Severe pediatric hepatitis including pediatric acute liver failure (PALF) can be caused by a disparate group of etiologies including infectious, autoimmune / immune mediated, genetic, drug / toxin induced, oncologic, and hemodynamic causes, with a definitive cause found in less than half of cases. While unexplained cases of PALF have always existed, the incidence has been quite low.

The US Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have begun to report large increases in cases of severe hepatitis in previously healthy children who tested negative for the commonly known infectious and toxic agents that cause hepatitis, including hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). These reports involved patients from 40 countries, located in Europe, the Americas, Asia, and the Eastern Mediterranean and Western Pacific regions. Most of these patients were young, with a median age of 3-4 years, and presented with symptoms including scleral icterus (95%), jaundice (69%), vomiting (58%), acholic stools (43%), diarrhea (43%), abdominal pain (36%), nausea (26%), lethargy (23%), and dark urine (14%). Less common symptoms included fever, pruritus, and coryza. Encephalopathy was rarely reported. Generally, transaminase levels (AST/ALT) are greater than 500 IU/L, and other causes of hepatitis, including known infectious, metabolic, congenital, and mechanical causes, have been ruled out. Ultrasound of the liver showed thickening of the gallbladder wall in about half of the patients (a generally nonspecific finding in liver injury), with less than a quarter showing mild hepatomegaly or splenomegaly. Worldwide, 5% of patients progressed to liver failure and required liver transplantation, and 21 deaths have been reported.

Extensive research for a possible etiology has been undertaken in several countries. Case studies from both the United Kingdom and United States revealed that 90% of these patients were positive for adenovirus, predominantly subtype 41F, sampled from stool, blood, or respiratory cultures. However, immunohistochemical testing of liver biopsy specimens from patients have been negative for adenovirus and electron microscopy has been negative for viral inclusions, indicating that direct infection of hepatocytes with adenovirus is unlikely to be the cause. It is unclear if the finding of adenovirus in these patients is coincidental or if an indirect mechanism such as an overzealous host immune response to adenoviral infection is responsible. Other possible etiologies under investigation include SARS-CoV-2.