Liver Involvement in Children With SARS-COV-2 Infection

Two Distinct Clinical Phenotypes Caused by the Same Virus

Adriana Perez MD; Amanda Cantor MD; Bryan Rudolph MD, MPH; Jonathan Miller MD; Debora Kogan-Liberman MD; Qi Gao PhD; Bernardo Da Silva; Kara G. Margolis MD; Nadia Ovchinsky MD, MBA; Mercedes Martinez MD

Disclosures

Liver International. 2021;41(9):2068-2075. 

In This Article

Discussion

In our study, 36% of children developed E-ALT, which was also associated with mild cholestasis. Irrespective of their SARS-CoV-2 manifestations, those with E-ALT experienced more severe clinical courses. The association of E-ALT coupled with severe COVID-19 has been documented in the adult literature but only scarcely in pediatric literature.[13,17,18,21] The E-ALT mechanism in SARS-CoV-2 is not fully understood, but under investigation are an effect of viral lesions in hepatic/cholangiocyte cells, inflammatory damage, hypoxic/shock-related circulatory compromise, endothelial dysfunction, microthrombi formation, and drug toxicity.[22–24] The direct viral cytopathic effect in the pathophysiology of E-ALT via the cell receptors for angiotensin-converting enzyme II and transmembrane protease serine 2, invoked in the transmission of SARS-CoV-2, is supported by the demonstration of SARS-CoV-2 in the liver parenchyma in patients with higher liver enzyme elevation.[25]

As previously reported, children with E-ALT in the COVID-19 cohort more frequently carried an underlying medical condition such as immunocompromised state (including malignancy), or CLD, significantly contrasting with those with E-ALT in MIS-C.[3,4,26] In our study, although children with MIS-C had >2× higher odds of any degree of elevation in ALT levels compared to children with COVID-19 (51% vs 31%), severe elevation, defined as ALT >200 U/L was observed at a higher frequency in children with COVID-19 (8% vs 4%) (Figure 1). A possible explanation of why a higher percentage of children with COVID-19 (as opposed to MIS-C) had a severe elevation (ALT > 200 U/L) could be due to the significantly greater number of comorbidities that the COVID-19 population possessed that can contribute to hepatitis, including obesity. It mirrors prior observations that MIS-C affects previously healthy children,[27] but SARS-Cov2 can induce a severe cytokine storm with a hyperinflammatory state with either disease entity. The pathophysiology of organ damage is unknown, although differences in cytokines and autoantibodies profiles have been identified.[28]

Obesity was present in both cohorts, albeit significantly more prevalent in children with E-ALT in COVID-19. Among them, only six children were previously diagnosed with NAFLD. We cannot exclude the possibility of a higher prevalence of NAFLD within this cohort due to our retrospective design limitations. It has been proposed that patients with NAFLD may be susceptible to a worsening viral oxidative stress when infected with a hepatotoxic virus.[29]

It is worth noting that the three patients who died of COVID-19 and developed E-ALT and the single patient in the MIS-C cohort who developed acute liver failure were obese (Table S6). Adult literature also highlights the association between clinical course severity and obesity in COVID-19. It further implies that increased morbidity may be due to obesity-related impact on cytokine dysfunction or impaired immune response in leptin resistance, raising concerns that obesity influences disease behavior.[30–32] This observation is particularly relevant given the increasing prevalence of obesity in our children and is an essential practical point for the bedside physician.[33]

Racial disparities in SARS-CoV-2 infection, including a higher disease prevalence and mortality among adult Blacks and Hispanics, have been noted, but these observations are based on limited data.[34] Population-based data from MIS-C in NYC also concluded a disproportionate MIS-C burden among Black and Hispanic children.[35] It is unclear whether this finding represents an actual phenomenon or skewness due to missing race/ethnicity data for most confirmed, non-hospitalized, and nonfatal cases.[35] We did not identify any racial differences predisposing children to E-ALT in COVID-19. Black and Hispanic children with MIS-C were more frequently affected by E-ALT compared to those with COVID-19. Furthermore, children of Black race may be disproportionately impaired by E-ALT in MIS-C.

We cannot exclude that some children with COVID-19 or MIS-C had additional liver insults including ischemia, congestion, and/or drug-induced liver injury (DILI). No differences in antibiotics or Remdesivir use between children with and without E-ALT in both cohorts were observed, making DILI less probable.

There are multiple strengths to our study. We have analyzed one of the largest North American cohort of pediatric patients with E-ALT in MIS-C, and COVID-19 admitted to two tertiary care centers in a former epicenter of the pandemic. Our centers follow similar protocols for diagnosis, treatment, and management and serve diverse patient populations, allowing us to generalize the laboratory values and scrutinize patients' disease courses across both centers.

Our study cohort is significantly smaller than those of adult studies, limiting our ability to model all predictors of E-ALT used in multivariate analyses of adult populations. Additionally, we were unable to evaluate the full impact of CLD in the full etiology of elevated ALT levels due to lack of preadmission laboratory tests and imaging. Our study, similarly, to others, is burdened by missing race/ethnicity data due to retrospective design.

In conclusion, liver involvement associated with SARS-CoV-2 infection typically leads to a temporary moderate elevation of liver tests without significant hepatic synthetic function impairment. Patients with SARS-CoV-2 infection and E-ALT are at risk of a more severe disease course including longer hospitalization and ICU stays. Children require careful management and monitoring throughout their hospitalization and thereafter to establish resolution of elevated ALT values. Further studies need to provide mechanistic insights into the pathophysiology of underlying liver injury in both conditions.

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