Amyloid precursor protein as a fibrosis marker in infants with biliary atresia

Jan C Kamp; Omid Madadi-Sanjani; Marie Uecker; Christopher Werlein; Lavinia Neubert; Joachim F Kübler; Mikal Obed; Norman Junge; Tobias Welte; Jannik Ruwisch; Danny D Jonigk; Jan Stolk; Gertrud Vieten; Sabina Janciauskiene

doi:10.1038/s41390-024-03582-w

Amyloid precursor protein as a fibrosis marker in infants with biliary atresia

Pediatr Res. 2024 Sep 28. doi: 10.1038/s41390-024-03582-w. Online ahead of print.

Authors

Jan C Kamp^{1

2}, Omid Madadi-Sanjani³, Marie Uecker³, Christopher Werlein^{4

5}, Lavinia Neubert^{4

5}, Joachim F Kübler³, Mikal Obed³, Norman Junge⁶, Tobias Welte^{7

4}, Jannik Ruwisch^{7

4}, Danny D Jonigk^{4

8}, Jan Stolk⁹, Gertrud Vieten³, Sabina Janciauskiene^{7

4}

Affiliations

¹ Department of Respiratory and Infectious Medicine, Hannover Medical School, Hannover, Germany. Kamp.Jan-Christopher@mh-hannover.de.
² Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany. Kamp.Jan-Christopher@mh-hannover.de.
³ Centre of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
⁴ Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
⁵ Institute of Pathology, Hannover Medical School, Hannover, Germany.
⁶ Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
⁷ Department of Respiratory and Infectious Medicine, Hannover Medical School, Hannover, Germany.
⁸ Institute of Pathology, RWTH Aachen University Medical Faculty, Aachen, Germany.
⁹ Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, Leiden, The Netherlands.

PMID: 39341941
DOI: 10.1038/s41390-024-03582-w

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.