Acute liver failure with hemolytic anemia in children with Wilson's disease: Genotype-phenotype correlations?

Autor:	Pop TL; 2 Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania. tudor.pop@umfcluj.ro., Grama A; 2 Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania., Stefanescu AC; 2 Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania., Willheim C; Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Wien A-1090, Austria., Ferenci P; Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Wien A-1090, Austria.
Jazyk:	angličtina
Zdroj:	World journal of hepatology [World J Hepatol] 2021 Oct 27; Vol. 13 (10), pp. 1428-1438.
DOI:	10.4254/wjh.v13.i10.1428
Abstrakt:	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. Competing Interests: 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. (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu