Amyloid Precursor Protein As a Fibrosis Marker in Infants with Biliary Atresia

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2024 Sep 28

PMID 39341941

Authors

Jan C Kamp

Omid Madadi-Sanjani

Marie Uecker

Christopher Werlein

Lavinia Neubert

Joachim F Kubler

Mikal Obed

Norman Junge

Tobias Welte

Jannik Ruwisch

Danny D Jonigk

Jan Stolk

Gertrud Vieten

Sabina Janciauskiene

Affiliations

Soon will be listed here.

Abstract

Background: Biliary atresia (BA) is a rare condition of unknown origin in newborns with jaundice. In BA bile ducts are non-functional, causing neonatal cholestasis and following liver fibrosis and failure.

Methods: This retrospective study included liver biopsies of 14 infants with BA aged [mean ± SD] 63 ± 23 days. Patients were grouped according to the clinical course (jaundice-free vs recurrent jaundice vs required liver transplantation or liver fibrosis (Ishak fibrosis score)) and followed for 1.61-5.64 years (mean 4.03). Transcriptome profiles were assessed using a panel of 768 fibrosis-specific genes, reanalyzed via qRT-PCR, and confirmed via immunostaining. Plasma from an additional 30 BA infants and 10 age-matched controls were used for amyloid precursor protein (APP) quantification by ELISA.

Results: Different clinical outcome groups showed a homogeneous mRNA expression. Altered amyloid-metabolism-related gene expression was found between cases with Ishak fibrosis score greater than 4. Immunostaining confirmed a distinct presence of APP in the livers of all BA subjects. APP plasma levels were higher in BA than in age-matched controls and correlated with the histological fibrosis grade.

Conclusions: These results suggest that amyloidosis may contribute to BA and liver fibrosis, indicating that APP could serve as a potential liquid biomarker for these conditions.

Impact: Biliary atresia patients with higher fibrosis scores according to Ishak have higher hepatic expression of amyloid-related genes while amyloid precursor protein accumulates in the liver and increases in the circulation. After a recent study revealed beta-amyloid deposition as a mechanism potentially involved in biliary atresia, we were able to correlate amyloid-metabolism-related transcript levels as well as amyloid precursor protein tissue and plasma levels with the degree of hepatic fibrosis. These findings suggest that amyloid precursor protein is a fibrosis marker in infants with biliary atresia, reinforcing the role of amyloid metabolism in the pathogenesis of this serious disease.

References

Jiang J, Wan R, He S, Wu Y, Shen Z, Chen G . Epidemiological characteristics and risk factors of biliary atresia: a case-control study. BMJ Open. 2021; 11(12):e049354. PMC: 8671910. DOI: 10.1136/bmjopen-2021-049354. View

Livesey E, Cortina Borja M, Sharif K, Alizai N, McClean P, Kelly D . Epidemiology of biliary atresia in England and Wales (1999-2006). Arch Dis Child Fetal Neonatal Ed. 2009; 94(6):F451-5. DOI: 10.1136/adc.2009.159780. View

The N, Honein M, Caton A, Moore C, Siega-Riz A, Druschel C . Risk factors for isolated biliary atresia, National Birth Defects Prevention Study, 1997-2002. Am J Med Genet A. 2007; 143A(19):2274-84. DOI: 10.1002/ajmg.a.31926. View

Medappil N, Jacob M, Lochan R, Asthana S, Reddy J, Saif R . Kasai portoenterostomy for biliary atresia - Surgical precautions for better outcomes. J Pediatr Surg. 2018; 54(4):868-869. DOI: 10.1016/j.jpedsurg.2018.09.028. View

Davenport M, Madadi-Sanjani O, Chardot C, Verkade H, Karpen S, Petersen C . Surgical and Medical Aspects of the Initial Treatment of Biliary Atresia: Position Paper. J Clin Med. 2022; 11(21). PMC: 9656543. DOI: 10.3390/jcm11216601. View

