Case Report
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2017; 23(44): 7930-7938
Published online Nov 28, 2017. doi: 10.3748/wjg.v23.i44.7930
Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis
Ivan Ivanovski, Miloš Ješić, Ana Ivanovski, Livia Garavelli, Petar Ivanovski
Ivan Ivanovski, Livia Garavelli, Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio Emilia, 42123 Reggio Emilia, Italy
Ivan Ivanovski, Department of Surgical, Medical, Dental and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy
Miloš Ješić, Petar Ivanovski, School of Medicine University of Belgrade, Belgrade 11000, Serbia
Miloš Ješić, Petar Ivanovski, University Children’s Hospital, Belgrade 11000, Serbia
Ana Ivanovski, Faculty of Chemistry University of Belgrade, Belgrade 11000, Serbia
Author contributions: All authors equally contributed to the acquisition of data, writing, and revision of this manuscript.
Informed consent statement: The patient died, no consent obtained.
Conflict-of-interest statement: All the authors have no conflicts of interests to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Dr. Petar Ivanovski, School of Medicine University of Belgrade, Belgrade 11000, Serbia. petar.ivanovski@udk.bg.ac.rs
Telephone: +381-11-2060666 Fax: +381-11-2684672
Received: February 7, 2017
Peer-review started: February 9, 2017
First decision: April 17, 2017
Revised: May 15, 2017
Accepted: June 18, 2017
Article in press: June 18, 2017
Published online: November 28, 2017
Abstract

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.

Keywords: Urea cycle disorder, Citrullinemia, Neonatal liver iron overload, Fumaric acid, Succinic acid, Krebs’ cycle, Transferrin, Zinc fumarate supplementation

Core tip: Underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. We hypothesize that the key is deficient fumaric acid production in urea cycle in UCDs, which causes several sequentially intertwined metabolic disturbances with the final result of liver iron overload. Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate.