Abnormal liver enzymes in children and infants with <scp>COVID</scp>‐19: A narrative review of case‐series studies

Abstract

To the Editor As of April 17, 2020, the outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.0 million infections and 130 000 deaths.1 Current research suggests that obesity is a high risk factor for the severity of COVID-19 in adults.2 However, there is a lack of relevant evidence among children. Current evidence suggests that the virus may also adversely affect extra-pulmonary organs, such as the liver.3 It is possible that some differences in COVID-19 related abnormal liver enzymes might also exist between the adult and pediatric infected populations. To date, the aggregated data on abnormal liver enzymes in children with COVID-19 are rare. This article summarizes the findings of a narrative literature review of the current knowledge of COVID-19 related abnormal liver enzymes in children. We searched PubMed database for relevant studies published up to March 29, 2020, for pediatric patients (aged <18 years) with laboratory-confirmed COVID-19, including seven case reports and seven case series articles (Supplementary Material 1). “Newborn/child/pediatric and COVID-19/SARS-CoV-2” as key words of literature search. Also, we included seven pediatric patients from our center (Table 1). Among the 280 (165 boys, 58.9% of total) cases of children with COVID-19, the age ranged from new born infants to 17 years of age. As shown in the table, although in the large majority of these pediatric cases, COVID-19 related possible liver involvement [abnormal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] was found to be mild, its overall prevalence was approximately 29%. Of the 32 cases for which specific data are available, 5 (15.6%) had abnormal ALT (Table 1). From our data, it appears that there might be some differences in COVID-19 related abnormal liver enzymes between infected adults and children. Evidence in adult patients suggests that the occurrence of COVID-19 related abnormal liver enzymes is more common in men,3 this increase in abnormal liver enzymes is not present in children (Table 1). Although it is different to be certain whether sex differences in risk of abnormal liver enzymes occur in children with the small sample size, it is also possible to speculate that there exist some protective mechanisms towards COVID-19 in children. In our study, COVID-19 related possible liver involvment was found to be more prevalent amongst children aged 0-3 years than amongst those aged >3 years (91.7% vs 26.1%, P < 0·001). Four out of the five children with abnormal ALT concentrations were 0-3 years of age. It might be speculated that a more immature liver predisposes to higher risk of abnormal liver enzymes amongst children aged <3 years infected with SARS-CoV-2, although further research is required to corroborate this hypothesis. Although it is possible that SARS-Cov-2 may cause liver damage through the ACE-2 receptor binding of the virus to bile duct epithelial cells,3 there is still no clear evidence to support this view in children to date. Abnormal liver enzymes in adult patients are likely promoted by the release of inflammatory cytokines as the result of SARS-CoV-2 infection.4 Conversely, in pediatric COVID-19 reports, increasing levels of serum interleukin (IL)-6 and IL-10 are also associated with greater COVID-19 disease severity, although the levels of these cytokines are not significantly different between infected children with and without elevated serum liver enzymes (Supplementary Material). This suggests that interleukins do not play a key role in COVID-19 related abnormal liver enzymes amongst pediatric patients. Although there is currently no targeted anti-viral treatment for COVID-19, many infected patients have been treated with some antiviral drugs, which may have hepatotoxic effects.3 While COVID-19 related abnormal liver enzymes is usually observed in adult patients during their second week of hospitalization,5 pediatric patients usually exhibit increased serum liver enzymes at hospital admission. This suggests that drug-induced abnormal liver enzymes amongst infected children are less likely than in adults. However, one significant symptom of COVID-19 disease is fever and it is a widely accepted practice to give children paracetamol to control the fever before admission. Therefore, we cannot completely exclude the possibility that any AST/ALT abnormality is caused by paracetamol administration in children. In summary, the presence of mild COVID-19 related abnormal liver enzymes is not uncommon amongst infected children and new born infants. Since SARS-CoV-2 infection is likely to persist in the general population worldwide, physicians should be aware that younger children may also be affected by COVID-19 related abnormal liver enzymes. Although preliminary evidence suggests that COVID-19 related abnormal liver enzymes in pediatric patients may not share the same underlying mechanisms as in adults, further mechanistic studies are certainly needed to better understand these observations. This study provides more data for the International Child Liver Injury Study co-sponsored by NASPGHAN/TTS/ans SPLIT (https://covid19.cac.queensu.ca/PRAQ/surveys/index.php?s=9ATXNW7W3H). GT is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. CDB is supported in part by the Southampton NIHR Biomedical Research Centre (IS-BRC-20004), UK. YHZ and MHZ conceived and designed the study. YHZ, KIZ and MHZ acquired, analyzed and interpreted the data. YHZ and KIZ drafted the initial manuscript. MHZ, GT and CDB critically revised the manuscript for important intellectual content. All authors approved the final version of the report. We declare no competing interests. Ethical approval for the study was obtained from the ethics committee of the First Affiliated Hospital of Wenzhou Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from all our individual participants (seven patients) included in the study. Appendix S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Topics & Concepts