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

First published: 01 September 2020
 

Yong‐Hai Zhou and Kenneth I. Zheng are co‐first authors.

Funding information: Southampton NIHR Biomedical Research Centre; University School of Medicine of Verona

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).

TABLE 1. Liver enzymes characteristics of pediatric patients with COVID‐19, based on published case series and case reports
Literature No.AuthorCountry (Province)Sample size (n)Case No.Abnormal AST (n, %)AST (U/L)Abnormal ALT (n, %)ALT (U/L)Male sex, n (%)AgeCritically‐ill cases, n (%)
Case series
1Xia WChina (Hubei)20NANA5 (25.0%)NA13 (65.0%)2y1.5 m (1d‐14.6y)NA
2Lu XChina (Hubei)17125 (14.6%)30 (24‐42)c21 (12.3%)15 (11‐27)c104 (60.8%)6.7y (1d‐15y)3 (1.7%)1 Death
3Wang DChina (Multi‐center)316/27 (22.2%)a15 (43.4%)7.1y (6 m‐17y)0 (0%)
4Zheng FChina (Hubei)25NANANA12 (10‐13)c14 (56.0%)3y (3 m‐14y)2 (8.0%)
1NA12Male8 mYES
2NA20Female1yYES
5Cai JChina (Multi‐center)1013317Male7yNO
221.47.7Female10.9yNO
327.519.8Female10.9yNO
419.726.2Male9yNO
5142100Female7 mNO
624.513.6Female6yNO
75140Female3 mNO
82819Female4yNO
92018Male8yNO
103414Male5yNO
6Liu WChina (Hubei)61456Female3yYES
23014Female7yNO
34211Female3yNO
46423Male1yNO
53643Female3yNO
63715Male4yNO
7Zeng LChina (Hubei)31811Male1ddNO
22417Male1ddNO
36388Male1ddYESb
Case reports
8Cui YChina (Guizhou)110084Female55dYES
9Wang SChina (Hubei)1143NAMale1ddNO
10Chen FChina (Hubei)1NormalNormalMale13 mYES
11Zeng LKChina (Hubei)1NormalNormalMale17dNO
12Dong LChina (Hubei)16511Female1ddNO
13Chan JFChina (Guangdong‐Shenzhen)128.223.9Male10yNO
14Le HTVietnam159.934.8Female3 mNO
15Cases from our centerChina (Zhejiang‐Wenzhou)712413Male11yNO
22022Male10yNO
32116Male13yNO
43212Female5yNO
51510Male16yNO
61614Female14yNO
73577Male10yNO
  • Abbreviations: AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: glutamyl‐transpeptidase; y: years; m: months; d: days; NA: not available. These cited literatures in this table are shown in supplementary material 1.
  • a The author simply described it as abnormal liver function, without specific distinction between AST and ALT.
  • b Gestational age: 31wk + 2d, mechanical ventilation for acute respiratory distress syndrome.
  • c Median and interquartile range.
  • d These cases were all COVID‐19 pregnant women delivered in hospital. Before the birth of these babies, the pregnant mothers had been diagnosed with SARS‐COV‐2 infection, so we calculated the age of these infants as 1 day.

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).



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