This article is a commentary on:
Commentary: Case Report: Hyperbilirubinemia in Gilbert Syndrome Attenuates Covid-19-Induced Metabolic Disturbances
Hayder M. Al-kuraishy1
Ali I. Al-Gareeb1
Saleh M. Abdullah2
Natália Cruz-Martins3,4,5*
Gaber El-Saber Batiha6*- 1Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
- 2Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
- 3Faculty of Medicine, University of Porto, Porto, Portugal
- 4Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- 5Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Gandra, Portugal
- 6Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
A Commentary on
Case Report: Hyperbilirubinemia in Gilbert Syndrome Attenuates Covid-19-Induced Metabolic Disturbances
by Minucci, A., Onori, M. E., and Urbani, A. (2021). Front. Cardiovasc. Med. 8:685835. doi: 10.3389/fcvm.2021.685835
This is in response to the letter by Minucci et al. (1) addressing our recent article published in Frontiers in Cardiovascular Medicine (2). In the commentary, the authors suspected that the reported case was Crigler–Najjar syndrome type II (CNS-II) and not Gilbert syndrome (GS), based on the level of total serum bilirubin (TSB) and unconjugated fraction. CNS-II is a rare autosomal recessive disorder due to a mutation in the UGT1A1 gene, whose mutation can even cause other metabolic disorders, like CNS-I and GS, resulting in a reduction of the UDP-glucuronosyl transferase function, which is responsible for the conjugation of bilirubin (3). In addition, CNS-II is usually identified with persistent jaundice in the neonate and early childhood and very rarely in adults.
The TSB level in CNS-II patients commonly ranges from 10 to 20 mg/dL (mostly unconjugated), and increased up to 40 mg/dL during exacerbation and partly responds to the effect of phenobarbitone within 2–3 weeks (4). In a study, Kumar and colleagues (5) illustrated that CNS-II is an unwanted cause of jaundice in adults. In contrast, the prevalence of GS is between 4 and 16% for the general population compared to 1 per million for CNS-II. Moreover, hyperbilirubinemia in GS is completely normalized following phenobarbitone therapy and rarely exceeds 6 mg/dL (mostly unconjugated) (6). However, the serum TSB level in our reported case had a slightly higher serum TSB level (6.5 mg/dL), which might be due to the inflammatory burden caused by COVID-19. Skierka et al. (7) and Sood et al. (8) have shown that GS cases can have higher bilirubin levels than usually reported, despite that the TSB level varies continuously from GS to CNS-II, depending on genotypes. In fact, because of the combination of polymorphisms and mutations, many patients experience intermediate TSB level between the two syndromes (9).
These findings rule out of CNS-II as a cause of inherited hyperbilirubinemia in the present study. Indeed, the case report presented is well-diagnosed since the age of 4 years by genetic analysis; however, this genetic analysis was not performed for other family members, as we mentioned in the limitations to the study. TSB alone is considered a hurdle in differentiating GS from CNS-II; nonetheless, the reduction in TSB level following phenobarbitone is regarded as a diagnostic clincher in differentiating GS (complete response) from CNS-II (partial response).
It is also worth noting that COVID-19 therapies used in our reported case, such as montelukast and prophylactic antibiotics (ceftriaxone), may increase the serum bilirubin level (5, 10). Besides, a pooled analysis study confirmed that the TSB level is associated and correlated with COVID-19 severity due to the alteration in bilirubin dynamics by an unknown mechanism (11).
Taken together, these points endorse the original diagnosis of GS, but not CNS-II, in contrast to the suggestion of Minucci et al. in their commentary.
Author Contributions
All authors have significantly contributed to this work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Minucci A, Onori ME, Urbani A. Commentary: case report: hyperbilirubinemia in gilbert syndrome attenuates COVID-19-induced metabolic disturbances. Front Cardiovasc Med. 8:685835. doi: 10.3389/fcvm.2021.685835
2. Al-Kuraishy HM, Al-Gareeb AI, Cruz-Martins N, Batiha GE. Hyperbilirubinemia in Gilbert syndrome attenuates COVID-19 induced-metabolic disturbances: a case-report study. Front Cardiovasc Med. (2021) 8:71. doi: 10.3389/fcvm.2021.642181
3. Raffay EA, Liaqat A, Khan M, Awan AI, Mand B. A rare case report of crigler najjar syndrome type II. Cureus. (2021) 13:e12669. doi: 10.7759/cureus.12669
4. Liaqat A, Shahid A, Attiq H, Ameer A, Imran M. Crigler-Najjar Syndrome Type II diagnosed in a patient with jaundice since birth. J Coll Physicians Surg Pak. (2018) 28:806–8.
5. Kumar P, Sasmal G, Gupta S, Saxena R, Kohli S. Crigler Najjar Syndrome Type 2 (CNS Type 2): an unwonted cause of jaundice in adults. J Clin Diagnost Res. (2017) 11:OD05. doi: 10.7860/JCDR/2017/28195.10221
6. Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr. (2011) 171:11–5. doi: 10.1007/s00431-011-1641-0
7. Skierka JM, Kotzer KE, Lagerstedt SA, O'Kane DJ, Baudhuin LM. UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia. J Pediatr. (2013) 162:1146–52. doi: 10.1016/j.jpeds.2012.11.042
8. Sood V, Lal BB, Sharma S, Khanna R, Siloliya MK, Alam S. Gilbert's syndrome in children with unconjugated hyperbilirubinemia–an analysis of 170 cases. Indian J Pediatr. (2021) 88:154–7. doi: 10.1007/s12098-020-03271-6
9. Maruo Y, Nakahara S, Yanagi T, Nomura A, Mimura Y, Matsui K, et al. Genotype of UGT1A1 and phenotype correlation between Crigler–Najjar syndrome type II and Gilbert syndrome. J Gastroenterol Hepatol. (2016) 31:403–8. doi: 10.1111/jgh.13071
10. Goldstein MF, Anoia J, Black M. Montelukast-induced hepatitis. Ann Intern Med. (2004) 140:586–7. doi: 10.7326/0003-4819-140-7-200404060-00042
Keywords: Gilbert syndrome (GS), SARS-CoV-2 (2019-nCoV), hyperbilirubinemia, COVID - 19, Crigler–Najjar syndrome type II
Citation: Al-kuraishy HM, Al-Gareeb AI, Abdullah SM, Cruz-Martins N and Batiha GE-S (2021) Response: Commentary: Case Report: Hyperbilirubinemia in Gilbert Syndrome Attenuates Covid-19-Induced Metabolic Disturbances. Front. Cardiovasc. Med. 8:738798. doi: 10.3389/fcvm.2021.738798
Received: 09 July 2021; Accepted: 09 September 2021;
Published: 05 October 2021.
Edited by:
Mingxing Xie, Huazhong University of Science and Technology, ChinaReviewed by:
Andrew F. James, University of Bristol, United KingdomVikrant Sood, The Institute of Liver and Biliary Sciences (ILBS), India
Copyright © 2021 Al-kuraishy, Al-Gareeb, Abdullah, Cruz-Martins and Batiha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Natália Cruz-Martins, bmNtYXJ0aW5zJiN4MDAwNDA7bWVkLnVwLnB0; Gaber El-Saber Batiha, Z2FiZXJiYXRpaGEmI3gwMDA0MDtnbWFpbC5jb20=