Madadi-Sanjani O, Kuebler J, Dippel S, Gigina A, Falk C, Vieten G . Long-term outcome and necessity of liver transplantation in infants with biliary atresia are independent of cytokine milieu in native liver and serum. Cytokine. 2018; 111:382-388. DOI: 10.1016/j.cyto.2018.09.010. View

Leyva-Vega M, Gerfen J, Thiel B, Jurkiewicz D, Rand E, Pawlowska J . Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3. Am J Med Genet A. 2010; 152A(4):886-95. PMC: 2914625. DOI: 10.1002/ajmg.a.33332. View

Ningappa M, So J, Glessner J, Ashokkumar C, Ranganathan S, Min J . The Role of ARF6 in Biliary Atresia. PLoS One. 2015; 10(9):e0138381. PMC: 4574480. DOI: 10.1371/journal.pone.0138381. View

Chen Y, Gilbert M, Grochowski C, McEldrew D, Llewellyn J, Waisbourd-Zinman O . A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1. PLoS Genet. 2018; 14(8):e1007532. PMC: 6107291. DOI: 10.1371/journal.pgen.1007532. View

10.

Garcia-Barcelo M, Yeung M, Miao X, Tang C, Cheng G, Chen G . Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2. Hum Mol Genet. 2010; 19(14):2917-25. PMC: 2893814. DOI: 10.1093/hmg/ddq196. View

11.

Rajagopalan R, Tsai E, Grochowski C, Kelly S, Loomes K, Spinner N . Exome Sequencing in Individuals with Isolated Biliary Atresia. Sci Rep. 2020; 10(1):2709. PMC: 7026070. DOI: 10.1038/s41598-020-59379-4. View

12.

Glessner J, Ningappa M, Ngo K, Zahid M, So J, Higgs B . Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes. J Hepatol. 2023; 79(6):1385-1395. PMC: 10729795. DOI: 10.1016/j.jhep.2023.07.039. View

13.

Luo Z, Shivakumar P, Mourya R, Gutta S, Bezerra J . Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents. Gastroenterology. 2019; 157(4):1138-1152.e14. PMC: 6756963. DOI: 10.1053/j.gastro.2019.06.017. View

14.

Everhart J, Wright E, Goodman Z, Dienstag J, Hoefs J, Kleiner D . Prognostic value of Ishak fibrosis stage: findings from the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology. 2010; 51(2):585-94. PMC: 3814134. DOI: 10.1002/hep.23315. View

15.

Kamp J, Kappe N, Moro C, Fuge J, Kuehnel M, Wrenger S . Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses. Int J Mol Sci. 2023; 24(3). PMC: 9916468. DOI: 10.3390/ijms24032485. View

16.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T . Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9(7):676-82. PMC: 3855844. DOI: 10.1038/nmeth.2019. View

17.

Liu X, Liu Y, Ji S . Secretases Related to Amyloid Precursor Protein Processing. Membranes (Basel). 2021; 11(12). PMC: 8706128. DOI: 10.3390/membranes11120983. View

18.

Ozdogan E, Arikan C . Liver fibrosis in children: a comprehensive review of mechanisms, diagnosis, and therapy. Clin Exp Pediatr. 2022; 66(3):110-124. PMC: 9989719. DOI: 10.3345/cep.2022.00367. View

19.

Schoen B, Lee H, Sullivan K, Ricketts R . The Kasai portoenterostomy: when is it too late?. J Pediatr Surg. 2001; 36(1):97-9. DOI: 10.1053/jpsu.2001.20020. View

20.

Davenport M, Gonde C, Narayanaswamy B, Mieli-Vergani G, Tredger J . Soluble adhesion molecule profiling in preoperative infants with biliary atresia. J Pediatr Surg. 2005; 40(9):1464-9. DOI: 10.1016/j.jpedsurg.2005.05.050. View