Acute Liver Failure in a Healthy Young Female With COVID-19

**Background:** Most symptomatic cases of COVID-19 present with fever and respiratory symptoms, but elevated liver enzymes are seen in 14-78% of cases. Acute liver failure (ALF) with concurrent COVID-19 has been reported in only a few cases, and direct evidence of hepatocellular infection by SARS-CoV-2 has been lacking. This case reports a pediatric ALF ostensibly precipitated by COVID-19 in an otherwise asymptomatic patient with biopsy findings demonstrating replicating SARS-CoV-2 RNA in hepatocytes.

**Methods:** This is a case report of a 15-year-old nonobese girl with a history of menorrhagia who presented with 3 days of anosmia, ageusia, and 2 days of nausea and vomiting, without pulmonary symptoms. She had a confirmed recent SARS-CoV-2 exposure at school. She denied any medications, drugs, alcohol, or tobacco, except initiation of norethindrone acetate 1.5 mg and ethinyl estradiol 30 µg for menorrhagia 7 weeks before presentation. She transferred to the authors' facility for dehydration, anemia, and transaminitis. On arrival, she was hemodynamically stable and neurologically intact. Initial testing demonstrated worsening transaminitis and SARS-CoV-2 positivity by RT-PCR from the respiratory tract. She developed ALF on hospital day (HD) 2. Extensive testing to determine ALF etiology was unrevealing. Treatment included vitamin K, broad-spectrum antibiotics, lactulose, rifaximin, dexamethasone, continuous renal replacement therapy (CRRT) for hyperammonemia, and N-acetyl cysteine. On HD5, she received 2.4 g of casirivimab/imdevimab (REGN10933/REGN10987) under emergency compassionate use. Liver biopsy on HD15 was performed, including in-situ hybridization using RNAscope Probe-nCoV2019-orf1ab-sense-C2 to detect replicating SARS-CoV-2 RNA, and immunohistochemistry for SARS-CoV-2 nucleocapsid protein.

**Key Results:** The patient developed ALF on HD2 with worsening transaminitis and coagulopathy. On HD5, she was intubated for worsening mental status. On HD6, she demonstrated improvement in coagulopathy, hyperammonemia, and mental status. She was extubated on HD7, and CRRT was discontinued on HD8. Liver biopsy on HD15 showed an acute hepatitis pattern of injury with predominantly centrizonal areas of confluent necrosis and lobular cholestasis. Necrotic areas were focally hemorrhagic with mild lymphoplasmacytic infiltrate, histiocytes, few eosinophils, and neutrophils. Portal inflammation was minimal and interlobular bile ducts were largely intact. No fibrin thrombi were identified. Residual hepatocytes showed ballooning degeneration, some with prominent nucleoli, apoptosis, pseudoacini formation, and mild steatosis (<10%). In-situ hybridization detected replicating SARS-CoV-2 RNA in hepatocytes, and immunostaining confirmed expression of SARS-CoV-2 nucleocapsid protein. The patient discharged on HD16 and was doing well 5 months postdischarge with normal liver tests.

**Clinical Implications:** This case provides direct evidence of SARS-CoV-2 replication in hepatocytes causing submassive liver necrosis in a patient with minimal extrahepatic symptoms. It suggests that COVID-19 can cause severe liver injury progressing to ALF even in otherwise healthy individuals without significant respiratory disease. The temporal association with monoclonal antibody administration and clinical improvement, though not definitive, raises the possibility of benefit. Clinicians should maintain vigilance for SARS-CoV-2-related liver injury that progresses to ALF, even in patients without pulmonary symptoms.