Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Oct 27, 2021; 13(10): 1428-1438
Published online Oct 27, 2021. doi: 10.4254/wjh.v13.i10.1428
Acute liver failure with hemolytic anemia in children with Wilson’s disease: Genotype-phenotype correlations?
Tudor Lucian Pop, Alina Grama, Ana Cristina Stefanescu, Claudia Willheim, Peter Ferenci
Tudor Lucian Pop, Alina Grama, Ana Cristina Stefanescu, 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania
Tudor Lucian Pop, Alina Grama, 2nd Pediatric Clinic, Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca 400177, Romania
Claudia Willheim, Peter Ferenci, Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Wien A-1090, Austria
Author contributions: Pop TL performed the study design, literature research, data acquisition and analysis, resources, writing the original draft, reviewed and edited the draft; Grama A and Stefanescu A performed the data acquisition and analysis, reviewed the draft; Willheim C performed the genetic investigations, data acquisition and interpretation, reviewed the draft; Ferenci P performed the study design, data analysis, resources, review of the draft, supervision; all authors have read and approved the final manuscript.
Institutional review board statement: The data analyzed in this manuscript came from research approved by the Emergency Clinical Hospital for Children Cluj-Napoca Institutional Review Board.
Informed consent statement: All involved subjects (or parents or legal representatives) signed a written informed consent that clinical and laboratory data might be used in further research. All details that might disclose the identity of the subjects under study were omitted or anonymized.
Conflict-of-interest statement: Pop TL, Grama A, Stefanescu AC, Willheim C have no conflicting interests related to the present work. Ferenci P reports personal fees from Alexion, personal fees from Univar, personal fees from Vivet Therapeutics, grants from Gilead, during the conduct of the study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tudor Lucian Pop, MD, PhD, Associate Professor, 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Str. Crisan nr 5, Cluj-Napoca 400177, Romania. tudor.pop@umfcluj.ro
Received: April 30, 2021
Peer-review started: April 30, 2021
First decision: June 17, 2021
Revised: June 23, 2021
Accepted: September 3, 2021
Article in press: September 3, 2021
Published online: October 27, 2021
Processing time: 175 Days and 1.7 Hours
Abstract
BACKGROUND

Wilson’s disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.

AIM

To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.

METHODS

The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations.

RESULTS

We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%).

CONCLUSION

It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.

Keywords: Wilson’s disease; Children; Acute liver failure; Hemolytic anemia; ATP7B variant; Genotype-phenotype correlation

Core Tip: Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of Wilson’s disease (WD) in children, with a possible fatal evolution. There is no definite genotype-phenotype correlation in WD, but many studies try to solve this puzzle. Our research reports a higher presence of a missense [p.Trp939Cys (c.2817G>T)] and frame-shift variant [p.Lys844Ter (c.2530A>T)] in children with ALF and hemolytic anemia, while in less severe form, p.His1069Gln (c.3207A>G) was more frequent. HSD17B13:TA variant may be associated with less severe liver disease, as it was proved to have a protective role against liver toxins.