source for atypical RDC [ 43 – 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Biliary atresia (BA) is a typical obstructive chronic cholestatic liver disease that has been the most common indicator for pediatric liver transplantation for several decades [ 1 – 3 ]. Diverse reactive ductular cells (RDCs) accompanying the cholestatic progression of BA are associated with the development of liver fibrosis and decreased native liver survival [ 4 – 6 ]. Though RDCs have been considered to participate in liver regeneration in animals [ 7 – 12 ], the heterogeneity underlying either the origin or evolution of RDCs in humans remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Lin

Zhang

et al. 2022

Stem Cell Res Ther

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Background The progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression. Methods Twenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs. Results The prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis. Conclusions LPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Lin

Zhang

et al. 2022

Stem Cell Res Ther

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“…At the time of PE, an inflammatory infiltrate associated with DR and fibrosis along the portal tracts occurs [ 16 , 18 ]. Liver fibrosis progresses, also following successful PE surgery, for largely unknown reasons [ 15 ], but has been attributed to activation of hepatic stellate cells and portal myofibroblasts by cytokines derived from Kupffer cells and reactive cholangiocytes of DR [ 3 , 5 , 19 , 20 ], leading to the deposition of an extra cellular matrix and collagen. In accordance with previous experimental observations [ 11 ], our findings suggest that IL-8 is involved with the above outlined liver injury cascade in BA, and that the involvement was specific to IL-8 as several other cytokines studied failed to show enhanced expression to a comparable degree.…”

Section: Discussionmentioning

confidence: 99%

“…The highly variable surgical prognosis of BA necessitates intensive postoperative monitoring [ 5 ]. Reliable tools for prediction of the outcome of PE and progression of liver injury are limited [ 5 , 6 ], but urgently needed for individualized patient follow-up, family counselling and early prediction of the need for LT as well as interventional studies [ 7 ]. A chemokine, interleukin (IL)-8 or CXCL8, mediates innate immune activation and regulates neutrophil recruitment and degranulation [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia

Godbole

Nyholm

Hukkinen

et al. 2021

JCM

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Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed in liver utilizing quantitative polymerase chain reaction (qPCR), immunohistochemistry and in situ hybridization and in serum using an enzyme-linked immunosorbent assay, among 115 BA patients, 10 disease controls and 68 normal controls. Results were correlated to portoenterostomy (PE) outcomes, biochemical and histological liver injury, transcriptional markers of fibrosis and cholangiocytes, and expression of other related cytokines. IL-8 was markedly overexpressed in liver and serum of BA patients at PE (n = 88) and in serum samples obtained during postoperative follow-up (n = 40). IL-8 expression in the liver was predominantly in cholangiocytes within areas of ductular reaction. Liver IL-8 mRNA expression correlated positively with its serum concentration, bile ductular proliferation, Metavir fibrosis stage, and transcriptional markers of activated myofibroblasts (ACTA2) and cholangiocytes (KRT19). Taken together, IL-8 may mediate liver injury in BA by promoting ductular reaction and associated liver fibrogenesis. Prognostic value of serum IL-8 to predict native liver survival was limited and confined to the postoperative period after PE.

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“…Although previous studies have identified some clinical risk factors for unsuccessful CJ (14)(15)(16), it is still difficult to make an early and precise prediction of CJ in clinical practice. However, an early and precise prediction of CJ is essential for clinicians to asses risk stratification, estimate the prognosis, develop individualized treatment, and prepare for further liver transplantation, such as ethics application, implementation of intensified nutritional support, and monitoring of potential complications related to progressive liver disease (17,18). We hypothesized that a visual prediction model based on clinical factors can accurately predict the CJ.…”

Section: Introductionmentioning

confidence: 99%

A Novel Model for Predicting the Clearance of Jaundice in Patients With Biliary Atresia After Kasai Procedure

Zhang

Wang

et al. 2022

Front. Pediatr.

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BackgroundThe failed clearance of jaundice (CJ) in patients with biliary atresia (BA) after the Kasai procedure (KP) often leads to a shorter native liver survival (NLS) time and earlier liver transplantation. We aimed to investigate risk factors of failed CJ and establish a novel nomogram model to predict the status of CJ.MethodsWe retrospectively reviewed institutional medical records from January 2015 to April 2020 and enrolled BA patients post-KP, randomly divided into training and testing cohorts at a ratio of 7:3, and further subdivided into cleared and uncleared jaundice groups. Univariate and multiple logistic regression analyses were used to select risk factors to establish the nomogram in the training cohort. The performance of the nomogram was evaluated by calculating the areas under the receiver operating curve (AUC) in both cohorts.ResultsThis study included 175 BA patients post-KP. After univariate and multiple logistic regression analyses, Cytomegalovirus IgM +ve associated BA (OR = 3.38; 95% CI 1.01–11.32; P = 0.04), ln γ-glutamyl transpeptidase (GGT) (OR = 0.41; 95% CI 0.22–0.80; P = 0.009), thickness of the fibrous portal plate (OR = 0.45; 95% CI 0.27–0.76; P = 0.003), liver stiffness measurement (LSM) (OR = 1.19; 95% CI 1.06–1.34; P = 0.002), and multiple episodes of cholangitis (OR = 1.65; 95% CI 1.13–2.41; P = 0.01) were identified as independent risk factors of unsuccessful CJ to construct the nomogram. The receiver operating characteristic curve (ROC) analysis suggested good nomogram performance in both the training (AUC = 0.96) and testing cohorts (AUC = 0.91).ConclusionOur nomogram model including several risk factors effectively predicts CJ in patients post-KP, which could aid in clinical decision-making.

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Predicting native liver injury and survival in biliary atresia

Cited by 21 publications

References 78 publications

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia

A Novel Model for Predicting the Clearance of Jaundice in Patients With Biliary Atresia After Kasai Procedure

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