Table 1.

Possible causes of acute hepatitis of unknown etiology in children

Etiological speculation	Possible causes	Ref.
Association with adenovirus infection
Adenovirus infection	Adenovirus was detected by PCR in 209 (20.7%) patients with AHUCD.	World Health Organization[4]
Adenovirus mutation	Adenoviruses generate new viruses exhibiting various tissue tropism and increased virulence through molecular mutations of homologous recombination.	Tian X et al[22]
Secondary adenovirus infection "superantigen hypothesis"	Viral reservoirs emerge in the intestine after COVID-19 infection, followed by adenovirus infection, which triggers aberrant host immune-mediated hepatitis.	Brodin P et al[20]
Association with COVID-19 infection
COVID-19 infection	SARS-CoV-2-specific CD4+ and CD8+ memory T cells can be detected not only in patients recovering from COVID-19, but also in close contacts. Memory T-cell response after close contact with SARS-CoV-2 infection. During reinfection with SARS-CoV-2, a dysregulated immune response leads to rapid liver damage and acute liver failure.	Wang Z et al[26]; Zhu M et al[27]
Secondary multisystem inflammatory syndrome in children	Hepatitis is common in children with multisystem inflammatory syndrome, and MIS-C appears after COVID-19 infection, resulting in liver sequelae.	Cantor A et al[25]; Yasuhara J et al[21]
Pathogen exposure reduction	Children are not exposed to the viruses that children are generally exposed to; therefore, when they are first exposed to these viruses, it has an unexpected and serious impact.	Samarasekera U[28]
Association with vaccination against COVID-19	Vaccination against COVID-19 induces antigen-specific immune responses in children.	Sergi CM[29]
Adenovirus and SARS-CoV-2 co-infection
Co-infection ofadenovirus and SARS-CoV-2 or other pathogens	Adenovirus-associated hepatitis mainly occurs in immunosuppressed patients. Co-infection with adenovirus and SARS-CoV-2 or other pathogens leads to immune dysfunction, increasing the likelihood of adenovirus-associated hepatitis infection.	Lion T[18]; Li L et al[19]; Mendez-Sanchez N et al[9]

AHUCD: Acute hepatitis of unknown etiology in children; MIS-C: Multi-system inflammatory syndrome in children; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; PCR: Polymerase chain reaction.